Racial and regional disparities in deaths in breast cancer.

Breast cancer is the second most diagnosed malignancy in American women with a lifetime occurrence of 1 in 8 women in the United States. There has been a dearth of research focusing on regional differences in breast cancer mortality with respect to race in the US. It is crucial to identify regions that are lagging to uplift the outreach of breast cancer care to certain races. Data for this study were obtained from the 2016-2018 Nationwide Inpatient Sample. In-hospital mortality, race and hospital regions for the patients with the primary diagnosis of Malignant Neoplasms of Breast were studied. Baseline characteristics of participants were summarized using descriptive statistics. The patient population was stratified as per race, hospital region, gender, therapy received and family history. Logistic regression was performed to derive the odds ratio while adjusting for different variables. 99, 543 patients with metastatic breast cancer were identified. African Americans (AAs) were found to have the highest reported deaths at 5.54%, followed by Asians and Pacific Islanders at 4.80% and Caucasians 4.09% (p < 0.0001). The odds of dying were significantly higher in the AA population when compared to Caucasian population (OR 1.391 (1.286-1.504)), and the odds were consistently higher across all regions of the US. In terms of regional disparities with respect to race, AA's had highest mortality in the south whereas all other races had the highest mortality in the west. It was seen that races identifying as "others" had significantly higher odds of dying in the Northeast. It is crucial to identify racial differences in the various regions across the US in order to implement appropriate outreach strategies to tackle these disparities.

Wandering Cancer Cells: Metastatic Renal Cell Carcinoma Without Evidence of a Primary Tumor.

Renal cell carcinoma (RCC) usually presents clinically in the advanced stage including bone metastasis. However metastatic RCC without evidence of a primary tumor in the kidney is extremely rare. We herein report a case of a 70-year-old male initially evaluated for bone lesion and diagnosed with biopsy-proven metastatic clear cell RCC without a renal primary. Given the rare nature of the disease, there is no standardized course of treatment that has yet been established. We believe that our case will add to the body of knowledge about uncommon oncologic instances and consolidate the information that has already been published.

Hydroxychloroquine pre-exposure prophylaxis for COVID-19 among healthcare workers: Initial experience from India.

Background: Hydroxychloroquine (HCQ) had generated considerable interest for coronavirus disease 2019 (COVID-19) prophylaxis. We conducted a prospective observational study at a tertiary care hospital in India, with dedicated COVID-19 care facilities. Objectives: Primary objective was incidence of adverse effects, secondary objective being efficacy in preventing COVID-19. Methods: Healthcare workers were recruited and grouped based on voluntary HCQ prophylaxis as per national guidelines. Side effects in HCQ group were graded in accordance with national cancer institute-common terminology criteria for adverse events (NCI-CTCAE) version 5.0. At 3-7-week follow-up, groups were compared for COVID-19 exposure, symptoms development and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR results. Results: Among 358 participants recruited, 216 (60.3%) were males and mean age was 31.2 ± 6.6 years. Chemoprophylaxis was initiated by 258 (72%) participants. After loading dose, 7 (2.7%) reported grade 2 and 1 (0.4%) grade 3 adverse effects. Discontinuation of HCQ due to side effects was reported in 11 (4.3%) participants. Electrocardiogram was done by 50 (19.4%) participants on HCQ; no abnormalities were noted. A total of 106 (41%) among those taking and 63 (63%) among those not taking HCQ were tested for SARS-CoV-2 due to influenza-like illness or significant exposure. Among all participants, 25 (6.9%, 95% confidence interval [CI] 4.3-9.6) developed COVID-19 during the study period. In the group taking HCQ, 10 (3.9%) tested positive compared to 15 (15%) in the group not taking HCQ (P < 0.001). Odds ratio with HCQ intake was 0.34 (95% CI 0.13-0.83, P = 0.01) and the number needed to treat was 12. Conclusion: HCQ is safe at the recommended dose for pre-exposure prophylaxis of COVID-19.

Evaluating the Correlation of Bariatric Surgery and the Prevalence of Cancers in Obese Patients: A Study of the National Inpatient Sample (NIS) Database.

Purpose Obesity is a global pandemic that exerts a significant burden on healthcare worldwide. Multiple cancers, as well as deaths from the same, are more prevalent in obese patients. Bariatric surgery has been shown to be the most effective way of treating obesity once other measures have been exhausted. There is no concordant data available to support that bariatric surgery can reduce the prevalence of cancer. Using one of the largest data samples, we evaluate the correlation of bariatric surgery in morbidly obese patients with the prevalence of obesity-related cancers (breast, endometrial, esophageal, colorectal, prostate, and renal) in morbidly obese patients. Patients and methods A sample of 7,672,508 morbidly obese patients was identified from the 1994 to 2004 records of the National Inpatient Sample (NIS) database, divided into those who did and did not undergo bariatric surgery, and studied for the prevalence of obesity-associated cancers. Results Obesity was predominantly seen in the Caucasian population (68.22%). The mean age of cases who underwent bariatric surgery was younger when compared to those who did not undergo the procedure (43.89±25.16 vs. 54.90±36.40, p-value <0.0001). The highest bariatric surgery rate was seen in the Northeast (5.57%), followed by the West (4.15%), South (3.02%), and Midwest (2.96%) (p-value <0.0001). Overall, the odds of morbidly obese patients who underwent bariatric surgery and developed cancer are: esophageal cancer 0.19 (0.1218-0.3078, p <0.0001), colorectal cancer 0.0368 (0.0275- 0.0493, p <0.0001), endometrial cancer 0.0155 (0.0099-0.0244, p <0.0001), breast cancer 0.0712 (0.0582-0.0871, p <0.0001), prostate cancer 0.0285 (0.0199-0.0408, p <0.0001) and renal cancer 0.0182 (0.0106-0.0314, p <0.0001). The odds of cancer post-bariatric surgery remained significantly lower even after matching certain confounding factors. Conclusions The odds of developing breast, esophageal, prostate, renal, and colorectal cancers are significantly lower in morbidly obese patients who undergo bariatric surgery.

HIV-Associated Anal Cancer.

Anal cancer, despite being a rare malignancy, is increasing in incidence, accounting for 0.5% of all new cancer cases in the United States, with rate of new cases being 1.9 per 100,000 men and women. It is common in immunocompromised individuals, especially those with malignancy, human immunodeficiency virus (HIV) and human papillomavirus (HPV) infection. Despite similar treatment of anal cancer in both HIV-positive and negative patients, guidelines for prevention and treatment of therapy-related side effects are rarely studied. While these patients have a better prognosis on HAART, limited guidelines exist regarding appropriate therapy. There is a common link between HPV and HIV and the transmission of one is associated with increased risk of transmission of the other. HPV vaccine which is known to prevent high-grade cervical intraepithelial neoplasia is thought to also decrease the incidence of anal intraepithelial neoplasia. The association of HPV vaccine in the prevention of anal cancer in high-risk groups with HIV is a scarcely studied subject that requires further research.

PSMA: a game changer in the diagnosis and treatment of advanced prostate cancer.

Although management of advanced prostate cancer is evolving, a lot of work remains to be done for patients who have exhausted all options. Molecular targeting of prostate specific membrane antigen (PSMA) is valuable not only for diagnostic but also for therapeutic reasons. PSMA is thus considered to be useful in a theranostic approach. PSMA scans are upcoming diagnostic modalities which detect metastatic lesions that are missed by conventional imaging modalities. PSMA ligand therapy is also an upcoming treatment modality that has been proven to be beneficial with minimal toxicity in patients with advanced prostate cancer that have progressed on prior therapy. In this review article, we summarize the current knowledge regarding PSMA diagnostics and PSMA ligand therapies and discuss their implication in the treatment of advanced prostate cancer.

High prevalence of plasma EBV DNA among the HIV positive individuals, with or without malignancies, attending the clinic at AIIMS, New Delhi.

Epstein-Barr Virus (EBV) is associated with the Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL respectively). HIV is a risk factor for EBV infections and previously published data indicate that HIV infected individuals have higher chances of getting EBV infections compared to HIV uninfected individuals. Very limited information is available from India about the the prevalence of EBV in HIV positivity, with or without malignancy. In a recent study (Sinha et al. Current HIV Res 16:1-6, 2018) from All India Institute of Medical Sciences (AIIMS), New Delhi, we have shown that 2% among the HIV-1 infected individuals have malignancies including HL and NHL. To determine the prevalence of EBV among these individuals, clinical specimen obtained from ART clinic of AIIMS were tested for the presence of EBV DNA in plasma samples by quantitative real-time PCR. We have observed high prevalence of EBV (30%) among the 92 specimen tested. Prevalence is higher in patients with malignancy (37%) compared to those without maliganancy (27%). No correlation was observed with the CD4 counts or HIV viral load with EBV positivity.

PARP inhibitors: shifting the paradigm in the treatment of pancreatic cancer.

Pancreatic cancer, being one of the most fatal cancers, is the 7th leading cause of death globally. Cancer that is resistant to current treatment proves that there is a need for personalized and targeted therapy, based on the tumor and genomic markers. Pembrolizumab and Larotrectinib are examples of current medications used as targeted therapy in pancreatic cancer. Pancreatic cancer has many different molecular subgroups, providing the opportunity for the development of new drugs that can target these groups. Poly (ADP-Ribose) polymerase inhibitors (PARPi) are a group of drugs inhibiting PARP to decrease the stability of the cancer cells. Currently, PARPi are mostly used in ovarian and breast cancer. There are multiple studies that have shown positive effects of PARPi in decreasing the tumor burden in advanced pancreatic cancer. PARPi are the future of pancreatic cancer management, and hence it is important to understand their mechanism, resistance pathways, and their application in the real world.

Role of Voriconazole in the Management of Invasive Central Nervous System Aspergillosis: A Case Series from a Tertiary Care Centre in India.

Invasive central nervous system (CNS) aspergillosis is acquired by either hematogenous dissemination or direct spread from a sinus infection. We describe a series of nine patients with CNS aspergillosis from a tertiary care teaching institute in North India who were treated with voriconazole alone or in combination with surgery. All patients who had clinical and radiological features consistent with fungal CNS infection, showed the presence of septate hyphae on histopathology/microscopy and were either culture positive for Aspergillus spp. or had serum galactomannan positivity were diagnosed as CNS aspergillosis. Clinical features, risk factors, diagnostic modalities, treatment details and outcome at last follow-up were recorded for all patients diagnosed with CNS aspergillosis. A total of nine patients were diagnosed with CNS aspergillosis. The median duration of presentation at our hospital was six months (IQR-2-9 months). Six patients had concomitant sinus involvement, while two patients had skull-base involvement as well. All patients were treated with voriconazole therapy, and three of these patients underwent surgery. All but one patient survived at the last follow-up (median duration was 14 months (IQR- 8-21.5). Two patients had complete resolution, and voriconazole was stopped at the last follow-up, and the rest of the patients were continued on voriconazole. Of the six patients who were continued on voriconazole, all but one had more than 50% radiological resolution on follow-up imaging. Invasive CNS aspergillosis is an important cause of CNS fungal infection that is often diagnosed late and requires long-term voriconazole-based therapy.

Levosulpiride-induced neuroleptic malignant syndrome in rheumatoid arthritis.

A 53-year-old woman, known case of diabetes mellitus and rheumatoid arthritis, presented with a 4-day history of hyperthermia, rigidity, tremor and altered sensorium. She developed these symptoms after having been administered parenteral levosulpiride to control vomiting due to secondary adrenal insufficiency. We managed her as a case of life-threatening neuroleptic malignant syndrome (NMS) requiring mechanical ventilation, bromocriptine and other supportive care. She subsequently recovered and was discharged in a stable condition. To the best of our knowledge, this is the first documented case report describing levosulpiride-induced NMS.

Aging influences multiple indices of oxidative stress in the heart of the Fischer 344/NNia x Brown Norway/BiNia rat.

We report the influence of aging on multiple markers of oxidative-nitrosative stress in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd x Brown Norway/BiNia (F344/NXBN) rats. Compared to adult (6-month) hearts, indices of oxidative (superoxide anion [O2*-], 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were 34.1 +/- 28.1%, 186 +/- 28.1% and 94 +/- 5.8% higher, respectively, in 36-month hearts and these findings were highly correlated with increases in left ventricular wall thickness (r > 0.669; r > 0.710 and P < 0.01, respectively). Regression analysis showed that increases in cardiac oxidative-nitrosative stress with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in transcriptional (NF-kappaB) activities, signaling (mitogen-activated protein kinases along with Src), apoptotic (Bcl-2, Traf-2), and cellular stress (HSPs). These results suggest that the aging F344/NXBN heart may be highly suited for unraveling the molecular events that lead to age-associated alterations in cardiac oxidative stress.

Uniaxial stretch-induced regulation of mitogen-activated protein kinase, Akt and p70 S6 kinase in the ageing Fischer 344 x Brown Norway rat aorta.

The effects of ageing on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signalling molecules that may be of particular importance in mediating numerous cellular responses, including control of cell growth, differentiation and adaptation, are the proteins associated with the mitogen-activated protein kinase (MAPK) signalling systems. The MAPKs, in conjunction with the p70 S6k signalling cascade, have emerged as critical components for regulating numerous mechanotransduction-related cellular responses. Here we investigate the ability of uniaxial stretch to activate the MAPK and p70 S6k pathways in adult (6-month-old), aged (30-month-old) and very aged (36-month-old) Fischer 344/NNiaHSd x Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signal-regulated kinase (Erk) 1/2, p38- and c-Jun NH(2)-terminal kinase (Jnk)-MAPKs showed differential expression and activation between these proteins with age. An acute 15 min interval of 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of Erk1/2, p38- and Jnk-MAPK. However, ageing altered uniaxial induced p70 S6k pathway signalling. These observations confirm previous data demonstrating that MAPK proteins are mechanically regulated and also suggest that p70 S6k signalling expression and activation are controlled differently with ageing. Taken together, these data may help to explain, in part, the age-related changes in vascular morphology, function and response to injury.

Acetaminophen protects against iron-induced cardiac damage in gerbils.

There are few effective agents that safely remove excess iron from iron-overloaded individuals. Our goal was to evaluate the iron-removing effectiveness of acetaminophen given ip or orally in the gerbil iron-overload model. Male gerbils were divided into 5 groups: saline controls, iron-overloaded controls, iron-overloaded treated with ip acetaminophen, iron-overloaded treated with oral acetaminophen, and iron-overloaded treated with ipdeferoxamine. Iron dextran was injected iptwice/wk for 8 wk. Acetaminophen and deferoxamine treatments were given on Mondays, Wednesdays, and Fridays during the same 8 wk and continued for 4 wk after completion of iron-overloading. Echocardiograms were performed after completion of the iron-overloading and drug treatments. Liver and cardiac iron contents were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Iron-overloaded controls had 232-fold and 16-fold increases in liver and cardiac iron content, respectively, compared to saline controls. In iron-overloaded controls, echocardiography showed cardiac hypertrophy, right and left ventricular distension, significant reduction in left ventricular ejection fraction (-22%), and fractional shortening (-31%) during systole. Treatments with acetaminophen (ip or oral) or deferoxamine (ip) were equally effective in reducing cardiac iron content and in preventing cardiac structural and functional changes. Both agents also significantly reduced excess hepatic iron content, although acetaminophen was less effective than deferoxamine. The results suggest that acetaminophen may be useful for treatment of iron-induced pathology.

Diabetes alters vascular mechanotransduction: pressure-induced regulation of mitogen activated protein kinases in the rat inferior vena cava.

BACKGROUND: Diabetes mellitus is an important risk factor for increased vein graft failure after bypass surgery. However, the cellular and molecular mechanism(s) underlying vessel attrition in this population remain largely unexplored. Recent reports have suggested that the pathological remodeling of vein grafts may be mediated by mechanically-induced activation of the mitogen activated protein kinase (MAPK) signaling pathways and the MAPK-related induction of caspase-3 activity. On the basis of these findings, we hypothesized that diabetes may be associated with alterations in how veins "sense" and "respond" to altered mechanical loading. METHODS: Inferior venae cavae (IVC) from the non-diabetic lean (LNZ) and the diabetic obese (OSXZ) Zucker rats were isolated and incubated ex vivo under basal or pressurized conditions (120 mmHg). Protein expression, basal activation and the ability of increased pressure to activate MAPK pathways and apoptosis-related signaling was evaluated by immunoblot analysis. RESULTS: Immunoblot analyses revealed differential expression and activation of extracellular signal-regulated kinase (ERK1/2), p38 and c-Jun NH2-terminal kinase (JNK) MAPKs in the IVCs of diabetic rats as compared to non-diabetic rats. In particular, the expression and basal phosphorylation of p38beta- (52.3 +/- 11.8%; 45.8 +/- 18.2%), JNK 1- (21.5 +/- 9.3%; 19.4 +/- 11.6%) and JNK3-MAPK (16.8 +/- 3.3%; 29.5 +/- 17.6%) were significantly higher (P < 0.05) in the diabetic vena cava. An acute increase in IVC intraluminal pressure failed to increase the phosphorylation of ERK1-, JNK-2, or any of the p38-MAPKs in the diabetic obese Zucker rats. Also, IVC loading in the LNZ led to a 276.0 +/- 36.0% and 85.8 +/- 25.1% (P < 0.05) increase in the cleavage of caspase-3 and caspase-9, respectively, with no effect on these molecules in the OSXZ. No differences were found in the regulation of Bax and Bcl-2 between groups. However, basal expression levels of Akt, phospho-Akt, PTEN, phospho-PTEN and phospho-Bad were higher in the diabetic venae cavae (P < 0.05). CONCLUSION: These data suggest that diabetes is associated with significant alteration in the ability of the vena cava to activate MAPK- and apoptosis-related signaling. Whether these changes are associated with the increased vein graft attrition seen in the diabetic population will require further investigation.

Hypoxia augments TNF-alpha-mediated endothelin-1 release and cell proliferation in human optic nerve head astrocytes.

The effect of hypoxia (24 h) on TNF-alpha-mediated release of endothelin-1 (ET-1) from human optic nerve head astrocytes (hONAs) and TNF-alpha- and ET-1-induced hONA proliferation was determined. ET-1 synthesis and release was quantitated using ELISA while TNF-alpha (10 nM)- and ET-1 (100 nM)-mediated hONA proliferation was assessed by CellTiter 96 aqueous one-solution cell proliferation assay, respectively. hONAs appeared to be more rounded with fewer processes following 24 h hypoxia compared to thodr seen in normoxia. Hypoxia enhanced TNF-alpha-mediated ET-1 synthesis and release (by 5-fold) and also significantly increased TNF-alpha- and ET-1-mediated hONA proliferation. PD142893 (1 microM), an ET(A/B) receptor antagonist, blocked ET-1-mediated hONA proliferation both under normoxia and hypoxia, while doing so only under normoxia following TNF-alpha treatment. Also, U0126 (10 microM; an upstream ERK1/2 inhibitor) completely blocked agonist-induced hONA proliferation in normoxia and partially blocked the same in hypoxia. These results demonstrate for the first time that hONAs secrete ET-1 and that TNF-alpha and hypoxia can regulate its levels. Moreover, hypoxia augments the proliferative responses of hONAs to TNF-alpha and ET-1. These agonist-mediated effects following hypoxia could contribute to astroglial activation as seen in glaucomatous optic nerve heads.