The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility.

Placental malaria infection is mediated by the binding of the malarial VAR2CSA protein to the placental glycosaminoglycan, chondroitin sulfate. Recombinant subfragments of VAR2CSA (rVAR2) have also been shown to bind specifically and with high affinity to cancer cells and tissues, suggesting the presence of a shared type of oncofetal chondroitin sulfate (ofCS) in the placenta and in tumors. However, the exact structure of ofCS and what determines the selective tropism of VAR2CSA remains poorly understood. In this study, ofCS was purified by affinity chromatography using rVAR2 and subjected to detailed structural analysis. We found high levels of N-acetylgalactosamine 4-O-sulfation (∼80-85%) in placenta- and tumor-derived ofCS. This level of 4-O-sulfation was also found in other tissues that do not support parasite sequestration, suggesting that VAR2CSA tropism is not exclusively determined by placenta- and tumor-specific sulfation. Here, we show that both placenta and tumors contain significantly more chondroitin sulfate moieties of higher molecular weight than other tissues. In line with this, CHPF and CHPF2, which encode proteins required for chondroitin polymerization, are significantly upregulated in most cancer types. CRISPR/Cas9 targeting of CHPF and CHPF2 in tumor cells reduced the average molecular weight of cell-surface chondroitin sulfate and resulted in a marked reduction of rVAR2 binding. Finally, utilizing a cell-based glycocalyx model, we showed that rVAR2 binding correlates with the length of the chondroitin sulfate chains in the cellular glycocalyx. These data demonstrate that the total amount and cellular accessibility of chondroitin sulfate chains impact rVAR2 binding and thus malaria infection.

The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis.

IMPORTANCE: Tumour-infiltrating lymphocytes (TILs) have previously been found to influence patient prognosis in other gastrointestinal cancers, for instance in colorectal cancer. An immunosuppressive phenotype often characterizes pancreatic cancer with a low degree of immune cell infiltration. Cytotoxic CD8+ T cell infiltration in tumours is found to be the best predictive variable for response to immune checkpoint inhibitor therapy, emphasizing the importance of investigating TILs in pancreatic cancer, especially focussing on CD8+ T cells. OBJECTIVE: Here, we systematically review the literature and perform meta-analyses to examine the prognostic value of TILs in human pancreatic ductal adenocarcinomas (PDAC). Secondarily, we review the literature regarding the histological localization of TILs and the impact on survival in PDAC. EVIDENCE REVIEW: A literature search was conducted on PubMed, Embase, The Cochrane Library and Web of Science. Studies examining patients with PDAC and the impact of high vs. low infiltration of immune cells on long-term oncological survival measures were included. Time-to-event meta-analysis and frequency analysis were conducted using a random effects model. The risk of bias was assessed using the Newcastle-Ottowa Scale. Quality of the cumulative evidence was evaluated using the GRADE approach for prognostic studies. FINDINGS: In total, 1971 articles were screened, of which 43 studies were included in the systematic review and 39 in the meta-analysis. High infiltration of CD8+ lymphocytes was significantly associated with improved overall survival (OS) [hazard ratio (HR) = 0.58, 95% confidence intervals (CIs): 0.50-0.68], disease-free survival (DFS) [HR = 0.64, 95% CI: 0.52-0.78], progression-free survival [HR = 0.66, 95% CI: 0.51-0.86] and cancer-specific survival [HR = 0.56, 95% CI: 0.32-0.99]. A high infiltration of CD3+ T cells was correlated with increased OS [HR = 0.58, 95% CI: 0.50-0.68] and DFS [HR = 0.74, 95% CI: 0.38-1.43]. Infiltration of CD4+ lymphocytes was associated with improved 12-months OS [risk ratio = 0.59, 95% CI: 0.35-0.99] and DFS [risk ratio = 0.68, 95% CI: 0.53-0.88]. High expression of FoxP3+ lymphocytes was associated with poor OS [HR = 1.48, 95% CI: 1.20-1.83]. The greatest impact on survival was observed in the CD8+ T cell and OS group, when infiltration was located to the tumour centre [HR = 0.53, 95% CI: 0.45-0.63]. However, subgroup analysis on the impact of the histological location of infiltration revealed no significant differences between the subgroups (tumour centre, invasive margin, stroma and all locations) in any of the examined cell types and outcomes. CONCLUSIONS AND RELEVANCE: Subsets of TILs, especially CD3+, CD8+ and FoxP3+ T cells are strongly associated with long-term oncological outcomes in patients with PDAC. To our knowledge, this is the first systematic review and meta-analysis on the prognostic value of TILs in pancreatic cancer.

Circumferential Resection Margin After Laparoscopic and Open Rectal Resection: A Nationwide Propensity Score Matched Cohort Study.

BACKGROUND: Recent studies suggest better oncological results after open versus laparoscopic rectal resection for cancer. The external validity of these results has not been tested on a nationwide basis. OBJECTIVE: This study aimed to identify risk factors for positive circumferential resection margin in patients undergoing surgery for rectal cancer with special emphasis on surgical approach. DESIGN: This database study was based on the Danish nationwide colorectal cancer database. To identify risk factors for positive circumferential resection margin, we performed uni- and multivariate logistic regression analyses. To assess the role of surgical approach, a propensity score-matched analysis was performed. SETTINGS: This study was conducted at public hospitals across Denmark. PATIENTS: Patients undergoing elective rectal resection from October 2009 through December 2013 were included. MAIN OUTCOME MEASURES: The primary outcome measured was the risk of a positive circumferential resection margin. RESULTS: Included in the final analyses were 2721 cases (745 operated on by an open approach; 1976 by laparoscopy). On direct comparison, positive circumferential resection margin occurred more often after open resection (6.3% vs 4.7%; p = 0.047). After multivariate analyses, tumors located low in the rectum, neoadjuvant chemoradiation therapy, increasing T and N stage, tumor fixated in the pelvis, and dissection in the muscularis plane increased the risk of a positive circumferential resection margin. In the propensity score-matched sample (541 exact matched pairs), the laparoscopic approach did not influence the risk of a positive circumferential resection margin (OR, 0.9; 95% CI, 0.6-1.5; p = 0.77). LIMITATIONS: This was a retrospective review of prospectively collected data, and thereby contained possible selection bias. CONCLUSIONS: Based on this nationwide database study, and after multivariate and propensity score-matched analyses, there was no increased risk of positive circumferential resection margin after laparoscopic vs open rectal resection. See Video Abstract at http://links.lww.com/DCR/A996. MARGEN DE RESECCIÓN CIRCUNFERENCIAL DESPUÉS DE LA RESECCIÓN RECTAL LAPAROSCÓPICA Y ABIERTA: UN ESTUDIO DE COHORTE DE PUNTUACIÓN DE PROPENSIÓN A NIVEL NACIONAL: Estudios recientes sugieren mejores resultados oncológicos después de la resección rectal abierta versus laparoscópica. La validez de estos resultados no se ha probado a nivel nacional. OBJETIVO: Identificar los factores de riesgo del margen de resección circunferencial positivo en pacientes sometidos a cirugía por cáncer de recto con especial énfasis en el abordaje quirúrgico. DISEÑO:: Estudio de la base de datos nacional de Dinamarca de cáncer colorrectal. Para identificar los factores de riesgo del margen de resección circunferencial positivo, realizamos análisis de regresión logística uni y multivariable. Para evaluar el papel del abordaje quirúrgico, se realizó un análisis emparejado de puntuación de propensión. AJUSTES: Hospitales públicos en toda Dinamarca. PACIENTES: Pacientes sometidos a resección rectal electiva en el período comprendido entre octubre de 2009 y diciembre de 2013. PRINCIPALES MEDIDAS DE RESULTADOS: Riesgo del margen de resección circunferencial positivo. RESULTADOS: 2721 casos (745 operados por abordaje abierto; 1976 por laparoscopia) se incluyeron en el análisis final. En la comparación directa, el margen de resección circunferencial positivo ocurrió más a frecuentemente, después de la resección abierta (6.3 vs 4.7%; p = 0.047). Posterior a los análisis multivariados, tumores localizados en el recto bajo, quimioterapia con radioterapia neoadyuvante, incremento de etapas T y la N, tumor fijo en pelvis y la disección en el plano muscular, aumentaron el riesgo del margen de resección circunferencial positivo. En la muestra emparejada del puntaje de propensión (541 pares coincidentes exactos), el abordaje laparoscópico no influyó en el riesgo del margen de resección circunferencial positivo (razón de probabilidades (IC 95%) 0.9 (0.6-1.5); p = 0.77). LIMITACIONES: Revisión retrospectiva de los datos recopilados prospectivamente y por lo tanto, posible sesgo de selección. CONCLUSIONES: El estudio de la base de datos a nivel nacional y después de los análisis emparejados multivariados y de puntuación de propensión, no hubo un mayor riesgo del margen de resección circunferencial positivo después de la resección laparoscópica versus resección abierta. Vea el Resumen del video en http://links.lww.com/DCR/A996.

Risk Factors for Compromised Surgical Resection: A Nationwide Propensity Score-Matched Study on Laparoscopic and Open Resection for Colonic Cancer.

BACKGROUND: High-quality surgical resection of colonic cancer, including dissection along the embryologic mesocolic plane, translates into improved long-term oncological outcomes. OBJECTIVE: This study aimed to identify risk factors for compromised specimen quality and to evaluate the specimen quality of patients undergoing laparoscopic and open resection for colonic cancer. DESIGN: This is a retrospective observational study. SETTINGS: This database study is based on the prospective national Danish Colorectal Cancer Database including patients undergoing intended curative elective colonic cancer surgery from January 1, 2010 through December 2013. PATIENTS: A total of 5143 patients (1602 open resections; 3541 laparoscopic resections) with colonic cancer were included. MAIN OUTCOME MEASURES: Risk factors for poor resection quality were identified through uni- and multivariate logistic regression analysis. The surgical approach was assessed by propensity score-matched regression analysis. Poor resection quality was defined as resections in the muscularis plane accompanied by R0 resection, or resections in any resection plane accompanied by R1 resection. RESULTS: Overall, 4415 (85.8%) of the resections were considered good and 728 (14.2%) were considered poor. After multivariate analysis, neoadjuvant oncological treatment, advanced tumor stage (T3-4), advancing N stage (N1-2), open tumor perforation, and open surgery significantly increased the risk of poor resection quality. In a propensity score-matched sample (n = 1508 matched pairs), matched for age, sex, ASA score, BMI, neoadjuvant treatment, tumor stage, and tumor location, open resection was still associated with a higher risk of poor resection quality compared with laparoscopic resection (OR, 1.4; 95% CI, 1.1-1.8; p = 0.002). LIMITATIONS: Retrospective design was a limitation of this study. CONCLUSIONS: In this nationwide propensity score-matched database study, laparoscopic resection was associated with a higher probability of good resection quality compared with open resection for colonic cancer. Risk factors for compromised specimen quality were neoadjuvant oncological treatment, locally advanced tumor stage (T3-4), advanced N stage (N1-2), open tumor perforation, and open surgery. See Video Abstract at http://links.lww.com/DCR/A830.