City tumour board Karachi: an innovative step in multidisciplinary consensus meeting and its two years audit.

Management of cancer patients is a team work which usually comprises of surgeons, oncologists, radiologists, pathologists, psychiatrist, nutritionist and a nurse. Any patient who is suffering from any tumour needs a multimodality meeting as cancer treatment is not a single persons job. Most of the time, it is difficult to get the whole team together for a plan discussion due to their busy schedule. This problem was overcome by starting a tumour board meeting early morning of Sunday in Karachi which was named City Tumour Board (CTB) Karachi . Its first meeting was held on Sunday March 28, 2010 and since then it takes place regularly fortnightly. Till March 2012, 44 sessions were conducted and total 264 cases were discussed. Here we present an audit of these two years. On average, in 60% of cases, tumour was up (36%) or down staged (12%) while in 52% of cases the stage remained unchanged. In 70% of cases (inclusive of above 60%), initial treatment plan was changed after discussion in the tumour board. This data signifies the importance of tumour board especially in a Pakistani setup where patient and even referring persons are not well aware of this disease and its outcome. It is advisable that every case should be discussed in tumour board before embarking on any treatment so that the best treatment plan can be given. It is also important that all relevant specialists should be present in the tumour board when planning for any treatment

PRIMARY MALIGNANT MELANOMA UTERINE CERVIX

A 40-year-old premenopausal female presented with foul-smelling per vaginal discharge for 3 months. Diagnostic work revealed a locally advanced primary malignant melanoma of uterine cervix. The patient declined pelvic surgery and was treated with Dacarbazine. Malignant melanoma is a rare tumour of skin and has been ranked in the top ve cancers of Australia and Sweden. It is a tumour of melanocytes which forms melanin pigment in the skin. In men, the most common site is trunk while in females common site is limbs. However, melanoma can arise from mucosal surfaces where the melanocytes are present. Most common mucosal sites are head and neck followed by female genital tract. Key words: Cervix, dacarbazine, malignant melanoma

Solar Pond Technology for Brine Management and Heat Extraction: A Critical Review

Heat is one of the basic constituents of energy which can be stored as well as extracted from solar ponds. Different types of solar ponds are available but main focus in this paper is on salinity gradient solar pond which is one of the emerging technologies. It can recover energy from brine water sources present in Pakistan with minimum land utilization and capturing maximum solar radiations. Numerous renewable technological sources are currently under use all across the world. However, inadequate research has been done upon salinity gradient solar ponds, which are cheaper and easy to operate and maintain. The salinity gradient solar ponds constitutes of three layers or zones: the lower convective zone with maximum brine concentration, non- convective zone with highest salinity gradient and the upper convective zone which has minimum concentration of brine. The brine water can be sourced from post reverse osmosis or through any other saline water source. Solar pond technologies may have numerous feasible applications including brine management, electricity production and providing heat for different industrial processes. The paper reviews different ways to optimize the efficiency of solar ponds while making it cost effective at the same time. Most of the research on salinity gradient solar ponds has experimented on external heat exchangers in which the heat is usually extracted from lower convective zone. Heat extracted is studied on independent variables such as brine load, height of solar pond, conductivity of heat exchanger, temperature and pH of the water.  The heat extracted was further considered for steam generation. The steam could be utilized as a driving force for electricity generation and workability of industrial power plants. The economic feasibility based on the current conditions of Pakistan is also discussed

Factors influencing in-hospital length of stay and mortality in cancer patients suffering from febrile neutropenia

Introduction: Febrile neutropenia (FN) is a major complication of chemotherapy, costly in terms of morbidity, mortality and associated financial expenditure. The present study was conducted with the goal of highlighting FN as a serious problem in Pakistan, with the longer term objective of improved cancer survival, reduction in length of stay (LOS) in hospital, morbidity, mortality and costs in our existing developing country scenario. Methods: A cross-sectional descriptive study was conducted on Patients, \u3e or =18 years, admitted with FN as a consequence of chemotherapy at a referral hospital in Karachi from 1st September 2006 to 30th April 2007. Results: A total of 80 Patients [43 (53.8%) males and 37 (46.2%) females] were selected. The mean age was 47.4 (SD +/-16.6, range 18-79) years. Sixty eight Patients (86%) were \u3c or = 65 years, 50% were \u3c or = 50 years. Overall, inhospital mortality was 11%, 4% for Patients on granulocyte colony stimulating factor (G-CSF) prophylaxis as against 20% for those without. The cause of death was either pneumonia or septic shock. Mean LOS was 7.53 (SD +/-3.8, range 2-17) days. Hematological malignancies, older age, severity of dehydration, pneumonia and culture positivity were significantly associated with LOS and death. Those above 50 years of age were 1.5 times as likely to be hospitalized longer and \u3e three times as likely to die. Bacteremia conferred a 5-fold and pneumonia an 8-fold increase in the risk of death. Conclusion: The results of this study indicate that age, vital instability, dehydration, high creatinine, culture positivity and hematological malignancies are high risk factors in chemotherapy induced FN. Identification of FN risk factors with poor outcomes may help in devising protocols for modified dosage or including GCFs initially. This may help reduce the cost of cancer care as well as mortality and morbidity. Prospective studies of FN in multiple centers in Pakistan may be beneficial in evaluating these risk factors further

Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy

Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers. We then discuss the importance of neoantigens for cancer immunotherapy using checkpoint blockers, vaccination, and adoptive T-cell transfer. Finally, we give an overview over emerging aspects in cancer immunity, including tumor heterogeneity and immunoediting, and give an outlook on future prospects

Intratumor genetic heterogeneity in squamous cell carcinoma of the oral cavity

BackgroundWe sought to evaluate intratumor heterogeneity in squamous cell carcinoma of the oral cavity (OCC) and specifically determine the effect of physical separation and histologic differentiation within the same tumor.MethodsWe performed whole exome sequencing on five biopsy sites—two from well‐differentiated, two from poorly differentiated regions, and one from normal parenchyma—from five primary OCC specimens.ResultsWe found high levels of intratumor heterogeneity and, in four primary tumors, identified only 0 to 2 identical mutations in all subsites. We found that the heterogeneity inversely correlated with physical separation and that pairs of well‐differentiated samples were more similar to each other than analogous poorly differentiated specimens. Only TP53 mutations, but not other purported “driver mutations” in head and neck squamous cell carcinoma, were found in multiple biopsy sites.ConclusionThese data highlight the challenges to characterization of the mutational landscape of OCC with single site biopsy and have implications for personalized medicine.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150549/1/hed25719.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150549/2/hed25719_am.pd

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+) tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements