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Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response ( r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

SummaryBackground Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.

This randomized trial comparing retropubic and transobturator slings for the treatment of stress urinary incontinence showed equivalent rates of treatment success according to objective criteria; the rates of treatment success in the two groups according to subjective criteria were similar but did not meet the criteria for equivalence. Complications differed in the two groups, with more voiding dysfunction requiring surgery in the retropubic-sling group and more neurologic symptoms in the transobturator-sling group. In this randomized trial, two surgical approaches for the treatment of stress urinary incontinence had similar cure rates, although the complications differed by group. Urinary incontinence affects up to 50% of women, resulting in substantial medical, social, and economic burdens. 1 , 2 Among U.S. women with urinary incontinence, 15 to 80% have a component of stress incontinence, 3 which results in leakage of urine during physical exertion, sneezing, and coughing. 4 Of these women, 4 to 10% undergo surgery. 5 In 1996, Ulmsten et al. 6 introduced a procedure that involved the placement of a retropubic midurethral mesh sling for the treatment of stress incontinence; this procedure was less invasive than the Burch colposuspension and the autologous rectus fascial sling procedures that were the reference standards at the time. . . .

This multicenter, randomized clinical trial compared two surgical procedures — the Burch colposuspension and the autologous fascial pubovaginal sling — in women with urinary stress incontinence. Success rates (in terms of overall urinary-incontinence measures and stress-incontinence measures specifically) were higher at 2 years for the sling group, but this group also had greater morbidity. These findings inform decision making with respect to surgical treatment of stress incontinence and underscore the importance of surgical randomized trials. This trial compared two surgical procedures — the Burch colposuspension and the fascial sling — in women with urinary stress incontinence. Success rates were higher at 2 years for the sling group, but this group also had greater morbidity. Urinary incontinence affects an estimated 15 to 50% of women, 1 , 2 resulting in a significant medical, social, and economic burden. 1 In 1995 dollars, the annual direct costs of incontinence in the United States were estimated to be more than $16 billion. 3 Among women with incontinence, 50 to 80% are identified as having stress incontinence, 4 or involuntary leakage of urine resulting from physical exertion or sneezing and coughing. 5 Although the initial treatment of stress incontinence is often nonsurgical (behavioral therapy, pelvic-floor exercises, or incontinence devices), surgical treatment is considered for patients who are bothered by persistent symptoms. An estimated 4 to . . .

We sought to describe the relationship between patient symptoms and pelvic organ prolapse (POP) and report the sensitivity, specificity, and positive and negative predictive value of these POP symptoms. Two urologists and four urogynecologists developed a standardized pelvic floor questionnaire based on face validation for use at three female pelvic floor disorder clinics. Specific questions related to prolapse included questions on urinary splinting, digital assistance for defecation, and a bulge per vagina. Prolapse was assessed with the standardized Pelvic Organ Prolapse Quantitative (POP-Q) terminology. The analysis included 1912 women. Urinary splinting was uncommon (<10%) when Ba <0, but ranged between 23 and 36% for stage III and IV Ba prolapse. Digital assistance was equally common in stage II Bp prolapse (21-38%) and stage III-IV Bp prolapse (26-29%). Only 6-11% of women with stage 0 or I POP reported symptoms of bulge, but with stage II it increased to 77%. Urinary splinting is 97% specific for anterior prolapse. The report of a bulge has an 81% positive predictive value and a 76% negative predictive value. Very few patients without anterior prolapse will report urinary splinting. Digital assistance for fecal evacuation is no more common with massive posterior prolapse than with moderate posterior prolapse. Patient report of a bulge is a valuable screening tool for POP and should prompt a careful exam.[PUBLICATION ABSTRACT]

Introduction and hypothesisLimited data exist comparing different surgical approaches in women with advanced vaginal prolapse. This study compared 2-year surgical outcomes of uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) in women with advanced prolapse (stage III–IV) and stress urinary incontinence.MethodsThis was a secondary analysis of a multicenter 2 × 2 factorial randomized trial comparing (1) ULS versus SSLF and (2) behavioral therapy with pelvic floor muscle training versus usual care. Of 374 subjects, 117/188 (62.7%) in the ULS and 113/186 (60.7%) in the SSLF group had advanced prolapse. Two-year surgical success was defined by the absence of (1) apical descent > 1/3 into the vaginal canal, (2) anterior/posterior wall descent beyond the hymen, (3) bothersome bulge symptoms, and (4) retreatment for prolapse. Secondary outcomes included individual success outcome components, symptom severity measured by the Pelvic Organ Prolapse Distress Inventory, and adverse events. Outcomes were also compared in women with advanced prolapse versus stage II prolapse.ResultsSuccess did not differ between groups (ULS: 58.2% [57/117] versus SSLF: 58.5% [55/113], aOR 1.0 [0.5–1.8]). No differences were detected in individual success components (p > 0.05 for all components). Prolapse symptom severity scores improved in both interventions with no intergroup differences (p = 0.82). Serious adverse events did not differ (ULS: 19.7% versus SSLF: 16.8%, aOR 1.2 [0.6–2.4]). Success was lower in women with advanced prolapse compared with stage II (58.3% versus 73.2%, aOR 0.5 [0.3–0.9]), with no retreatment in stage II.ConclusionsSurgical success, symptom severity, and overall serious adverse events did not differ between ULS and SSLF in women with advanced prolapse.ClinicalTrials.gov Identifier: NCT01166373.

Introduction and hypothesis Mixed urinary incontinence (MUI) can be a challenging condition to manage. We describe the protocol design and rationale for the Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) trial, designed to compare a combined conservative and surgical treatment approach versus surgery alone for improving patient-centered MUI outcomes at 12 months. Methods ESTEEM is a multisite, prospective, randomized trial of female participants with MUI randomized to a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone. We describe our methods and four challenges encountered during the design phase: defining the study population, selecting relevant patient-centered outcomes, determining sample size estimates using a patient-reported outcome measure, and designing an analysis plan that accommodates MUI failure rates. A central theme in the design was patient centeredness, which guided many key decisions. Our primary outcome is patient-reported MUI symptoms measured using the Urogenital Distress Inventory (UDI) score at 12 months. Secondary outcomes include quality of life, sexual function, cost-effectiveness, time to failure, and need for additional treatment. Results The final study design was implemented in November 2013 across eight clinical sites in the Pelvic Floor Disorders Network. As of 27 February 2016, 433 total/472 targeted participants had been randomized. Conclusions We describe the ESTEEM protocol and our methods for reaching consensus for methodological challenges in designing a trial for MUI by maintaining the patient perspective at the core of key decisions. This trial will provide information that can directly impact patient care and clinical decision making.

Summary Purpose To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of tanespimycin when given in combination with bortezomib. Experimental design Phase I dose - escalating trial using a standard cohort “3+3” design performed in patients with advanced solid tumors. Patients were given tanespimycin and bortezomib twice weekly for 2 weeks in a 3 week cycle (days 1, 4, 8, 11 every 21 days). Results Seventeen patients were enrolled in this study, fifteen were evaluable for toxicity, and nine patients were evaluable for tumor response. The MTD was 250 mg/m 2 of tanespimycin and 1.0 mg/m 2 of bortezomib when used in combination. DLTs of abdominal pain (13 %), complete atrioventricular block (7 %), fatigue (7 %), encephalopathy (7 %), anorexia (7 %), hyponatremia (7 %), hypoxia (7 %), and acidosis (7 %) were observed. There were no objective responses. One patient had stable disease. Conclusions The recommended phase II dose for twice weekly 17-AAG and PS341 are 250 mg/m 2 and 1.0 mg/m 2 , respectively, on days 1, 4, 8 and 11 of a 21 day cycle.

Serial serum samples from a 2-year human trial of outer surface protein (Osp) A vaccine were analyzed by Borrelia burgdorferi growth-inhibition assay (GIA) and anti-OspA ELISA to assess the antibody responses of vaccine recipients and subjects with Lyme disease. Although 74% of OspA recipients had a reciprocal GIA titer ⩾64 after 3 vaccinations, none of the placebo recipients, even those with Lyme disease, had a GIA titer this high. The correlation between GIA and ELISA titers after 3 doses of vaccine was .84; however, more vaccine recipients had an elevated ELISA titer paired with low GIA titer than had a low ELISA titer with a high GIA titer. OspA-vaccine recipients who acquired Lyme disease had significantly lower serum GIA and ELISA titers after 3 immunizations than did age- and sex-matched OspA recipients without Lyme disease. Thus, vaccinated subjects had antibodies to native antigen on viable cells, and antibody assays with this specificity may predict protection of vaccinees against infection.