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Summary: Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21–43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50–0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39–0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48–1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

Introduction: Diffuse parenchymal lung disease (DPLD) describes a heterogenous group of disorders of the lower respiratory tract characterized by inflammation and derangement of the interstitium and loss of functional alveolar units. The disease is not restricted to the interstitium, it involves the entire pulmonary parenchyma. The present study was undertaken to detect and study the profile of computed tomographic (CT) patterns of diffuse parenchymal lung diseases. Methodology: The present study comprised of 60 patients of DPLD. Patients were evaluated by CT scan in Department of Radio -diagnosis from October 2014 to October 2016. Pregnant women and diagnosed cases of tuberculosis (sputum positive) were excluded. Results: The most commonly identified diffuse parenchymal lung disease was idiopathic interstitial pneumonia (26.7%) followed by tuberculosis and post tubercular disease (16.7%) of the total cases. Conclusion: Diffuse parenchymal lung diseases commonly occur in the middle age, the presenting complaint being unremitting dyspnea of long duration in most of the cases. Idiopathic interstitial pneumonia forms the major group of diffuse parenchymal lung diseases in our society. The extent and distribution of disease identified on HRCT scans correlates well with the clinical impairment.

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.

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.

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.

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.

Spontaneous pneumothorax is a very uncommon occurrence in patients having coronavirus disease 2019 (COVID-19) pneumonia. It is mostly seen due to barotrauma in patients receiving mechanical ventilation. Although it may occur at different courses of COVID pneumonia and in patients with no underlying lung disease, it has been seen in patients having underlying asthma, chronic obstructive pulmonary disease, and bronchiectasis. This report describes spontaneous pneumothorax in a silicosis patient during the course of COVID-19 pneumonia with successful outcomes. Possible mechanism of pneumothorax in COVID-19 pneumonia and contributing the role of silicosis is also mentioned with the importance of detecting such complications in time to reduce mortality in such patients.

Burkitt lymphoma (BL) is one of the aggressive subtypes of non-Hodgkin lymphoma commonly seen among pediatric and young population. Primary BL of pelvic bone presenting with back pain, paraparesis, and multifocal osteolytic lesion in the elderly is a rare entity. We report a case of primary BL of pelvic bone in a 65-year-old female presenting with back pain and paraparesis, facing diagnostic dilemma as the lesions were radiologically mimicking multiple myeloma. Subsequently, bone marrow flowcytometry and cytogenetic evaluation by fluorescence insitu hybridization confirmed the diagnosis. We highlight the diagnostic challenge, clinical presentation, and treatment strategy in such a rare case along with a review of literature.

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. Keywords: Cyber physical systems, Internet of Things, Surgical training, Telemedicine, Virtual reality, Internet of Medical Things

Abstract 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.

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.

BackgroundSingle 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.Methods and findingsWe 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.ConclusionsThis 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.

Purpose: This paper focuses on the development of a cyber training framework for an orthopedic surgical process termed Less Invasive Stabilization System (LISS) plating surgery. Research methodology: The overall methodology involves the design and use of the Virtual Reality based simulators to train surgical medical students and residents. Expert surgeons played an important role in the design and development of this network based training simulator. Hypothesis: The hypothesis was that the Virtual Reality based simulations can be used to educate and train surgical residents in target surgical processes. Results: An assessment of the impact on the residents’ learning confirmed the hypothesis using such simulators did improve the residents’ understanding of the LISS plating surgical process. Conclusion: This paper demonstrated the impact of using such network based simulation frameworks for medical education and training.

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.

Use of circulating tumour DNA (ctDNA) as a liquid biopsy has been proposed for potential identification and monitoring of solid tumours. We investigate a next-generation sequencing approach for mutation detection in ctDNA in two related studies using a targeted panel. The first study was retrospective, using blood samples taken from melanoma patients at diverse timepoints before or after treatment, aiming to evaluate correlation between mutations identified in biopsy and ctDNA, and to acquire a first impression of influencing factors. We found good concordance between ctDNA and tumour mutations of melanoma patients when blood samples were collected within one year of biopsy or before treatment. In contrast, when ctDNA was sequenced after targeted treatment in melanoma, mutations were no longer found in 9 out of 10 patients, suggesting the method might be useful for detecting treatment response. Building on these findings, we focused the second study on ctDNA obtained before biopsy in lung patients, i.e. when a tentative diagnosis of lung cancer had been made, but no treatment had started. The main objective of this prospective study was to evaluate use of ctDNA in diagnosis, investigating the concordance of biopsy and ctDNA-derived mutation detection. Here we also found positive correlation between diagnostic lung biopsy results and pre-biopsy ctDNA sequencing, providing support for using ctDNA as a cost-effective, non-invasive solution when the tumour is inaccessible or when biopsy poses significant risk to the patient.

Intravascular hemolysis increases the risk of hypercoagulation and thrombosis in hemolytic disorders. Our study shows a novel mechanism by which extracellular hemoglobin directly affects platelet activation. The binding of Hb to glycoprotein1bα activates platelets. Lower concentrations of Hb (0.37–3 μM) significantly increase the phosphorylation of signaling adapter proteins, such as Lyn, PI3K, AKT, and ERK, and promote platelet aggregation in vitro. Higher concentrations of Hb (3–6 μM) activate the pro-apoptotic proteins Bak, Bax, cytochrome c, caspase-9 and caspase-3, and increase platelet clot formation. Increased plasma Hb activates platelets and promotes their apoptosis, and plays a crucial role in the pathogenesis of aggregation and development of the procoagulant state in hemolytic disorders. Furthermore, we show that in patients with paroxysmal nocturnal hemoglobinuria, a chronic hemolytic disease characterized by recurrent events of intravascular thrombosis and thromboembolism, it is the elevated plasma Hb or platelet surface bound Hb that positively correlates with platelet activation.

The selective BRAF inhibitors, vemurafenib and dabrafenib, yield high response rates and improved overall survival in patients with BRAF V600E-mutant metastatic melanoma. Acquired drug resistance and drug toxicity are key challenges when using these drugs. We investigated whether vemurafenib toxicity could successfully be managed with intermittent dosing, and if its therapeutic efficacy could be maintained on intermittent dosing. Six patients with BRAF V600E-mutated metastatic melanoma were treated with an intermittent dosing regimen of vemurafenib. In three patients, toxicities were successfully managed with an intermittent dosing regimen. In the other three patients, intolerable toxicities continued on intermittent dosing. Our experience shows that intermittent dosing can successfully manage vemurafenib toxicities where continuous dosing at a reduced dose does not. Intermittent treatment improves drug tolerability and can achieve or maintain melanoma shrinkage. We recommend that in clinical practice, intermittent dosing should be considered as an alternative to dose reduction/termination in the management of vemurafenib toxicity.

Ipilimumab and vemurafenib have changed the clinical landscape in melanoma. Both drugs offer effective treatment for metastatic melanoma, but with limitations. Ipilimumab benefits only a minority of those treated, with no means to identify them prospectively. The efficacy of vemurafenib is tied to the presence of an activating mutation in BRAF, and so is more predictable. However, acquired resistance develops within months. As we understand these, and similar, agents better, the means to select patients for treatment, to increase the duration of response and to identify the best stage at which to intervene will lead to improved outcomes for patients. Several trials are already under way or being developed to build upon these exciting discoveries.