Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer

Introduction/Background. Nonmetastatic castrate resistant prostate cancer (CRPC) is a challenging disease state. The objective of this study was to evaluate the efficacy and tolerability of bevacizumab in nonmetastatic CRPC patients. Patients. Patients with prostate cancer who developed PSA recurrence after local therapy were included if they had absence of bone or visceral metastases and PSA progression despite androgen deprivation therapy. Methods. Bevacizumab 10 mg/kg intravenously was administered every 14 days until PSA progression, development of metastasis, or unacceptable toxicity. Results. 15 patients were enrolled and treated with bevacizumab for a median duration of 3.1 months. Median baseline PSA was 27 ng/mL, and seven patients had Gleason Score ≥8. Five patients had declined in PSA during the treatment. Median PSA doubling time was prolonged from 4.7 months pretreatment to 6.5 months. Median time to PSA progression and new metastasis were 2.8 and 7.9 months, respectively. There were three grade 3 adverse events (one proteinuria and two hypertension) and one pulmonary embolism. There was no treatment-related mortality. Conclusion. Bevacizumab therapy had minimal impact on the disease course of nonmetastatic CRPC, and investigation of novel strategies is needed

Phase II Study of Gemcitabine and Docetaxel Combination in Patients with Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Purpose. To explore the safety and efficacy of gemcitabine and docetaxel (GEMDOC) in previously treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods. Patients with advanced SCCHN previously pretreated with one or two lines of palliative chemotherapy were treated with gemcitabine and docetaxel until disease progression. Results. Thirty-six patients were enrolled, and 29 were response evaluable. 16 (55%) experienced clinical benefit (response or stable disease). Six (21%) patients achieved partial response (PR), none achieved complete response (CR), and the overall response rate (ORR) was 21% (95% CI: 0.10–0.38). Ten (28%) patients had stable disease. The median response duration (RD) for the 6 PR patients was 3.2 months (80% CI: 2.0–6.1 months). Median overall survival was 4.2 months (95% CI: 2.4–7.0 months). Among the 33 treated patients: 13 (39%) patients had grade 3-4 anemia, 10 (30%) had grade 3-4 neutropenia. Conclusion. The study drugs were relatively safe, and the clinical benefit (PR + SD) rate was 55%. However, the efficacy objective for this regimen was not met. Given the good safety profile, further investigation of this regimen with the addition of a targeted agent may lead to better efficacy

Phase II Study of Celecoxib and Docetaxel in Non-small Cell Lung Cancer (NSCLC) Patients with Progression after Platinum-Based Therapy

IntroductionTo evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy.MethodsPatients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate.ResultsTwenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0–25%) and the 6-month survival rate was 59% (95% CI 37–80%). Median survival time was 6.9 months (95% CI, 2.8–15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15–57%) and 1% (95% CI, 0–10%), respectively. The most frequent grade ≥3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial.ConclusionsThe addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel

Anti-androgenic activity of absorption-enhanced 3, 3\u27-diindolylmethane in prostatectomy patients

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3\u27-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706

The impact of probiotic supplementation on cognitive, pathological and metabolic markers in a transgenic mouse model of Alzheimer’s Disease

Brain degenerative disorders such as Alzheimer’s disease (AD) can be exacerbated by aberrant metabolism. Supplementation with probiotic bacteria is emerging as a promising preventative strategy for both neurodegeneration and metabolic syndrome. In this study, we assess the impact of the Lab4b probiotic consortium on (i) cognitive and pathological markers of AD progression and (ii) metabolic status in 3xTg-AD mice subjected to metabolic challenge with a high fat diet. The group receiving the probiotic performed better in the novel object recognition test and displayed higher hippocampal neuronal spine density than the control group at the end of the 12 weeks intervention period. These changes were accompanied by differences in localised (brain) and systemic anti-inflammatory responses that favoured the Probiotic group together with the prevention of diet induced weight gain and hypercholesterolaemia and the modulation of liver function. Compositional differences between the faecal microbiotas of the study groups included a lower Firmicutes:Bacteroidetes ratio and less numbers of viable yeast in the Probiotic group compared to the Control. The results illustrate the potential of the Lab4b probiotic as a neuroprotective agent and encourage further studies with human participants

Integration of vegetation classification with land cover mapping: lessons from regional mapping efforts in the Americas

Aims: Natural resource management and biodiversity conservation rely on inventories of vegetation that span multiple management or political jurisdictions. However, while remote sensing data and analytical tools have enabled production of maps at increasing spatial resolution and reliability, there are limited examples where national or continental-scaled maps are produced to represent vegetation at high thematic detail. We illustrate two examples that have bridged the gap between traditional land cover mapping and modern vegetation classification. Study area: Our two case studies include national (USA) and continental (North and South America) vegetation and land cover mapping. These studies span conditions from subpolar to tropical latitudes of the Americas. Methods: Both case studies used a supervised modeling approach with the International Vegetation Classification (IVC) to produce maps that provide for greater thematic detail. Georeferenced locations for these vegetation types are used by machine learning algorithms to train a predictive model and generate a distribution map. Results: The USA LANDFIRE (Landscape Fire and Resource Management Planning Tools Project) case study illustrates how a history of vegetation-based classification and availability of key inputs can come together to generate standard map products covering more than 9.8 million km2 that are unsurpassed anywhere in the world in terms of spatial and thematic resolution. That being said, it also remains clear that mapping at the thematic resolution of the IVC Group and finer resolution require very large and spatially balanced inputs of georeferenced samples. Even with extensive prior data collection efforts, these remain a key limitation. The NatureServe effort for the Americas - encompassing 22% of the global land surface - demonstrates methods and outputs suitable for worldwide application at continental scales. Conclusions: Continued collection of input data used in the case studies could enable mapping at these spatial and thematic resolutions around the globe. Abbreviations: CART = Classification and Regression Tree; CONUS = Conterminous United States; DSWE = Dynamic Surface Water Extent; EPA = United States Environmental Protection Agency; FGDC = Federal Geographic Data Committee; IVC = International Vegetation Classification; LANDFIRE = Landscape Fire and Resource Management Planning Tools Project; LFRDB = LANDFIRE Reference Database; LiDAR = Light Detection and Ranging; NDVI = Normalized Difference Vegetation Index; NLCD = National Land Cover Database; USNVC = United States National Vegetation Classification; USA = United States of America; WWF = World Wildlife Fund or Worldwide Fund for Nature

An unusual variation of a right-sided aortic arch with a common subclavian trunk

Introduction: A right-sided aortic arch is a rare congenital cardiovascular anomaly that arises from persistence of the right fourth aortic arch and regression of the left fourth aortic arch. This variation commonly gives rise to an aberrant left subclavian artery (ALSA). In this report, we present an unusual variation of a right-sided aortic arch with an isolated common subclavian trunk (CST). Methods: During a routine dissection of a female cadaver, a right-sided aortic arch variation with an aberrant left subclavian artery was observed. The thorax was further dissected to reveal the right-sided aortic arch and anomalous origin of the ALSA from a CST. Results: The ascending aorta arose from the heart to form a right-sided aortic arch which branched into 1) a CST, 2) a left common carotid artery, and 3) a right common carotid artery. The CST branched into a right subclavian artery and an ALSA which traversed posteriorly to the esophagus to its normal anatomical position. The descending thoracic aorta passed along the right lateral aspect of the vertebral column, traversed posteriorly to the esophagus, and continued descending in its anatomical position through the aortic hiatus. Conclusion: Rare aortic arch congenital anomalies such as a common subclavian trunk predispose the body to numerous clinical complications. A common subclavian trunk can cause cardiovascular complications and gastrointestinal complications due to compression of the esophagus. A deep understanding of the variations in the aortic arch and its branches is necessary for all physicians when managing patients with cardiovascular and upper gastrointestinal symptoms