Worldwide Esophageal Cancer Collaboration : clinical staging data

Peer reviewe

Development of New Treatments for Prostate Cancer

The Dean and Betty Gallo Prostate Cancer Center (GPCC) was established with the goal of eradicating prostate cancer and improving the lives of men at risk for the disease through research, treatment, education and prevention. GPCC was founded in the memory of Dean Gallo, a beloved New Jersey Congressman who died tragically of prostate cancer diagnosed at an advanced stage. GPCC unites a team of outstanding researchers and clinicians who are committed to high-quality basic research, translation of innovative research to the clinic, exceptional patient care, and improving public education and awareness of prostate cancer. GPCC is a center of excellence of The Cancer Institute of New Jersey, which is the only NCI-designated comprehensive cancer center in the state. GPCC efforts are now integrated well as part of our Prostate Program at CINJ, in which Dr. Robert DiPaola and Dr. Cory Abate-Shen are co-leaders. The Prostate Program unites 19 investigators from 10 academic departments who have broad and complementary expertise in prostate cancer research. The overall goal and unifying theme is to elucidate basic mechanisms of prostate growth and oncogenesis, with the ultimate goal of promoting new and effective strategies for the eradication of prostate cancer. Members' wide range of research interests collectively optimize the chances of providing new insights into normal prostate biology and unraveling the molecular pathophysiology of prostate cancer. Cell culture and powerful animal models developed by program members recapitulate the various stages of prostate cancer progression, including prostatic intraepithelial neoplasia, adenocarcinoma, androgen-independence, invasion and metastases. These models promise to further strengthen an already robust program of investigator-initiated therapeutic clinical trials, including studies adopted by national cooperative groups. Efforts to translate laboratory results into clinical studies of early detection and chemoprevention are underway. The specific goals of this program are: (1) To investigate the molecular mechanisms underlying normal prostate growth and differentiation and elucidate the molecular mechanisms underlying prostate oncogenesis. (2) To build on fundamental knowledge to develop effective therapeutic approaches for the treatment of prostate cancer. (3) To improve the control of prostate cancer through early detection, chemoprevention, and outreach and education. This new disease-based program is structured to improve interdisciplinary interactions and translational results. Already, through the dynamic leadership of Drs. Cory Abate-Shen and Robert DiPaola, new investigators were attracted to the field, new collaborations engendered, and numerous investigator-initiated trials implemented. Progress in GPCC and the program overall has been outstanding. The Center has success in uniting investigators with broad and complementary expertise in prostate cancer research. The overall goal and unifying theme is to elucidate basic mechanisms of prostate growth and oncogenesis, with the ultimate goal of promoting new and effective strategies for the eradication of prostate cancer in patients and populations at risk. Members wide range of research interests collectively optimize the chances of providing new insights into normal prostate biology and unraveling the molecular pathophysiology of prostate cancer. Studies in cell culture and powerful animal models developed recapitulate the various stages of prostate cancer progression, including prostatic intraepithelial neoplasia, adenocarcinoma, androgen-independence, invasion and metastases. These models promise to further strengthen an already robust program of investigator-initiated therapeutic clinical trials, including studies adopted by national cooperative groups. Efforts to translate laboratory results into clinical studies of early detection and chemoprevention are underway

ECOG-ACRIN (E4805) Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients with Metastatic Renal Cell Carcinoma

Background—Aflibercept is a recombinantly-produced fusion protein that has potent anti-VEGF activity. We tested whether aflibercept has clinical activity in clear cell renal cell carcinoma (ccRCC). The recommended Phase 2 dose was 4 mg/kg but several patients treated at 1 mg/kg demonstrated prolonged progression-free survival (PFS). We therefore tested both doses in a parallel group randomized trial. Methods—Eligible patients (pts) had histologically confirmed advanced or metastatic ccRCC and previous treatments including prior exposure to a VEGF RTKI. Patients received aflibercept (either 1 mg/kg or 4 mg/kg) day 1 of a 14-day cycle until progression. Patients randomized to 1 mg/kg could crossover to 4 mg/kg at progression. The primary endpoint was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts/arm enrolled in stages 1 and 2. Results—94 pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. 72% had 1 prior tx most commonly sunitinib. 16 eligible pts crossed over at progression to the 4 mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36/59 (61%) pts PFS at 8 wks, the 4-mg/kg dose met protocol specified efficacy criteria. Conclusions—Aflibercept is active in previously treated ccRCC and may be worthy of further study

Varicocele and retrograde adrenal catabolites flow: an experimental study on rats

BACKGROUND: Idiopathic varicocele is one of the causes of potentially correctable male subfertility. The mechanisms causing spermatogenesis impairment have yet to be clarified. The aim of this study is to analyze the effects of renal and adrenal metabolite reflux on testicular exocrine function in a rat experimental model.MATERIALS AND METHODS: In the study, 45 male Lewis Stock adult rats, each weighing 300 g, were used. The rats were subdivided into three groups of 15 rats. In group A (control group) testicular volume and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were measured at the beginning of the study and after 9 months. In group B, varicocele was induced by means of rings introduced in the left renal vein in order to cause a renospermatic reflux. In group C, similarly to group B, varicocele was induced after removal of left adrenal gland. The effects of varicocele on testicular function were then analyzed 3, 6 and 9 months after surgery. After 9 months, all rats underwent testicular biopsy.RESULTS: Both groups B and C showed a reduction in testicular volume, an increase in FSH and a decrease in testosterone levels. These levels were higher in group B. Testicular histological assessment showed important structural abnormalities in group B rats.CONCLUSIONS: These data support the hypothesis that renal and adrenal metabolites enhance varicocele-induced testicular damage. This theory is supported both by hormonal impairment and testicular histological analysis

Syncope time frames for adverse events after emergency department presentation : An individual patient data meta-analysis

Background and Objectives: Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. Materials and Methods: We combined individual patients’ data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7–10 days, 1 month and 1 year after ED evaluation. Results: We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7–10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7–10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7–10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Conclusions: The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial

Personalized risk stratification through attribute matching for clinical decision making in clinical conditions with aspecific symptoms: the example of syncope

Background Risk stratification is challenging in conditions, such as chest pain, shortness of breath and syncope, which can be the manifestation of many possible underlying diseases. In these cases, decision tools are unlikely to accurately identify all the different adverse events related to the possible etiologies. Attribute matching is a prediction method that matches an individual patient to a group of previously observed patients with identical characteristics and known outcome. We used syncope as a paradigm of clinical conditions presenting with aspecific symptoms to test the attribute matching method for the prediction of the personalized risk of adverse events. Methods We selected the 8 predictor variables common to the individual-patient dataset of 5 prospective emergency department studies enrolling 3388 syncope patients. We calculated all possible combinations and the number of patients in each combination. We compared the predictive accuracy of attribute matching and logistic regression. We then classified ten random patients according to clinical judgment and attribute matching. Results Attribute matching provided 253 of the 384 possible combinations in the dataset. Twelve (4.7%), 35 (13.8%), 50 (19.8%) and 160 (63.2%) combinations had a match size 6550, 6530, 6520 and <10 patients, respectively. The AUC for the attribute matching and the multivariate model were 0.59 and 0.74, respectively. Conclusions Attribute matching is a promising tool for personalized and flexible risk prediction. Large databases will need to be used in future studies to test and apply the method in different conditions

Preliminary Research on a COVID-19 Test Strategy to Guide Quarantine Interval in University Students

Following COVID-19 exposure, the Centers for Disease Control (CDC) recommends a 10–14-day quarantine for asymptomatic individuals and more recently a 7-day quarantine with a negative PCR test. A university-based prospective cohort study to determine if early polymerase chain reaction (PCR) negativity predicts day 14 negativity was performed. A total of 741 asymptomatic students in quarantine was screened and 101 enrolled. Nasopharyngeal swabs were tested on days 3 or 4, 5, 7, 10, and 14, and the proportion of concordant negative results for each day versus day 14 with a two-sided 95% exact binomial confidence interval was determined. Rates of concordant negative test results were as follows: day 5 vs. day 14 = 45/50 (90%, 95% CI: 78–97%); day 7 vs. day 14 = 47/52 (90%, 95% CI: 79–97%); day 10 vs. day 14 = 48/53 (91%, 95% CI:79–97%), with no evidence of different negative rates between earlier days and day 14 by McNemar’s test, p \u3e 0.05. Overall, 14 of 90 (16%, 95% CI: 9–25%) tested positive while in quarantine, with seven initial positive tests on day 3 or 4, 5 on day 5, 2 on day 7, and none on day 10 or 14. Based on concordance rates between day 7 and 14, we anticipate that 90% (range: 79–97%) of individuals who are negative on day 7 will remain negative on day 14, providing the first direct evidence that exposed asymptomatic students ages 18–44 years in a university setting are at low risk if released from quarantine at 7 days if they have a negative PCR test prior to release. In addition, the 16% positive rate supports the ongoing need to quarantine close contacts of COVID-19 cases

Samarium-153-EDTMP (Quadramet®) With or Without Vaccine in Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase 2 Trial

PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline \u3e 30% compared with four patients (of 21) in the combination arm, including three with PSA decline \u3e 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM