Does adjuvant chemoradiotherapy improve the prognosis of gastric cancer after an r1 resection? Results from a dutch cohort study.

OBJECTIVE: The aim of this study was to investigate the impact of adjuvant chemoradiotherapy (CRT) on survival of non-metastatic gastric cancer patients who had undergone an R1 resection. METHODS: We compared the survival of patients after an R1 gastric cancer resection from the population-based Netherlands Cancer Registry who did not receive adjuvant CRT (no-CRT group) with the survival of resected patients who had been treated with adjuvant CRT (CRT group) at our institute. Patients who had a resection between 2002 and 2011 were included. CRT consisted of radiotherapy (45 Gy) combined with concurrent cisplatin- or 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival was assessed using multivariable Cox regression and stratified propensity score analysis. RESULTS: A series of 409 gastric cancer patients who had undergone an R1 resection were studied (no-CRT, N = 369; CRT, N = 40). In the no-CRT group, median age was higher (70 vs. 57 years; p < 0.001) and the percentage of patients with diffuse-type tumors was lower (43 vs. 80 %; p < 0.001). There were no significant differences in pathological T- and N-classification. There was a significant difference in median overall survival between the no-CRT and CRT group (13 vs. 24 months; p = 0.003). In a multivariable analysis, adjuvant CRT was an independent prognostic factor for improved overall survival (hazard ratio 0.54; 95 % confidence interval 0.35-0.84). This effect of CRT was further supported by propensity score analysis. CONCLUSIONS: Adjuvant CRT was associated with an improved survival in patients who had undergone an R1 resection for gastric cancer.

The prognostic significance of an R1 resection in gastric cancer patients treated with adjuvant chemoradiotherapy.

BACKGROUND: A microscopically irradical (R1) resection is a well-known adverse prognostic factor after gastric cancer surgery. However, the prognostic significance of an R1 resection in gastric cancer patients who are treated with chemoradiotherapy (CRT) after the operation has been poorly studied. Therefore, the aim of this study was to evaluate the effect of an R1 resection on (recurrence-free) survival in gastric cancer patients who were treated with CRT after surgery. METHODS: Gastric cancer patients who had undergone a resection with curative intent followed by adjuvant CRT at our institute between 2001 and 2011 were included. CRT consisted of radiotherapy (45 Gy/25 fractions) combined with concurrent capecitabine (with or without cisplatin) or 5-fluorouracil/leucovorin. RESULTS: A consecutive series of 110 patients was studied, including 80 (73 %) patients who had undergone an R0 resection and 30 (27 %) patients with an R1 resection. Pathologic T-classification (p = 0.26), N-classification (p = 0.77), and histologic subtype according to Laurén (p = 0.071) were not significantly different between these groups. Three-year recurrence-free survival (45 vs. 35 %, p = 0.34) and overall survival (47 vs. 48 %, p = 0.58) did not significantly differ between patients who had undergone an R0 or R1 resection. In a multivariate analysis, pathologic T-classification and N-classification were independent prognostic factors for survival. CONCLUSIONS: A R1 resection was not an adverse prognostic factor in gastric cancer patients who had undergone CRT after the operation.

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features.

Nodal marginal zone lymphoma is a poorly defined entity in the World Health Organization classification, based largely on criteria of exclusion and the diagnosis often remains subjective. Follicular lymphoma lacking t(14;18) has similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution array comparative genome hybridization: nodal marginal zone lymphoma, t(14;18)-negative follicular lymphoma, localized t(14:18)-positive follicular lymphoma and disseminated t(14;18)-positive follicular lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive follicular lymphoma than in localized t(14:18)-positive follicular lymphoma (P<0.01) and the majority of alterations in localized t(14:18)-positive follicular lymphoma were also found in disseminated t(14;18)-positive follicular lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative follicular lymphoma compared to t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma is characterized by specific (focal) gains on chromosome 3, as observed in nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive follicular lymphoma represents an early phase of disseminated t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma bears aberrations that are more like those in nodal marginal zone lymphoma, suggesting a relation between these groups.

Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer.

Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis.