Diagnosis of Pancreatic Cancer after Cholecystectomy in the Elderly.

BACKGROUND: Previous studies evaluating whether recent cholecystectomy is associated with a pancreas cancer diagnosis are limited. We aimed to examine if cholecystectomy was performed more frequently in the year prior to cancer diagnosis than would be expected in a similar non-cancer population. METHODS: SEER-Medicare linked files were used to identify patients with pancreatic adenocarcinoma. Cancer diagnoses were considered to be "timely" if within 2 months of cholecystectomy or "delayed" if 2-12 months after cholecystectomy. Clinical factors and survival outcomes were compared using chi-square and Kaplan-Meier analyses. RESULTS: Rate of cholecystectomy in the year prior to diagnosis of cancer was 1.9% for the cancer group, compared to .4% in the non-cancer group (OR = 4.7, 95% CI 4.4-5.1). Differences in the cancer vs non-cancer cohorts at the time of cholecystectomy included a higher age (74 vs 70, P < .0001), more males (49.9% vs 41.7%, P < .0001), and more frequent open technique (21.0% vs 9.4%, P < .0001). Acute pancreatitis was nearly twice as common in the cancer cohort (19.1%) vs the non-cancer cohort (10.7%), P < .0001. There were no differences between patients who had a timely diagnosis after cholecystectomy compared to a delayed diagnosis with regard to age, gender, comorbidity index, race, or rural/urban designation. The rates of localized disease and subsequent resection were also similar between the delayed and timely groups. Overall unadjusted survival was no different between timely and delayed diagnoses, P = .96. DISCUSSION: Elderly patients diagnosed with pancreatic adenocarcinoma are more likely to have had a recent cholecystectomy compared to those without.

Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.

Success in pediatric surgery: An updated survey of Program Directors 2020.

BACKGROUND: One of the most competitive surgical sub-specialty fellowships remains Pediatric Surgery (PS), which requires candidates to develop a strong and research-oriented curriculum vitae. Although some objective factors of matriculation are known, factors for the interview selection and ranking per the program directors (PDs) have not been reviewed in over a decade. METHODS: A web-based survey of US and Canadian PS program directors (PDs) (n = 58) was used to evaluate a comprehensive list of factors in the selection criteria for PS fellowships. A mix of dichotomous, ranking, five-point Likert scale, and open-ended questions evaluated applicant characteristics, ABSITE scores, research productivity, interview day, and rank order criteria. RESULTS: Fifty-five programs responded to the survey for a 95% participation rate. PDs desired an average of two years in dedicated research and weighted first authorship and total number of publications heavily. Only 38% of programs used an ABSITE score cutoff for offering interviews; however, the majority agreed that an overall upward trend was important. Quality letters of recommendation, especially from known colleagues, carried weight when deciding to offer interviews. Interview performance, being a team player, observed interpersonal interactions, perceived operative skills and patient care, and leadership were some of the notable factors when finalizing rank lists. CONCLUSIONS: A multitude of factors define a successful matriculant, including quality of letters of recommendation, quality and quantity of publications, supportive phone calls, observed interactions, interview performance, perceptions of being team player with leadership skills as well as perceptions of good operative skills and patient care. LEVEL OF EVIDENCE: Type II. TYPE OF STUDY: Prognostic (retrospective).

Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma.

PURPOSE: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL. PATIENTS AND METHODS: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response. RESULTS: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti-programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti-PD-1 (aPD-1). Among patients with BRAF V600E/K-mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1-naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%. CONCLUSIONS: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma. See related commentary by Sznol, p. 5156.

Identification and Validation of T-cell Receptors Targeting RAS Hotspot Mutations in Human Cancers for Use in Cell-based Immunotherapy.

PURPOSE: Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for "off-the-shelf" adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes. EXPERIMENTAL DESIGN: In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested. RESULTS: Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS. CONCLUSIONS: The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for "off-the-shelf" ACTs.

Evaluation of Factors Associated With Successful Matriculation to Colon and Rectal Surgery Fellowship.

BACKGROUND: As an increasing number of general surgery residents apply for fellowship positions, it is important to identify factors associated with successful matriculation. For applicants to colon and rectal surgery, there are currently no objective data available to distinguish which applicant attributes lead to successful matriculation. OBJECTIVE: The purpose of this study was to identify objective factors that differentiate colon and rectal surgery fellowship applicants who successfully matriculate with those who apply but do not matriculate. DESIGN: This was a retrospective analysis of colon and rectal surgery applicant characteristics. SETTINGS: Deidentified applicant data provided by the Association of American Medical Colleges from 2015 to 2017 were included. MAIN OUTCOME MEASURES: Applicant demographics, medical school and residency factors, number of program applications, number of publications, and journal impact factors were analyzed to determine associations with successful matriculation. RESULTS: Most applicants (n = 371) and subsequent matriculants (n = 248) were white (61%, 62%), male (65%, 63%), US citizens (80%, 88%) who graduated from US allopathic medical schools (66%, 75%). Statistically significant associations included graduation from US allopathic medical schools (p < 0.0001), US citizenship (p < 0.0001), and number of program applications (p = 0.0004). Other factors analyzed included American Osteopathic Association membership (p = 0.57), university-based residency (p = 0.51), and residency association with a colon and rectal surgery training program (p = 0.89). Number of publications and journal impact factors were not statistically different between cohorts (p = 0.067, p = 0.150). LIMITATIONS: American Board of Surgery In-Training Examination scores, rank list, and subjective characteristics, such as strength of interview and letters of recommendation, were not available using our data source. CONCLUSIONS: Successful matriculation to a colon and rectal surgery fellowship program was found to be associated with US citizenship, graduation from a US allopathic medical school, and greater number of program applications. The remaining objective metrics analyzed were not associated with successful matriculation. Subjective and objective factors that were unable to be measured by this study are likely to play a determining role. See Video Abstract at http://links.lww.com/DCR/B415. EVALUACIN DE FACTORES VINCULADOS EN LA INMATRICULACIN EXITOSA PARA BECAS DE CIRUGA COLORRECTAL: ANTECEDENTES:A medida que un número cada vez mayor de residentes de Cirugía General solicitan una beca, es importante identificar los factores vinculados con una inmatriculación exitosa. Para los candidatos a una beca en Cirugía Colorrectal, hoy en día no existen datos objetivos disponibles para distinguir qué atributos del solicitante conducen a una inmatriculación exitosa.OBJETIVO:Identificar objetivamente los factores que diferencian un candidato a una beca en Cirugía Colorrectal que se inmatricula con éxito de aquel que aplica pero no llega a inmatricularse.DISEÑO:Análisis retrospectivo de las características de los solicitantes de beca para Cirugía Colorrecatl.AJUSTES:Datos de los solicitantes no identificados, proporcionados por la Asociación de Colegios Médicos Estadounidenses de 2015 a 2017.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron los factores demográficos del solicitante, las facultades de medicina y los factores de la residencia, el número de solicitudes de programas, el número y el factor de impacto de las publicaciones realizadas para determinar la asociación con una inmatriculación exitosa.RESULTADOS:La mayoría de los solicitantes (n = 371) que posteriormente fueron inmatriculados exitosamente (n = 248) eran blancos (61%, 62%, respectivamente), hombres (65%, 63%), ciudadanos estadounidenses (80%, 88%) que se graduaron de Facultades de medicina alopática en los EE. UU. (66%, 75%). Las asociaciones estadísticamente significativas incluyeron la graduación de las escuelas de medicina alopática de los EE. UU. (P <0,0001), la ciudadanía de los EE. UU. (P <0,0001) y el número de solicitudes de programas (p = 0,0004). Otros factores analizados incluyeron: membresía AOA (p = 0,57), la residencia universitaria (p = 0,51) y asociación de la residencia con un programa de formación en Cirugía Colorrectal (p = 0,89). El número de publicaciones y los factores de impacto de las revistas no fueron estadísticamente diferentes entre las cohortes (p = 0,067, p = 0,15, respectivamente).LIMITACIONES:El Score ABSITE, la posición en lista de clasificación y las características subjetivas como el de una buena entrevista y las cartas de recomendación no se encontraban disponibles en la fuente de datos.CONCLUSIONES:Se encontró que la inmatriculación exitosa a un programa de becas de Cirugía Colorreectal estaba asociada con la ciudadanía estadounidense, la graduación en una Facultad de medicina alopática en los EE. UU, y al mayor número de solicitudes de programas. El analisis de las medidas objetivas restantes no se asociaron con una inmatriculación exitosa. Es probable que los factores subjetivos y objetivos que no pudieron ser medidos por este estudio jueguen un papel determinante. Consulte Video Resumen en http://links.lww.com/DCR/B415. (Traducción-Dr Xavier Delgadillo).

Pancreatic insufficiency following pancreatectomy: Does underlying tumor syndrome confer a greater risk?

BACKGROUND: The risk of postoperative pancreatic exocrine insufficiency (PPEI) is unknown in patients with multiple endocrine neoplasia type I (MEN1) and von Hippel-Lindau (VHL) who require resection of pancreatic neuroendocrine tumors (PNETs). METHODS: A retrospective review of patients who underwent resection of PNETs at the National Institutes of Health from 2007 to 2019 was performed. RESULTS: Our cohort included 82 patients (VHL n = 25, MEN1 n = 20, sporadic n = 37), 6 of whom developed PPEI. While VHL compared to all non-VHL patients (p = 0.046), non-functional PNETs (p = 0.050), and pancreaticoduodenectomy (PD) (p=<0.001) were associated with higher rates of PPEI on univariate analysis, only PD was found to be an independent predictor of PPEI on multivariate analysis (OR 14.43, 95% CI 1.43-145.8, p = 0.024). CONCLUSIONS: The rate of PPEI in patients with hereditary tumor syndromes was similar to that of sporadic PNETs. PD was independently associated with PPEI, and this increased risk should be included in preoperative counseling.

mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.

BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.

Incidence of Asymptomatic Brain Metastases in Metastatic Colorectal Cancer.

BACKGROUND: Current literature suggests that brain metastasis is an infrequent occurrence in metastatic colorectal cancer. Outside of rare autopsy studies, these retrospective reports describe the incidence of symptomatic brain metastasis and therefore lack a description of the incidence in asymptomatic patients. With improved survival and a lack of routine brain imaging, the true incidence of brain metastasis among patients with metastatic colorectal cancer is likely under-recognized. At our research institution, protocol criteria require brain imaging regardless of neurologic symptoms. Therefore, we aim to describe the incidence of asymptomatic brain metastases in patients with metastatic colorectal cancer. PATIENTS AND METHODS: This study included patients with metastatic colorectal cancer enrolled onto a clinical trial screening protocol at the National Cancer Institute that underwent brain imaging (n = 171) between 2010 and 2019. RESULTS: The median age of patients at initial colorectal cancer diagnosis was 48.1 years. Most had stage IV disease with synchronous metastases. Twenty-five (14.6%) patients were identified with brain metastases, of which 19 (76%) were asymptomatic. Those with asymptomatic lesions were more likely to have presented with synchronous metastases, have a shorter time from primary diagnosis to development of metastatic disease, and have smaller brain metastases. CONCLUSION: We identified a high number of asymptomatic brain metastasis and subsequently a higher cumulative incidence of brain metastases in patients with metastatic colorectal cancer than historical reports would suggest. This may represent a heretofore unknown aspect of the natural course of disease now being exposed owing to an increasing life expectancy of these patients and could play a pivotal role in therapeutic decisions.

Elevated Serum α-Fetoprotein is Associated with Abbreviated Survival for Patients with Fibrolamellar Hepatocellular Carcinoma Who Undergo a Curative Resection.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS: The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS: Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). CONCLUSIONS: Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.

Single-Agent Thalidomide for Treatment of Malignant Paraganglioma of the Organ of Zuckerkandl.

The standard of care for benign pheochromocytomas and paragangliomas is surgical resection; however, there is no definitive curative or standard therapy for the treatment of malignant pheochromocytomas or paragangliomas. Current therapeutic options include surgical resection, chemotherapy (CVD therapy), MIBG-radiotherapy, somatostatin analogues, and combination targeted therapies such as temozolomide and thalidomide. Although some patients demonstrate short-lived responses to these various therapies, there has been no statistically significant survival benefit with any of the current regimens and therefore the aim is palliation and symptom control. Here, we present a 38-year-old man found to have an unresectable metastatic paraganglioma located in the Organ of Zuckerkandl who has been treated with single-agent thalidomide for over 15 years with minimal growth and stabilization of metastatic lesions. The management of our patient with single-agent therapy for this extended period of time challenges the efficacy and role of chemotherapy and other accepted therapies for malignant pheochromocytoma and paraganglioma.

Role of Surgery in Combination with Immunotherapy.

Improvements in systemic immunotherapy are changing the treatment of patients with advanced melanoma and many other tumors. Surgeons may be increasingly called on to manage isolated sites of immunorefractory disease or to provide palliative surgery as a bridge to systemic therapy. Here, the authors describe the biologic rationale for using surgery in patients with immunorefractory disease, provide background on the evolving role of metastasectomy for advanced melanoma, and summarize data on the use of neoadjuvant immunotherapy. Finally, the authors discuss the direction of clinical research in this rapidly evolving field.

The interaction of ifosfamide and aprepitant in gynecologic malignancies.

•Aprepitant combined with ifosfamide may lead to encephalopathy.•Aprepitant-ifosfamide induced encephalopathy was of short duration in these cases.