AbstractBackgroundThe novel Coronavirus (SARS‐CoV‐2) has caused almost 2 million deaths worldwide. Both Food and Drug Administration and European Medicines Agency have recently approved the first COVID‐19 vaccines, and a few more are going to be approved soon.MethodsSeveral different approaches have been used to stimulate the immune system in mounting a humoral response. As more traditional approaches are under investigation (inactivated virus vaccines, protein subunit vaccines, recombinant virus vaccines), more recent and innovative strategies have been tried (non‐replicating viral vector vaccines, RNA based vaccines, DNA based vaccines).ResultsSince vaccinations campaigns started in December 2020 in both the US and Europe, gastroenterologists will be one of the main sources of information regarding SARS‐CoV 2 vaccination for patients in their practice, including vulnerable patients such as those with Inflammatory Bowel Disease (IBD), patients with chronic liver disease, and GI cancer patients.ConclusionsThus, we must ourselves be well educated and updated in order to provide unambiguous counseling to these categories of vulnerable patients. In this commentary, we aim to provide a comprehensive review of both approved COVID‐19 vaccines and the ones still under development, and explore potential risks, benefits and prioritization of vaccination.
Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma.
4100 Background: Checkpoint inhibition with anti-PD1 is able to elicit objective response rates (ORR) of ̃ 20% in patients with advanced hepatocellular carcinoma (aHCC) but molecular biomarkers predicting response remain unknown. Here, we define biomarkers of response and primary resistance to anti-PD1 in aHCC by analyzing molecular features prior to systemic therapy. Methods: Through an international consortium of 13 referral centers, we gathered 111 fresh and archived tumor samples from patients with advanced HCC treated with single agent anti- PD1 therapy. Genomic analysis was performed with whole genome expression arrays, CTNNB1 exon 3 mutation assessment and histological evaluation. Results: Overall, we performed transcriptomic analysis in 83 patients, 28 of which were treated in first-line (ORR: 42.9%) while the remaining 55 patients were treated either in 2nd (41 patients, ORR 29.3%) or 3rd line (14 patients, ORR 7.1%) after prior therapy with tyrosine- kinase inhibitors (TKI) sorafenib or lenvatinib. In patients treated in frontline, response was associated with a significant upregulation in Interferon-γ signaling (IFNγ) and genesets relatedto the antigen presentation machinery (FDR < 0.05). Through differential expression analysis we defined an 11-gene signature that was significantly associated with both major pathways (FDR < 0.01) and was capable of predicting OR as well as progression-free- (PFS) and overall survival (OS) in patients with aHCC. The signature was validated in three independent cohorts of melanoma, lung cancer, and head and neck squamous cell cancer patients were high expression was associated with a significant increase in ORR and longer PFS. In HCC, high expression of the signature was associated with a distinct profile in the immune infiltrate, where an increase in M1 macrophages (p = 0.003), CD4 memory T cell (p < 0.01) and CD4 naïve T cell-infiltration (p = 0.026) was observed. Conversely, low expression of the signature was associated with a marked upregulation of regulatory T cells (p < 0.001). No association was found, however, between either the overall immune infiltrate or CTNNB1 mutations and response. In patients that were treated with TKIs in frontline before receiving subsequent anti-PD1 therapy, the signature was no longer able to predict either OR or PFS/OS, suggesting that TKIs may reshape the microenvironment in a way that renders previously inflamed tumors no longer amenable to anti-PD1. Conclusions: Here, we define an 11-gene signature of response to anti-PD1 in first line aHCC. The signature was validated in patients with other solid cancer types, where it retained its predictive ability. Of note, the signature was not able to identify responders among HCC patients that were treated with TKIs prior to anti-PD1 therapy. The molecular changes induced by different treatment lines would, thus, require fresh biopsies prior to anti-PD1to enable biomarker-driven treatment.
Reply to Karakonstantis, et al; Zervou and Zacharioudakis; and Rasmussen, et al
Objective Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. Design We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. Results We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. Conclusion HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Abstract Objectives Corona virus-induced disease 19 (COVID-19) pandemic has globally affected the surgical treatment of cancer patients and has challenged the ethical principles of surgical oncologists around the world. Not only treatment but also diagnosis and follow-up have been disrupted. Methods An online survey was sent through Twitter and by the surgical societies worldwide. The survey consisted of 29 closed-ended questions and was conducted over a period of 24 days beginning in March 26, 2020. Results Overall, 394 surgical oncologists from 41 different countries answered the questionnaire. The predominant guiding principle was “saving lives” 240 (62%), and the different aspects of lock-down found hence large support (mean 7.1–9.3 out of 10). Shut-down of elective surgery and modification of cancer care found a mean support of 7.0 ± 3.0 and 5.8 ± 3.1, respectively. Modification of cancer care longer than two weeks was considered unacceptable to 114 (29%) responders. Hundred and fifty six (40%) and 138 (36%) expect “return to normal” beyond six months for surgical practice and cancer care, respectively. Conclusions Surgical oncologists show strong and long-lasting support for lock-down measures aiming to save lives. The impact of the pandemic on surgical oncology is perceived controversially, but the majority was forced already now to accept what is inacceptable for many of their colleagues.
Cost drivers of locally advanced rectal cancer treatment—An analysis of a leading healthcare insurer
AbstractBackgroundTo evaluate the economic burden of locally advanced rectal cancer (LARC) treatment from a society perspective through analysis of health insurance‐derived data of commercially insured and Medicare Advantage (MA) patients.MethodsRetrospective cost analysis of patients undergoing rectal resection within a multimodal (neoadjuvant chemoradiation + adjuvant chemotherapy) treatment strategy between January 1, 2010 and October 31, 2018, using the claims OptumLabs Data Warehouse database.ResultsIn total, 1738 (935 commercial and 803 MA) patients were included. Overall treatment costs totaled $230,881,746 (on average $183 653 ± 82 384 per commercially insured and $73 681 ± 32 917 per MA patient). Cost distribution according to category (commercially insured patients) was: 29.92% related to outpatient care (follow‐up visits/diagnostics), radiotherapy: 21.83%, index resection: 20.62%, chemotherapy: 17.44%, surgical inpatient: 6.32%, medical inpatient: 3.28%, emergency room: 0.58%. Relative cost distribution of the index resection itself differed marginally between the three approaches and was 21.49% for open, 19.30% for laparoscopic, and 20.93% for robotic surgery. Relative cost distributions of neoadjuvant, adjuvant, and outpatient treatments remained unchanged, independently of the surgical approach. This representation was similar in MA patients.ConclusionIndex‐surgery related costs were outweighed by costs related to oncological and outpatient workup/follow‐up treatments independently of both surgical approach and insurance type.
Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate Size through Altering Stem Dynamics
AbstractThe multimeric plasma glycoprotein (GP) von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to loss of hemostatic activity and thus the bleeding disorder von Willebrand disease. By employing cone and platelet aggregometry and microfluidic assays, we uncovered a platelet GPIIb/IIIa-dependent prothrombotic gain of function (GOF) for variant p.Pro2555Arg, located in the C4 domain, leading to an increase in platelet aggregate size. We performed complementary biophysical and structural investigations using circular dichroism spectra, small-angle X-ray scattering, nuclear magnetic resonance spectroscopy, molecular dynamics simulations on the single C4 domain, and dimeric wild-type and p.Pro2555Arg constructs. C4-p.Pro2555Arg retained the overall structural conformation with minor populations of alternative conformations exhibiting increased hinge flexibility and slow conformational exchange. The dimeric protein becomes disordered and more flexible. Our data suggest that the GOF does not affect the binding affinity of the C4 domain for GPIIb/IIIa. Instead, the increased VWF dimer flexibility enhances temporal accessibility of platelet-binding sites. Using an interdisciplinary approach, we revealed that p.Pro2555Arg is the first VWF variant, which increases platelet aggregate size and shows a shear-dependent function of the VWF stem region, which can become hyperactive through mutations. Prothrombotic GOF variants of VWF are a novel concept of a VWF-associated pathomechanism of thromboembolic events, which is of general interest to vascular health but not yet considered in diagnostics. Thus, awareness should be raised for the risk they pose. Furthermore, our data implicate the C4 domain as a novel antithrombotic drug target.
Surgical Approach to Transverse Colon Cancer: Analysis of Current Practice and Oncological Outcomes Using the National Cancer Database
BACKGROUND: Surgical treatment for transverse colon cancer involves either extended colectomy or segmental resection, depending on the location of the tumor and surgeon perspective. However, the oncological safety of segmental resection has not yet been established in large cohort studies. OBJECTIVE: This study aims to compare segmental resection versus extended colectomy for transverse colon cancer in terms of oncological outcomes. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted using a nationwide cohort. PATIENTS: A total of 66,062 patients who underwent colectomy with curative intent for transverse stage I to III adenocarcinoma were identified in the National Cancer Database (2004–2015). MAIN OUTCOME MEASURES: Patients were divided in 2 groups based on the type of surgery received (extended versus segmental resection). The primary outcome was overall survival. Secondary outcomes were 30- and 90-day mortality, length of hospital stay, and readmission rate within 30 days of surgical discharge. RESULTS: Extended colectomy was performed in 44,417 (67.2%) patients, whereas 21,645 (32.8%) patients underwent segmental resection. Extended colectomy was associated with lower survival at multivariate analysis (HR, 1.07; 95% CI, 1.04–1.10; p < 0.001). The subgroup analysis showed that extended resection was independently associated with poorer survival in mid transverse colon cancers (HR, 1.08; 95% CI, 1.04–1.12; p < 0.001) and in stage III tumors (HR, 1.11; 95% CI, 1.04–1.18; p < 0.001). The number of at least 12 harvested lymph nodes was an independent predictor of improved survival in both overall and subgroup analyses. LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Extended colectomy was not associated with a survival advantage compared with segmental resection. On the contrary, extended colectomy was associated with slightly poorer survival in mid transverse cancers and locally advanced tumors. Segmental resection was found to be safe when appropriate margins and adequate lymph node harvest were achieved. See Video Abstract at http://links.lww.com/DCR/B454. ABORDAJE QUIRÚRGICO DEL CÁNCER DE COLON TRANSVERSO: ANÁLISIS DE LA PRÁCTICA ACTUAL Y LOS RESULTADOS ONCOLÓGICOS UTILIZANDO LA BASE DE DATOS NACIONAL DE CÁNCER ANTECEDENTES: El tratamiento quirúrgico para el cáncer de colon transverso implica colectomía extendida o resección segmentaria, según la ubicación del tumor y la perspectiva del cirujano. Sin embargo, la seguridad oncológica de la resección segmentaria aún no se ha establecido en estudios de cohortes grandes. OBJETIVO: Este estudio tiene como objetivo comparar la resección segmentaria versus la colectomía extendida para el cáncer de colon transverso en términos de resultados oncológicos. DISEÑO: Este fue un estudio de cohorte retrospectivo. ESCENARIO: Este estudio se realizó utilizando una cohorte a nivel nacional. PACIENTES: Un total de 66,062 pacientes que se sometieron a colectomía con intención curativa por adenocarcinoma de colon transverso en estadio I-III fueron identificados en la Base de Datos Nacional del Cáncer (2004-2015). PRINCIPALES MEDIDAS DE RESULTADO: Los pacientes se dividieron en dos grupos según el tipo de cirugía recibida (resección extendida versus resección segmentaria). El resultado primario fue la supervivencia global. Los resultados secundarios fueron la mortalidad a los 30 y 90 días, la duración de la estancia hospitalaria y la tasa de reingreso dentro de los 30 días posteriores al alta quirúrgica. RESULTADOS: Se realizó colectomía extendida en 44,417 (67.2%) casos, mientras que 21,645 (32.8%) pacientes fueron sometidos a resección segmentaria. La colectomía extendida se asoció con una menor supervivencia en el análisis multivariado (HR 1.07 IC 95% 1.04-1.10; p <0.001). El análisis de subgrupos mostró que la resección extendida se asoció de forma independiente con una menor supervivencia en los cánceres de colon transverso medio (HR 1.08 IC 95% 1.04-1.12; p <0.001) y en tumores en estadio III (HR 1.11 IC 95% 1.04-1.18; p <0.001). Un número de al menos 12 ganglios linfáticos cosechados fue un predictor independiente de una mejor supervivencia en los análisis general y de subgrupos. LIMITACIONES: Este estudio estuvo limitado por su diseño retrospectivo. CONCLUSIÓN: La colectomía extendida no se asoció con una ventaja de supervivencia en comparación con la resección segmentaria. Por el contrario, la colectomía extendida se asoció con una supervivencia levemente menor en cánceres de colon transverso medio y tumores localmente avanzados. Se encontró que la resección segmentaria es segura cuando se logran los márgenes apropiados y la cosecha adecuada de ganglios linfáticos. Consulte Video Resumen en http://links.lww.com/DCR/B454.
Evaluation of Progress Toward Gender Equity Among Departmental Chairs in Academic Medicine