Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection.

BACKGROUND: The prognosis of patients with pancreatic cancer remains poor and novel therapeutic targets are required urgently. Treatment resistance could be due to the tumour microenvironment, a desmoplastic stroma consisting of cancer-associated fibroblasts and tumour-infiltrating lymphocytes (TILs). The aim of the study was to evaluate the prognostic value of TILs and cancer-associated fibroblasts (CAFs) in pancreatic cancer of the body and tail. METHODS: Using tissue microarray from resected left-sided pancreatic cancer specimens, the immunohistochemistry of TILs (cluster of differentiation (CD) 45, CD3, CD4, FoxP3 and CD8), CAFs (vimentin and α-smooth muscle actin (αSMA)) and functional markers (PD-L1 and Ki-67) was examined, and the association with disease-free (DFS) and overall (OS) survival investigated using a computer-assisted quantitative analysis. Patients were classified into two groups, with low or high levels or ratios, using the 75th percentile value as the cut-off. RESULTS: Forty-three patients were included in the study. Their median DFS and OS were 9 and 27 months respectively. A high CD4/CD3 lymphocyte ratio was associated with poorer DFS (8 months versus 11 months for a low ratio) (hazard ratio (HR) 2·23, 95 per cent c.i. 1·04 to 4·61; P = 0·041) and OS (13 versus 27 months respectively) (HR 2·62, 1·11 to 5·88; P = 0·028). A low αSMA/vimentin ratio together with a high CD4/CD3 ratio was correlated with poorer outcomes. No significant association was found between Ki-67, PD-L1 and survival. CONCLUSION: In patients with resected left-sided pancreatic cancer, a tumour microenvironment characterized by a high CD4/CD3 lymphocyte ratio along with a low αSMA/vimentin ratio is correlated with poorer survival.

ANTECEDENTES: El pronóstico del cáncer de páncreas sigue siendo malo y se requieren nuevas dianas terapéuticas de forma urgente. La resistencia al tratamiento podría ser atribuida al microambiente tumoral, un estroma desmoplásico compuesto por fibroblastos asociados al cáncer y linfocitos infiltrantes de tumor. El objetivo del estudio fue evaluar el valor pronóstico de los linfocitos infiltrantes de tumor y de los fibroblastos asociados al cáncer en el cáncer de cuerpo y cola de páncreas. MÉTODOS: Utilizando microarray para el análisis de muestras de tejido obtenidas tras la resección de cáncer de páncreas del lado izquierdo, se realizó inmunohistoquímica de linfocitos infiltrantes de tumor (CD45, CD3, CD4, FoxP3 y CD8), fibroblastos asociados al cáncer (vimentina y actina del músculo liso alfa (αSMA)) y marcadores funcionales (PD-L1 y Ki67), y se investigó la asociación con la supervivencia libre de enfermedad y la supervivencia global. Los resultados se obtuvieron tras un análisis cuantitativo asistido por ordenador. Los pacientes se clasificaron en dos grupos, de bajo y alto riesgo, utilizando el valor del percentil 75 como punto de corte. RESULTADOS: Se incluyeron 43 pacientes en el estudio. En esta población, la mediana de supervivencia libre de enfermedad y de supervivencia global fueron 9 meses y 27 meses, respectivamente. Una alta proporción de linfocitos CD4/CD3 se asoció a peor supervivencia libre de enfermedad (8 meses versus 11 meses; cociente de riesgos instantáneos, hazard ratio, HR 2,2; i.c. del 95% 1,0-4,6; P = 0,041) y supervivencia global (13 meses versus 27 meses; HR 2,6; i.c. del 95% 1,1-5,9; P = 0.028). Una baja proporción αSMA/vimentina junto con una alta proporción CD4/CD3 se correlacionó con peores resultados. No se encontró asociación significativa entre Ki67, PD-L1 y la supervivencia. CONCLUSIÓN: En pacientes con cáncer de páncreas izquierdo resecado, un microambiente tumoral caracterizado por una alta proporción de linfocitos CD4/CD3 junto con una baja proporción de αSMA/vimentina se correlaciona con una peor supervivencia.

Pancreatic neuroendocrine tumor: A multivariate analysis of factors influencing survival.

BACKGROUND: The outcomes of pancreatic neuroendocrine tumors are extremely diverse, and determining the best strategy, optimal timing of therapy and the therapeutic results depend on understanding prognostic factors. We determined the clinical, radiological and histological factors associated with survival and tumor recurrence for patients with pancreatic neuroendocrine tumor. METHODS: From January 1, 1991 to December 31, 2011, 127 patients with pancreatic neuroendocrine tumor underwent pancreatectomy. The variables including clinical characteristics, surgical data and pathological findings were examined by univariate and multivariate analyses. RESULTS: There were 103 patients with non-functional tumors (81%). Sixty-four patients (50%) underwent left pancreatectomy, 51 (42%) patients underwent pancreatico-duodenectomy, 12 (9%) patients underwent enucleation and 2 patients (1%) underwent central pancreatectomy. Forty-eight patients (38%) had synchronous liver metastases. Six patients (5%) required portal vein resection, and 19 (15%) patients required enlarged "en-bloc" resection of adjacent organs. The overall morbidity and mortality rates were 48% and 2.3%, respectively. The 1-, 3- and 5-year overall survival rates were 94%, 84%, and 74%, respectively. In multivariate analyses, synchronous liver metastases (p = 0.02) and portal vein resection (p < 0.01) were independent prognostic factors of survival. CONCLUSIONS: Synchronous liver metastases and portal vein resection were found to be independent factors influencing survival.

Locally advanced gallbladder cancer: which patients benefit from resection?

OBJECTIVES: Patients with T3-4 gallbladder cancers (GBCs) often require extended surgical procedures, and up to 30% of patients have N2 metastases. This study investigated which patients with T3-4 GBC benefit from resection. METHODS: Consecutive patients (n = 78) with T3-4 GBC who underwent resection between 1990 and 2011 were analysed (38 before 2003, 40 in 2003-2011). Forty patients required common bile duct (CBD) resection, 10 pancreatoduodenectomy, 4 right colectomy and 2 gastric resection. Fifty-two (67%) patients had LN metastases, including 22 with N2 metastases. RESULTS: The in-hospital mortality rate was 8%, 11% before 2003 vs. 5% in 2003-2011. The morbidity rate (47%) remained stable during the study. Undergoing liver and pancreatic resection did not increase severe morbidity (0%) or mortality (10%). Sixty-seven (86%) patients had R0 resection. The 5-year survival rate was 17% (median follow-up, 65 months). Survival improved after 2002 (26% vs. 9%, p = 0.04). R1 patients had poor 3-year survival (0% vs. 32%, p = 0.001). N+ patients also had low survival (5-year survival, 10% vs. 32% in N0, p = 0.019), but N1 and N2 patients had similar outcomes. CBD resection and major hepatectomy did not worsen prognosis. Patients requiring pancreatoduodenectomy, gastric or colonic resection had 0% 3-year survival (p = 0.036 in multivariate analysis). CONCLUSIONS: Resection of T3-4 GBC is worthwhile only if R0 surgery is achievable. Outcomes improved in most recent years. N2 metastases should not preclude surgery. Good results are possible even with CBD resection or major hepatectomy, while benefits from surgery are doubtful if pancreatoduodenectomy or other organ resection is needed.