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Abstract Background Dupuytren’s contracture (DC) is a progressive fibroproliferative disorder characterized by development of nodules and collagen cords within the palmar fascia of the hand. Collagenase clostridium histolyticum (CCH) is currently approved in adults with DC for the nonsurgical treatment of a single palpable cord during a 30-day treatment cycle. This open-label pilot study was designed to examine the safety, efficacy, and multiple-dose pharmacokinetics of injecting two cords (affected joints) with multiple doses of CCH concurrently into the same hand in subjects with DC and multiple contractures. Methods Twelve subjects with DC were enrolled, each with ≥3 contractures caused by palpable cords. Efficacy assessments were taken 30 days after treatment and adverse events (AEs) were recorded throughout. In the first treatment period, all subjects were injected with a single dose of CCH (0.58 mg) into a single cord. The same subjects entered a second treatment period 30 days later, where two different cords (affected joints) were injected concurrently on the same hand. A finger extension procedure was performed 24 hours after each administration of CCH to disrupt the enzymatically weakened cord. Results For metacarpophalangeal (MP) joints, mean contracture reduction per joint treated was 29.0 ± 20.7 degrees following single injection vs 30.3 ± 10.9 degrees per treated joint following multiple injections. For proximal interphalangeal (PIP) joints, mean reduction in contracture was 30.7 ± 21.1 and 22.1 ± 4.9 degrees per treated joint, respectively, for the two periods. All patients (100%) were either “quite satisfied” or “very satisfied” following either treatment cycle. The most common treatment-related AEs were edema peripheral, contusion, and pain in the treated extremity; the differences in severity for local effects of the injections were minimal between treatment periods. No serious treatment-related AEs or systemic complications were reported. Conclusion These results provide preliminary evidence that two cords (affected joints) can be treated concurrently with CCH with similar efficacy and safety as cords treated individually in a sequential fashion. Multiple concurrent injections would eliminate the 30-day wait between single treatments and allow for rapid and effective treatment of patients with multiple affected joints, a significant advantage for both patient and physician. Trial registration Australian New Zealand Clinical Trials Registry #ACTRN12610001045000.

Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used.Trial number: NCT01740427., (© 2024. The Author(s).)

Antiplatelet therapy represents a fundamental part of preventive management for patients who are at risk of a secondary cardiovascular disease (CVD) event. In most cases, the antiplatelet regimen is based on low-dose aspirin, a drug that is highly effective in reducing the incidence of CVD events, but is associated with a substantial risk of gastrointestinal (GI) toxicity. The dyspeptic symptoms, which can result from aspirin administration, and which may occur with or without associated ulceration and bleeding, may lead patients to discontinue therapy, thus increasing their CVD risk. For patients in whom aspirin is indicated and who are deemed to be at increased risk of upper GI events, concomitant therapy with a proton pump inhibitor (PPI) is currently recommended. These agents are highly effective in reducing the upper GI lesions associated with aspirin therapy and have been associated with increased aspirin adherence. However, widespread under-prescribing of PPIs and potential noncompliance with their use means that substantial numbers of patients are at unnecessary risk of upper GI toxicity and-if aspirin therapy is discontinued-CVD events. Provision of aspirin and an immediate-release PPI as a coordinated-delivery combination tablet has been shown to both reduce the risk of gastric ulcer formation and improve patient compliance. This strategy, which may ultimately reduce the incidence of CVD outcomes because of the associated reduction in GI symptoms and the potential for greater patient adherence to aspirin, warrants further investigation under both randomized controlled conditions (explanatory trials), and in real-life settings (pragmatic trials)., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer., Patients and Methods: Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed., Results: Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively)., Conclusion: Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low., (© 2016 by American Society of Clinical Oncology.)

Background: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown., Methods: We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review., Results: Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life., Conclusions: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Introduction: Peyronie's disease (PD) is a localized penile collagen disorder of the tunica albuginea associated with significant physical deformity and psychological impairment. Current understanding of pretreatment characteristics in patients with chronic PD is limited by small samples, varied quality of assessments, and the lack of a PD-specific, validated measure of the psychosexual impact of PD., Aims: Reporting baseline demographic and disease characteristics of the large multinational cohort of subjects with chronic PD who participated in the collagenase clostridium histolyticum (CCH, an investigational intralesional injection and minimally invasive intervention) phase 3 clinical study program. Findings from well-defined assessments, including the Peyronie's Disease Questionnaire (PDQ), the first validated PD-specific patient-reported measure of psychosexual impact, are reported., Methods: Subjects included men≥18 years old with PD symptoms≥12 months and penile deformity between 30° and 90°. Analysis data included demographics, disease history, and psychosexual impact., Main Outcome Measures: Penile deformity, disease symptoms, the International Index of Erectile Function, and the PDQ were assessed., Results: Eight hundred thirty-two subjects were enrolled from 64 sites across the United States and Australia. The mean age was 57.7 years; mean PD duration was 4.1 years. The majority of subjects had penile deformity≤60° (77.3%); mean penile deformity was 50.5°. Subjects reported having intercourse a mean of 10.2 times in the previous 3 months, 70.8% reported difficulty in performing vaginal intercourse, and 80.4% reported less frequent vaginal intercourse. Approximately 71.5% of subjects with severe (>60°) and 58.1% of subjects with mild/moderate (≤60°) penile deformity were "very bothered" or "extremely bothered" upon last look at their erect penis (P=0.0041), as measured by the PDQ., Conclusions: These data add to the body of knowledge regarding the clinical impact of chronic phase PD, including the PD-specific patient-reported psychosexual symptoms, using a large multinational chronic PD cohort in the CCH phase 3 clinical program., (© 2013 International Society for Sexual Medicine.)

Purpose: We validated the Peyronie's Disease Questionnaire (http://www.auxilium.com/PDQ), a 15-question self-reported survey that measures the impact and severity of Peyronie's disease symptoms in 3 domains, including 1) psychological and physical symptoms, 2) penile pain and 3) symptom bother., Materials and Methods: We used baseline data from 2 phase 3 clinical trials (334 and 345 patients, respectively) of collagenase clostridium histolyticum treatment for Peyronie's disease associated penile curvature and bother. Collected data included PDQ domain scores, International Index of Erectile Function scores, objective penile curvature measures and patient reported Peyronie's disease symptom severity. Psychometric analyses included confirmatory factor analysis, inter-item reliability, and tests of convergent and discriminant validity, all related to the overall construct validity of the scale., Results: Confirmatory factor analysis supported the conceptual framework of the PDQ with 3 confirmed subdomains. Each scale showed good consistency, ie internal reliability (each Cronbach α >0.70). Convergent and discriminant validity were noted in the pattern of associations between PDQ domains and other Peyronie's disease measures. PDQ domain scores significantly differed between patients with vs without erectile dysfunction and between patients with vs without Peyronie's disease related symptom distress, further supporting PDQ construct validity., Conclusions: This study confirms the conceptual framework, factor structure, and convergent and discriminant validity of the PDQ psychological and physical symptoms, penile pain, and symptom bother domains. Used in conjunction with objective penile curvature measurements, the PDQ can serve as a valuable diagnostic tool or outcome measure to assess treatment related improvements in Peyronie's disease symptoms., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: IMPRESS (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies) I and II examined the clinical efficacy and safety of collagenase Clostridium histolyticum intralesional injections in subjects with Peyronie disease. Co-primary outcomes in these identical phase 3 randomized, double-blind, placebo controlled studies included the percent change in the penile curvature abnormality and the change in the Peyronie disease questionnaire symptom bother score from baseline to 52 weeks., Materials and Methods: IMPRESS I and II examined collagenase C. histolyticum intralesional injections in 417 and 415 subjects, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks. Men received up to 8 injections of 0.58 mg collagenase C. histolyticum, that is 2 injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling. Men were stratified by baseline penile curvature (30 to 60 vs 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo 2:1 in favor of the former., Results: Post hoc meta-analysis of IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34% improvement in penile curvature, representing a mean ± SD -17.0 ± 14.8 degree change per subject, compared with a mean 18.2% improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p <0.0001). The mean change in Peyronie disease symptom bother score was significantly improved in treated men vs men on placebo (-2.8 ± 3.8 vs -1.8 ± 3.5, p = 0.0037). Three serious adverse events (corporeal rupture) were surgically repaired., Conclusions: IMPRESS I and II support the clinical efficacy and safety of collagenase C. histolyticum for the physical and psychological aspects of Peyronie disease., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Collagenase Clostridium histolyticum is an investigational nonsurgical treatment for Peyronie disease. In this phase 2b, double-blind, randomized, placebo controlled study we determined the safety and efficacy of collagenase C. histolyticum and assessed a patient reported outcome questionnaire., Materials and Methods: A total of 147 subjects were randomized into 4 groups to receive collagenase C. histolyticum or placebo (3:1) with or without penile plaque modeling (1:1). Per treatment cycle 2 injections of collagenase C. histolyticum (0.58 mg) were given 24 to 72 hours apart. Subjects received up to 3 cycles at 6-week intervals. When designated, investigator modeling was done 24 to 72 hours after the second injection of each cycle. We evaluated penile curvature by goniometer measurement, patient reported outcomes and adverse event profiles., Results: After collagenase C. histolyticum treatment significant improvements in penile curvature (29.7% vs 11.0%, p=0.001) and patient reported outcome symptom bother scores (p=0.05) were observed compared to placebo. In modeled subjects 32.4% improvement in penile curvature was observed in those on collagenase C. histolyticum compared to 2.5% worsening of curvature in those on placebo (p<0.001). Those treated with collagenase C. histolyticum who underwent modeling also showed improved Peyronie disease symptom bother scores (p=0.004). In subjects without modeling there were minimal differences between the active and placebo cohorts. Most adverse events in the collagenase C. histolyticum group occurred at the injection site and were mild or moderate in severity. No treatment related serious adverse events were reported., Conclusions: Collagenase C. histolyticum treatment was well tolerated. We noted significant improvement in penile curvature and patient reported outcome symptom bother scores, suggesting that this may be a safe, nonsurgical alternative for Peyronie disease., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients., Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection., Results: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor., Conclusion: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2).

Purpose: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer., Patients and Methods: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles., Results: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF., Conclusion: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.

Background: Laparoscopic cholecystectomy is becoming a popular surgical option in the management of gallstone disease. Reports on complications of this procedure have usually focused on prolonged operative time, bleeding, and infections. We describe a case of cholelithiasis of the ovary following laparoscopic cholecystectomy., Case: A 70-year-old woman, para 5-0-0-5, presented with a 2-month history of a pelvic mass following a laparoscopic cholecystectomy. Exploratory laparotomy demonstrated a 4 x 4-cm para-ovarian cyst as well as multiple rectal and pelvic implants. Pathologic findings confirmed gallstones of the ovary and pelvic peritoneum. These gallstones elicited mesothelial proliferation, local hemorrhage, and adhesion formation., Conclusion: The pathologic consequences of pelvic cholelithiasis can be marked. This was demonstrated in a postmenopausal woman, but has direct implications for the premenopausal patient as well. Our experience suggests that gallstones lost during laparoscopic cholecystectomy should be removed if possible.

Neutralizing monoclonal antibodies were derived to human rotaviruses RV-4 (serotype 1), RV-5 (serotype 2), and ST-3 (serotype 4). By enzyme immunoassay and fluorescent focus neutralization, eight of the antibodies appeared to be specific for the immunizing serotype, and so have potential as reagents for rotavirus serotyping by enzyme immunoassay. Seven of these were shown by Western blotting, enzyme immunoassay for antibody additivity, and reaction with rotavirus reassortants, to be directed against the major outer capsid glycoprotein. The remaining serotype-specific antibody immunoprecipitated the 84-kD outer capsid protein. One antibody reacted with all serotype 1 and 3 rotaviruses but not with serotypes 2 or 4. When tested with virus mutants, this antibody recognized an immunodominant determinant of neutralization shared between serotypes 1 and 3 on the major outer shell glycoprotein. Our results suggest that two outer capsid proteins possess determinants of neutralization, and that viruses of different serotypes may share immunodominant neutralization sites.