Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial

<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

A Comparative Study between SVM and Fuzzy Inference System for the Automatic Prediction of Sleep Stages and the Assessment of Sleep Quality

This paper compares two supervised learning algorithms for predicting the sleep stages based on the human brain activity. The first step of the presented work regards feature extraction from real human electroencephalography (EEG) data together with its corresponding sleep stages that are utilized for training a support vector machine (SVM), and a fuzzy inference system (FIS) algorithm. Then, the trained algorithms are used to predict the sleep stages of real human patients. Extended comparison results are demonstrated which indicate that both classifiers could be utilized as a basis for an unobtrusive sleep quality assessment

Turning calcined waste egg shells and wastewater to Brushite: Phosphorus adsorption from aqua media and anaerobic sludge leach water

Calcined egg shells are exploited for Phosphorus adsorption purposes and the resulting product is investigated for the purposes of transforming this waste material into a higher value product. The effect of particle size, calcination temperature (600 °C for 4 h, 800 °C for 2 h, and 900 °C for 30 min), and presence of ions (NO3−, NH4+, and CH3COOH) are investigated. Both, stock solutions prepared by dissolving anhydrous potassium dihydrogen phosphate (KH2PO4) with laboratory-grade water and wastewater from anaerobic digester effluent were used as Phosphorus containing aqua media. Calcined egg shells appear as an efficient material for phosphorous removal and their adsorption capacity increases as the calcination temperature increases and as the particle size reduces. This is attributed primarily to the increased specific surface area with calcination temperature as quantified through gas sorption and scan electron microscopy images. Egg shells calcinated at 900 °C for 30 min with particle sizes less than 1 mm exhibited the best performance among all material tested within this study. The presence of NO3− and NH4+ contributed positively to Phosphorus removal whereas the presence of CH3COOH supressed the Phosphorus removal process especially during the first 1 h; this effect is however reduced after 24 h. The experimental kinetic data were better represented with the non-linear form of the Langmuir isotherm and followed a pseudo-second-order model. Calcined egg shells that reacted with phosphorous in stock solutions or reject anaerobic sludge leached with H2SO4 transformed part into Brushite (CaHPO4·2H2O) as evidenced by X-ray diffractometry. The synthesis of Brushite under these conditions could be of great interest due to its high solubility (logKso = 6.59) and high Ca/P ratio that render it a potential fertilizer. This is the first study that notes the ecological production of Brushite using waste egg shells and anaerobic sludge as source materials

Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts

Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment

Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers on Acute Kidney Injury in Emergency Medical Admissions

Background: Acute kidney injury (AKI) has been observed in up to 20% of adult hospital admissions. Sepsis, diarrhea and heart failure, all causing reduced effective volume, are considered risk factors for AKI, especially among patients treated with medications that block the Renin-Angiotensin System (RAS), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). We aimed to determine the incidence of acute kidney injury (AKI) in emergency medical admissions in relation to the use and dosage of ACEi/ARB. Methods: A single-center observational study conducted in 577 consecutive medical admissions via the Emergency Room (ER) at a University General Hospital in Athens, Greece, between June and July 2018. Patients with incomplete medical records, discharged within 24 h, maintained on chronic renal replacement therapy, admitted to the Cardiology Department or the ICU were excluded. Thus, a total of 309 patients were finally included in this analysis. Results: We compared 86 (28%) patients who presented in the ER with AKI (AKIGroup) with 223 (72%) patients without AKI (non-AKI Group) at the time of admission. Patients in the AKI Group were more frequently male (58% vs. 46%, p = 0.06), with a higher frequency of diarrhea (16% vs. 6%, p = 0.006), edema (15% vs. 6%, p = 0.014) and lower systolic blood pressure (120 (107–135) vs. 126 (113–140), p = 0.007) at presentation, despite higher prevalence of hypertension (64% vs. 47%, p = 0.006). Overall, ACEi/ARB were more likely to have been prescribed in the AKI Group than in the non-AKI Group (49% vs. 28%, p = 0.001). Interestingly, AKI was more frequently observed in patients treated with the target or above target dosage of ACEi/ARB, but not in those receiving lower than the recommended dosage. Conclusion: The risk of AKI in emergency medical admissions is higher among users of ACEIs/ARB at target or above target dosages. Physicians should adjust RAS blockade according to estimated Glomerular Filtration Rate (eGFR) and advise their patients to withhold ACEi/ARB in cases of acute illness

Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers on Acute Kidney Injury in Emergency Medical Admissions

Background: Acute kidney injury (AKI) has been observed in up to 20% of adult hospital admissions. Sepsis, diarrhea and heart failure, all causing reduced effective volume, are considered risk factors for AKI, especially among patients treated with medications that block the Renin-Angiotensin System (RAS), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). We aimed to determine the incidence of acute kidney injury (AKI) in emergency medical admissions in relation to the use and dosage of ACEi/ARB. Methods: A single-center observational study conducted in 577 consecutive medical admissions via the Emergency Room (ER) at a University General Hospital in Athens, Greece, between June and July 2018. Patients with incomplete medical records, discharged within 24 h, maintained on chronic renal replacement therapy, admitted to the Cardiology Department or the ICU were excluded. Thus, a total of 309 patients were finally included in this analysis. Results: We compared 86 (28%) patients who presented in the ER with AKI (AKIGroup) with 223 (72%) patients without AKI (non-AKI Group) at the time of admission. Patients in the AKI Group were more frequently male (58% vs. 46%, p = 0.06), with a higher frequency of diarrhea (16% vs. 6%, p = 0.006), edema (15% vs. 6%, p = 0.014) and lower systolic blood pressure (120 (107&ndash;135) vs. 126 (113&ndash;140), p = 0.007) at presentation, despite higher prevalence of hypertension (64% vs. 47%, p = 0.006). Overall, ACEi/ARB were more likely to have been prescribed in the AKI Group than in the non-AKI Group (49% vs. 28%, p = 0.001). Interestingly, AKI was more frequently observed in patients treated with the target or above target dosage of ACEi/ARB, but not in those receiving lower than the recommended dosage. Conclusion: The risk of AKI in emergency medical admissions is higher among users of ACEIs/ARB at target or above target dosages. Physicians should adjust RAS blockade according to estimated Glomerular Filtration Rate (eGFR) and advise their patients to withhold ACEi/ARB in cases of acute illness

Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma

Purpose A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively. Patients and Methods We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m(2) IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B). Results Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. Conclusion There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment