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Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS‐associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One‐year overall survival was 61%, and progression‐free survival was 58%. The 48‐week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well‐controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease. [ABSTRACT FROM AUTHOR]

Curcumin inhibits UDP‐glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m2 of i.v. infusion irinotecan on days 1 and 15 of a 28‐day cycle, to determine the maximum tolerated dose (MTD) of PC. Thirteen participants received 4 g of PC (MTD) to assess the effect on the pharmacokinetic (PK) properties of irinotecan and its metabolites, SN‐38 and SN‐38G. Irinotecan, SN‐38, and SN‐38G exposure equivalence with and without curcumin was assessed using area under the plasma concentration‐time curves from 0 to 6 h (AUC0‐6h). Safety assessments and disease responses were also evaluated. The combination of irinotecan and PC was well‐tolerated. Because there was no dose limiting toxicity, the maximum dose administered (4 g) was defined as the recommended phase II dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan‐associated toxicities. The objective response rate was 3/19 (22%, 95% confidence interval [CI]: 5–39%), median progression free survival and overall survival (n = 23) were 4 months (95% CI: 2.9–8.9 months) and 8.4 months (95% CI: 3.7 – not evaluable [NE]), respectively. Future studies are required to evaluate the efficacy of this combination. [ABSTRACT FROM AUTHOR]

Background: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: Twelve patients with intermediate‐risk/high‐risk HNSCC were enrolled, including those with p16‐negative tumors of the oropharynx, p16‐positive tumors of the oropharynx with ≥10 tobacco pack‐years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8‐week course of concurrent intensity‐modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1‐7), cisplatin 30 mg/m2 weekly (in weeks 1‐7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12‐week objective response rate and progression‐free and overall survival. Results: Three patients (25%) experienced a dose‐limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose‐limiting toxicities occurred with adavosertib at 150 mg. The median follow‐up was 14.7 months. The 12‐week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1‐year progression‐free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. Conclusions: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity‐modulated radiotherapy and cisplatin 30 mg/m2, is the recommended phase 2 dose for patients with HNSCC. In a phase 1b trial, the safety of adavosertib in combination with definitive chemoradiotherapy is evaluated in patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma. The maximum tolerated dose and the recommended phase 2 dose of adavosertib for these patients is 100 mg in combination with 70 grays of intensity‐modulated radiation and cisplatin 30 mg/m2. [ABSTRACT FROM AUTHOR]

BACKGROUND: Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double‐blind, placebo‐controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer who progressed on first‐line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28‐day cycle. Crossover was not allowed. The primary endpoint was progression‐free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1‐sided α value of .1. RESULTS: One hundred eighty‐one patients were randomized (120 to regorafenib‐FOLFIRI and 61 to placebo‐FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib‐FOLFIRI than placebo‐FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53‐1.01; log‐rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71‐1.44). The response rate was higher with regorafenib‐FOLFIRI (34%; 95% CI, 25%‐44%) than placebo‐FOLFIRI (21%; 95% CI, 11%‐33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS: The addition of regorafenib to FOLFIRI as second‐line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective To improve and individualise estimates of treatment outcomes for men diagnosed with prostate cancer, we examined the impact of baseline comorbidity on health-related quality of life ( HRQL) outcomes in an analysis of two pooled, prospective cohort studies. Patients and Methods We studied 697 patients from three academic hospitals who received radical prostatectomy ( RP), external beam radiation therapy ( EBRT), or brachytherapy ( BT). Measures of patient-reported bowel, urinary, and sexual symptoms along with physical and mental health were prospectively collected before treatment and 3, 12, 24, and 36 months after treatment. We assessed baseline comorbidity by the validated Index of Co-Existent Disease ( ICED), abstracted from medical records. Regression mixed-models were built for each treatment group and HRQL outcome controlling for baseline age, education, marital status, risk group and patient-reported general health. Results About 71% of patients had one or more comorbid conditions at baseline. After adjusting for covariates, we found baseline comorbidity was independently associated with poorer sexual function after BT ( P = 0.04) and RP ( P = 0.03) but not EBRT ( P = 0.35). Physical health was significantly worse for men receiving BT with more comorbidities ( P = 0.02). Baseline comorbid conditions were not associated with urinary incontinence or bowel functioning. Conclusions Comorbidity at baseline is significantly associated with poorer sexual function after prostate BT or RP. This information may help patients and their physicians anticipate outcomes after surgical and radiation treatments. [ABSTRACT FROM AUTHOR]

BACKGROUND: Intraoperative radiation therapy (IORT) allows delivery of high-dose radiation at the time of lumpectomy, potentially sparing adjuvant daily radiation. A phase 2 study of pre-excision IORT was performed for early-stage breast cancer. METHODS: Patients ≥ 48 years of age with invasive ductal carcinoma, ≤ 3 cm, and clinically node-negative were eligible for this study, which was approved by institutional review board. Ultrasound was used to select electron energy and cone size to cover the tumor plus 1.5- to 2.0-cm lateral margins and 1-cm-deep margins (90% isodose). Fifteen Gy was delivered with a Mobetron irradiator, and immediate needle-localized partial mastectomy followed. Local event results were updated using the Kaplan-Meier method. RESULTS: A total of 53 patients received IORT alone. Median age was 63 years, and median tumor size was 1.2 cm. Of these, 81% were positive for estrogen receptor or progesterone receptor, 11% were positive for human epidermal growth factor receptor 2, and 15% were triple-negative. Also, 42%, 49%, and 9% would have fallen into the Suitable, Cautionary, and Unsuitable groups, respectively, of the American Society of Therapeutic Radiation Oncology consensus statement for accelerated partial breast irradiation. Median follow-up was 69 months. Ipsilateral events occurred in 8 of 53 patients. The 6-year actuarial rate of ipsilateral events was 15% (95% confidence interval = 7%-29%). The crude event rate for Suitable and Cautionary groups was 1 of 22 (5%) and 7 of 26 (27%), respectively. Overall survival was 94.4%, and breast cancer-specific survival was 100%. CONCLUSIONS: The rate of local events in this study is a matter of concern, especially in the Cautionary group. On the basis of these findings, pre-excision IORT, as delivered in this study, may not provide adequate local control for less favorable early-stage breast cancers. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Introduction: Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. Methods: Axonal excitability studies were performed on median nerve at the palm and wrist in 20 healthy controls, with responses recorded over the abductor pollicis brevis. Results: The strength-duration time constant was significantly shorter (palm: 0.35 ± 0.01 ms; wrist: 0.48 ± 0.03 ms; P < 0.001), whereas rheobase was significantly increased (palm: 2.90 ± 1.12 mA; wrist: 2.09 ± 1.11 mA; P < 0.05) at the palm. In addition, there was a significant increase in depolarizing threshold electrotonus at 90-100 ms ( P < 0.001) and a reduction in S2 accommodation ( P < 0.001) and late subexcitability ( P < 0.001) at the palm. The changes in excitability were independent of factors influencing median nerve cross-sectional area. Conclusions: The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PHT) is reported to be associated with measures of renal function in patients with sickle cell disease (SCD). The purpose of this exploratory study was to determine the relationship between albuminuria and both clinical and laboratory variables in SCD. Design and methods: This cross-sectional study was performed using a cohort of adult patients with SCD and control subjects without SCD. Spot urine for microalbumin/creatinine ratio, measures of hemolysis, inflammation and other laboratory studies were obtained. Pulmonary artery systolic pressure was determined by Doppler echocardiography, and the diagnosis of PHT was defined using age-, sex- and body mass index-adjusted reference ranges. Results: Seventy-three patients with SCD and 21 healthy, race-matched control subjects were evaluated. In patients with SCD, normoalbuminuria was observed in 34 patients (46.6%), microalbuminuria in 24 patients (32.9%) and macroalbuminuria in 15 patients (20.5%). There was a significant correlation between urine albumin excretion and age. In patients with HbSS and Sβ0 thalassemia, the levels of sFLT-1, soluble VCAM and NT pro-BNP were significantly higher in those with macroalbuminuria, compared to patients with microalbuminuria and normoalbuminura, but no significant differences were observed in the levels of laboratory measures of hemolysis. Urine albumin excretion was associated with PHT and a history of stroke. Conclusions: Our study confirms the high prevalence of albuminuria in SCD. The association of urine albumin excretion with sFLT-1 suggests that this vascular endothelial growth factor receptor family member may contribute to the development of albuminuria in SCD. By inducing endothelial activation and endothelial dysfunction, sFLT-1 appears to be a link between glomerulopathy and PHT in SCD. [ABSTRACT FROM AUTHOR]

OBJECTIVE To prospectively evaluate the acute and short-term effects of radical retropubic prostatectomy (RRP) on health-related quality of life (HRQoL) using a validated generic HRQoL instrument that measures overall health status, as although there is increasing interest in the HRQoL of patients being treated for prostate cancer, most studies have focused on long-term outcomes. PATIENTS AND METHODS In all, 121 men undergoing RRP for clinically localized prostate cancer were prospectively evaluated for short-term HRQoL using an acute Short Form-12 version-2 Physical and Mental Health Survey Acute Form before and serially each week from 1 to 6 weeks after RRP. The physical (PCS) and mental component score (MCS) were calculated from the questionnaires at each time and the data analysed by random coefficient modelling. Separate models were fitted for MCS and PCS using covariates of race, age, estimated blood loss (EBL), time after RRP, and their interaction terms. RESULTS The PCS initially declined and improved linearly. and the baseline level was not achieved by 6 weeks, but modelling lines showed an expected return to baseline at 7–8 weeks for all patients. Age had a significant relationship with the PCS; older men (>60 years) scored higher, and their PCS remained significantly higher after RRP than younger men (≤60 years) until 5 weeks. EBL also had a significant relationship with PCS; men with an EBL of >500 mL had a significantly lower PCS at 1 week and this remained significantly lower than for men with an EBL of ≤ 500 mL until ≈ 7 weeks. The MCS improved immediately after RRP and remained higher throughout the study than at baseline. Race was the only covariate for which there were significant differences in the MCS. The MCS was significantly lower at baseline for African-Americans than for Caucasian Americans, and remained lower until 6 weeks after RRP. CONCLUSIONS There were significant changes in HRQoL during in the short-term after RRP. Younger men and those with a higher EBL might have a slower recovery of the PCS after RRP. African-Americans had a slower increase in MCS and might have a different initial emotional or mental health response to RRP than have Caucasians. [ABSTRACT FROM AUTHOR]