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stringclasses 2
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38.2M
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0
|
Is the long-term rate of overall lymphocyst formation higher, lower, or the same when comparing retroperitoneal drainage to no drainage?
|
no difference
|
high
|
no
|
['17466514']
| 28,660,687
| 2,017
|
{'17466514': {'article_id': '17466514', 'content': "Drainage, following radical hysterectomy and pelvic lymph node dissection to prevent postoperative lymphocyst formation and surgical morbidity, is controversial. To study the clinical significance of drainage, 253 patients were registered and 234 patients were randomised into two arms. In one arm (n=117) postoperative drainage was performed, in the other arm (n=117) no drains were inserted. In both arms closure of the peritoneum of the operating field was omitted. The main exclusion criteria were blood loss of more than 3000 ml during surgery or persistent oozing at the end of the operation. Clinical and ultrasound or CT-scan evaluation was done at one and 12 months postoperatively. The median follow-up amounted to 13.3 months. No difference in the incidence of postoperative lymphocyst formation or postoperative complications was found between the two study arms. The late (12 months) incidence of symptomatic lymphocysts was 3.4% (drains: 5.9%; no drains: 0.9%). The difference showed a p-value of 0.06 in Fisher's Exact test. The operating time was related to the occurrence of postoperative lymphocyst formation. It was concluded that drains can be safely omitted following radical hysterectomy and pelvic node dissection without pelvic reperitonisation in patients without excessive bleeding during or oozing at the end of surgery.", 'title': 'Randomised trial of drains versus no drains following radical hysterectomy and pelvic lymph node dissection: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) study in 234 patients.', 'date': '2007-05-01'}}
| 1
|
Surgery
|
1
|
Is the short-term rate of overall lymphocyst formation higher, lower, or the same when comparing retroperitoneal drainage to no drainage?
|
no difference
|
moderate
|
no
|
['9190979', '12214830']
| 28,660,687
| 2,017
|
{'9190979': {'article_id': '9190979', 'content': 'To evaluate the clinical effectiveness of retroperitoneal drainage following lymphadenectomy in gynecologic surgery.\nOne hundred thirty-seven consecutive patients undergoing systematic lymphadenectomy for gynecologic malignancies were randomized to receive (Group A, 68) or not (Group B, 69) retroperitoneal drainage. The pelvic peritoneum and the paracolic gutters were not sutured after node dissection. Perioperative data and complications were recorded.\nClinical and surgical parameters were comparable in the two groups. Postoperative hospital stay was significantly shorter in Group B (P < 0.001), whereas the complication rate was significantly higher in Group A (P = 0.01). This was mainly due to a significant increase in lymphocyst and lymphocyst-related morbidity. Sonographic monitoring for lymphocyst showed free abdominal fluid in 18% of drained and 36% of not-drained patients (P = 0.03). Symptomatic ascites developed in 2 drained (3%) and 3 not-drained (4%) patients (NS), respectively.\nProphylactic drainage of the retroperitoneum seems to increase lymphadenectomy-related morbidity and postoperative stay. Therefore, routine drainage following lymphadenectomy seems to be no longer indicated when the retroperitoneum is left open.', 'title': 'A randomized study comparing retroperitoneal drainage with no drainage after lymphadenectomy in gynecologic malignancies.', 'date': '1997-06-01'}, '12214830': {'article_id': '12214830', 'content': 'To evaluate the postoperative morbidity and lymphocyst formation in invasive cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy (RHPL) with no drainage and no peritonization compared with retroperitoneal drainage and peritonization.\nBetween July 1999 and May 2000, 100 patients with stage IA-IIA cervical cancer undergoing RHPL in Chiang Mai University Hospital were prospectively randomized to receive either no peritonization and no drainage (Group A = 48 cases) or retroperitoneal drainage and peritonization (Group B = 52 cases). Perioperative data and morbidity were recorded. Transabdominal and transvaginal sonography were performed at 4, 8 and 12 weeks postoperatively to detect lymphocyst formation.\nBoth groups were similar regarding age, size and gross appearance of tumor, tumor histology and stage. There was no difference between groups in respect of operative time, need for blood transfusion, intraoperative complications, hospital stay, number of nodes removed, nodal metastases, and need for adjuvant radiation and chemotherapy. Asymptomatic lymphocysts were sonographically detected at 4, 8 and 12 weeks postoperatively in 3 (6.8%), 2 (4.6%), and 3 (7.7%) of 44, 43, and 39 patients, respectively in Group A, whereas none was found in Group B (P = 0.2). No significant difference was found in term of postoperative morbidity in the two groups.\nRoutine retroperitoneal drainage and peritonization after RHPL for invasive cervical cancer can be safely omitted.', 'title': 'A prospective randomized study comparing retroperitoneal drainage with no drainage and no peritonization following radical hysterectomy and pelvic lymphadenectomy for invasive cervical cancer.', 'date': '2002-09-07'}}
| 0.5
|
Surgery
|
2
|
Is the rate of clinician impression of cognitive change higher, lower, or the same when comparing cholinase inhibitors to placebo in patients with MS?
|
higher
|
high
|
no
|
['15534239', '21519001']
| 25,734,590
| 2,015
|
{'15534239': {'article_id': '15534239', 'content': 'To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS).\nThis single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change.\nDonepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).\nDonepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.', 'title': 'Donepezil improved memory in multiple sclerosis in a randomized clinical trial.', 'date': '2004-11-10'}, '21519001': {'article_id': '21519001', 'content': "The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).\nDonepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.\nA total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.\nDonepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.\nThis study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.", 'title': 'Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.', 'date': '2011-04-27'}}
| 0.5
|
Psychiatry & Neurology
|
3
|
Is the rate of patient self-reported impression of memory change higher, lower, or the same when comparing cholinase inhibitors to placebo in patients with MS?
|
uncertain effect
|
high
|
no
|
['15534239', '21519001']
| 25,734,590
| 2,015
|
{'15534239': {'article_id': '15534239', 'content': 'To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS).\nThis single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change.\nDonepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).\nDonepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.', 'title': 'Donepezil improved memory in multiple sclerosis in a randomized clinical trial.', 'date': '2004-11-10'}, '21519001': {'article_id': '21519001', 'content': "The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).\nDonepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.\nA total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.\nDonepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.\nThis study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.", 'title': 'Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.', 'date': '2011-04-27'}}
| 0
|
Psychiatry & Neurology
|
4
|
Is the number of people with at least one neoplastic lesion detected higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
higher
| null |
no
|
['12196768', '16527699', '21159889', '16767577']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}}
| 0.25
|
Internal Medicine & Subspecialties
|
5
|
Is total polyp detection higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
higher
| null |
no
|
['12196768', '14960519', '20179689', '16527699', '21159889', '16767577', '19139000']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '14960519': {'article_id': '14960519', 'content': 'Diminutive and flat colorectal lesions can be difficult to detect using conventional colonoscopic techniques. Previous data have suggested that pan-chromoscopy may improve detection rates. No randomised control trial has been performed examining detection rates of such lesions while controlling for extubation time and lavage effect.\nWe conducted a randomised controlled trial of pan-colonic chromoscopic colonoscopy for the detection of diminutive and flat colorectal lesions while controlling for extubation time and lavage effect.\nConsecutive patients attending for routine colonoscopy were randomised to either pan-chromoscopy using 0.5% indigo carmine (IC) or targeted chromoscopy (control group). A minimum diagnostic extubation time was set at eight minutes with controls undergoing a matched volume of saline wash.\nA total of 260 patients were randomised; 132 controls and 128 to pan-colonic chromoscopy. Extubation times did not differ significantly between the control (median 15 minutes (range 8-41)) and chromoscopy (median 17 minutes (range 8-39)) groups. The volume of IC used in the pan-chromoscopy group (median 68 ml (range 65-90)) and normal saline used in the control group (69 ml (range 60-93)) did not differ significantly. There was a statistically significant difference between the groups regarding the total number of adenomas detected (p<0.05) with significantly more diminutive (<4 mm) adenomas detected in the pan-chromoscopy group (p = 0.03). Pan-chromoscopy diagnosed more diminutive and flat lesions in the right colon compared with controls (p<0.05), with more patients with multiple adenomas (>3) detected using pan-chromoscopy (p<0.01). Hyperplastic lesions were more commonly detected in the pan-chromoscopy group compared with controls (p<0.001). More hyperplastic polyps were detected in the left colon (86% rectosigmoid) using chromoscopy compared with controls.\nChromoscopy improves the total number of adenomas detected and enhances the detection of diminutive and flat lesions. Importantly, eight diminutive lesions had foci of high grade dysplasia. Chromoscopy may benefit patients, assuming a high risk of colorectal cancer, and help in risk stratification and planning follow up colonoscopy intervals.', 'title': 'Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy.', 'date': '2004-02-13'}, '20179689': {'article_id': '20179689', 'content': 'Flat and depressed colon neoplasms are an increasingly recognized precursor for colorectal cancer (CRC) in Western populations. High-definition chromoscopy is used to increase the yield of colonoscopy for flat and depressed neoplasms; however, its role in average-risk patients undergoing routine screening remains uncertain.\nAverage-risk patients referred for screening colonoscopy at four U.S. medical centers were randomized to high-definition chromocolonoscopy or high-definition white light colonoscopy. The primary outcomes, patients with at least one adenoma and the number of adenomas per patient, were compared between the two groups. The secondary outcome was patients with flat or depressed neoplasms, as defined by the Paris classification.\nA total of 660 patients were randomized (chromocolonoscopy: 321, white light: 339). Overall, the mean number of adenomas per patient was 1.2+/-2.1, the mean number of flat polyps per patient was 1.4+/-1.9, and the mean number of flat adenomas per patient was 0.5+/-1.0. The number of patients with at least one adenoma (55.5% vs. 48.4%, absolute difference 7.1%, 95% confidence interval (-0.5% to 14.7%), P=0.07), and the number of adenomas per patient (1.3+/-2.4 vs. 1.1+/-1.8, P=0.07) were marginally higher in the chromocolonoscopy group. There were no significant differences in the number of advanced adenomas per patient (0.06+/-0.37 vs. 0.04+/-0.25, P=0.3) and the number of advanced adenomas<10 mm per patient (0.02+/-0.26 vs. 0.01+/-0.14, P=0.4). Two invasive cancers were found, one in each group; neither was a flat neoplasm. Chromocolonoscopy detected significantly more flat adenomas per patient (0.6+/-1.2 vs. 0.4+/-0.9, P=0.01), adenomas<5 mm in diameter per patient (0.8+/-1.3 vs. 0.7+/-1.1, P=0.03), and non-neoplastic lesions per patient (1.8+/-2.3 vs. 1.0+/-1.3, P<0.0001).\nHigh-definition chromocolonoscopy marginally increased overall adenoma detection, and yielded a modest increase in flat adenoma and small adenoma detection, compared with high-definition white light colonoscopy. The yield for advanced neoplasms was similar for the two methods. Our findings do not support the routine use of high-definition chromocolonoscopy for CRC screening in average-risk patients. The high adenoma detection rates observed in this study may be due to the high-definition technology used in both groups.', 'title': 'High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening.', 'date': '2010-02-25'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}, '19139000': {'article_id': '19139000', 'content': 'Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.', 'title': 'Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.', 'date': '2009-01-14'}}
| 0.285714
|
Internal Medicine & Subspecialties
|
219
|
Is the risk of adverse events higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
insufficient data
| null |
no
|
['12196768', '14960519', '20179689', '16527699', '21159889', '16767577', '19139000']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '14960519': {'article_id': '14960519', 'content': 'Diminutive and flat colorectal lesions can be difficult to detect using conventional colonoscopic techniques. Previous data have suggested that pan-chromoscopy may improve detection rates. No randomised control trial has been performed examining detection rates of such lesions while controlling for extubation time and lavage effect.\nWe conducted a randomised controlled trial of pan-colonic chromoscopic colonoscopy for the detection of diminutive and flat colorectal lesions while controlling for extubation time and lavage effect.\nConsecutive patients attending for routine colonoscopy were randomised to either pan-chromoscopy using 0.5% indigo carmine (IC) or targeted chromoscopy (control group). A minimum diagnostic extubation time was set at eight minutes with controls undergoing a matched volume of saline wash.\nA total of 260 patients were randomised; 132 controls and 128 to pan-colonic chromoscopy. Extubation times did not differ significantly between the control (median 15 minutes (range 8-41)) and chromoscopy (median 17 minutes (range 8-39)) groups. The volume of IC used in the pan-chromoscopy group (median 68 ml (range 65-90)) and normal saline used in the control group (69 ml (range 60-93)) did not differ significantly. There was a statistically significant difference between the groups regarding the total number of adenomas detected (p<0.05) with significantly more diminutive (<4 mm) adenomas detected in the pan-chromoscopy group (p = 0.03). Pan-chromoscopy diagnosed more diminutive and flat lesions in the right colon compared with controls (p<0.05), with more patients with multiple adenomas (>3) detected using pan-chromoscopy (p<0.01). Hyperplastic lesions were more commonly detected in the pan-chromoscopy group compared with controls (p<0.001). More hyperplastic polyps were detected in the left colon (86% rectosigmoid) using chromoscopy compared with controls.\nChromoscopy improves the total number of adenomas detected and enhances the detection of diminutive and flat lesions. Importantly, eight diminutive lesions had foci of high grade dysplasia. Chromoscopy may benefit patients, assuming a high risk of colorectal cancer, and help in risk stratification and planning follow up colonoscopy intervals.', 'title': 'Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy.', 'date': '2004-02-13'}, '20179689': {'article_id': '20179689', 'content': 'Flat and depressed colon neoplasms are an increasingly recognized precursor for colorectal cancer (CRC) in Western populations. High-definition chromoscopy is used to increase the yield of colonoscopy for flat and depressed neoplasms; however, its role in average-risk patients undergoing routine screening remains uncertain.\nAverage-risk patients referred for screening colonoscopy at four U.S. medical centers were randomized to high-definition chromocolonoscopy or high-definition white light colonoscopy. The primary outcomes, patients with at least one adenoma and the number of adenomas per patient, were compared between the two groups. The secondary outcome was patients with flat or depressed neoplasms, as defined by the Paris classification.\nA total of 660 patients were randomized (chromocolonoscopy: 321, white light: 339). Overall, the mean number of adenomas per patient was 1.2+/-2.1, the mean number of flat polyps per patient was 1.4+/-1.9, and the mean number of flat adenomas per patient was 0.5+/-1.0. The number of patients with at least one adenoma (55.5% vs. 48.4%, absolute difference 7.1%, 95% confidence interval (-0.5% to 14.7%), P=0.07), and the number of adenomas per patient (1.3+/-2.4 vs. 1.1+/-1.8, P=0.07) were marginally higher in the chromocolonoscopy group. There were no significant differences in the number of advanced adenomas per patient (0.06+/-0.37 vs. 0.04+/-0.25, P=0.3) and the number of advanced adenomas<10 mm per patient (0.02+/-0.26 vs. 0.01+/-0.14, P=0.4). Two invasive cancers were found, one in each group; neither was a flat neoplasm. Chromocolonoscopy detected significantly more flat adenomas per patient (0.6+/-1.2 vs. 0.4+/-0.9, P=0.01), adenomas<5 mm in diameter per patient (0.8+/-1.3 vs. 0.7+/-1.1, P=0.03), and non-neoplastic lesions per patient (1.8+/-2.3 vs. 1.0+/-1.3, P<0.0001).\nHigh-definition chromocolonoscopy marginally increased overall adenoma detection, and yielded a modest increase in flat adenoma and small adenoma detection, compared with high-definition white light colonoscopy. The yield for advanced neoplasms was similar for the two methods. Our findings do not support the routine use of high-definition chromocolonoscopy for CRC screening in average-risk patients. The high adenoma detection rates observed in this study may be due to the high-definition technology used in both groups.', 'title': 'High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening.', 'date': '2010-02-25'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}, '19139000': {'article_id': '19139000', 'content': 'Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.', 'title': 'Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.', 'date': '2009-01-14'}}
| 1
|
Internal Medicine & Subspecialties
|
6
|
Is stroke prevention higher, lower, or the same when comparing Transcatheter Device Closure (TDC) to medical therapy?
|
no difference
| null |
no
|
['22417252', '23514285', '23514286']
| 26,346,232
| 2,015
|
{'22417252': {'article_id': '22417252', 'content': 'The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke.\nWe conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.\nA total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.\nIn patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).', 'title': 'Closure or medical therapy for cryptogenic stroke with patent foramen ovale.', 'date': '2012-03-16'}, '23514285': {'article_id': '23514285', 'content': 'The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy.\nWe performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population.\nThe mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56).\nClosure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).', 'title': 'Percutaneous closure of patent foramen ovale in cryptogenic embolism.', 'date': '2013-03-22'}, '23514286': {'article_id': '23514286', 'content': 'Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. We conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age.\nIn this prospective, multicenter, randomized, event-driven trial, we randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated.\nWe enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two groups was unequal (1375 patient-years in the closure group vs. 1184 patient-years in the medical-therapy group, P=0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 95% confidence interval [CI], 0.22 to 1.11; P=0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort (6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P=0.03) and in the as-treated cohort (5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P=0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group (P=0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2%), but the rate of atrial fibrillation or device thrombus was not increased.\nIn the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.).', 'title': 'Closure of patent foramen ovale versus medical therapy after cryptogenic stroke.', 'date': '2013-03-22'}}
| 1
|
Surgery
|
7
|
Is the composite endpoint of recurrent stroke or TIA higher, lower, or the same when comparing Transcatheter Device Closure (TDC) to medical therapy?
|
no difference
| null |
no
|
['22417252', '23514285']
| 26,346,232
| 2,015
|
{'22417252': {'article_id': '22417252', 'content': 'The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke.\nWe conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.\nA total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.\nIn patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).', 'title': 'Closure or medical therapy for cryptogenic stroke with patent foramen ovale.', 'date': '2012-03-16'}, '23514285': {'article_id': '23514285', 'content': 'The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy.\nWe performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population.\nThe mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56).\nClosure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).', 'title': 'Percutaneous closure of patent foramen ovale in cryptogenic embolism.', 'date': '2013-03-22'}}
| 1
|
Surgery
|
8
|
Is the length of hospital stay higher, lower, or the same when comparing Pancreatojejunostomy (PJ) to Pancreatogastrostomy (PG)?
|
no difference
|
low
|
no
|
['16327486', '19092337', '7574936']
| 28,898,386
| 2,017
|
{'16327486': {'article_id': '16327486', 'content': 'To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.\nWhile several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.\nA total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).\nThe 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.\nWhen compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.', 'title': 'Reconstruction by pancreaticojejunostomy versus pancreaticogastrostomy following pancreatectomy: results of a comparative study.', 'date': '2005-12-06'}, '19092337': {'article_id': '19092337', 'content': 'To compare the results of postoperative morbidity rate of a new pancreatogastrostomy technique, pylorus-preserving pancreaticoduodenectomy (PPPD) with gastric partition (PPPD-GP) with the conventional technique of pancreaticojejunostomy (PJ).\nPancreatojejunostomy and pancreatogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreatoduodenectomy (PD). All randomized controlled trials failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally results. However, postoperative morbidity remains high. The best technique in pancreatic anastomosis is still debated.\nDescribed here is a new technique, PPPD-GP; in this technique the gastroepiploic arcade is preserved. Gastric partition was performed using 2 endo-Gia staplers along the greater curvature of the stomach, 3 cm from the border. This gastric segment, 10 to 12 cm in length is placed in close proximity to the cut edge of the pancreatic stump. An end-to-side, duct-to-mucosa anastomosis (with pancreatic duct stent) is constructed. One hundred eight patients undergoing PPPD for benign and malignant diseases of the pancreatic head and the periampullary region were randomized to receive PG (PPPD-GP) or end-to-side PJ (PPPD-PJ).\nThe two treatment groups showed no differences in preoperative parameters and intraoperative factors. The overall postoperative complications were 23% after PPPD-GP and 44% after PPPD-PJ (P < 0.01). The incidence of pancreatic fistula was 4% after PPPD-GP and 18% after PPPD-PJ (P < 0.01). The mean + SD hospital stay was 12 +/- 2 days after PPPD-GP and 16 +/- 3 days after PPPD-PJ.\nThis study shows that PPPD-GP can be performed safely and is associated with less complication than PPPD-PJ. The advantage of this technique over other PG techniques is that the anastomosis is outside the area of the stomach where the contents empty into the jejunum, but pancreatic juice drains directly into the stomach.', 'title': 'Pancreatogastrostomy with gastric partition after pylorus-preserving pancreatoduodenectomy versus conventional pancreatojejunostomy: a prospective randomized study.', 'date': '2008-12-19'}, '7574936': {'article_id': '7574936', 'content': 'The authors hypothesized that pancreaticogastrostomy is safer than pancreaticojejunostomy after pancreaticoduodenectomy and less likely to be associated with a postoperative pancreatic fistula.\nPancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, occurring in 10% to 20% of patients. Nonrandomized reports have suggested that pancreaticogastrostomy is less likely than pancreaticojejunostomy to be associated with postoperative complications.\nBetween May 1993 and January 1995, the findings for 145 patients were analyzed in this prospective trial at The Johns Hopkins Hospital. After giving their appropriate preoperative informed consent, patients were randomly assigned to pancreaticogastrostomy or pancreaticojejunostomy after completion of the pancreaticoduodenal resection. All pancreatic anastomoses were performed in two layers without pancreatic duct stents and with closed suction drainage. Pancreatic fistula was defined as drainage of greater than 50 mL of amylase-rich fluid on or after postoperative day 10.\nThe pancreaticogastrostomy (n = 73) and pancreaticojejunostomy (n = 72) groups were comparable with regard to multiple parameters, including demographics, medical history, preoperative laboratory values, and intraoperative factors, such as operative time, blood transfusions, pancreatic texture, length of pancreatic remnant mobilized, and pancreatic duct diameter. The overall incidence of pancreatic fistula after pancreaticoduodenectomy was 11.7% (17/145). The incidence of pancreatic fistula was similar for the pancreaticogastrostomy (12.3%) and pancreaticojejunostomy (11.1%) groups. Pancreatic fistula was associated with a significant prolongation of postoperative hospital stay (36 +/- 5 vs. 15 +/- 1 days) (p < 0.001). Factors significantly increasing the risk of pancreatic fistula by univariate logistic regression analysis included ampullary or duodenal disease, soft pancreatic texture, longer operative time, greater intraoperative red blood cell transfusions, and lower surgical volume (p < 0.05). A multivariate logistic regression analysis revealed the factors most highly associated with pancreatic fistula to be lower surgical volume and ampullary or duodenal disease in the resected specimen.\nPancreatic fistula is a common complication after pancreaticoduodenectomy, with an incidence most strongly associated with surgical volume and underlying disease. These data do not support the hypothesis that pancreaticogastrostomy is safer than pancreaticojejunostomy or is associated with a lower incidence of pancreatic fistula.', 'title': 'A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy.', 'date': '1995-10-01'}}
| 0.333333
|
Surgery
|
9
|
Is the overall risk of postoperative pancreatic fistula higher, lower, or the same when comparing Pancreatojejunostomy (PJ) to Pancreatogastrostomy (PG)?
|
no difference
|
low
|
no
|
['24467711', '16327486', '15910726', '19092337', '24264781', '25799130', '26135690', '23643139', '7574936']
| 28,898,386
| 2,017
|
{'24467711': {'article_id': '24467711', 'content': 'The optimal strategy for the reconstruction of the pancreas following pancreaticoduodenectomy (PD) is still debated. The aim of this study was to compare the outcomes of isolated Roux loop pancreaticojejunostomy (IRPJ) with those of pancreaticogastrostomy (PG) after PD.\nConsecutive patients submitted to PD were randomized to either method of reconstruction. The primary outcome measure was the rate of postoperative pancreatic fistula (POPF). Secondary outcomes included operative time, day to resumption of oral feeding, postoperative morbidity and mortality, and exocrine and endocrine pancreatic functions.\nNinety patients treated by PD were included in the study. The median total operative time was significantly longer in the IRPJ group (320\u2009min versus 300\u2009min; P = 0.047). Postoperative pancreatic fistula developed in nine of 45 patients in the IRPJ group and 10 of 45 patients in the PG group (P = 0.796). Seven IRPJ patients and four PG patients had POPF of type B or C (P = 0.710). Time to resumption of oral feeding was shorter in the IRPJ group (P = 0.03). Steatorrhea at 1 year was reported in nine of 42 IRPJ patients and 18 of 41 PG patients (P = 0.029). Albumin levels at 1 year were 3.6\u2009g/dl in the IRPJ group and 3.3\u2009g/dl in the PG group (P = 0.001).\nIsolated Roux loop PJ was not associated with a lower rate of POPF, but was associated with a decrease in the incidence of postoperative steatorrhea. The technique allowed for early oral feeding and the maintenance of oral feeding even if POPF developed.', 'title': 'Isolated Roux loop pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: a prospective randomized study.', 'date': '2014-01-29'}, '16327486': {'article_id': '16327486', 'content': 'To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.\nWhile several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.\nA total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).\nThe 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.\nWhen compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.', 'title': 'Reconstruction by pancreaticojejunostomy versus pancreaticogastrostomy following pancreatectomy: results of a comparative study.', 'date': '2005-12-06'}, '15910726': {'article_id': '15910726', 'content': 'Only 2 large (more than 100 patients) prospective trials comparing pancreatogastrostomy (PG) with pancreatojejunostomy (PJ) after pancreatoduodenectomy (PD) have been reported until now. One nonrandomized study showed that there were less pancreatic and digestive tract fistula with PG, whereas the other, a randomized trial from a single high-volume center, found no significant differences between the two techniques.\nSingle blind, controlled randomized, multicenter trial. The main endpoint was intra-abdominal complications (IACs).\nOf 149 randomized patients, 81 underwent PG and 68 PJ. No significant difference was found between the two groups concerning pre- or intraoperative patient characteristics. The rate of patients with one or more IACs was 34% in each group. Twenty-seven patients sustained a pancreatoenteric fistula (18%), 13 in PG (16%; 95% confidence interval [CI] 8-24%) and 14 in PJ (20%; 95% CI 10.5-29.5%). No statistically significant difference was found between the 2 groups concerning the mortality rate (11% overall), the rate of reoperations and/or postoperative interventional radiology drainages (23%), or the length of hospital stay (median 20.5 days). Univariate analysis found the following risk factors: (1) age > or =70 years old, (2) extrapancreatic disease, (3) normal consistency of pancreas, (4) diameter of main pancreatic duct <3 mm, (5) duration of operation >6 hours, and (6) a center effect. Significantly more IAC, pancreatoenteric fistula, and deaths occurred in one center (that included the most patients) (P = .05), but there were significantly more high-risk patients in this center (normal pancreas consistency, extrapancreatic pathology, small pancreatic duct, higher transfusion requirements, and duration of operation >6 hours) compared with the other centers. In multivariate analysis, the center effect disappeared. Independent risk factors included duration of operation >6 hours for IAC and for pancreatoenteric fistula (P = .01), extrapancreatic disease for pancreatoenteric fistulas (P < .04), and age > or =70 years for mortality (P < .02).\nThe type of pancreatoenteric anastomosis (PJ or PG) after PD does not significantly influence the rate of patients with one or more IAC and/or pancreatic fistula or the severity of complications.', 'title': 'A controlled randomized multicenter trial of pancreatogastrostomy or pancreatojejunostomy after pancreatoduodenectomy.', 'date': '2005-05-25'}, '19092337': {'article_id': '19092337', 'content': 'To compare the results of postoperative morbidity rate of a new pancreatogastrostomy technique, pylorus-preserving pancreaticoduodenectomy (PPPD) with gastric partition (PPPD-GP) with the conventional technique of pancreaticojejunostomy (PJ).\nPancreatojejunostomy and pancreatogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreatoduodenectomy (PD). All randomized controlled trials failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally results. However, postoperative morbidity remains high. The best technique in pancreatic anastomosis is still debated.\nDescribed here is a new technique, PPPD-GP; in this technique the gastroepiploic arcade is preserved. Gastric partition was performed using 2 endo-Gia staplers along the greater curvature of the stomach, 3 cm from the border. This gastric segment, 10 to 12 cm in length is placed in close proximity to the cut edge of the pancreatic stump. An end-to-side, duct-to-mucosa anastomosis (with pancreatic duct stent) is constructed. One hundred eight patients undergoing PPPD for benign and malignant diseases of the pancreatic head and the periampullary region were randomized to receive PG (PPPD-GP) or end-to-side PJ (PPPD-PJ).\nThe two treatment groups showed no differences in preoperative parameters and intraoperative factors. The overall postoperative complications were 23% after PPPD-GP and 44% after PPPD-PJ (P < 0.01). The incidence of pancreatic fistula was 4% after PPPD-GP and 18% after PPPD-PJ (P < 0.01). The mean + SD hospital stay was 12 +/- 2 days after PPPD-GP and 16 +/- 3 days after PPPD-PJ.\nThis study shows that PPPD-GP can be performed safely and is associated with less complication than PPPD-PJ. The advantage of this technique over other PG techniques is that the anastomosis is outside the area of the stomach where the contents empty into the jejunum, but pancreatic juice drains directly into the stomach.', 'title': 'Pancreatogastrostomy with gastric partition after pylorus-preserving pancreatoduodenectomy versus conventional pancreatojejunostomy: a prospective randomized study.', 'date': '2008-12-19'}, '24264781': {'article_id': '24264781', 'content': 'Anastomotic leakage of pancreaticojejunostomy (PJ) remains the single most important source of morbidity after pancreaticoduodenectomy (PD). The primary aim of this randomized clinical trial comparing PG with PJ after PD was to test the hypothesis that invaginated PG would result in a lower rate and severity of pancreatic fistula.\nPatients undergoing PD were randomized to receive either a duct-to-duct PJ or a double-layer invaginated PG. The primary endpoint was the rate of pancreatic fistula, using the definition of the International Study Group on Pancreatic Fistula. Secondary endpoints were the evaluation of severe abdominal complications (Clavien-Dindo grade IIIa or above), endocrine and exocrine function.\nOf 123 patients randomized, 58 underwent PJ and 65 had PG. The incidence of pancreatic fistula was significantly higher following PJ than for PG (20 of 58 versus 10 of 65 respectively; P\u2009=\u20090.014), as was the severity of pancreatic fistula (grade A: 2 versus 5 per cent; grade B-C: 33 versus 11 per cent; P\u2009=\u20090.006). The hospital readmission rate for complications was significantly lower after PG (6 versus 24 per cent; P\u2009=\u20090.005), weight loss was lower (P\u2009=\u20090.025) and exocrine function better (P\u2009=\u20090.022).\nThe rate and severity of pancreatic fistula was significantly lower with this PG technique compared with that following PJ.\nISRCTN58328599 (http://www.controlled-trials.com).', 'title': 'Randomized clinical trial of pancreaticogastrostomy versus pancreaticojejunostomy on the rate and severity of pancreatic fistula after pancreaticoduodenectomy.', 'date': '2013-11-23'}, '25799130': {'article_id': '25799130', 'content': 'It has been suggested that pancreaticogastrostomy (PG) is a safer reconstruction than pancreaticojejunostomy (PJ), resulting in lower morbidity, including lower pancreatic leak rates and decreased postoperative mortality. We compared PJ and PG after pancreaticoduodenectomy (PD).\nA randomized clinical trial was designed. It was stopped with 50% accrual. Patients underwent either PG or PJ reconstruction. The primary outcome was the pancreatic fistula rate, and the secondary outcomes were overall morbidity and mortality. We used the Student t, Mann-Whitney U and χ(2) tests for intention to treat analysis. The effect of randomization, American Society of Anesthesiologists score, soft pancreatic texture and use of pancreatic stent on overall complications and fistula rates was calculated using logistic regression.\nOur trial included 98 patients. The rate of pancreatic fistula formation was 18% in the PJ and 25% in the PG groups (p = 0.40). Postoperative complications occurred in 48% of patients in the PJ and 58% in the PG groups (p = 0.31). There were no significant predictors of overall complications in the multivariate analysis. Only soft pancreatic gland predicted the occurrence of pancreatic fistula (odds ratio 5.89, p = 0.003).\nThere was no difference in the rates of pancreatic leak/fistula, overall complications or mortality between patients undergoing PG and and those undergoing PJ after PD.\nSelon certains, la pancréatogastrostomie (PG) est une technique de reconstruction plus sécuritaire que la pancréatojéjunostomie (PJ) et entraîne une morbidité moindre, y compris un taux moins élevé de fuites pancréatiques et une mortalité postopératoire diminuée. Nous avons comparé la PJ et la PG post-pancréatoduodénectomie.\nUn essai clinique randomisé a été conçu et cessé à l’atteinte d’un taux de participation de 50 %. Les patients ont subi une reconstruction par PG ou par PJ. Le paramètre principal était le taux de fistules pancréatiques et les paramètres secondaires étaient la morbidité et la mortalité globales. Nous avons utilisé les tests \nNotre essai a regroupé 98 patients. Le taux de fistules pancréatiques a été de 18 % dans le groupe soumis à la PJ et de 25 % dans le groupe soumis à la PG (\nNous n’avons noté aucune différence quant aux taux de fuites ou de fistules pancréatiques, de complications globales ou de mortalité entre les patients soumis à la PG et à la PJ post-pancréatoduodénectomie.', 'title': 'In search of the best reconstructive technique after pancreaticoduodenectomy: pancreaticojejunostomy versus pancreaticogastrostomy.', 'date': '2015-03-24'}, '26135690': {'article_id': '26135690', 'content': "Ann SurgAnn. SurgANSUAnnals of Surgery0003-49321528-1140Lippincott, Williams, and Wilkins26135690474141710.1097/SLA.000000000000124000006Randomized Controlled TrialsPancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767)Perioperative and Long-term Results of a Multicenter Randomized Controlled TrialKeckTobiasMD, MBA, FACS∗†WellnerU. F.MD∗†BahraM.MD‡KleinF.MD‡SickO.MSc†NiedergethmannM.MD§WilhelmT. J.MD§FarkasS. A.MD¶BörnerT.MD¶BrunsC.MD||KleespiesA.MD||KleeffJ.MD∗∗MihaljevicA. L.MD∗∗UhlW.MD††ChromikA.MD††FendrichV.MD‡‡HeegerK.MD‡‡PadbergW.MD§§HeckerA.MD§§NeumannU. P.MD¶¶JungeK.MD¶¶KalffJ. C.MD||||GlowkaT. R.MD||||WernerJ.MD∗∗∗KnebelP.MD∗∗∗PisoP.MD†††MayrM.MD†††IzbickiJ.MD‡‡‡VashistY.MD‡‡‡BronsertP.MD§§§¶¶¶BrucknerT.PhD||||||LimprechtR.MSc||||||DienerM. K.MD∗∗∗∗∗∗∗RossionI.MD∗∗∗∗WegenerI.MD∗∗∗∗HoptU. T.MD†∗Klinik für Chirurgie, UKSH Campus Lübeck, Lübeck, Germany†Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany‡Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum, Berlin, Germany§Chirurgische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany¶Klinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Germany||Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum der Universität München, Munich, Germany∗∗Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München und CHIR-Net München, Munich, Germany††Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Bochum, Germany‡‡Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Marburg, Marburg, Germany§§Klinik für Allgemein-, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie des Universitätsklinikums Gießen, Gießen, Germany¶¶Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Aachen, Aachen, Germany||||Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Germany∗∗∗Abteilung für Allgemeine, Viszerale und Transplantationschirurgie, Universität Heidelberg, Heidelberg, Germany†††Klinik für Allgemein- und Viszeralchirurgie, Krankenhaus Barmherzige Brüder, Regensburg, Germany‡‡‡Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany§§§Institut für Pathologie, Universitätsklinikum Freiburg, Freiburg, Germany¶¶¶Comprehensive Cancer Center Freiburg, Freiburg Germany||||||Institut für Medizinische Biometrie und Informatik (IMBI), Universität Heidelberg, Heidelberg, Germany∗∗∗∗Studienzentrum der Deutschen Gesellschaft für Chirurgie (SDGC), Heidelberg, Germany.Reprints: Tobias Keck, MD, MBA, FACS, Klinik für Chirurgie, University Hospital Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: tobias.keck@uksh.de.3201608220162633440449Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Objectives:To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial.Background:PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications.Methods:A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up.Results:From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters.Conclusions:The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.Keywordspancreatoduodenectomypancreatogastrostomypancreatojejunostomypostoperative pancreatic fistulapostoperative pancreatic functionOPEN-ACCESSTRUEThe first successful pancreatoduodenectomy was performed as a 2-stage procedure by Walter Kausch in 1909.1 Later, Allen O. Whipple popularized the procedure by a series of 37 pancreatoduodenectomies during his career.2 Because of high mortality, the operation was nearly abandoned in the 1970s.2 In the 1990s, large retrospective series from specialized centers around the world set a benchmark for operative mortality of below 5%.2 Nevertheless, morbidity remains substantial after pancreatoduodenectomy.3–10 The main contributing factor is postoperative pancreatic fistula (POPF), involving leakage of pancreatic juice from the pancreatic anastomosis, which can lead to severe secondary complications such as intra-abdominal abscesses and erosion bleeding.9,11,12 Data regarding the prevention of POPF by application of somatostatin analogues have been controversial thus far,13,14 but a recent randomized trial strongly suggests that pasireotide successfully reduces POPF rates.15 Numerous attempts at improving pancreatic anastomosis techniques to lower POPF rates have been proposed.2,16,17 The hypothesis of this trial dates back to Walter Kausch, who discussed the possibility of anastomosis of the pancreatic remnant to the jejunum (pancreatojejunostomy, PJ) or the stomach (pancreatogastrostomy, PG) in his 1912 original publication of the first successful pancreatoduodenectomy.1Almost all retrospective studies suggest superiority of PG over PJ in terms of reduced POPF and other complications.18 To date, however, conflicting results have been reported from 8 prospective randomized controlled trials (RCTs) published from 1995 to 201419–26 (see Supplemental Digital Content Table S1, available at): Only 3 RCTs22,24,25 have demonstrated a reduced rate of POPF after PG, and 4 RCTs20,22,24,25 found advantages of PG over PJ in terms of postoperative complications. Soft pancreatic texture was identified as a risk factor for POPF and other complications in 4 RCTs.19,21,23,25 However, the available RCTs have some limitations. With the exception of the recent Belgian multicenter RCT24 including 329 patients, total case numbers of the RCTs are relatively low (n = 90–151) and only 2 RCTs are multicenter trials. Definitions of perioperative outcomes vary as early trials did not use the current consensus definitions of specific complications in pancreatic surgery established by the International Study Group for Pancreatic Surgery (ISGPS). Although many technical variations of PG and PJ have been reported,16,17 all 8 RCTs were restricted to specific subtypes of PG and PJ. Only 2 RCTs with contradictory results report on postoperative pancreatic function measured during follow-up of 3 to 12 months: the Egyptian trial26 reports worse and the Spanish trial25 reports better pancreatic function. None of the RCTs report on quality of life during follow-up.Here we present data collected at 14 high-volume centers for pancreatic surgery in Germany from the currently largest multicenter randomized trial comparing PG with PJ with respect to perioperative complications and long-term pancreatic function and quality of life.PATIENTS AND METHODSStudy Design, Hypothesis, and Inclusion CriteriaThe RECOnstruction after PANCreatoduodenectomy Study (RECOPANC) was designed as a randomized, controlled, observer- and patient-blinded multicenter trial with 2 parallel treatment arms (PG and PJ) (see Supplemental Digital Content, available at). The hypothesis was that the rate of clinically relevant POPF is lower after PG. Inclusion criteria were planned pancreatoduodenectomy at one of the participating academic centers and age more than 18 years. Exclusion criteria were participation in interfering clinical trials and expected lack of compliance. With the rationale to increase willingness of participating surgeons to recruit patients and to achieve greater generalizability of the results, we did not restrict PG or PJ to a special technique. Fourteen German academic centers (RECOPANC Trial Group27) with a median case load of 78 major pancreatic resections per year (range: 29–499, figures for year 2012 from the Association of German University Clinics, http://www.uniklinika.de) participated in the trial.Primary Endpoint and Sample SizePOPF is defined by ISGPS as the occurrence of amylase activity in abdominal drain fluid of 3 times the upper serum limit on postoperative day 3 or later.28,29 In brief, grade A fistula is self-limited and does not need specific treatment, grade B requires medical or invasive interventional treatment, and grade C leads to reoperation and/or severe secondary complications. The primary endpoint chosen for this trial was clinically relevant POPF, that is, ISGPS grade B or C, with the modification that application of somatostatin analogues was not considered a criterion for grading. The primary endpoint was assessed on postoperative day 3 at hospital discharge and on postoperative day 30 to detect all POPFs.Based on the prior assumption of a POPF B/C rate of 6% and 16% with PG and PJ, respectively, α = 5% and β = 20%, a sample size of 153 per treatment arm (PG vs PJ) was calculated with the 2-sided χ2 test. An adaptive interim analysis of the primary endpoint according to Bauer and Koehne30 was planned after recruitment of 152 patients to allow for premature trial termination (with 1-sided stopping boundaries of P < 0.0038) and sample size recalculation.Secondary Endpoints and Follow-upSecondary surgical endpoints were death, relaparotomy, completion pancreatectomy, anastomotic leak other than pancreatic fistula, wound infection, delayed gastric emptying, postpancreatectomy hemorrhage according to the ISGPS definitions,31,32 intra-abdominal abscess requiring invasive treatment, operation time (skin incision to skin closure), and postoperative hospital stay. Further secondary endpoints included septic shock, respiratory failure, deep venous thrombosis, lung embolism, myocardial infarction, and stroke. Pancreatic endocrine and exocrine functions and quality of life were evaluated in long-term follow-up at baseline, 6 and 12 months after the operation by the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) C30 and the pancreatic cancer module PAN26.33,34Randomization and BlindingCenter-based block randomization was performed by the participating centers using a centralized Web-based tool (Randomizer Software, Institute for Medical Informatics, Statistics and Documentation of the Medical University of Graz, www.randomizer.at) with allocation concealment. To avoid a possible intraoperative selection of low-risk patients,23 randomization was performed preoperatively. Obviously, the surgeons were not blinded concerning the intervention. Therefore, blinded observers at the participating centers assessed the primary endpoint. Patients were kept blinded regarding the intervention and unblinded only in the case of emergencies where necessary.Ethical Approval, Safety, and RegistrationThe study protocol was approved by the local ethics committees of the participating centers and carried out according to the rules of Good Clinical Practice and the Declaration of Helsinki.35 Written informed consent was obtained from each patient. An independent institution served as the Data Safety Monitoring Board and was responsible for on-site clinical monitoring, source data verification, and management of severe adverse event reports (Center for Clinical Studies, Freiburg, Germany). The trial was assigned a Universal Trial Number (UTN U1111-1117-9588) and registered in the German Trials Register (DRKS 00000767) on March 23, 2011. The study protocol was published in Trials.27Statistical AnalysisThe primary endpoint was analyzed according to the intention-to-treat principle (see Supplemental Digital Content, available at). A multivariate logistic regression model adjusting a priori for age, center, surgeon volume/experience, and pancreatic texture was applied to compare POPF rates in both treatment groups. Missing values for the primary endpoint were replaced by imputed case analysis according to Higgins et al.36 Exploratory analysis was planned for secondary endpoints. SAS software 9.1 (SAS 9.1 software, SAS, Cary NC) and 2-sided tests were used for all calculations.RESULTSTrial FlowA total of 618 patients were screened and 440 patients were randomized from May 31, 2011, through December 5, 2012. The number of patients randomized per center is shown in Supplemental Digital Content Fig. S1, available at, and ranged from 6 to 84, with 5 centers recruiting less than 20 patients and 2 centers recruiting more than 50 patients. After the interim analysis of the first 152 included patients, the Data Safety and Monitoring Board advised continuation of the trial. A total of 120 randomized patients were excluded from the final analysis: 3 patients were randomized by mistake (randomized but not eligible), 5 did not undergo laparotomy, and 112 did not receive pancreatoduodenectomy and were, therefore, excluded from further analysis. Fifteen patients randomized to PG received PJ and 12 patients randomized to PG received PJ because of the surgeon's technical preference. Reasons given for PJ instead of PG included technical problems with PG: short pancreatic remnant (n = 9), difficult pancreatic remnant mobilization (n = 2), and gastric ulcer (n = 1); reasons for PG instead of PJ were soft pancreas with small duct (n = 11) and pancreas divisum (n = 1). In total, 320 patients were included in the intention-to-treat analysis of the primary endpoint: 149 patients randomized for PJ and 171 randomized for PG. Ninety-six patients did not finish the whole 12-month follow-up because of prior death (n = 75), loss to follow-up (n = 10), withdrawal of consent (n = 5), and other reasons (n = 6) (Fig. 1).FIGURE 1Trial flow chart. ITT indicates intention to treat; PP, per protocol.Patient Baseline Characteristics and OperationsPatient baseline parameters are shown in Table 1. The treatment groups were balanced in terms of age, sex, body mass index, indications, symptoms, preoperative biliary drainage, comorbidities, American Society of Anesthesiologists (ASA) Classification, medication, and standard laboratory parameters. The treatment groups were also comparable in terms of operation technique, surgeon experience/volume, and blood loss/intraoperative transfusion requirement. In particular, the rates of soft pancreata (PG vs PJ, 59% vs 57%) and nondilated pancreatic ducts (PG vs PJ, 58% vs 55%), which are indicators for increased risk of fistula formation,5,37–40 were not significantly different between the 2 groups (Table 1).Supplemental Digital Content Table S2, available at, shows the technical varieties used for PG and PJ at the trial centers. According to the ISGPS classification for pancreatic anastomoses,16 the most commonly performed techniques were nonstented duct-mucosa anastomosis (ISGPS type I-A-S0) with 2 interrupted monofilament resorbable suture rows for PJ and nonstented dunking PG (ISGPS type II-B-S0) anastomosis with purse-string plus interrupted monofilament resorbable suture.Primary Endpoint AnalysisThe rate of clinically relevant POPF was 20% after PG and 22% after PJ in the control group (P = 0.62, 2-sided χ2 test, Table 2). In a multivariate logistic regression model (Table 2), including anastomotic technique (PG vs PJ), age, center (north vs south), pancreatic texture (soft vs hard) and surgeon volume (pancreatic resections per year), and soft pancreatic texture was the only significant factor affecting POPF B/C, with an odds ratio estimate of 2.1 (P = 0.016) (Table 2).As there were 12 patients allocated to PG receiving PJ instead and 15 patients with PG instead of PJ, we also performed an as-treated analysis of the primary endpoint (see Supplemental Digital Content Table S3, available at). The results did not differ from those of the intention-to-treat analysis.Assessment of Learning EffectsThe odds ratio estimate for fistula rate in surgeons with less than 10 pancreatoduodenectomies was 1.2 to 6.8 (95% confidence interval) but did not reach the significance level (P = 0.064 in multivariate analysis, see Table 2). Surgeons with less than 10 pancreatoduodenectomies per year had a higher fistula rate with PJ (46%) than with PG (27%), and this effect was gradually lost with increasing individual case load (see Supplemental Digital Content Table S4, available at); however, these differences did not reach statistical significance. There was also no significant center effect as to the preferred type of anastomosis in the participating centers (see Supplemental Digital Content Table S4, available at).Perioperative Secondary Endpoint AnalysisOperation time did not differ between PG and PJ. There were no significant differences between PG and PJ with regard to the frequency of surgical complications such as delayed gastric emptying, intra-abdominal abscesses, relaparotomy, completion pancreatectomy, anastomotic leaks, and surgical site infection. There was also no difference in the incidence of systemic complications such as septic shock, respiratory failure, deep vein thrombosis, lung embolism, and myocardial infarction. There were more (n = 5) stroke events in the PG group but none in the PJ group (P = 0.035) and significantly more postpancreatectomy hemorrhage events in the PG group (P = 0.023), the latter due to more grade A (5% vs 1%) and B (9% vs 4%) hemorrhages. Stroke and grade A/B bleeding were not associated, however (P = 0.998). Perioperative in-house mortality in the treatment groups (PG vs PJ, 6% vs 5%, P = 0.963) and 90-day mortality (PG vs PJ, 10% vs 5%, P = 0.167) were not statistically different. Postoperative hospital stay was equal with a median of 16 days (Table 3).Survival During Follow-upOverall survival curves are given in Supplemental Digital Content Fig. S2, available at. One-year (365 days) Kaplan-Meier survival estimates (±standard error) were 77%\u200a±\u200a3% in PG and 76%\u200a±\u200a4% in PJ and thus comparable (P = 0.675 in 2-sided log-rank test) (see Supplemental Digital Content Fig. S2, available at).Pancreatic Function and Long-term Follow-upThe percentage of patients receiving oral enzyme replacement rose from 8% preoperatively to around 80% during 6- and 12-month follow-up. Exploratory analysis also suggested a significantly reduced rate of oral enzyme replacement therapy in patients with PG at 6 months after the operation (PG vs PJ, 72% vs 89%, P < 0.001). This difference did not persist at 12-month follow-up because of a slightly decreasing percentage of PJ patients using oral enzyme supplementation (PG vs PJ, 72% vs 81%, P = 0.11). However, simultaneously the rate of patients reporting steatorrhea in the PJ group increased (from 17% at 6 months to 22% at 12 months), suggesting now insufficient enzyme supplementation in some patients. This was not the case with PG, where reported steatorrhea decreased from 20% to 13%. The amount of enzyme units taken per day was comparable in both treatment groups.The prevalence of diabetes mellitus rose only slightly after pancreatoduodenectomy (from 25% at operation to 31% at 12-month follow-up) and was comparable after PG and PJ. Among diabetic patients, there was an increase of insulin dependence from around 50% to around 70% after pancreatoduodenectomy, whereas the percentage of patients with dietary therapy dropped only from 23% preoperatively to 13% and 9% at 6 and 12 months, respectively. There was no significant difference between both treatment arms (Table 4).Quality of Life and Long-term Follow-upAt the time of operation, EORTC QLQ-C30 and PAN26 scores were balanced between the treatment groups except for the physical functioning scale scores, which were higher in the PG group (P = 0.002). The patients assigned the lowest scores to role functioning and body image. Other major reported problems were fatigue, insomnia, pain, and digestive symptoms such as altered bowel habit. At 6 and 12 months after the operation, the most severe impairments were observed in role functioning, altered bowel habit, and fatigue. On the contrary, appetite, nausea, and hepatic symptoms improved. At 6 months, a reduced score on the financial problems scale could be observed (P = 0.044) in PG compared with PJ, which persisted at 12-month follow-up. Furthermore, emotional and social functioning scale scores were significantly better after PG than after PJ (P = 0.039 and 0.019) (see Supplemental Digital Content Table S5, available at).DISCUSSIONWe report the currently largest RCT to compare PG and PJ in terms of POPF and perioperative complications and long-term outcome including quality of life. Of note, this multicenter trial was independently monitored. In contrast to previous RCTs, PG or PJ was not restricted to a specific subtype. The results of this trial have several implications for clinical practice. First, although it was designed to confirm the hypothesis of a reduction of clinically relevant POPF in patients with PG, the results show similar rates of grade B/C POPF regardless of the reconstruction method with an overall rate of 21%. This is higher than the reported range of 4% to 18% from large retrospective benchmark series (see Supplemental Digital Content Table S1, available at). The previous RCTs report fistula rates between 12% and 24% (see Supplemental Digital Content Table S1, available at). In comparison with the other RCTs, RECOPANC included the oldest patients (average 68 years vs 56–67 years in other RCTs) with the highest body mass index (average 25 vs 21–25 in other RCTs). Of note, RECOPANC is also the first RCT to report independent monitoring. Taken together, the observed POPF rate must be considered valid in view of an ageing general population with increased operative risk.Also, overall in-hospital mortality of 6% and the 90-day mortality of 7% in this trial do not meet the usually cited 5% benchmark for pancreatoduodenectomy. It is above the reported range of 0.7% to 3.7% from current large-scale retrospective series (see Supplemental Digital Content Table S1, available at), whereas some RCTs report comparable perioperative mortality rates of 0% to 11% (see Supplemental Digital Content Table S1, available at). In agreement with a current study,41 our data highlight the relevance of 90-day mortality figures in pancreatic surgery. It seems appropriate to accept that clinically relevant fistula rates of 20% and perioperative mortality of more than 5% mirror clinical reality even in high-volume pancreatic surgery. A similar effect was observed in the distal pancreatectomy trial, which reported a pancreatic fistula rate after distal pancreatic resection more than twice as high as previously reported in several retrospective series.42,43Meta-analysis of the available RCTs19–26 incorporating data from this trial suggests no significant reduction in POPF rates (odds ratio: 0.66; 95% confidence interval: 0.43–1.01; P = 0.056) (see Supplemental Digital Content Table S6, available at for details). This stands in contrast to current meta-analysis.44In a multivariate analysis, the single most important factor influencing POPF rates was the quality and texture of the organ. Soft pancreatic texture, as judged intraoperatively by the surgeon, has been demonstrated to bear a higher risk for secondary complications, erosion bleeding, and mortality in previous studies.6,9,11,24,37,38,40 It has been shown that subjective evaluation of the pancreatic hardness and texture strongly correlates with the histopathological degree of fibrosis.40 On the one hand, pancreatic cancer and chronic pancreatitis are usually associated with hardening of the whole organ including the pancreatic remnant; on the other hand, prophylactic surgery for benign lesions such as cystic neoplasms or small tumors such as ampullary cancer is usually associated with soft pancreatic tissue.9,19,40As outlined, all participating clinics were high-volume academic centers for pancreatic surgery, and there was no statistically significant center effect regarding POPF rate. Nevertheless, a high odds ratio for POPF in the low-volume surgeons indicates that besides center volume, individual surgeon volume is a relevant factor influencing complication rates in pancreatoduodenectomy.Furthermore, from our data, it might be speculated that PG offers an easier-to-learn technique suited for less experienced surgeons, but this effect did not reach statistical significance. This opinion has also been expressed by other authors of previous RCTs19,20,24,26 on the basis of the assumption that it is technically easier to achieve secure invagination of the pancreatic remnant with PG, especially in case of a bulky soft pancreas. Reasons given for conversion to PG instead of PJ (soft pancreas in 11 of 12 cases) in the current trial may reflect this assumption. However, operation time was not reduced with PG in the current trial, and only 2 previous RCTs23,26 found a shorter operation time with PG.The incidence of grade A and B postpancreatectomy hemorrhages was increased after PG. By ISGPS definition, grade A bleeding has no therapeutic consequence, but grade B events require conservative or even invasive therapy and may be sentinels of later grade C hemorrhage. The feared life-threatening (grade\u200aC) bleeding events were not increased with PG. These findings confirm previous retrospective and prospective observations, which showed increased bleeding events from PGs.23,45,46 Meticulous hemostatic measures at the pancreatic cut surface are, therefore, advised. There was a higher rate of perioperative stroke events in patients with PGs that were not associated with the bleeding events, however. For lack of a rational explanation, this might be interpreted as an artifact of exploratory data analysis.Our reported length of hospital stay (median, 16 days) is about twice as long as that usually reported from high-volume North American centers (see Supplemental Digital Content Table S1, available at). Our explanations are that due to law-enforced universal health care insurance in Germany, patients usually do not experience financial pressure to be discharged early, and the common practice is to discharge patients home after full recovery. Even in a fast-track surgery program applied to major pancreatic resections in a German center,47 patients were discharged at median on day 10, with a 30-day readmission rate of only 3.5%, whereas readmission rates of 15% to 20% after pancreatoduodenectomy are currently reported from the United States.48,49 In consequence, readmission has been highlighted as a significant problem by American scientific studies and is financially penalized in the United States but not in Germany.47–51The results of long-term pancreatic function follow-up in the current trial may be interpreted as suggestive of better exocrine function in patients with PG. However, pancreatic function was not measured directly but by means of the surrogate parameters oral enzyme supplementation and steatorrhea, and the drawback of exploratory data analysis must be kept in mind. Previous RCTs with smaller case numbers have reported inconsistent outcomes.25,26 The current study represents the largest prospective evaluation of this issue and will be followed by a prospective long-term observation of the included patients. Regarding the usually encountered opinion that pancreatic function is worse after PG compared with PJ, our results suggest that this is not the case.Only one previous retrospective study compared quality of life after pancreatoduodenectomy with PG and PJ and found no difference, but it was unbalanced with regard to the preoperative patient status.52 Follow-up in the present trial did not reveal differences between the treatment groups in most aspects covered by the EORTC QLQ-C30/PAN26 questionnaires. On the contrary, the few detected that differences are not large enough to be considered clinically relevant. We also interpret these as an artifact of explorative analysis of the many quality-of-life aspects. Our results, however, provide valuable data to identify major problems that impair the quality of life of patients before and after pancreatoduodenectomy: role functioning, altered bowel habit, and fatigue.CONCLUSIONSIn summary, this trial demonstrated several salient findings. Reconstruction by PG, when not restricted to a specific subtype and evaluated in a multicenter setting, did not reduce perioperative complications. Soft pancreatic tissue quality remains the most influential factor for POPF rate. PG may offer a technically less demanding but safe anastomotic technique. However, a higher rate of postoperative grade A/B hemorrhage was observed, advocating increased awareness toward hemostatic measures with PG. The rate of POPF remains substantial and is currently underestimated. Perioperative mortality can surpass the 5% margin even in the high-volume academic pancreatic surgery setting. Both may be attributed to extended indications for pancreatoduodenectomy in an ageing population. Quality of life in pancreatoduodenectomy patients is most severely impaired regarding role functioning and body image. The operation seems to ameliorate gastrointestinal and hepatic symptoms but does not improve fatigue and role functioning. Long-term exocrine pancreatic function after PG does not seem to be inferior to PJ.Supplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentAcknowledgmentsT. Keck and U. F. 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Ann Surg\n2012; 256:529–537.2286837351.KristensenSRBechMQuentinW\nA roadmap for comparing readmission policies with application to Denmark, England and the United States. Health Policy\n2015; 119:264–273.2554740152.SchmidtUSimunecDPisoP\nQuality of life and functional long-term outcome after partial pancreatoduodenectomy: pancreatogastrostomy versus pancreatojejunostomy. Ann Surg Oncol\n2005; 12:467–472.15886907TABLE 1Patients, Baseline Parameters, and OperationsPJPGTotalParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePTotal149171320—Baseline DataAge, yr6629–876835–866829–870.787Sex\u2003Male9362%9556%18859%0.214\u2003Female5638%6744%13241%BMI (kg/m2)2515–432516–392515–430.706Chronic pancreatitis149%148%289%Pancreatic adenocarcinoma9866%10461%20263%Ampullary adenocarcinoma117%106%217%Indications0.695\u2003CNP43%85%124%\u2003NET21%32%52%\u2003Other2013%3219%5216%\u2003Weight loss8960%9757%18658%0.587Symptoms\u2003Pain7953%8449%16351%0.487\u2003Jaundice7248%8852%16050%0.575Preop biliary drainage\u2003ERD6040%6136%12138%0.396\u2003PTD43%74%113%0.488History of acute pancreatitis2013%1710%3712%0.331Chronic pancreatitis4027%4526%8527%0.915Prior abdominal surgery6946%8047%14947%0.932Cardiac5839%6840%12639%0.878pulmonary149%1911%3310%0.615Comorbidities\u2003Renal1510%159%309%0.692\u2003Hepatic96%106%196%0.942\u2003Ex-smoker4027%3319%7323%0.074\u2003Active smoker4430%4225%8627%\u2003Ex-alcohol abuse1711%1911%3611%0.673\u2003Active alcohol abuse1611%2414%4013%ASA\u2003I1410%1811%3210%\u2003II8156%8652%16753%\u2003III5034%6137%11136%0.881\u2003IV11%21%31%\u2003NA32%42%72%Medication\u2003Glucocorticoids43%32%72%0.570\u2003Immunosuppressives21%11%31%0.483\u2003Analgesics2920%4526%7423%0.147\u2003Somatostatin analog21%00%21%0.129\u2003Neoadjuvant cx43%32%72%0.570\u2003Neoadjuvant rx21%11%31%0.483Laboratory\u2003Amylase [U/L]5113–360589–536569–5360.168\u2003Creatinine (μmol/L)6115–3286237–51962156–5190.581\u2003Bilirubin (μmol/L)123–598152–371142–5980.951\u2003C-reactive protein (mg/L)60–11160–17760–1770.618\u2003Total protein (g/L)7044–5587155–857044–5580.442\u2003CA 19–9 (U/mL)421–11,000481–4,491471–11,0000.503\u2003Hemoglobin (mmol/L)84–1084–1084–100.418\u2003Leukocytes (1000/mL)73–1873–1973–190.436\u2003Thrombocytes (1000/mL)26095–56927037–62526837–6250.926OperationsSurgeon experience*\u2003<52920%2414%5317%\u20035–105034%5432%10433%0.301\u2003>106947%9254%16151%\u2003NA11%11%21%\u2003<10139%159%289%Surgeon volume†\u200310–254329%4929%9229%\u2003>259262%10662%19862%0.999\u2003NA11%11%21%Technique\u2003PPPD12181%13478%25580%0.528\u2003Classic Whipple2819%3722%6520%\u2003NA53%116%165%LAD\u2003Standard10671%12473%23072%0.331\u2003Extended3826%3621%7423%\u2003Portal venous resection3020%2917%5918%0.465\u2003Additional organ resection3926%3923%7824%0.484Blood loss5000–4,8005000–3,5005000–4,8000.581Intraoperative red blood cell transfusion\u2003No13289%14685%27887%\u2003132%64%93%0.708\u2003285%138%217%\u2003>266%66%1212%Pancreatic texture\u2003Hard6243%6641%12842%\u2003Soft8357%9559%17858%0.755\u2003NA43%106%144%MPD diameter\u2003Normal (≤3 mm)7855%9458%17256%\u2003Dilated (>3 mm)6445%6942%13344%0.630\u2003NA75%85%155%P values derived from 2-sided χ2 test and Student t test.*Years of pancreatic surgery.†Pancreatoduodenectomies per year.ASA indicates American Society of Anesthesiologists; BMI, body mass index; CA, 19-9, Carbohydrate antigen 19-9; CNP, cystic neoplasm of the pancreas; cx, chemotherapy; ERD, endoscopic retrograde drainage; LAD, lymphadenectomy; MPD, main pancreatic duct; NA, not assessed; NET, neuroendocrine tumor; PPPD, pylorus preserving pancreatoduodenectomy; PTD, percutaneous transhepatic drainage; rx, radiotherapy.TABLE 2Primary Endpoint AnalysisUnivariate AnalysisTotalNo/POPF APOPF B/CParameternn (%)n (%)PAll patients320253 (79%)67 (21%)—PJ149116 (78%)33 (22%)0.617PG171137 (80%)34 (20%)Multivariate AnalysisParameterOdds RatioLower CIUpper CIPPG vs PJ0.8640.4951.5070.607Age, yr0.9880.9661.0110.318Soft vs hard pancreatic texture2.0941.1453.8270.016Center location (north vs south)1.0480.581.8960.876Surgeon volume 10–25 vs >25 PD/yr1.5780.8223.0290.863Surgeon volume <10 vs >25 PD/yr2.8011.1556.7940.064P values derived from 2-sided χ2 test (univariate) and binary logistic regression (multivariate). CI indicates 95% confidence interval; PD, pancreatoduodenectomy; POPF, postoperative pancreatic fistula grade according to the International Study Group for Pancreatic Surgery definition.TABLE 3Perioperative Secondary Endpoint AnalysisPJPGTotalParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePTotal149171320—Operation time337165–565332165–600332165–6000.706DGE* (delayed gastric emptying)\u2003No8759%10763%19461%\u2003Grade A3927%4426%8326%\u2003Grade B96%148%237%0.301\u2003Grade C128%64%186%\u2003Missing202PPH* (postpancreatectomy hemorrhage)\u2003No13289%13579%16783%\u2003Grade A11%95%103%\u2003Grade B64%169%227%0.023\u2003Grade C107%116%217%IA with IPC drainage1913%1811%3712%IA with OP drainage128%159%278%0.814Other surgical complications\u2003Relaparotomy completion2718%2012%4715%0.100\u2003Pancreatectomy96%64%155%0.285\u2003Hepaticoenterostomy leak53%32%83%0.480\u2003Gastroenterostomy leak32%64%93%0.511\u2003SSI1812%2012%2812%1.000Systemic complications\u2003Septic shock43%64%103%0.672\u2003Respiratory failure86%127%207%0.542\u2003Deep vein thrombosis11%00%10%0.283\u2003Lung embolism21%32%52%0.766\u2003Myocardial infarction11%11%21%0.923\u2003Stroke00%53%52%0.035\u2003Missing6713—Postoperative hospital stay (d)163–129155–208163–2080.404In-house mortality†8/1485%10/1696%18/3176%0.96390-d mortality‡7/1435%16/16510%23/3087%0.167P values derived from 2-sided χ2 test, Student t test.*According to the International Study Group for Pancreatic Surgery (ISGPS) definition.†Missing data (n = 3) excluded.‡Censored cases (n = 12) excluded.DGE indicates delayed gastric emptying; IA, intra-abdominal abscess; IPC, interventional percutaneous; OP, operative; PPH, postpancreatectomy hemorrhage; SSI, surgical site infection requiring invasive treatment.TABLE 4Long-term Pancreatic FunctionPancreatic FunctionPJPGTotalTimeParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePOPTotal patients in follow-up149171320—Steatorrhea2315%2112%4414%0.414OES139%148%278%0.863DM3524%4526%8025%0.5606 moTotal patients in follow-up122143265—Steatorrhea2117%2820%4919%0.621OES10889%10372%21180%<0.001DM3831%4028%7829%0.57212 moTotal patients in follow-up101122223—Steatorrhea2222%1613%3817%0.092OES8281%8872%17076%0.114DM3424%3529%6931%0.424Therapy DetailsPJPGTotalTimePatient GroupParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePOPOESEnzyme per day (kU)12075–1959860–17012060–1950.375Dietary therapy only7/3520%11/4524%18/8023%0.637DMOral antidiabetics15/2854%20/3459%35/6257%0.678Insulin therapy15/2854%17/3450%32/6252%0.678Insulin units per day188–43246–50196–500.6256 moOESEnzyme per day (kU)9525–3207825–3208025–3200.751Dietary therapy only4/3811%6/4015%10/7813%0.555DMOral antidiabetics13/3538%12/3435%25/6837%0.801Insulin therapy24/3471%24/3471%48/6871%1.000Insulin units per day254–48258–130254–1300.58312 moOESEnzyme per day (kU)9025–3009540–2509025–3000.678Dietary therapy only2/346%4/3511%6/699%0.414DMOral antidiabetics12/3238%13/3142%25/6340%0.719Insulin therapy23/3272%19/3161%42/6367%0.373Insulin units per day282–45224–64252–640.739P values derived from 2-sided χ2 test and Student t test. DM indicates diabetes mellitus; OES, oral enzyme supplementation; OP, operation.", 'title': 'Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.', 'date': '2015-07-03'}, '23643139': {'article_id': '23643139', 'content': 'Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours.\nPatients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778.\nBetween June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35).\nIn patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula.\nFunding Johnson & Johnson Medical Devices, Belgium.', 'title': 'Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial.', 'date': '2013-05-07'}, '7574936': {'article_id': '7574936', 'content': 'The authors hypothesized that pancreaticogastrostomy is safer than pancreaticojejunostomy after pancreaticoduodenectomy and less likely to be associated with a postoperative pancreatic fistula.\nPancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, occurring in 10% to 20% of patients. Nonrandomized reports have suggested that pancreaticogastrostomy is less likely than pancreaticojejunostomy to be associated with postoperative complications.\nBetween May 1993 and January 1995, the findings for 145 patients were analyzed in this prospective trial at The Johns Hopkins Hospital. After giving their appropriate preoperative informed consent, patients were randomly assigned to pancreaticogastrostomy or pancreaticojejunostomy after completion of the pancreaticoduodenal resection. All pancreatic anastomoses were performed in two layers without pancreatic duct stents and with closed suction drainage. Pancreatic fistula was defined as drainage of greater than 50 mL of amylase-rich fluid on or after postoperative day 10.\nThe pancreaticogastrostomy (n = 73) and pancreaticojejunostomy (n = 72) groups were comparable with regard to multiple parameters, including demographics, medical history, preoperative laboratory values, and intraoperative factors, such as operative time, blood transfusions, pancreatic texture, length of pancreatic remnant mobilized, and pancreatic duct diameter. The overall incidence of pancreatic fistula after pancreaticoduodenectomy was 11.7% (17/145). The incidence of pancreatic fistula was similar for the pancreaticogastrostomy (12.3%) and pancreaticojejunostomy (11.1%) groups. Pancreatic fistula was associated with a significant prolongation of postoperative hospital stay (36 +/- 5 vs. 15 +/- 1 days) (p < 0.001). Factors significantly increasing the risk of pancreatic fistula by univariate logistic regression analysis included ampullary or duodenal disease, soft pancreatic texture, longer operative time, greater intraoperative red blood cell transfusions, and lower surgical volume (p < 0.05). A multivariate logistic regression analysis revealed the factors most highly associated with pancreatic fistula to be lower surgical volume and ampullary or duodenal disease in the resected specimen.\nPancreatic fistula is a common complication after pancreaticoduodenectomy, with an incidence most strongly associated with surgical volume and underlying disease. These data do not support the hypothesis that pancreaticogastrostomy is safer than pancreaticojejunostomy or is associated with a lower incidence of pancreatic fistula.', 'title': 'A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy.', 'date': '1995-10-01'}}
| 0.666667
|
Surgery
|
10
|
Is the breast cancer detection rate in women with dense breasts higher, lower, or the same when comparing screening with a combination of mammography and ultrasonography to screening with mammography alone?
|
higher
|
high
|
no
|
['34406400', '29571797', '23116728', '26549432']
| 36,999,589
| 2,023
|
{'34406400': {'article_id': '34406400', 'content': 'JAMA Netw OpenJAMA Netw OpenJAMA Netw OpenJAMA Network Open2574-3805American Medical Association34406400837460610.1001/jamanetworkopen.2021.21505zoi210636ResearchOriginal InvestigationFeaturedOnline OnlyOncologyEvaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening MammographyA Secondary Analysis of a Randomized Clinical TrialAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityHarada-ShojiNarumiMDPhD\n1\nSuzukiAkihikoMDPhD\n2\nIshidaTakanoriMDPhD\n1\nZhengYing-FangMDPhD\n1\nNarikawa-ShionoYokoPhD\n1\nSato-TadanoAkikoMDPhD\n1\nOhtaRie\n1\nOhuchiNoriakiMDPhD\n1\n1Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan2Department of Breast and Endocrine Surgery, Tohoku Medical and Pharmaceutical University, Sendai, JapanArticle InformationAccepted for Publication: May 26, 2021.Published: August 18, 2021. doi:10.1001/jamanetworkopen.2021.21505Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Harada-Shoji N et al. JAMA Network Open.Corresponding Author: Noriaki Ohuchi, MD, PhD, Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan (noriaki-ohuchi@med.tohoku.ac.jp).Author Contributions: Dr. Ohuchi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Harada-Shoji and Suzuki contributed equally to this work.Concept and design: Harada-Shoji, Suzuki, Ishida, Zheng, Narikawa-Shiono, Sato-Tadano, Ohuchi.Acquisition, analysis, or interpretation of data: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohta, Ohuchi.Drafting of the manuscript: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohuchi.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Harada-Shoji, Suzuki, Zheng, Sato-Tadano, Ohuchi.Obtained funding: Shiono, Ohuchi.Administrative, technical, or material support: Harada-Shoji, Suzuki, Ishida, Narikawa-Shiono, Sato-Tadano, Ohta, Ohuchi.Supervision: Suzuki, Ishida, Ohuchi.Conflict of Interest Disclosures: None reported.Funding/Support: The J-START study was funded by the third Comprehensive Control Research for Cancer, the Ministry of Health, Labor and Welfare of Japan (grants H18-Senryaku-001, H23-Shitei-002, and H25-Shitei-005), and Japan Agency for Medical Research and Development (grants JP17ck0106278h0001, JP18ck0106278h0002, JP19ck0106278h0003, and JPck0106563h0001).Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See Supplement 3.Additional Contributions: We thank all those involved in the J-START study, including the participants and the research associates at all the research sites.188202182021188202148e212150516320212652021Copyright 2021 Harada-Shoji N et al. JAMA Network Open.https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-e2121505.pdfKey PointsQuestionDoes the performance of adjunctive ultrasonography for breast cancer detection among women undergoing screening mammography change according to breast tissue density?FindingsIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography improved sensitivity both in dense and nondense breasts.MeaningThese findings suggest that adjunctive ultrasonography has the potential to improve the detection of early-stage and invasive cancers across both dense and nondense breasts and to mitigate the flaws of mammographic screening.This secondary analysis of a randomized clinical trial evaluates the performance of adjunctive ultrasonography for breast cancer screening in asymptomatic women aged 40 to 49 years undergoing screening mammography according to differences in breast density.ImportanceMammography has limited accuracy in breast cancer screening. Ultrasonography, when used in conjunction with mammography screening, is helpful to detect early-stage and invasive cancers for asymptomatic women with dense and nondense breasts.ObjectiveTo evaluate the performance of adjunctive ultrasonography with mammography for breast cancer screening, according to differences in breast density.Design, Setting, and ParticipantsThis study is a secondary analysis of the Japan Strategic Anti-cancer Randomized Trial. Between July 2007 and March 2011, asymptomatic women aged 40 to 49 years were enrolled in Japan. The present study used data from cases enrolled from the screening center in Miyagi prefecture during 2007 to 2020. Participants were randomly assigned in a 1:1 ratio to undergo either mammography with ultrasonography (intervention group) or mammography alone (control group). Data analysis was performed from February to March 2020.ExposuresUltrasonography adjunctive to mammography for breast cancer screening regardless of breast density.Main Outcomes and MeasuresSensitivity, specificity, recall rates, biopsy rates, and characteristics of screen-detected cancers and interval breast cancers were evaluated between study groups and for each modality according to breast density.ResultsA total of 76\u2009119 women were enrolled, and data for 19\u2009213 women (mean [SD] age, 44.5 [2.8] years) from the Miyagi prefecture were analyzed; 9705 were randomized to the intervention group and 9508 were randomized to the control group. A total of 11\u2009390 women (59.3%) had heterogeneously or extremely dense breasts. Among the overall group, 130 cancers were found. Sensitivity was significantly higher in the intervention group than the control group (93.2% [95% CI, 87.4%-99.0%] vs 66.7% [95% CI, 54.4%-78.9%]; P\u2009<\u2009.001). Similar trends were observed in women with dense breasts (sensitivity in intervention vs control groups, 93.2% [95% CI, 85.7%-100.0%] vs 70.6% [95% CI, 55.3%-85.9%]; P\u2009<\u2009.001) and nondense breasts (sensitivity in intervention vs control groups, 93.1% [95% CI, 83.9%-102.3%] vs 60.9% [95% CI, 40.9%-80.8%]; P\u2009<\u2009.001). The rate of interval cancers per 1000 screenings was lower in the intervention group compared with the control group (0.5 cancers [95% CI, 0.1-1.0 cancers] vs 2.0 cancers [95% CI, 1.1-2.9 cancers]; P\u2009=\u2009.004). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone in both dense (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P\u2009=\u2009.02) and nondense (85.7% [95% CI, 42.1%-99.6%] vs 25.0% [95% CI, 5.5%-57.2%]; P\u2009=\u2009.02) breasts. However, sensitivity of mammography or ultrasonography alone did not exceed 80% across all breast densities in the 2 groups. Compared with the control group, specificity was significantly lower in the intervention group (91.8% [95% CI, 91.2%-92.3%] vs 86.8% [95% CI, 86.2%-87.5%]; P\u2009<\u2009.001). Recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly higher in the intervention group than the control group.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography was associated with increased sensitivity. These findings suggest that adjunctive ultrasonography has the potential to improve detection of early-stage and invasive cancers across both dense and nondense breasts. Supplemental ultrasonography should be considered as an appropriate imaging modality for breast cancer screening in asymptomatic women aged 40 to 49 years regardless of breast density.Trial RegistrationNIPH Clinical Trial Identifier: UMIN000000757IntroductionGlobally, breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-related death in women.1 In Japan, breast cancer is also the leading cancer in women, with breast cancer incidence rates peaking among women aged 45 to 49 years.2 Mammography is the only screening modality that has been shown to be associated with reduced deaths caused by breast cancer. However, the sensitivity of mammography is variable and ranges from as high as 80% to 98% in women with fatty breast tissue to as low as 30% to 48% in women with dense breast tissue.3,4 Because of the limitations of mammography and increase in breast cancer awareness, a few study groups have investigated the performance characteristics of supplementary screening tools, including breast ultrasonography, tomosynthesis, and magnetic resonance imaging.5,6,7,8Breast density has been shown to be independently associated with increased risk of the incidence of and mortality attributable to breast cancer in younger women compared with older women,9,10 with increased risk of interval cancers between screening.6,11,12 Multiple studies6,11,13 have demonstrated that supplemental screening using ultrasonography generates an incremental cancer detection rate at the expense of lower specificity and lower positive predictive values. However, because most studies have focused on women at high risk3,6,7 or those with dense breast tissue but negative mammography findings,3,8,14,15 the performance of ultrasonography as an adjunct to mammography according to differences in breast density classification or among women at average risk remains unknown.4,11,13,16 Consequently, the effect of supplemental screening on breast cancer outcomes is still unclear.17To our knowledge, the Japan Strategic Anti-cancer Randomized Trial (J-START) is the only multicenter randomized clinical trial (RCT) to date to directly compare adjunctive ultrasonography with standard mammography to screen asymptomatic women aged 40 to 49 years.18,19,20 The primary analysis in the original report18 revealed that sensitivity was significantly higher in the intervention group (mammography with ultrasonography) than in the control group (mammography alone), whereas specificity was significantly lower. More cancers were detected in the intervention group than in the control group and were more frequently stages 0 and I. Furthermore, there was a significant reduction in interval cancers.20 However, results according to breast density were not described in detail,21,22 and further studies investigating specific breast density groups have been solicited.21,23 This secondary analysis of the J-START RCT aimed to address issues related to performance of each modality according to differences in breast density.MethodsStudy Design and ParticipantsThe J-START research design of has been published in detail elsewhere.18,19,20 Participants were randomly assigned in a 1:1 ratio to undergo screening by either mammography plus ultrasonography (intervention group) or mammography alone (control group), with or without clinical breast examination, once a year for 2 years.Following a planned protocol (Supplement 1), randomization was centrally conducted by the Japan Clinical Research Support Unit, which is responsible for data management and support for trial operations and independently from Tohoku University. An independent data safety and monitoring board was established to monitor the progress of the trial, which met every 6 months. The study protocol was developed in accordance with the principles of the Declaration of Helsinki. Ethics guidelines for clinical studies issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan were followed. Ethics approval was granted by Tohoku University School of Medicine Research Ethics Committee and the Japan Cancer Society. Written informed consent was obtained from all participants. This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for RCTs.Participants who had a personal history of breast cancer, including in situ cancer, or other cancers in the previous 5 years, or life expectancy of no more than 5 years, were ineligible for the study. Between July 2007 and March 2011, 76\u2009119 asymptomatic women aged 40 to 49 years were enrolled from 42 study sites in 23 of 47 prefectures in Japan. In this study, we used cases enrolled from the screening center in Miyagi prefecture, because we could examine and confirm the breast density.Screening Method and AssessmentStandard mammography and ultrasonography techniques were used at all participating facilities. The physicians and technicians involved in J-START completed a 2-day, 16-hour education program for the standardization of ultrasonography screening for breast cancer.24 Handheld ultrasonography was performed by a technician or by a physician, and later, the ultrasonography image was interpreted by another physician. The ultrasonography examination was performed, on average, in 10 minutes. Mammography acquisition, practice, apparatus, and interpretation were certified by the Japan Central Organization on Quality Assurance of Breast Cancer Screening. Ultrasonography acquisition, practice, apparatus, and interpretation were certified by the Japan Association of Breast and Thyroid Sonology.18Mammography, ultrasonography, and clinical breast examination were performed and interpreted independently from one another, and images were interpreted with double reading by 2 authorized physicians.18,19 The independently assessed findings of mammography, ultrasonography, and clinical examination were classified into 5 categories that are used locally and internationally: 1, no findings; 2, benign; 3, probably benign but further assessment needed; 4, probably malignant; and 5, malignant.19,25,26 Further assessment was considered test-positive if any of the findings were categorized as 3 or higher.For the purpose of this secondary analysis, which was conducted from March to September 2019, 3 expert physicians revaluated mammographic density of the first screening image. All information on screening results, medical interview record, and follow-up data were blinded. By use of the fifth edition of the Breast Imaging Reporting and Data System (BI-RADS),27 we classified visual judgment data as follows: almost entirely fatty; scattered areas of fibroglandular density; heterogeneously dense, which may obscure detection of small masses; and extremely dense, which lowers the sensitivity of mammography screening. In the present article, fatty and scattered are referred to as nondense, and heterogeneously dense and extremely dense are referred to as dense.Follow-upBreast cancers were ascertained by diagnostic assessment of first and second screening results or by a mail survey questionnaire to patients who did not attend the second screening. If data were not available, resident registers were used to identify the patient’s living status. In addition, date linkage with both hospital discharge records and cancer registry databases was used to identify breast cancer diagnosis information. Miyagi prefecture has a sophisticated system of local registration for cancer that contains data on virtually all patients with breast cancer in Miyagi prefecture. Therefore, it was possible to identify interval cancers exactly, and follow-up for this study was updated in February 2020.Screen-detected breast cancers were defined as those categorized as categories 3 to 5 at the first-round screening, and interval cancers were defined as those diagnosed between the first round and the second round of screening for which the initial category had been 1 or 2. Recall was defined as the need for any additional diagnostic testing after screening, including imaging and/or biopsy. The clinical stage and histopathological data were classified by the seventh edition of the TNM classification system.28 The outcome definitions and measure methods were prespecified before data release. Breast cancers diagnosed by the second-round screening were not counted for this study analysis.Statistical AnalysisThe preliminary sample size determination in J-START has been published in detail elsewhere.19,20 We used data from the participants at screening center in Miyagi prefecture. The special feature of the present study was not only to clarify differences between the intervention and control groups, but also differences in breast density composition. Sensitivity, specificity, recall rates, cancer detection rates, interval cancer rates, biopsy rates, and characteristics of screen-detected and interval breast cancers of the first-round screening were examined.All outcomes were analyzed according to the intention-to-treat principle. Performance outcomes were assessed with generalized estimating equations with an exchangeable working correlation matrix and robust SEs. Fisher exact test was used to detect significant differences in the clinical stage and histological findings between cancers detected by ultrasonography and mammography within the intervention group. All tests were 2-sided, and significance was set at P < .05. All statistical analyses were done with SAS statistical software version 9.\u20094 (SAS Institute). Data analysis was performed from February to March 2020.ResultsParticipant CharacteristicsThe baseline characteristics of study participants are shown in Table 1. Of 72\u2009998 asymptomatic women aged 40 to 49 years enrolled in J-START, 19\u2009213 women (9705 in the intervention group and 9508 in the control group) were analyzed in this study because they were residents in Miyagi Prefecture where the cancer registry had been established.Table 1. Baseline Characteristics of Study ParticipantsCharacteristicParticipants, No. (%) (N\u2009=\u200919\u2009213)aTotal intervention group (n\u2009=\u20099705)Total control group (n\u2009=\u20099508)Intervention group by breast densityControl group by breast densityDense (n\u2009=\u20095797)Nondense (n\u2009=\u20093908)bDense (n\u2009=\u20095593)bNondense (n\u2009=\u20093915)bAge, mean (SD), y44.5 (2.9)44.6 (2.9)44.5 (2.9)44.7 (2.9)44.5 (2.9)44.6 (2.9)Ever undergo breast cancer screening No1687 (17.4)1895 (19.9)995 (17.2)692 (17.7)1094 (19.6)801 (20.5) Yes8018 (82.6)7613 (80.1)4802 (82.8)3216 (82.3)4499 (80.4)3114 (79.5)Time since most recent breast cancer screening, mo <12716 (8.9)681 (9.0)441 (9.2)275 (8.6)424 (9.4)257 (8.3) 12-242942 (36.7)2773 (36.4)1759 (36.6)1183 (36.8)1620 (36.0)1153 (37.0) 25-362916 (36.4)2806 (36.9)1710 (35.6)1206 (37.5)1667 (37.1)1139 (36.6) >361391 (17.4)1308 (17.2)859 (17.9)532 (16.5)762 (16.9)546 (17.5) Unknown or data missing53 (0.7)45 (0.6)33 (0.7)20 (0.6)26 (0.6)19 (0.6)Method of most recent breast cancer screening Mammography No2342 (29.2)2191 (28.8)1419 (29.6)923 (28.7)1308 (29.1)883 (28.4) Yes5676 (70.8)5422 (71.2)3383 (70.5)2293 (71.3)3191 (70.9)2231 (71.6) Ultrasonography No6406 (79.9)6221 (81.7)3800 (79.1)2606 (81.0)3647 (81.1)2574 (82.7) Yes1612 (20.1)1392 (18.3)1002 (20.9)610 (19.0)852 (18.9)540 (17.3) Clinical breast examination No356 (4.4)332 (4.4)215 (4.5)141 (4.4)194 (4.3)138 (4.4) Yes7662 (95.6)7281 (95.6)4587 (95.5)3075 (95.6)4305 (95.7)2976 (95.6)Age at menarche, y ≤925 (0.3)25 (0.3)12 (0.2)13 (0.3)9 (0.2)16 (0.4) 10-159559 (98.5)9383 (98.7)5709 (98.5)3850 (98.5)5517 (98.6)3866 (98.8) ≥16121 (1.3)100 (1.1)76 (1.3)45 (1.2)67 (1.2)33 (0.8)Menopausal status Premenopausal7353 (75.8)7285 (76.6)4502 (77.7)2851 (73.0)4399 (78.7)2886 (73.7) Perimenopausal1699 (17.5)1615 (17.0)948 (16.4)751 (19.2)876 (15.7)739 (18.9) Postmenopausal652 (6.7)603 (6.3)347 (6.0)305 (7.8)315 (5.6)288 (7.4) Unknown or data missing1 (<0.1)5 (<0.1)01 (<0.1)3 (<0.1)2 (<0.1)Pregnancies, No. 0813 (8.4)742 (7.8)606 (10.5)207 (5.3)520 (9.3)222 (5.7) 11192 (12.3)1170 (12.3)768 (13.3)424 (36.5)762 (13.6)408 (10.4) 23659 (37.7)3603 (37.9)2233 (38.5)1426 (36.5)2154 (38.5)1449 (37.0) 3-43425 (35.3)3328 (35.0)1875 (38.5)1550 (39.7)1757 (31.4)1571 (40.1) 5-10372 (3.8)400 (4.2)159 (2.7)213 (5.5)212 (3.8)188 (4.8) Unknown or data missing244 (2.5)265 (2.8)156 (2.7)88 (2.3)188 (3.4)77 (2.0)Pregnancies delivered, No. Nulliparous130 (1.5)124 (1.5)96 (1.9)34 (0.9)85 (1.7)39 (1.1) 11427 (16.5)1423 (16.7)924 (18.4)503 (13.9)929 (19.0)494 (13.7) 24499 (52.0)4448 (52.3)2690 (18.4)1809 (50.1)2625 (53.7)1823 (50.4) 32270 (26.3)2202 (25.9)1191 (23.7)1079 (29.9)1113 (22.8)1089 (30.1) 4-8291 (3.4)257 (3.0)118 (2.3)173 (4.8)105 (2.2)152 (4.2) Unknown or data missing31 (0.4)47 (0.6)16 (2.3)15 (0.4)28 (0.6)19 (0.5)Age at first parturition, y <20102 (1.2)80 (0.9)58 (1.2)44 (1.2)44 (0.9)36 (1.0) 20-241626 (18.8)1470 (17.3)897 (17.8)729 (20.2)783 (16.0)687 (19.0) 25-293245 (37.5)3184 (37.5)1901 (37.8)1344 (37.2)1811 (37.1)1373 (38.0) 30-391882 (21.8)2022 (23.8)1132 (22.5)750 (20.8)1239 (25.4)783 (21.7) 40-4948 (0.6)47 (0.6)36 (0.7)12 (0.3)27 (0.6)20 (0.6) Unknown or data missing1745 (20.2)1698 (20.0)1011 (20.1)734 (20.3)981 (20.1)717 (19.8)Ever breastfed children Yes7754 (90.9)7570 (90.4)4507 (91.1)3247 (90.6)4338 (90.4)3232 (90.4) No758 (8.9)792 (9.5)428 (8.7)330 (9.2)455 (9.5)337 (9.4) Unknown or data missing21 (0.3)16 (0.2)15 (0.3)6 (0.2)8 (0.2)8 (0.2)First-degree female relatives with breast cancer, No. 09214 (94.9)9024 (94.9)5503 (94.9)3711 (95.0)5299 (94.7)3725 (95.2) 1485 (5.0)477 (5.0)291 (5.0)194 (5.0)289 (5.2)188 (4.8) >16 (<0.1)7 (<0.1)3 (<0.1)3 (<0.1)5 (<0.1)2 (<0.1)Ever had breast surgery227 (1.2)214 (1.1)170 (1.8)57 (0.6)140 (1.5)74 (0.8)Ever had benign neoplasm154 (0.8)143 (0.7)121 (1.3)33 (0.3)97 (1.0)46 (0.5)Ever had breast inflammation71 (0.4)70 (0.4)46 (0.5)25 (0.3)45 (0.5)25 (0.3)aPercentages might not total 100% because of rounding.bThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, conventionally, the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.An overview of participant flow is shown in the eFigure in Supplement 2. A total of 19\u2009280 participants were enrolled and randomly allocated either study arms. Eligibility was assessed for inclusion in the analyses; 26 participants in the intervention group and 41 participants in the control group were excluded because of ineligibility and were withdrawn. Of 19\u2009213 participants, 11\u2009390 (59.3%) were categorized as having dense breast tissue (ie, heterogeneously or extremely dense) (eTable in Supplement 2).The mean (SD) age of participants was 44.5 (2.8) years (Table 1). A total of 975 participants (5.0%) reported a history of breast cancer in first-degree female relatives, and 297 participants (1.5%) reported having ever had benign breast diseases. There were no differences in demographic characteristics or risk factors between the intervention and control groups. On the other hand, the percentages of participants who had never been pregnant were significantly higher among women with dense breasts than among women with nondense breasts in both the intervention group (10.5% [95% CI, 9.9%-11.6%] vs 5.3% [95% CI, 4.7%-6.1%]; P\u2009<\u2009.001) and control group (9.3% [95% CI, 8.8%-10.4%] vs 5.7% [95% CI, 5.1%-6.5%] P\u2009<\u2009.001).Screening PerformanceTable 2 and Table 3 summarize the screening performance. In 19\u2009213 women, 130 cancers were found. More screen-detected cancers were found in the intervention group than in the control group (68 cancers [7.0 cancers per 1000 screenings; 95% CI, 5.3 to 8.7 cancers per 1000 screenings] vs 38 cancers [4.0 cancers per 1000 screenings; [95% CI, 2.7 to 5.3 cancers per 1000 screenings]; P\u2009=\u2009.004). Among women with dense breasts, there were more screen-detected cancer in the intervention group than the control group (41 cancers [7.1 cancers per 1000 screenings; 95% CI, 4.9 to 9.2 cancers per 1000 screenings] vs 24 cancers [4.3 cancers per 1000 screenings; 95% CI, 2.6 to 6.0 cancers per 1000 screenings]; P\u2009=\u2009.04). A similar tendency is seen in women with nondense breasts (27 cancers [6.9 cancers per 1000 screenings; 95% CI, 4.3 to 9.5 cancers per 1000 screenings] in the intervention group vs 14 cancers [3.6 cancers per 1000 screenings; 95% CI, 1.7 to 5.4 cancers per 1000 screenings] in the control group; P\u2009=\u2009.04). Five interval cancers (0.5 cancers per 1000 screenings; 95% CI, 0.1 to 1.0 cancers per 1000 screenings) were detected in the intervention group compared with 19 (2.0 cancers per 1000 screenings; 95% CI, 1.1 to 2.9 cancers per 1000 screenings) in the control group (P\u2009=\u2009.004), with a significant difference between the 2 groups among women with dense breasts (3 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.1 to 1.1 cancers per 1000 screenings] vs 10 cancers [1.8 cancers per 1000 screenings; 95% CI, 0.7 to 2.9 cancers per 1000 screenings]; P\u2009=\u2009.04) as well as women with nondense breasts (2 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.2 to 1.2 cancers per 1000 screenings] vs 9 cancers [2.3 cancers per 1000 screenings; 95% CI, 0.8 to 3.8 cancers per 1000 screenings]; P\u2009=\u2009.03). Sensitivity in the intervention group was higher than that in the control group (93.2% [95% CI, 87.4% to 99.0%] vs 66.7% [95% CI, 54.4% to 78.9%]; P\u2009<\u2009.001) for both dense breasts and nondense breasts. In contrast, specificity was significantly lower in the intervention group than the control group (86.8% [95% CI, 86.2% to 87.5%] vs 91.8% [95% CI, 91.2% to 92.3%]; P\u2009<\u2009.001) regardless of breast tissue density (Table 2).Table 2. Performance According to Breast Density CategoryVariableTotal participants (N\u2009=\u200919 213)Dense breastsaNondense breastsaIntervention group (n\u2009=\u20099705)Control group (n\u2009=\u20099508)P valueIntervention group (n\u2009=\u20095797)Control group (n\u2009=\u20095593)P valueIntervention group (n\u2009=\u20093908)Control group (n\u2009=\u20093915)P valueScreen-detected cancers No. of cancers/total No.68/970538/9508.00441/579724/5593.0427/390814/3915.04 No. of cancers per 1000 screenings (95% CI)7 (5.3 to 8.7)4 (2.7 to 5.3)7.1 (4.9 to 9.2)4.3 (2.6 to 6.0)6.9 (4.3 to 9.5)3.6 (1.7 to 5.4)Interval cancers No. of cancers/total No.5/970519/9508.0043/579710/5593.042/39089/3915.03 No. of cancers per 1000 screenings (95% CI)0.5 (0.1 to 1.0)2.0 (1.1 to 2.9)0.5 (−0.1 to 1.1)1.8 (0.7 to 2.9)0.5 (−0.2 to 1.2)2.3 (0.8 to 3.8)Sensitivity, % (95% CI)93.2 (87.4 to 99.0)66.7 (54.4 to 78.9)<.00193.2 (85.7 to 100)70.6 (55.3 to 85.9)<.00193.1 (83.9 to 102.3)60.9 (40.9 to 80.8)<.001Specificity, % (95% CI)86.8 (86.2 to 87.5)91.8 (91.2 to 92.3)<.00185.4 (84.5 to 86.3)91.7 (91.0 to 92.4)<.00189.0 (88.0 to 90.0)91.9 (91.1 to 92.8)<.001aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3. Sensitivity of Each Modality According to Breast Densities and Study GroupsGroup and modalityCancers, No. (%) [95% CI]P valueDense breastsaNondense breastsaIntervention group (n\u2009=\u20099705) Screen-detected cancers (n\u2009=\u200968) Mammography positive, ultrasonography positive or negative, CBE positive or negative24 (54.6) [39.8-69.3]20 (69.0) [52.1-85.8].20 Mammography positive or negative, ultrasonography positive, CBE positive or negative29 (65.9) [51.9-79.9]15 (51.7) [33.5-69.9].22 Mammography positive, ultrasonography positive, CBE positive or negative12 (27.3) [14.1-40.3]8 (27.6) [11.3-43.9].98 Mammography positive or negative, US positive or negative, CBE positive10 (22.7) [10.3-35.1]10 (34.5) [17.2-51.8].28 Only mammography positive12 (27.3) [14.1-40.3]12 (41.4) [23.5-59.3].21 Only ultrasonography positive17 (38.6) [24.3-53.0]7 (24.1) [8.6-39.7].18 Only CBE positive0 (NA)0 (NA)NA Any positive41 (93.2) [85.7-100.0]27 (93.1) [83.9-102.3].98 Interval cancers (n\u2009=\u20095), all modalities negative3 (NA)2 (NA)NAControl group (n\u2009=\u20099508) Screen-detected cancers (n\u2009=\u200938) Mammography positive, CBE positive or negative22 (64.7) [48.6-80.8]14 (60.9) [40.9-80.8].77 Mammography positive or negative, CBE positive9 (26.5) [11.6-41.3]6 (26.1) [8.1-44.0].97 Only mammography positive15 (44.1) [27.3-60.8]8 (34.8) [15.3-54.3].48 Only CBE positive2 (NA)0 (NA)NA Either mammography or CBE positive24 (70.6) [55.3-85.9]14 (60.9) [40.9-80.8].45 Interval cancers (n\u2009=\u200919), all modalities negative10 (NA)9 (NA)NAAbbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3 summarizes sensitivity of each modality according to density. Neither modality exceeded 80% sensitivity alone (Table 3). In the intervention group, sensitivity of mammography was 69.0% (95% CI, 52.1%-85.8%) in nondense breasts and 54.6% (95% CI, 39.8%-69.3%) in dense breasts, whereas the sensitivity of mammography with adjunct ultrasonography was 93.1% (95% CI, 83.9%-102.3%) in nondense breasts and 93.2% (95% CI, 85.7%-100.0%) in dense breasts. The sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% [95% CI, 55.3%-85.9%] vs 60.9% [95% CI, 40.9%-80.8%]).The frequency of clinical stage 0 and I breast cancer was 85.4% in dense breasts and 88.9% in nondense breasts within the intervention group, whereas in the control group, the frequency was 79.2% for dense breasts and 64.3% for nondense breasts. The differences in stage between the 2 groups were similar for dense and nondense breasts (Table 4). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone, in both dense breasts (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P = .02) and nondense breasts (85.7% [95% CI, 42.1%-99.6%] vs 25% [95% CI, 5.5%-57.2%]; P = .02). In the control group, however, the clinical stage and each pathological finding of invasive cancers detected by mammography alone were not meaningfully different between dense and nondense breasts (Table 4).Table 4. Clinical Stage and Histological Findings of Screen-Detected Cancers and Interval Cancers According to Breast DensityPatients, No. (%)aIntervention groupControl groupScreen-detected cancers (n\u2009=\u200968)Interval cancers (n\u2009=\u20095)Screen-detected cancers (n\u2009=\u200938)Interval cancers (n\u2009=\u200919)Any modality positive (n\u2009=\u200968)Only mammography positive (n\u2009=\u200924)Only US positive (n\u2009=\u200924)Only CBE positive (n\u2009=\u20090)Either positive (n\u2009=\u200938)Only mammography positive (n\u2009=\u200923)Only CBE positive (n\u2009=\u20092)Extremely and heterogeneously denseb Breast cancers, No.411217032415210 Clinical stagec 0 and I35 (85.4)12 (100)2 (76.5)01 (33.3)19 (79.2)15 (100)1 (50)9 (90) II or higher6 (14.6)04 (23.5)02 (66.7)5 (20.8)01 (50)1 (10) Histopathological cancer type Noninvasived13 (31.7)7 (58.3)3 (17.7)006 (25)6 (40)03 (30) Invasivee28 (68.3)5 (41.7)14 (82.4)03 (100)18 (75)9 (60)2 (100)7 (70) Size of invasive tumors on histological examination, mm <1011 (39.3)5 (100)4 (28.6)01 (33.3)9 (50)6 (66.7)1 (50)1 (14.3) 11-2015 (53.6)08 (57.1)004 (22.2)2 (22.2)1 (50)4 (57.1) >202 (7.1)02 (14.3)02 (66.7)4 (22.2)000 Data missing000001 (5.6)1 (11.1)02 (28.6) Node status of invasive cancers Negative23 (82.1)5 (100)11 (78.6)01 (33.3)15 (83.3)8 (88.9)2 (100)6 (85.7) Positive5 (17.9)03 (21.4)02 (66.7)2 (11.1)000 Data missing000001 (5.6)1 (11.1)01 (14.3)Scattered fibroglandular tissue and almost entirely fattyb Breast cancers, No.271270214809 Clinical stagec 0 and I24 (88.9)11 (91.7)6 (86.7)01 (50)9 (64.3)5 (62.5)09 (100) II or higher3 (11.1)1 (8.3)1 (14.3)01 (50)5 (35.7)3 (37.5)00 Histopathological cancer type Noninvasived13 (48.2)9 (75)1 (14.3)003 (21.4)3 (37.5)02 (22.2) Invasivee14 (51.9)3 (25)6 (85.7)02 (100)11 (78.6)5 (62.5)07 (77.8) Size of invasive tumors on histological examination, mm ≤105 (35.7)04 (66.7)01 (50)4 (36.4)3 (60)02 (28.6) 11-209 (64.3)3 (100)2 (33.3)005 (45.5)1 (20)04 (57.1) >2000001 (50)2 (18.2)1 (20)00 Data missing000000001 (14.3) Node status of invasive cancers Negative11 (78.6)2 (66.7)5 (83.3)02 (100)6 (54.6)3 (60)06 (85.7) Positive3 (21.4)1 (33.3)1 (16.7)005 (45.5)2 (40)00 Data missing000000001 (14.3)Abbreviations: CBE, clinical breast examination; US, ultrasonography.aPercentages might not total 100% because of rounding.bNo cancer was found in the category of almost entirely fatty.cBased on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.dIncludes ductal carcinoma in situ and lobular carcinoma in situ.eIncludes invasive ductal carcinoma and special type.Data of screening recalls and biopsy are presented in Table 5. Of 2147 participants who were recalled, 734 underwent biopsies. The recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly greater in the intervention group vs the control group. Recall rates for mammography alone were similar in the 2 groups regardless of breast density. In the intervention group, the recall rate by ultrasonography alone was higher for women with dense breasts than for women with nondense breasts (7.0% vs 3.9%), and the same was true for the biopsy rate (4.4% vs 2.6%).Table 5. Recall Rate and Biopsy Rate of Each Modality According to Study GroupVariableParticipants, No. (%)Intervention groupControl groupTotal (n\u2009=\u20099705)Dense breastsaTotal (n\u2009=\u20099508)Dense breastsaYes (n\u2009=\u20095797)No (n\u2009=\u20093908)Yes (n\u2009=\u20095593)No (n\u2009=\u20093915)Recalled after first-round screening Any modality positive1334 (13.8)880 (15.2)454 (11.6)813 (8.6)485 (8.7)328 (8.4) Only mammography positive606 (6.2)356 (6.1)250 (6.4)663 (7.0)374 (6.7)290 (7.4) Only ultrasonography positive558 (5.8)404 (7.0)154 (3.9)NANANA Only CBE positive59 (0.6)44 (0.8)15 (0.4)85 (0.9)69 (1.2)16 (0.4)Biopsy rateb Biopsy done538 (5.5)360 (6.2)178 (4.6)196 (2.1)127 (2.3)69 (1.8) Only mammography positive107 (1.1)56 (1.0)51 (1.3)128 (1.4)77 (1.4)51 (1.3) Only ultrasonography positive355 (3.7)255 (4.4)100 (2.6)NANANA Only CBE positive7 (<0.1)4 (<0.1)3 (<0.1)27 (0.3)22 (0.4)5 (<0.1)Abbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.bIndicates a need for biopsy on first-round screening. When clinically indicated, participants might have undergone 2 or more types of biopsy.DiscussionTo our knowledge, J-START is the first large-scale RCT to assess the performance of ultrasonography screening in combination with mammography for breast cancer in women aged 40 to 49 years with average risk. Now, the question is raised as to whether adjunctive ultrasonography improves the balance of breast cancer screening in women with different breast densities. In the present secondary analysis, we further evaluated the performance of each screening modality (ie, mammography and ultrasonography) according to breast density, which has been shown to be a factor independently associated with increased risk of breast cancer across age group.9 Heterogeneity of tissue density is associated with not only increased cancer risk but also complications of mammographic interpretation; even small amounts of dense tissue can mask cancer. The fifth edition of the BI-RADS lexicon for breast density27 recommends that breast imagers assign breast composition descriptors that better convey whether there are dense areas of tissue that could mask or obscure cancer. In this respect, a major strength of this study is that we used the fifth edition of the BI-RADS lexicon to assess breast density and conducted double readings to reduce variation, which provided reproducible estimates and verification of density assessment quality. With awareness of these issues (breast density and lower screening sensitivity of mammography) as the starting point, we analyzed the performance of adjunctive ultrasonography compared with mammography in breasts with different densities. The principal findings between the intervention and control groups were consistent with those of the J-START,20 as adjunct ultrasonography to mammography exhibited higher sensitivity and lower specificity than mammography alone, with more cancers detected, more cancers that were stages 0 and I, and lower numbers of interval cancers than in the control group.20 Adjunct ultrasonography improved the sensitivity and detection rate of small, early-stage (stage 0 and stage I) and invasive cancers, consistent with other studies.3,7,11In addition, this study revealed that adjunctive ultrasonography improved the detection of early invasive cancers not only in dense breasts but also in nondense breasts. Moreover, we found ultrasonography to be potentially superior to mammography in detecting early and node-negative invasive cancers in both dense and nondense breasts.It should be noted that sensitivity of mammography alone and that of ultrasonography alone were both lower than the sensitivity of the combination of these modalities. In this study, the sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% vs 60.9%). One of the explanations is that the sensitivity of mammography did not depend on breast density, because even nondense tissue might hide or mask cancer in women aged 40 to 49 years. However, sensitivity was improved when ultrasonography was used as an adjunct to mammography, suggesting that adjunctive ultrasonography has an advantage in breast cancer screening for young women regardless of dense breasts. Taking these results into account, we can conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified. Because of the limitations of mammography in breast density, studies have investigated performance of supplementary screening tools, including tomosynthesis and magnetic resonance imaging.5,6,7,8 Tomosynthesis is unlikely to be an optimal solution, and magnetic resonance imaging is expensive and not easy to access for screening.With regard to the harms associated with breast cancer screening, supplemental ultrasonography had lower specificity and higher recall and biopsy rates than mammography alone, which are major limitations of screening ultrasonography.14,29 Ultrasonography and mammography findings were interpreted independently according to the J-START protocol, which consequently increased recall and biopsy rates and decreased specificity. In addition, ultrasonography-guided histological examination using core-needle biopsy is easy to perform and more accurate for diagnosing the lesion, which suggests that it is the main reason for the increased biopsy rate. A study30 of the European mammography screening programs showed overall further assessment rates to be 9.3% and 4.0% for initial and subsequent mammography screening tests, respectively. The overall rates of needle biopsy rates were 2.2% and 1.1%, respectively.30 A previous study31 in Japan reported that recall rate of mammography screening among 33\u2009924 women in their 40s was 9.9%. The recall rate of the first round in J-START31 was 8.8% in the control group (mammography only), which is within the accepted range.LimitationsThe sensitivity and specificity in this study were calculated with the data from the first-round screening. Our findings cannot be extended beyond the first round, because characteristics of breast cancer would differ between the first and later rounds of screening.7,12 Except for women at increased and high risk, estimates indicate a nearly 40% breast cancer mortality reduction when screening women annually starting at age 40 years.32 Improving cancer detection in younger and middle-aged women is crucial for increasing the effectiveness of breast cancer screening.23 To evaluate screening benefits avoiding lead time bias, and to determine balance of benefits and harms, further investigation providing hard evidence about the contributions of adjunctive ultrasonography screening to breast cancer mortality is necessary.ConclusionsIn this secondary analysis of an RCT, adjunctive ultrasonography had good screening balance with mammography regardless of breast density, detecting early-stage and invasive malignant lesions for asymptomatic women with average risk of breast cancer. Thus, adjunctive ultrasonography should be considered as an optimal solution in young women with average risk.References1TorreLA, BrayF, SiegelRL, FerlayJ, Lortet-TieulentJ, JemalA. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262256517872HoriM, MatsudaT, ShibataA, KatanodaK, SobueT, NishimotoH; Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2015;45(9):884-891. doi:10.1093/jjco/hyv088261424373KolbTM, LichyJ, NewhouseJH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225(1):165-175. doi:10.1148/radiol.2251011667123550014BuchbergerW, Geiger-GritschS, KnappR, GautschK, OberaignerW. Combined screening with mammography and ultrasound in a population-based screening program. Eur J Radiol. 2018;101:24-29. doi:10.1016/j.ejrad.2018.01.022295717975TagliaficoAS, CalabreseM, MariscottiG, . Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial. J Clin Oncol. 2016;34(16):1882-1888. doi:10.1200/JCO.2015.63.4147269620976BergWA, BlumeJD, CormackJB, ; ACRIN 6666 Investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151-2163. doi:10.1001/jama.299.18.2151184777827BergWA, BandosAI, MendelsonEB, LehrerD, JongRA, PisanoED. Ultrasound as the primary screening test for breast cancer: analysis from ACRIN 6666. J Natl Cancer Inst. 2015;108(4):djv367. doi:10.1093/jnci/djv367267121108MelnikowJ, FentonJJ, WhitlockEP, . Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(4):268-278. doi:10.7326/M15-1789267570219BoydNF, GuoH, MartinLJ, . Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227-236. doi:10.1056/NEJMoa0627901722995010CheckaCM, ChunJE, SchnabelFR, LeeJ, TothH. The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol. 2012;198(3):W292-W295. doi:10.2214/AJR.10.60492235802811CorsettiV, HoussamiN, GhirardiM, . Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021-1026. doi:10.1016/j.ejca.2010.12.0022121196212BergWA, ZhangZ, LehrerD, ; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-1404. doi:10.1001/jama.2012.3882247420313DongH, HuangY, SongF, . Improved performance of adjunctive ultrasonography after mammography screening for breast cancer among Chinese females. Clin Breast Cancer. 2018;18(3):e353-e361. doi:10.1016/j.clbc.2017.07.0142888701014CorsettiV, HoussamiN, FerrariA, . Breast screening with ultrasound in women with mammography-negative dense breasts: evidence on incremental cancer detection and false positives, and associated cost. Eur J Cancer. 2008;44(4):539-544. doi:10.1016/j.ejca.2008.01.0091826735715YoukJH, KimEK, KimMJ, KwakJY, SonEJ. Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. Eur Radiol. 2011;21(4):667-675. doi:10.1007/s00330-010-1955-82085310816HooleyRJ, GreenbergKL, StackhouseRM, GeiselJL, ButlerRS, PhilpottsLE. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. Radiology. 2012;265(1):59-69. doi:10.1148/radiol.121206212272350117SiuAL; US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296. doi:10.7326/M15-28862675717018IshidaT, SuzukiA, KawaiM, . A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered. Jpn J Clin Oncol. 2014;44(2):134-140. doi:10.1093/jjco/hyt1992440783519OhuchiN, IshidaT, KawaiM, NarikawaY, YamamotoS, SobueT. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START): research design. Jpn J Clin Oncol. 2011;41(2):275-277. doi:10.1093/jjco/hyq2142113129520OhuchiN, SuzukiA, SobueT, ; J-START investigator groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341-348. doi:10.1016/S0140-6736(15)00774-62654710121BergWA. Current status of supplemental screening in dense breasts. J Clin Oncol. 2016;34(16):1840-1843. doi:10.1200/JCO.2015.65.86742696209622UematsuT. The need for supplemental breast cancer screening modalities: a perspective of population-based breast cancer screening programs in Japan. Breast Cancer. 2017;24(1):26-31. doi:10.1007/s12282-016-0707-22725934223ThigpenD, KapplerA, BremR. The role of ultrasound in screening dense breasts: a review of the literature and practical solutions for implementation. Diagnostics (Basel). 2018;8(1):E20. doi:10.3390/diagnostics80100202954753224TohnoE, TakahashiH, TamadaT, FujimotoY, YasudaH, OhuchiN. Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. Breast Cancer. 2012;19(2):138-146. doi:10.1007/s12282-010-0221-x2092473325OhuchiN, YoshidaK, KimuraM, . Improved detection rate of early breast cancer in mass screening combined with mammography. Jpn J Cancer Res. 1993;84(7):807-812. doi:10.1111/j.1349-7006.1993.tb02048.x839656926OhuchiN, YoshidaK, KimuraM, . Comparison of false negative rates among breast cancer screening modalities with or without mammography: Miyagi trial. Jpn J Cancer Res. 1995;86(5):501-506. doi:10.1111/j.1349-7006.1995.tb03084.x779032327American College of Radiology. ACR BI-RADS fifth edition. Published 2013. Accessed July 15, 2021. https://www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS-Reference-Card.pdf28SobinLH, GospodarowiczML, WittekindC, eds. TNM Classification of Malignant Tumours. 7th ed. Wiley;2011.29SpragueBL, StoutNK, SchechterC, . Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Ann Intern Med. 2015;162(3):157-166. doi:10.7326/M14-06922548655030HofvindS, PontiA, PatnickJ, ; EUNICE Project and Euroscreen Working Groups. False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes. J Med Screen. 2012;19(1)(suppl):57-66. doi:10.1258/jms.2012.0120832297281131KasaharaY, KawaiM, TsujiI, . Harms of screening mammography for breast cancer in Japanese women. Breast Cancer. 2013;20(4):310-315. doi:10.1007/s12282-012-0333-62228216432ArleoEK, HendrickRE, HelvieMA, SicklesEA. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123(19):3673-3680. doi:10.1002/cncr.3084228832983Supplement 1.\nTrial Protocol and Statistical Analysis Plan\nClick here for additional data file.Supplement 2.eFigure. Trial ProfileeTable. Distribution of Mammography Density Based on 5th Edition BI-RADS Density CategoriesClick here for additional data file.Supplement 3.\nData Sharing Statement\nClick here for additional data file.', 'title': 'Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial.', 'date': '2021-08-19'}, '29571797': {'article_id': '29571797', 'content': 'To compare the performance of screening with mammography combined with ultrasound versus mammography alone in women at average risk for breast cancer.\n66,680 women underwent physician-performed ultrasound as an adjunct to screening mammography. Histological results and follow-up at one year were used as reference standard for sensitivity. Main outcome measures were cancer detection rate, sensitivity, recall rate, biopsy rate, and positive predictive value of biopsy for combined screening with mammography plus ultrasound versus mammography alone.\nThe overall sensitivity of mammography only was 61.5% in women with dense breasts and 86.6% in women with non-dense breasts. The sensitivity of mammography plus ultrasound combined was 81.3% in women with dense breasts and 95.0% in women with non-dense breasts. Adjunctive ultrasound increased the recall rate from 10.5 to 16.5 per 1000 women screened, and increased the biopsy rate from 6.3 to 9.3 per 1000 women screened. The positive predictive value of biopsy was 55.5% (95% CI 50.6%-60.3%) for mammography alone and 43.3 (95% CI 39.4%-47.3%) for combined mammography plus ultrasound.\nSupplemental ultrasound improves cancer detection in screening of women at average risk for breast cancer. Recall rates and biopsy rates can be kept within acceptable limits.', 'title': 'Combined screening with mammography and ultrasound in a population-based screening program.', 'date': '2018-03-25'}, '23116728': {'article_id': '23116728', 'content': 'Automated breast ultrasound (ABUS)was performed in 3418 asymptomatic women with mammographically dense breasts. The addition of ABUS to mammography in women with greater than 50% breast density resulted in the detection of 12.3 per 1,000 breast cancers, compared to 4.6 per 1,000 by mammography alone. The mean tumor size was 14.3 mm and overall attributable risk of breast cancer was 19.92 (95% confidence level, 16.75 - 23.61) in our screened population. These preliminary results may justify the cost-benefit of implementing the judicious us of ABUS in conjunction with mammography in the dense breast screening population.', 'title': 'Improved breast cancer detection in asymptomatic women using 3D-automated breast ultrasound in mammographically dense breasts.', 'date': '2012-11-03'}, '26549432': {'article_id': '26549432', 'content': 'To determine which modalities [2D mammography (2D), digital breast tomosynthesis (DBT), whole breast sonography (WBS)] are optimal for screening depending on breast density.\nInstitutional retrospective cohort study of 2013 screening mammograms (16,789), sorted by modalities and density.\nCancer detection is increased by adding WBS to 2D (P=.02) for the overall study population. Recall rate was lowest with 2D+DBT (10.2%, P<.001) and highest with 2D+DBT+WBS (23.6%, P<.001) for the overall study population as well.\nWomen with dense and nondense breasts benefit from reduced recall rate with the addition of DBT; however, this benefit is negated with the addition of WBS.', 'title': '2D mammography, digital breast tomosynthesis, and ultrasound: which should be used for the different breast densities in breast cancer screening?', 'date': '2015-11-10'}}
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