Correlative Evaluation of Seven Cytological 3-Tier Grading Systems of Breast Carcinoma with the Standard Histological Grading: A 4 and ½ Year Study.

INTRODUCTION: The early diagnosis of breast carcinoma is of paramount importance in its management. Fine-needle aspiration cytology (FNAC) has the potential to play a pivotal role in providing the relevant information on the aggressiveness of this tumor. But there is no gold standard when it comes to cytological grading of breast carcinoma as there is no consensus between the pathologists and also the clinicians as to which grading is as par with the gold standard Elston-Ellis modification of Scarff-Bloom-Richardson (SBR) histological grading. This study was undertaken to study seven cytological 3-tier grading systems, namely, Robinson's, Fisher's, Mouriquand's, Dabbs', Khan's, Taniguchi's, and Howells's and to correlate them with the Elston-Ellis modification of SBR histological grading system so as to determine the finest cytological grading system which could be reliably used in our routine practice. MATERIAL AND METHODS: A total of 117 breast carcinoma cases diagnosed on FNAC were graded using seven 3-tier cytological grading systems and were correlated with Elston-Ellis modification of SBR histological grading system. Concordance, kappa measurement, and various correlation studies were done using SPSS software version 2021. RESULTS: Robinson's method showed a better concordance (84.61%), a better correlation (Spearman = 0.750, τ = 0.731, p < 0.001), and a substantial kappa value of agreement (κ = 0.701) with SBR grading system compared to other system closely followed by Fisher's system. CONCLUSIONS: Even though all the seven 3-tier cytological grading systems positively correlated with the SBR histologic grading of breast carcinoma, Robinson's method showed better concordance and correlation with a substantial kappa value of agreement in comparison to other 3-tier cytology grading systems. Hence, Robinson's grading which is simpler and also feasible should be incorporated in the routine cytology reporting of breast carcinoma.

Surveillance of Transfusion Related Adverse Reactions in a Tertiary Care Centre in Bangalore: A 4-Year Hemovigilance Initiative.

Even though blood transfusion is a life saving measure, it is nonetheless associated with a number of risks and hazards. The adverse reactions that can be potentially expected range anywhere in severity from mild to life threatening. The hemovigilance program deals with the systematic surveillance of these reactions as and when they occur in a hospital setting with an explicit aim of improving the quality and safety standards of the entire transfusion process. The current study was undertaken in the blood bank of a tertiary care centre in Bangalore to ascertain frequency of the blood transfusion related adverse reactions and to make a systematic profile assessment. Data was collected over a period of 4 years and 3 months. All adverse reactions caused by transfusion of blood and its products during the study period were included in the study. A total of 6910 units of blood and its components were issued to patients during the study period. Transfusion reactions accounted for 0.5% of transfusions. Febrile non-hemolytic transfusion reactions were the most common reactions (51.4%) followed by allergic reactions (40%), fluid overload (5.7%) and anaphylactic reactions (2.9%). Majority of these reactions were seen with PRBC transfusions (74.3%) followed by platelet transfusions (25.7%). The use of leukoreduced PRBCs will help in reducing the frequency of these reactions. The hemovigilance program of our institution helps in assessing the diversity of adverse reactions associated with transfusion of blood and its various components. It is also an efficient scheme for minimizing their occurrence by ensuring safety standards.

Validation of the Siggaard-Andersen Acid-Base Nomogram for Hemoglobin F: Implications for Fetal Cord Blood Gas Analysis.

OBJECTIVE: The calculation of HCO3 and base excess in current blood gas analysis is based on the Siggaard-Andersen equation. One of the constants in this equation is dependent on the known buffering capacity of hemoglobin A. We sought to investigate differences in buffering capacity between adult hemoglobin A and fetal hemoglobin F as a potential explanation for the observed poor correlation between calculated base excess in umbilical cord blood and newborn outcomes. Such differences would influence a key constant in the Van Slyke/Siggaard-Andersen equation used to calculate HCO3 and base excess and could be an explanation of these observations. STUDY DESIGN: This was a prospective observational study. We analyzed umbilical cord blood bicarbonate levels both as calculated values from a traditional blood gas analyzer and as measured values in 20 women giving birth at term. Since the calculated value is dependent upon the concentration and known buffering capacity of hemoglobin A, significant differences in these two analyses would imply differences in the buffering capacity of hemoglobins A and F. RESULTS: The mean calculated HCO3 value was 25 mEq/L (25.3 ± 1.9) compared with a mean measured value of 25 mEq/L (24.6 ± 1.7) over a range of pH levels of 7.16 to 7.42. This difference was not significant (p = 0.07). CONCLUSION: The buffering capacity of hemoglobin F, for clinical purposes, is not different than that of hemoglobin A and is not an explanation for the recognized poor correlation between base excess and neonatal outcome.

Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTENConclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639-47. ©2017 AACR.

Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

BACKGROUND: Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC. METHODS: We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab-PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC. RESULTS: Nab-PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab-PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab-PTX monotherapy was equivalent to nab-PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab-PTX could potentially stop the progression of late-stage pancreatic cancer. CONCLUSIONS: Our data confirmed that therapeutic efficacy of PTX and nab-PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a viable alternative to the current standard-of-care nab-PTX plus GEM regimen for the treatment of PDAC patients.

MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.

PURPOSE: Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus-associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown. EXPERIMENTAL DESIGN: Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplastic Barrett's esophagus, and esophageal adenocarcinoma using quantitative real-time PCR. miR-223 expression was validated in precursors and esophageal adenocarcinomas from 95 patients with esophageal adenocarcinoma by in situ hybridization (ISH). miR-223 was transfected into two esophageal adenocarcinoma cell lines, and in vitro assays were conducted. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens. RESULTS: miR-199 family members and miR-223 were significantly overexpressed in esophageal adenocarcinoma, however, only miR-223 showed a stepwise increase during esophageal adenocarcinoma carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment. miR-223-overexpressing cells had statistically significantly more migratory and invasive potential than scramble sequence-transfected cells. PARP1 was identified as a direct target gene of miR-223 in esophageal adenocarcinoma cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1. CONCLUSIONS: miR-223 is significantly upregulated during the Barrett's esophagus-dysplasia-esophageal adenocarcinoma sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that patients with esophageal adenocarcinoma with high miR-223 levels might benefit from treatment with DNA-damaging agents.

Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) remains a lethal human malignancy with historically limited success in treatment. The role of aberrant Notch signaling, which requires the constitutive activation of γ-secretase, in the initiation and progression of PDA is well defined and inhibitors of this pathway are currently in clinical trials. Here we investigated the in vivo therapeutic effect of PF-03084014, a selective γ-secretase inhibitor, alone and in combination with gemcitabine in pancreatic cancer xenografts. PF-03084014 treatment inhibited the cleavage of nuclear Notch 1 intracellular domain and Notch targets Hes-1 and Hey-1. Gemcitabine treatment showed good response but not capable of inducing tumor regressions and targeting the tumor-resident cancer stem cells (CD24(+)CD44(+) and ALDH(+) tumor cells). A combination of PF-03084014 and gemcitabine treatment resulted tumor regression in 3 of 4 subcutaneously implanted xenograft models. PF-03084014, and in combination with gemcitabine reduced putative cancer stem cells, indicating that PF-03084014 target the especially dangerous and resilient cancer stem cells within pancreatic tumors. Tumor re-growth curves plotted after drug treatments demonstrated that the effect of the combination therapy was sustainable than that of gemcitabine. Notably, in a highly aggressive orthotopic model, PF-03084014 and gemcitabine combination was effective in inducing apoptosis, inhibition of tumor cell proliferation and angiogenesis, resulting in the attenuation of primary tumor growth as well as controlling metastatic dissemination, compared to gemcitabine treatment. In summary, our preclinical data suggest that PF-03084014 has greater anti-tumor activity in combination with gemcitabine in PDA and provides rationale for further investigation of this combination in PDA.

Comparison of humoral immune responses to Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus using a viral proteome microarray.

BACKGROUND: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, and Kaposi's sarcoma-associated herpesvirus (KSHV) has a restricted seroprevalence. Both viruses are associated with malignancies that have an increased frequency in individuals who are coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS: To obtain an overview of humoral immune responses to these viruses, we generated a protein array that displayed 174 EBV and KSHV polypeptides purified from yeast. Antibody responses to EBV and KSHV were examined in plasma from healthy volunteers and patients with B cell lymphoma or with AIDS-related Kaposi's sarcoma or lymphoma. RESULTS: In addition to the commonly studied antigens, IgG responses were frequently detected to the tegument proteins KSHV ORF38 and EBV BBRF and BGLF2 and BNRF1 and to the EBV early lytic proteins BRRF1 and BORF2. The EBV vIL-10 protein was particularly well recognized by plasma IgA. The most intense IgG responses to EBV antigens occurred in HIV-1-positive patients. No clear correlation was observed between viral DNA load in plasma and antibody profile. CONCLUSIONS: The protein array provided a sensitive platform for global screening; identified new, frequently recognized viral antigens; and revealed a broader humoral response to EBV compared with KSHV in the same patients.

Exploring the technology readiness of nursing and medical students at a Canadian University.

Technology readiness is a well-established construct that refers to individuals' ability to embrace and adopt new technology. Given the increasing use of advanced technologies in the delivery of health care, this study uses the Technology Readiness Index (Parasuraman, 2000) to explore the technology readiness of nursing and medical students from the fall 2006 cohort at Memorial University of Newfoundland. The three major findings from this study are that (i) rural nursing students are more insecure with technology than their urban counterparts, (ii) male medical students score higher on innovation than their female counterparts and have a higher overall technology readiness attitude than female medical students, and (iii) medical students who are older than 25 have a negative technology readiness score whereas those under 25 had a positive score. These findings suggest health care professional schools would be well served to implement curricular changes designed to support the needs of rural students, women, and those entering school at a non-traditional age. In addition, patterns such as those observed in this study highlight areas of emphasis for current practitioners as health care organizations develop continuing education offerings for staff.