Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Molecular Characterization of Skeletal Muscle Dysfunction in Sigma 1 Receptor (Sigmar1) Knockout Mice.

Sigma 1 receptor (Sigmar1) is a widely expressed, multitasking molecular chaperone protein that plays functional roles in several cellular processes. Mutations in the Sigmar1 gene are associated with several distal neuropathies with strong manifestation in skeletal muscle dysfunction with phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle remains unknown. Herein, the physiological role of Sigmar1 in skeletal muscle structure and function in gastrocnemius, quadriceps, soleus, extensor digitorum longus, and tibialis anterior muscles was determined. Quantification of myofiber cross-sectional area showed altered myofiber size distribution and changes in myofiber type in the skeletal muscle of the Sigmar1-/- mice. Interestingly, ultrastructural analysis by transmission electron microscopy showed the presence of abnormal mitochondria, and immunostaining showed derangements in dystrophin localization in skeletal muscles from Sigmar1-/- mice. In addition, myopathy in Sigmar1-/- mice was associated with an increased number of central nuclei, increased collagen deposition, and fibrosis. Functional studies also showed reduced endurance and exercise capacity in the Sigmar1-/- mice without any changes in voluntary locomotion, markers for muscle denervation, and muscle atrophy. Overall, this study shows, for the first time, a potential physiological function of Sigmar1 in maintaining healthy skeletal muscle structure and function.

Preferences of cancer patients as a guide to cancer prevention: a retrospective willingness to pay study in Nepal.

OBJECTIVE: In developing countries, like Nepal, with no population-based cancer registry and low level of awareness, it is difficult to communicate the significance of cancer preventative measures to the general population. Only patients, who have faced or facing the economic and mental burden of cancer, can better understand the importance of early diagnosis. This led us to study the retrospective preference of cancer patients in valuing an annual comprehensive cancer screening program in Nepal. STUDY DESIGN: This is a primary survey-based study of 600 diagnosed cancer patients (aged 18+ years) randomly sampled from five hospitals of Nepal during December 2015-February 2016. METHODS: Using the contingent valuation estimation methods, we modelled patients' willingness to pay (WTP) for early cancer screening through the Structural Equation Modelling framework. RESULTS: About 59% of our sampled patients did not receive education and 65% earned below $100/month. Among other findings, we saw that the Risk of re-occurrence impacted WTP through two opposing channels. The direct effect of Risk of re-occurrence on WTP was positive (ß = 0.20; p < 0.05), but higher the risk of cancer relapses, the higher was the Pessimism among patients, which indirectly impacted WTP negatively (ß = -0.16; p < 0.1). In addition, we found the effect of Income on WTP to be positive (ß = 0.15; p < 0.05), whereas, one belonging to the backward Dalit section of the society had lower WTP for screening. CONCLUSION: Cancer patients value the importance of early diagnosis with multiple psychosocial factors impacting this preference. This direct account of patients could be used as evidence in policymaking.

Neurogranin regulates calcium-dependent cardiac hypertrophy.

Intracellular Ca2+-calmodulin (CaM) signaling plays an important role in Ca2+-CaM-dependent kinase (CaMKII) and calcineurin (CaN)-mediated cardiac biology. While neurogranin (Ng) is known as a major Ca2+-CaM modulator in the brain, its pathophysiological role in cardiac hypertrophy has never been studied before. In the present study, we report that Ng is expressed in the heart and depletion of Ng dysregulates Ca2+ homeostasis and promotes cardiac failure in mice. 10-month-old Ng null mice demonstrate significantly increased heart-to-body weight ratios compared to wild-type. Using histological approaches, we identified that depletion of Ng increases cardiac hypertrophy, fibrosis, and collagen deposition near perivascular areas in the heart tissue of Ng null mice. Ca2+ spark experiments revealed that cardiac myocytes isolated from Ng null mice have decreased spark frequency and width, while the duration of sparks is significantly increased. We also identified that a lack of Ng increases CaMKIIδ signaling and periostin protein expression in these mouse hearts. Overall, we are the first study to explore how Ng expression in the heart plays an important role in Ca2+ homeostasis in cardiac myocytes as well as the pathophysiology of cardiac hypertrophy and fibrosis.

Effectiveness of common macrophytes for phytoremediation of hexavalent Cr prevalent in chromite mining areas.

Hexavalent chromium Cr(VI) is carcinogenic. To reduce Cr(VI) toxicity, a study was undertaken to assess the effectiveness of common macrophytes in the range of Cr concentration prevalent in chromite mining areas at Sukinda, Odisha, India. The metal varied from 0.09 to 2.14 mg/L during 2016 - 2019 and indicated that ≅70% waterbodies are contaminated with Cr(VI). Phytoremediation experimentation using five common macrophytes resulted in Pistia stratiotes, Salvinia minima and Ipomoea aquatica as suitable species by remediating 57 to 100% Cr(VI) from 0.2 to 1.0 mg/L within 54 days. S. minima had then found to remove 1 to 1.8 and 1.6 to 2.8 times more Cr (total) than P. stratiotes and I. aquatica respectively from a level of 0.5 to 2.5 mg/L Cr(VI) within 49 days. Irrespective of plant-duration, P. stratiotes excelled over S. minima by 59 to 68% and I. aquatica by 55 to 89% in BCF value. S. minima thus proved best by removing maximum Cr per unit time while the combination of S. minima and P. stratiotes would have promise in respect of generating low volume of remediated biomass in phytoremediation of Cr(VI).Novelty statementMacrophytes differ in their response to remove metal, screening against a given metal concentration suggests the suitable species and testing signifies their effectiveness of remediating metal from contaminated sources.

Evaluation of Normothermic Machine Perfusion of Porcine Livers as a Novel Preclinical Model to Predict Biliary Clearance and Transporter-Mediated Drug-Drug Interactions Using Statins.

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study, we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion, and plasma exposure of drugs. For this evaluation, we dosed atorvastatin, pitavastatin, and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDIs) on these processes. After 120 minutes of perfusion, 0.104 mg atorvastatin (n = 3), 0.140 mg pitavastatin (n = 5), or 1.4 mg rosuvastatin (n = 4) was administered to the portal vein, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human-specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank order of the DDI between the various systems upon coadministration with rifampicin could be observed: atorvastatin (AUC ratio 7.2) > rosuvastatin (AUC ratio 3.1) > pitavastatin (AUC ratio 2.6), which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion, and plasma profile of drugs. SIGNIFICANCE STATEMENT: This study evaluated the use of normothermic machine perfusion (NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins, and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

The role of infrared dermal thermometry in the management of neuropathic diabetic foot ulcers.

AIM: This prospective observational study evaluated the role of infrared (IR) dermal thermometry in the management of diabetic foot ulcers. METHODS: Thirty participants with unilateral neuropathic diabetic foot ulcers of University of Texas grade 1 or 2 (stage A) were followed up monthly for 1 year. At each visit, skin temperatures were measured with an IR dermal thermometer at corresponding sites on both feet, using the contralateral feet without ulcers as controls. RESULTS: Average temperature and ulcer temperature in affected feet were significantly higher than in unaffected feet, with a mean difference of 1.2 °C [95% confidence interval (CI) 0.7 to 1.7] and 3.1 °C (95% CI 2.3 to 3.9), respectively. Although the gradient between average temperature of affected foot and that of unaffected foot normalized (mean difference 0.2 °C, 95% CI -0.2 to 0.7) at healing, the temperature gradient between the ulcer and a corresponding site on the unaffected foot decreased but did not normalize (mean difference 2.1 °C, 95% CI 1.2 to 3.1) even at healing, as documented by skin closure, and persisted for up to 1 month after skin closure. A gradient of ≥1 °C between average temperature of affected foot and that of unaffected foot at initial presentation or at any time during ulcer healing was found to predict impaired healing and should alert clinicians to ulcers requiring more attention. An incremental trend in temperature gradient (median difference 2.2 °C; range 0.1-6.3 °C) at a site on the foot was predictive of a recurrent ulcer involving the same site. CONCLUSIONS: IR dermal thermometry may have a role in predicting diabetic foot ulcer healing, in determining the completeness of healing and in guiding the duration of offloading. Serial monitoring of the temperature gradient may predict the development of recurrent diabetic foot ulcers.

Vascular Surgery Practice Guidelines during COVID-19 Pandemic in a Setting of High Work Volume Against Limited Resources: Perspective of a Developing Country.

BACKGROUND: The situation of coronavirus disease 2019 (COVID-19) pandemic in the Indian subcontinent is worsening. In Bangladesh, rate of new infection has been on the rise despite limited testing facility. Constraint of resources in the health care sector makes the fight against COVID-19 more challenging for a developing country like Bangladesh. Vascular surgeons find themselves in a precarious situation while delivering professional services during this crisis. With the limited number of dedicated vascular surgeons in Bangladesh, it is important to safeguard these professionals without compromising emergency vascular care services in the long term. To this end, we at the National Institute of Cardiovascular Diseases and Hospital, Dhaka, have developed a working guideline for our vascular surgeons to follow during the COVID-19 pandemic. The guideline takes into account high vascular work volume against limited resources in the country. METHODS: A total of 307 emergency vascular patients were dealt with in the first 4 COVID-19 months (March through June 2020) according to the working guideline, and the results were compared with the 4 pre-COVID-19 months. Vascular trauma, dialysis access complications, and chronic limb-threatening ischemia formed the main bulk of the patient population. Vascular health care workers were regularly screened for COVID-19 infection. RESULTS: There was a 38% decrease in the number of patients in the COVID-19 period. Treatment outcome in COVID-19 months were comparable with that in the pre-COVID-19 months except that limb loss in the chronic limb-threatening ischemia patients was higher. COVID-19 infection among the vascular health care professionals was low. CONCLUSIONS: Vascular surgery practice guidelines customized for the high work volume and limited resources of the National Institute of Cardiovascular Diseases and Hospital, Dhaka were effective in delivering emergency care during COVID-19 pandemic, ensuring safety of the caregivers. Despite the fact that similar guidelines exist in different parts of the world, we believe that the present one is still relevant on the premises of a deepening COVID-19 crisis in a developing country like Bangladesh.

Linear lesions in dermatology: a clinicoaetiopathological study.

BACKGROUND: Linear lesions are fairly common in our daily practice. However, the appearance of these lesions can vary, thus complicating the diagnosis. AIMS: To study the various clinical presentations, the demographic profile of patients and the clinicopathological correlations of dermatoses presenting with a linear distribution. METHODS: We conducted an institution-based, cross-sectional, descriptive study of 281 consecutive patients with linear lesions attending dermatology clinics. MedCalc software (V11.6) was used for statistical analysis. RESULTS: Patients were divided into eight groups: lesions along the lines of Blaschko (n = 136), lesions along blood vessels (n = 3), lesions along lymphatics (n = 3), Koebner phenomenon (n = 24), autoinoculation (n = 24), external factors (n = 45), infestations (n = 2) and 'other' (n = 44). The mean age at presentation was 24.50 ± 18.82 years and the male/female ratio was 1.32 : 1. The commonest symptom was itching/burning (56.94% of patients), while the commonest site was the arm (44.48%); followed by the leg (30.60%), trunk and abdomen (22.42%), head and neck (19.20%), and genitalia (0.35%). Apart from the common cases, there was a wide gamut of rare conditions (e.g. angiokeratoma circumscriptum naeviforme, porokeratotic eccrine ostial and dermal duct naevus, Blaschko-linear syringocystadenoma papilliferum, progressive cribriform and zosteriform hyperpigmentation, unilateral naevoid acanthosis nigricans, fixed drug eruption, discoid lupus erythematosus). CONCLUSION: Linear lesions act as diagnostic clues to many dermatological conditions, therefore, the importance of meticulous examination in clinical dermatology cannot be overemphasized.

Rationale, study design and methodology of the LANDMARC trial: a 3-year, pan-India, prospective, longitudinal study to assess management and real-world outcomes of diabetes mellitus.

AIM: India contributes towards a large part of the worldwide epidemic of diabetes and its associated complications. However, there are limited longitudinal studies available in India to understand the occurrence of diabetes complications over time. This pan-India longitudinal study was initiated to assess the real-world outcomes of diabetes across the country. METHODS: The LANDMARC study is the first prospective, multicentre, longitudinal, observational study investigating a large cohort of people with type 2 diabetes mellitus across India over a period of 3 years. The primary objective of this ongoing study is to determine the proportion of people developing macrovascular diabetes complications over the duration of the study (36 months ± 45 days) distributed over seven visits; the secondary objective is to evaluate microvascular diabetes complications, glycaemic control and time-to-treatment adaptation or intensification. Overall, 6300 participants (aged 25-60 years) diagnosed with type 2 diabetes for at least 2 years will be included from 450 centres across India. Data will be recorded for baseline demographics, comorbidities, glycaemic measurements, use of anti-hyperglycaemic medications and any cardiovascular or other diabetes-related events occurring during the observational study period. CONCLUSIONS: The LANDMARC study is expected to reveal the trends in complications associated with diabetes, treatment strategies used by physicians, and correlation among treatment, control and complications of diabetes within the Indian context. The findings of this study will help to identify the disease burden, emergence of early-onset complications and dose titration patterns, and eventually develop person-centred care and facilitate public health agencies to invest appropriate resources in the management of diabetes. (Trial Registration No: CTRI/2017/05/008452).

Chemical Architecture of Block Copolymers Differentially Abrogate Cardiotoxicity and Maintain the Anticancer Efficacy of Doxorubicin.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.

Role of Ni substitution on structural, magnetic and electronic properties of epitaxial CoCr2O4 spinel thin films.

Cubic spinel CoCr2O4 has recently attained attention due to its multiferroic properties. However, the Co site substitution effect on the structural and magnetic properties has rarely been studied in thin film form. In this work, the structural and magnetic properties of Co1-x Ni x Cr2O4 (x= 0, 0.5) epitaxial thin films deposited on MgAl2O4 (100) and MgO (100) substrates to manipulate the nature of strain in the films using pulsed laser deposition (PLD) technique are presented. The epitaxial nature of the films was manifested through x-ray diffraction (XRD), reciprocal space mapping (RSM) and Rutherford backscattering spectrometry (RBS) measurements. Raman measurements revealed a disappearance of characteristic A 1 g and F 2 g modes of the CoCr2O4 with increase in the Ni content. Atomic force microscopy (AFM) and field emission scanning electron microscopy (FE-SEM) studies show a modification of the surface morphology upon Ni substitution. Magnetic measurements disclose that the ferrimagnetic Curie temperature (T C) of the CoCr2O4 in thin film grown on MgAl2O4 (100) and MgO (100) substrates were found to be 100.6 ± 0.5 K and 93.8 ± 0.2 K, respectively. With Ni substitution the T C values were found to be enhanced to 104.5 ± 0.4 K for MgAl2O4 (100) and 108.5 ± 0.6 K for MgO (100) substrates. X-ray photoelectron spectroscopy (XPS) suggests Cr3+ oxidation states in the films, while Co ions are present in a mixed Co2+/Co3+ oxidation state. The substitution of Ni at Co site significantly modifies the line shape of the core level as well as the valence band. Ni ions are also found to be in a mixed 2+/3+ oxidation state. O 1s core level display asymmetry related to possible defects like oxygen vacancies in the films.

Measuring the societal burden of cancer: a case of lost productivity in Nepal.

OBJECTIVES: The global patterns of cancer incidences and mortality rates are slowly shifting towards low- and middle-income countries. Through our article, we highlight the societal cost associated with premature mortality and morbidity of cancer in Nepal. The monetary loss is indicative of the severity of the issue and it serves to motivate the policymakers realize the urgency in devising appropriate cancer control strategies. STUDY DESIGN: The study design is a cross-sectional study using the GLOBOCAN 2012 data. METHODS: Using the human capital approach, we measure the number of years of life lost (YLL) and the number of years of productive life lost (YPLL) due to cancer in Nepal. RESULTS: We found that following diagnosis, a Nepali patient with cancer is likely to lose out on 19.64 years of their life; the average number of YLL is higher for females (22.2 years vs 16.8 years in males). After adjusting for labor force participation rate and predicted growth rate of the economy, we found that cancer led to a total productivity loss of $149 million (males) and $121 million (females) in 2012. The burden of the top five cancers accounted for almost half of the total productivity loss in both the genders. Cervical and lung cancer incur the maximum cost to society, respectively, for females and males. CONCLUSIONS: The article highlighted the severity of the cancer issue and emphasized the urgency needed in devising cancer control policies in Nepal.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice.

Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P1)-mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P1 activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P1 knockout (TS1P1KO) mice generated by crossing S1pr1loxP/loxP mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1P1KO mice exhibited sustained deficiency of both CD4+ and CD8+ T cells in the blood. The TS1P1KO vehicle control mouse hearts featured an altered phenotype characterized by increased myocardial fibrosis and reduced cardiac contractility under normal levels of glucose. Compared with littermate diabetic mice, TS1P1KO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P1 signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P1 activation exerts antifibrotic effects in normoglycemia but exacerbates fibrosis under hyperglycemia.-Abdullah, C. S., Jin, Z.-Q. Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice.

Racial differences in myocardial deformation in obese children: Significance of inflammatory state.

BACKGROUND AND AIMS: The association between racial differences in myocardial deformation and cardiometabolic risk factors is unknown in obese children. Our objective was to: 1) investigate for racial differences in myocardial deformation between white and black obese children and 2) identify biomarkers associated with these observed racial differences. We hypothesized that decreased myocardial deformation observed in black obese children could be accounted for by the differences in the markers of metabolic syndrome between the groups. METHODS AND RESULTS: Obese children were recruited prospectively. All clinical and laboratory tests for the metabolic syndrome were conducted during a single assessment using a standardized protocol. Speckle-tracking echocardiography was performed to obtain longitudinal and circumferential measures of deformation. 310 patients were included in the analysis; 158 (51%) white and 152 (49%) black. The median age was 11.3 years (IQR 5.9). Blacks demonstrated worse longitudinal strain (-14.7 ± 2.7% vs. -15.4 ± 2.9%, p = 0.04). There was no difference in circumferential strain between the groups. Multivariable linear regression showed a significant relationship between longitudinal strain and hsCRP (ß = 0.16, p = 0.03) and HOMA-IR (ß = 0.15, p = 0.04); there was no independent association between longitudinal strain and race. CONCLUSION: Black subjects demonstrated worse longitudinal strain than whites. Only hsCRP and HOMA-IR levels, not race, had an independent association with longitudinal strain, suggesting that the observed racial differences in longitudinal strain may be secondary to differences in inflammation and insulin resistance between the groups.

Carcinogenesis Associated with Human Papillomavirus Infection. Mechanisms and Potential for Immunotherapy.

Human papillomavirus (HPV) infection is responsible for approximately 5% of all cancers and is associated with 30% of all pathogen-related cancers. Cervical cancer is the third most common cancer in women worldwide; about 70% of cervical cancer cases are caused by the high-risk HPVs (HR HPVs) of genotypes 16 and 18. HPV infection occurs mainly through sexual contact; however, viral transmission via horizontal and vertical pathways is also possible. After HPV infection of basal keratinocytes or ecto-endocervical transition zone cells, viral DNA persists in the episomal form. In most cases, infected cells are eliminated by the immune system. Occasionally, elimination fails, and HPV infection becomes chronic. Replication of HPVs in dividing epithelial cells is accompanied by increased expression of the E6 and E7 oncoproteins. These oncoproteins are responsible for genomic instability, disruption of the cell cycle, cell proliferation, immortalization, and malignant transformation of HPV-infected cells. Besides, E6 and E7 oncoproteins induce immunosuppression, preventing the detection of HPV-infected and transformed cells by the immune system. HPV integration into the genome of the host cell leads to the upregulation of E6 and E7 expression and contributes to HPV-associated malignization. Prophylactic HPV vaccines can prevent over 80% of HPV-associated anogenital cancers. The vaccine elicits immune response that prevents initial infection with a given HPV type but does not eliminate persistent virus once infection has occurred and does not prevent development of the HPV-associated neoplasias, which necessitates the development of therapeutic vaccines to treat chronic HPV infections and HPV-associated malignancies.