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.
Next-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.
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.
This paper discusses the adoption of information-centric systems engineering (ICSE) principles to design a cyber-human systems-based simulator framework to train orthopedic surgery medical residents ...using haptic and immersive virtual reality platforms; the surgical procedure of interest is a less invasive stabilization system plating surgery that is used to treat fractures of the femur. Developing such training systems is a complex task involving multiple systems, technologies, and human experts. The information-centric approach proposed provides a structured foundation to plan, design, and build the simulators using the ICSE approach; in addition, the information models of the surgical processes were built to capture the surgical complexities and relationships between the various systems/components in the simulator framework, along with the controlling factors, performing mechanisms, and decision outcomes at various levels of abstraction. The simulator platforms include a haptic-based training system and a fully immersive training system for six training environments. Next-generation networking principles were adopted to support the collaborative training activities within this framework. As part of the proposed approach, expert surgeons played an important role in the design of the training environments. The outcomes of the learning assessment conducted demonstrate the effectiveness of using such simulator-based cyber-human training frameworks.
Internet of Things based approaches and frameworks hold significant potential in changing the way in which engineering activities are accomplished. The information centric revolution underway has ...served as a catalyst in the design of innovative methods and practices in several engineering and other domains. In this paper, an Internet of Medical Things based framework for surgical training is discussed in the broader context of Next Generation frameworks. The design and development of this Internet of Medical Things based framework involving adoption of Global Environment for Network Innovations based networking principles is elaborated. The Virtual Reality based simulation environments incorporate haptic based interfaces which support collaborative training and interactions among expert surgeons and residents in orthopedic surgery from distributed locations. The impact of using this Internet of Medical Things based framework for medical education has also been studied; the outcomes underscore the potential of adopting such Internet of Medical Things based approaches for medical education.
Increased environmental temperature exerts a visible impact on an individual's physiology. At the onset of heat stress, there is an increase in core body temperature which triggers peripheral ...vasodilation and sweating in an effort to dissipate the elevated body heat. The increase in peripheral circulation however reduces blood flow to the internal organs which are thus adversely affected. In particular, the gastrointestinal (GI) tract gets adversely affected during hyperthermia resulting in loosening of the tight junctions (TJs) that finally leads to higher intestinal permeability. At the cellular level, elevated levels of heat shock proteins (HSPs) induced in response to heat stress mediated cytoprotection by maintaining proper protein folding, releasing survival signals and preserving cytoskeleton integrity. Recent studies have indicated that HSPs play a crucial role in maintaining the localization of TJ proteins. Dietary supplements have also shown to have a positive effect on the maintenance of intestinal TJs. Therefore, it becomes imperative to understand the cellular, molecular and physiological alterations in response to heat stress in GI tract. In the present report, the effect of thermal stress on GI tract has been summarized. Specific role of HSPs along with mitogen activated protein (MAP) kinase signaling pathway in response to hyperthermia has also been discussed.
Introduction: The fifth edition of WHO classification of myeloid neoplasms has introduced major changes in the defining criteria and grouping of MDS, MDS/MPNs and MPNs. Recently published literature ...has also cited the importance of new risk-scoring systems by integrating genomic profiling with hematologic and cytogenetic characteristics, in order to improve the prognostic discrimination of patients and represents a valuable tool for clinical decision-making. Aim: To find out the prevalence and molecular spectrum of Philadelphia-negative MPNs, MDS/MPNs and MDS in our subset of patients and henceforth to evaluate the impact on diagnosis, risk stratification and treatment decision-making of patients. Methods: This retrospective observational study included all newly diagnosed patients of non-Philadelphia positive MPNs, MDS, and MPN/MDS, in whom complete baseline diagnostic work-up was available including complete blood counts, bone marrow morphology and biopsy, cytogenetic and molecular studies. Results: The most frequent entities in our cohort of patients were primary myelofibrosis (32.8%), MDS (32.8%) and CMML (16.4%). In PIMF, 50% patients were JAK2- mutated while 30% were triple negative (JAK-, CALR-, MPL-). The commoner epigenetic modifiers among MPNs were ASXL1, TET2 and IDH2. The predominant CMML molecular signatures in our patients were NRAS, U2AF2, SETBP1, ASXL and SH2B3. There was no significant effect of WHO changes and recently introduced molecular scoring models on the diagnosis and risk stratification of all these MPN and MDS/MPN patients However, in MDS and PIMF patients, recent WHO subtyping plus IPSS-M & GIPSS scoring respectively enabled refining of risk groups. Conclusion: Molecular profiling helps in better risk stratification of patients across all groups as well as in making therapeutic decisions. However, in resource constrained settings, it is not always possible to stratify patients on the basis of molecular signatures and hence, scoring models such as DIPSS and IPSS-R holds their ground strongly even today for offering appropriate therapy to patients without compromising on quality care.
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 1a. More than 80% of tumour cells exhibited signet ring cell morphology that were arranged in sheets and diffusely infiltrating the prostatic stroma Figure 1b. 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.
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.
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