Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

IntroductionKRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA.MethodsComprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.Results and discussionOur cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Ductal Adenocarcinoma Ex Pleomorphic Adenoma of the Lacrimal Gland: a Rare and Morbid Malignancy

Carcinoma ex pleomorphic adenoma (Ca ex PA) is a rare malignant transformation of a benign primary pleomorphic adenoma (PA). We report the case of a 62-year-old male who presented with a swelling over his left temple. Imaging revealed a lytic lesion over the left orbital wall with soft tissue extension suggestive of malignancy. He underwent an en bloc resection of the mass with orbital exenteration, craniotomy, and reconstruction. Pathology demonstrated a lacrimal gland ductal adenocarcinoma arising from a PA which led to the diagnosis of ductal adenoCa ex PA. Postoperatively, he received chemotherapy with 6 cycles of cisplatin and concurrent radiation therapy (RT), but his course was complicated by recurrent bacterial meningitis and abscesses and he ultimately opted for comfort measures. Patients with PA of the lacrimal gland experience an insidiously enlarging painless swelling of the orbit with transformation to Ca ex PA highlighted by a rapid onset of bulbar enlargement, displacement, and often proptosis. Ductal adenoCa ex PA is aggressive with a poor prognosis and has no established standard of care. This case highlights the rarity of this condition and the need for more literature to help direct treatment

Molecular Targets in Salivary Gland Cancers: A Comprehensive Genomic Analysis of 118 Mucoepidermoid Carcinoma Tumors

Introduction: Salivary gland carcinomas (SGC) are histologically diverse cancers and next-generation sequencing (NGS) to identify key molecular targets is an important aspect in the management of advanced cases. Methods: DNA was extracted from paraffin embedded tissues of advanced SGC and comprehensive genomic profiling (CGP) was carried out to evaluate for base substitutions, short insertions, deletions, copy number changes, gene fusions and rearrangements. Tumor mutation burden (TMB) was calculated on approximately 1.25 Mb. Some 324 genes in the FoundationOne CDX panel were analyzed. Results: Mucoepidermoid carcinoma (MECa) mutations were assessed. CDKN2A and CDKN2B GA were common in mucoepidermoid carcinoma (MECa) (52.5 and 30.5%). PIK3CA was also common in MECa (16.9%). ERBB2 amplification/short variants (amp/SV) were found in MECa (5.9/0%). HRAS GA was common in MECa (14.4%) as well. Other targets, including BAP1, PTEN, and KRAS, were noted but had a low incidence. In terms of immunotherapy (IO)-predictive markers, TMB > 10 was more common in MECa (16.9%). PDL1 high was also seen in MECa (4.20%). Conclusion: SGC are rare tumors with no FDA-approved treatment options. This large dataset reveals many opportunities for IO and targeted therapy contributing to the continuously increased precision in the selection of treatment for these patients

Histomorphological study of the parathyroid gland in female Kuttanad ducks (Anas platyrhynchos domesticus)

Aim: The present work was targeted to form the baseline data of normal morphological and histological picture of parathyroid gland in female Kuttanad ducks.Materials and Methods: A Histomorphological study of the parathyroid gland was carried out in twelve adult female Kuttanad ducks (Anas platyrhynchos domesticus) of 20 weeks of age. Birds reared semintensively were procured from Kerala Veterinary and Animal Sciences University Poultry and Duck Farm and sacrificed humanely. Glands were collected and gross parameters were recorded. The glands were fixed in 10 percent neutral buffered formalin. The small sized glands were processed as such by routine histological methods, paraffin blocks were prepared and sectioned to a thickness of 5µ. The tissues were stained by Haematoxylin and Eosin (H&E) for routine histological studies and Gomori's rapid one step trichrome method for connective tissue fibres. Micrometric parameters were recorded using ocular micrometer. Results: Parathyroid glands in Kuttanad ducks lay just caudal to the division of the innominate artery into the subclavian and common carotid arteries. Parathyroids were oval to spherical in shape, yellow in colour and smaller than thyroid gland of the representative sides. The arterial blood supply was from common carotid artery and blood from gland was drained directly into jugular vein. Although it lied close to the thyroid, thymus and ultimobranchial gland, parathyroid tissue did not merge to any of the above mentioned three glands. Parenchyma was composed irregular anatomizing cords of cells supplied by connective tissue stroma penetrated by blood capillaries. Parenchyma was predominantly made of lightly stained cell, the chief cell. The nuclei were round and contain one or two nucleoli. Oxyphil cells present in parathyroid glands of other mammals were not seen in the present study. Conclusion: Histomorphological features or characteristics of Parathyroid gland in Kuttanad duck were studied. Cranial parathyroids were larger in size as compared to the caudal parathyroids. Parathyroid glands were enclosed by a well-developed connective tissue capsule made predominantly of collagen fibers. Parenchyma was composed of irregular anatomizing cords of cells supplied by connective tissue stroma and penetrated by blood capillaries. Oxyphil cells were absent similar to other aves. Parathyroid gland is very vital in maintaining the homeostasis of the plasma calciumReference?. Findings of this study will contribute to the anatomy literature as a valuable resource for future researchers focused on this subject and will also help other allied subjects on comparative basis

Genomic landscape of non‐small‐cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency

Abstract Introduction New treatment strategies for advanced non‐small‐cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP). Methods Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid‐capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD‐L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). Results 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large‐cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP‐intact versus MTAP‐lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP‐intact versus MTAP‐lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP‐intact compared to MTAP‐lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP‐intact versus MTAP‐lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP‐intact versus MTAP‐lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD‐L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups. Conclusions MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper‐dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies

Drosophila Transcription Factor Tramtrack69 Binds MEP1 To Recruit the Chromatin Remodeler NuRD ▿ †

ATP-dependent chromatin-remodeling complexes (remodelers) are essential regulators of chromatin structure and gene transcription. How remodelers can act in a gene-selective manner has remained enigmatic. A yeast two-hybrid screen for proteins binding the Drosophila transcription factor Tramtrack69 (TTK69) identified MEP1. Proteomic characterization revealed that MEP1 is a tightly associated subunit of the NuRD remodeler, harboring the Mi2 enzymatic core ATPase. In addition, we identified the fly homolog of human Deleted in oral cancer 1 (DOC1), also known as CDK2-associated protein 1 (CDK2AP1), as a bona fide NuRD subunit. Biochemical and genetic assays supported the functional association between MEP1, Mi2, and TTK69. Genomewide expression analysis established that TTK69, MEP1, and Mi2 cooperate closely to control transcription. The TTK69 transcriptome profile correlates poorly with remodelers other than NuRD, emphasizing the selectivity of remodeler action. On the genes examined, TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. Thus, there appears to be a hierarchical relationship in which transcription factor binding precedes remodeler recruitment

From an Fe2P3 complex to FeP nanoparticles as efficient electrocatalysts for water-splitting

In large-scale, hydrogen production from water-splitting represents the most promising solution for a clean, recyclable, and low-cost energy source. The realization of viable technological solutions requires suitable efficient electrochemical catalysts with low overpotentials and long-term stability for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) based on cheap and nontoxic materials. Herein, we present a unique molecular approach to monodispersed, ultra-small, and superiorly active iron phosphide (FeP) electrocatalysts for bifunctional OER, HER, and overall water-splitting. They result from transformation of a molecular iron phosphide precursor, containing a [Fe2P3] core with mixed-valence FeIIFeIII sites bridged by an asymmetric cyclo-P(2+1)3− ligand. The as-synthesized FeP nanoparticles act as long-lasting electrocatalysts for OER and HER with low overpotential and high current densities that render them one of the best-performing electrocatalysts hitherto known. The fabricated alkaline electrolyzer delivered low cell voltage with durability over weeks, representing an attractive catalyst for large-scale water-splitting technologies