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Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy. Precision medicine needs prognostic markers to select the patients that will benefit more from targeted therapy. Authors show here that high level of baseline T cell receptor diversity is an indicator of favourable prognosis in multiple cancer types, and monoclonal expansion of T-cells correlates with good response to immune checkpoint blockade therapy in metastatic melanoma patients.

Sequencing of circulating tumor DNA from cancer patients is a cost-efficient approach with turnaround time compatible with clinical practice to inform treatment decision-making in a phase 1 trial settingNext-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.

Oncolytic viruses exploit the cancer cell phenotype to complete their lytic life cycle, releasing progeny virus to infect nearby cells and repeat the process. We modified the oncolytic group B adenovirus EnAdenotucirev (EnAd) to express a bispecific single‐chain antibody, secreted from infected tumour cells into the microenvironment. This bispecific T‐cell engager (BiTE) binds to EpCAM on target cells and cross‐links them to CD3 on T cells, leading to clustering and activation of both CD4 and CD8 T cells. BiTE transcription can be controlled by the virus major late promoter, limiting expression to cancer cells that are permissive for virus replication. This approach can potentiate the cytotoxicity of EnAd, and we demonstrate using primary pleural effusions and peritoneal malignant ascites that infection of cancer cells with the BiTE‐expressing EnAd leads to activation of endogenous T cells to kill endogenous tumour cells despite the immunosuppressive environment. In this way, we have armed EnAd to combine both direct oncolysis and T cell‐mediated killing, yielding a potent therapeutic that should be readily transferred into the clinic. Synopsis Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM + cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates. Viruses can be “armed” without losing oncolytic potency to express and secrete BiTEs only in cells supporting virus replication. BiTE‐expressing virus can mediate targeted killing of tumour cells in clinical cancer biopsies by exogenous PBMC or endogenous T cells. BiTE‐mediated cytotoxicity in primary malignant exudates is independent of tumour‐associated immune suppression. Graphical Abstract Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM + cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates.

Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing. We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of \"real world\" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds. This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers.

Intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Our previous study showed that the binding of adult hemoglobin (HbA) to glycoprotein (GP) 1bα induced the activation of platelets. The elevated plasma Hb or platelet surface bound Hb positively correlated with platelet activation in patients with paroxysmal nocturnal hemoglobinuria (PNH). Furthermore, this study shows that the sickle Hb [HbS, occurs due to single nucleotide polymorphism at A>T of β-globin gene of Hb and causes sickle cell disease (SCD)] also bound to GP1bα and activated platelets in a concentration-dependent manner. The HbS bound to glycocalicin (extramembranous part of GP1bα) with KD ~ 10.46 ± 3 μM. HbS induced phosphorylation of signaling adapter proteins, such as Lyn, PI3K, Akt and ERK in platelets, and also increased the surface expression of platelet activation markers such as P-selectin (10.7 fold) and PAC1 binding (10.4 fold) in platelet surface in a concentration-dependent manner. HbS also increased the platelet microparticle-generation (4.7 fold) and thrombus-formation (4.3 fold) in a concentration-dependent manner. An elevated level of extracellular Hb in plasma correlated directly with platelet activation markers such as P-selectin (r = 0.7947), PAC1 binding (r = 0.5914) on platelet surface and plasma levels of platelet-derived microparticles (r = 0.7834) in patients with SCD. Our study therefore suggests that the HbS-induced platelet activation may play a crucial role in intravascular clot formation observed in SCD patients characterized by high propensity to vascular occlusion and hypercoagulable states.

With the clinical impression of benign prostatic hyperplasia patient underwent transurethral resection of prostate. Sections from prostatic tissue fragments were stained with Haematoxylin and Eosin stain, 50% of which showed tumour infiltration [Figure 1]a. More than 80% of tumour cells exhibited signet ring cell morphology that were arranged in sheets and diffusely infiltrating the prostatic stroma [Figure 1]b. Gleason's score of 10 (5+5) was assigned to the tumour. Histological identification of signet ring cells in prostatic malignancies warrants a pathologist to rule out metastasis from gastrointestinal tract or urogenital system in prostate which is more common than primary signet ring-like cell variant of prostatic adenocarcinoma.

Objective: This study was conducted to evaluate diffusion capacity of lung for carbon monoxide (DLCO) in patients with simple and complicated silicosis and to correlate abnormal findings detected, if any, with the computed tomography abnormalities in these patients. Methods: This study included 56 patients with simple and complicated silicosis and without tuberculosis, in whom we performed DLCO as per standard technique. Various computed tomography findings, that is, presence, size and distribution of nodules associated with relative parenchymal and vascular markings, were recorded in the study subjects and classified into standard grading to be finally compared with DLCO. Visual grading score system was used to describe the extent of emphysematous changes based on the area of abnormally low attenuation, vascular disruption, bullae and so on and data were recorded. Results: Results showed that 85.7% patients had small opacities of varying grades and 28.5% showed large opacities, with 16% of them having type 'C' large opacities. The mean DLCO (% predicted) of patients with category '0' high-resolution computed tomography (HRCT) abnormality was 92.3 ± 6.8 (within normal limits), and this gradually decreased with increasing HRCT category to 44.2 ± 11.2 in grade '4' of progressive massive fibrosis (PMF) patients in this study (P < 0.01). This reflects a significant inverse correlation between visual HRCT category and the DLCO % predicted (r > −0.89, P < 0.001). The mean DLCO (% predicted) was 51 ± 12.6 in patients with grade '1' emphysema in HRCT, 53 ± 13.5 in grade '2', 43 ± 6.4 in grade '3' and 37.7 ± 6.3 in grade '4'; however, there was no correlation between emphysema grading and pulmonary functional index (r = −0.33, P = 0.15). Conclusion: This study observed significant abnormality in DLCO among silicosis patients and its strong correlation with the extent of radiological abnormality. HRCT finding of large opacities could be an important indicator of the severity of silicosis, as reflected by significantly reduced DLCO in such patients.

Balantidiasis is a rare zoonotic disease in humans. Balantidium coli is the causative ciliated protozoan. We present a case of urinary balantidiasis in a patient having chronic obstructive pulmonary disease (COPD) who was on steroids for a long time. He has no symptoms of bowel or urinary involvement. We are reporting this case because of its rarity in human urine and also for future references.

Purpose: Dabrafenib and trametinib combination therapy (dab + tram) is indicated to treat BRAF V600 mutation–positive unresectable/metastatic melanoma and as adjuvant treatment for resected stage III disease. Dab + tram–related pyrexia may require early therapy discontinuation. A modified Delphi panel was conducted to develop consensus on the optimal management of dab + tram–related pyrexia in patients with melanoma. Methods: In all, 10 UK oncologists experienced in melanoma management participated in a three-round modified Delphi study (Round 1: one-to-one interview; Rounds 2 and 3: email survey). In each round, participants rated the extent of their agreement with statements about defining and managing dab + tram–related pyrexia. Consensus was defined as >80% agreement for critical management (CM) and >60% for non-critical management (NCM) statements. Results: All 10 participants completed Round 1; 9 completed Rounds 2 and 3. Consensus was reached on 42/66 statements (20 CM and 22 NCM). Drug-related pyrexia was agreed as being strictly an elevation of body temperature, although other symptoms may be present (89% agreement). Panelists agreed on the need for simple and generic guidance on dab + tram–related pyrexia management that does not differentiate between patient groups (100%), and that management of first and second dab + tram–related pyrexia episodes should be the same regardless of treatment intent (100%). Regarding CM, participants agreed that both dab and tram should be interrupted for pyrexia (100%) without considering the use of steroids (89%); patients on dab + tram presenting to non-oncology services with pyrexia should be directed to an oncology-specific service as soon as possible and assessed for infection (100%). NCM statements on steroid use following dab + tram interruption and when to restart dab + tram did not reach consensus. Conclusions: These consensus statements provide a framework on optimal management of dab + tram–related pyrexia in patients with melanoma which should inform future guidelines.