Citations

BACKGROUND: Medicare reimbursement rates have decreased across various specialties but have not yet been studied in colorectal surgery. OBJECTIVE: This study aimed to analyze Medicare reimbursement trends in colorectal surgery. DESIGN: Observational study. SETTING: The Centers for Medicare and Medicaid Services’ Physician Fee Schedule was evaluated for reimbursement data for the 20 most common colorectal surgery procedures from 2006 to 2020. MAIN OUTCOME MEASURES: Inflation-adjusted annual percentage change, compound annual growth rate, and total percentage change were the outcome measures. A subanalysis was performed comparing the changes in reimbursement between 2006 to 2016 and 2016 to 2020 because of legislative changes that went into effect in 2016. RESULTS: During the study period, the inflation-unadjusted mean Medicare reimbursement rate for the 20 most common colorectal surgery procedures increased by +15.6%. This rise was surpassed by the inflation rate of +31.3%. Consequently, the inflation-adjusted reimbursement rate decreased by –11%. The adjusted reimbursement rates decreased the most at –33.8% for a flexible colonoscopy with biopsy and increased the most at +45.3% for a diagnostic rigid proctosigmoidoscopy. Annual percentage change was –0.79%, and the compound annual growth rate was –0.98%. There was an accelerated decrease in annual reimbursement rates from 2016 to 2020 at –2.23% compared to 2006 to 2016 at –0.22% (p = 0.03). The only procedure that had an increase in adjusted reimbursement rate from 2016 to 2020 was the injection of sclerosing solution for hemorrhoids. LIMITATIONS: Only Medicare reimbursement data were analyzed. CONCLUSIONS: Medicare reimbursements for colorectal surgery procedures are decreasing at an accelerating rate. Although this study is limited to Medicare data, it still presents a representation of overall reimbursement changes because Medicare policies have a ripple effect in the commercial insurance market. It is vital to understand the financial trends to be able to structure future patient care teams and to advocate for the sustainability of colorectal surgery practices in the United States. See Video Abstract at http://links.lww.com/DCR/C136. REEMBOLSO DE MEDICARE EN CIRUGÍA COLORRECTAL: UN PROBLEMA CRECIENTE ANTECEDENTES: Las tasas de reembolso de Medicare han disminuido en varias especialidades, pero aún no han sido estudiado en cirugía colorrectal. OBJETIVO: Analizar las tendencias de reembolso de Medicare en cirugía colorrectal. DISEÑO: Estudio observacional. CONTEXTO: Se evaluó el programa de tarifas médicas de los Centros de Servicios de Medicare y Medicaid para obtener datos de reembolso de los 20 procedimientos más comunes en cirugía colorrectal entre los años 2006 y 2020. PRINCIPALES MEDIDAS DE RESULTADO: Variación porcentual anual ajustada por inflación, tasa de crecimiento anual compuesta y variación porcentual total. Se realizó un subanálisis comparando los cambios en el reembolso entre los años 2006 a 2016 y 2016 a 2020 debido a los cambios legislativos que entraron en vigencia en 2016. RESULTADOS: Durante el período de estudio, la tasa media de reembolso de Medicare sin ajuste por inflación para los 20 procedimientos más comunes en cirugía colorrectal aumentó en +15,6 %. Esta suba fue superada por la tasa de inflación del +31,3%. En consecuencia, la tasa de reembolso ajustada por inflación disminuyó un -11%. Lo máximo que disminuyeron las tasas ajustadas de reembolso fue a -33,8% para una colonoscopia flexible con biopsia y aumentaron más a +45,3% para una proctosigmoidoscopia rígida de diagnóstico. El cambio porcentual anual fue -0,79% y la tasa de crecimiento anual compuesto fue -0,98%. Hubo una disminución acelerada en las tasas de reembolso anual de 2016 a 2020 a -2,23 % en comparación con 2006 a 2016 a -0,22% (p = 0,03). El único procedimiento que tuvo un aumento en la tasa de reembolso ajustada de 2016 a 2020 fue la inyección de solución esclerosante para las hemorroides. LIMITACIONES: Solo se analizaron los datos de reembolso de Medicare. CONCLUSIONES: Los reembolsos de Medicare por procedimientos en cirugía colorrectal están disminuyendo a un ritmo acelerado. Aunque este estudio se limita a los datos de Medicare, aún presenta una representación de los cambios generales en los reembolsos, ya que las pólizas de Medicare tienen un efecto dominó en el mercado de seguros comerciales. Es fundamental comprender las tendencias financieras para poder estructurar futuros equipos de atención de pacientes y abogar por la sostenibilidad de las prácticas de cirugía colorrectal en los Estados Unidos. Consulte Video Resumen video en https://links.lww.com/DCR/C136. (Traducción—Dr. Osvaldo Gauto)

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia’s. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.

Abstract Immune checkpoint proteins such as programmed death-ligand 1 (PD-L1) retain general immune homeostasis and self-tolerance. PD-L1 binds to programmed cell death protein 1 (PD-1) and inhibits T cell activation or protects tumor cells from T cell-mediated killing. PD-L1 has recently been shown to be up-regulated in invasive lung fibroblasts by p53 and focal adhesion kinase (FAK), any potential role of transforming growth factor-beta (TGFβ) in PD-L1 action is unknown in fibrosis. TGFβ is a mysterious protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, fibrotic disorders, and immune modulation, et al. In the current study, we showed that TGFβ induces the expression of the immunoinhibitory molecule PD-L1 in human and murine fibroblasts in a Smad2/3- and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFβ-dependent induction of extracellular matrix proteins, including collagen Ia1 (colIa1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFβ signaling, TGFβ stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T-cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases.

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Abstract OBJECTIVE Using individual pharmacogenomic phenotypes to investigate the factors affecting the efficacy and tolerability of verapamil for migraine prevention. BACKGROUND Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. METHODS This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the minimum effective and maximum tolerable verapamil doses for migraine prevention were assessed. RESULTS The mean minimum effective and maximum tolerable doses for the 33 patients in final analysis were 178.2(20–320) mg and 227.9(20–480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status. CONCLUSIONS We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

Abstract Purpose: Mesenchymal stem cells (MSC) have emerged as cellular-based vehicles for the delivery of therapeutic genes in cancer therapy based on their inherent tumor-homing capability. As theranostic gene, the sodium iodide symporter (NIS) represents a successful target for noninvasive radionuclide-based imaging and therapy. In this study, we applied genetically engineered MSCs for tumor-targeted NIS gene transfer in experimental glioblastoma (GBM)—a tumor with an extremely poor prognosis. Experimental Design: A syngeneic, immunocompetent GL261 GBM mouse model was established by subcutaneous and orthotopic implantation. Furthermore, a subcutaneous xenograft U87 model was used. Bone marrow–derived MSCs were stably transfected with a NIS-expressing plasmid driven by the constitutively active cytomegalovirus promoter (NIS-MSC). After multiple or single intravenous injection of NIS-MSCs, tumoral iodide uptake was monitored in vivo using 123I-scintigraphy or 124I-PET. Following validation of functional NIS expression, a therapy trial with 131I was performed on the basis of the most optimal application regime as seen by 124I-PET imaging in the orthotopic approach. Results: A robust tumoral NIS-specific radionuclide accumulation was observed after NIS-MSC and radioiodide application by NIS-mediated in vivo imaging. NIS immunofluorescence staining of GBM and non-target tissues showed tumor-selective MSC homing along with NIS expression. Application of therapeutically effective 131I led to significantly delayed tumor growth and prolonged median survival after NIS-MSC treatment as compared with controls. Conclusions: A strong tumor-selective recruitment of systemically applied MSCs into GBM was found using NIS as reporter gene followed by successful therapeutic application of radioiodide demonstrating the potential use of NIS-based MSCs as therapy vehicles as a new GBM therapy approach.

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell–specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and TP53 mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs. While both Epstein–Barr Virus (EBV) and human papilloma virus (HPV) are observed, EBV is more frequently associated with nasopharyngeal cancers whereas HPV is associated with oropharyngeal cancers. HNSCCs are associated with high tumor mutational burden and loss of tumor suppressor gene function, especially in TP53 and X-linked genes. Multiple lines of evidence suggest that HNSCCs are subject to immunologic surveillance and immune-induced evolutionary pressure that correlate with negative clinical outcomes. This review will discuss genomic mechanisms related to immune-mediated pressures and propose prognostic and therapeutic implications of detectable immune escape mechanisms that drive tumorigenesis and disease progression.