Angiotensin-converting-Enzym-Hemmer (ACEI) und Angiotensin-Rezeptor-Blocker (ARB) sind häug verwendete Antihypertensiva. Weil Eekte auf aber-rante Gefäßbildung und veränderte Immunantwort beschrieben wurden, wurde geprüft, ob sie mit einem besseren Ansprechen auf die neoadjuvante Strahlentherapie des Rektumkarzinoms assoziiert sind. D azu werteten die Forscher retrospek-tiv zum einen die Daten von 115 Pa-tienten aus, die zwischen 1999 und 2012 an der Universität von Wisconsin wegen eines Rektumkarzinoms mit oder ohne begleitende Chemotherapie neoadjuvant bestrahlt worden waren, um eine kurati-ve Resektion zu ermöglichen. 25 von ih-nen (21,7 %) nahmen zum Zeitpunkt der Strahlentherapie ACEI oder ARB ein. Unabhängig davon wurden die Daten ei-ner Kohorte von 186 Patienten analysiert, die ebenfalls wegen eines Rektumkarzi-noms zwischen 1995 und 2010 an der Universität von Hawaii neoadjuvant be-strahlt worden waren, wobei 49 von ih-nen (26,3 %) ACEI/ARB einnahmen. Den Wisconsin-Daten zufolge war die Einnahme von ACE/ARB mit einer Ver-dreifachung der pathologischen Kom-plettremissionen (pCR) assoziiert (52 vs. 17 %; p = 0,001). In der 2. Kohorte zeigte sich eine signikante Verdoppelung der pCR-Rate bei ACEI/ARB-Einnahme (24 vs. 12 %, p = 0,03). Signikante Unter-schiede bezüglich Patientencharakteris-tika oder Art, Dauer und Intensität der onkologischen erapie bestanden zwi-schen den Gruppen mit und ohne Ein-nahme von Antihypertensiva nicht. Auch zeigten sich keine Assoziationen zwischen pCR-Rate und der Einnahme von anderen Medikamenten. In der mul-tivariaten Analyse aller Daten zusam-men war die Einnahme von ACEI/ARB ein starker Prädiktor für eine pCR (Odds Ratio 4,02; p < 0,001). Damit war die ACEI/ARB-Einnahme sogar ein stärkerer Prädiktor für pCR als klini-sches Stadium oder Grading in der Bi-opsie. Ein Eekt auf das lokalrezidiv-, metastasenfreie oder Gesamtüberleben ließ sich nicht zeigen. Das führen die Forscher auf die zu geringe Zahl der Pa-tienten und die zu kurze Dauer der Be-obachtung (4,1 bzw. 5,3 Jahre) zurück. Fazit: Bei Patienten mit Rektumkarzi-nom war die Einnahme von ACEI/ARB in 2 unabhängigen Kohorten mit einer signikanten Steigerung der pCR-Rate nach der neoadjuvanten erapie asso-ziiert. Morris ZS et al. Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer. 2016;122(16):2487-95. Intensivierung der neoadjuvanten Therapie beim lokal fortgeschrittenen Rektumkarzinom Standard beim lokal fortgeschrittenen Rektumkarzinom ist die totale meso-rektale Exzision mit einer Fluoruracil(FU)-basierten Radiochemotherapie vor und einer adjuvanten Chemotherapie nach der Operation. Ein deutlicher Überlebensvorteil gegenüber einer Operation alleine oder mit adjuvanter Chemotherapie konnte damit aber bisher nicht gezeigt werden. D eshalb wurde in einer Phase-III-Stu-die das Überleben nach modizier-ten multimodalen erapien untersucht. 495 erwachsene chinesische Patienten mit lokal fortgeschrittenem Rektumkar-...

PURPOSE In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% ( P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% ( P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% ( P = .971 by log-rank test), respectively. CONCLUSION mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.

Background and Aim: Hairy enhancer of split-1 (HES1) is a downstream transcriptional factor of Notch signaling pathway, which was found to be related to chemoresistance. This study was aimed to investigate the role of HES1 in chemoresistance of colorectal cancer (CRC).Methods: Tissue microarray was used to analyze the clinical significance of HES1 in radical resected (R0) stage II/III CRC patients that received adjuvant chemotherapy. 5-fluorouracil (5-Fu) chemoresistance was examined in CRC cell lines (RKO and HCT8, LOVO) with stable over-expression and inhibition of HES1 gene by cytotoxicity test. Gene expression microarray was used to investigate the enriched pathways and different expressed of genes in cells with over-expressed HES1. Expression changes of the chemoresistance related genes were confirmed by qPCR and western blot analysis.Results: Stage II CRC patients with higher HES1 expression showed higher recurrence rate after chemotherapy. Colon cancer cell lines which over-expressed HES1 were more resistant to 5-Fu treatment in vitro. Gene expression microarray revealed that HES1 was related to the signaling pathways of epithelial-mesenchymal transition (EMT) and drug metabolism. Immunofluorescence assay showed HES1 over-expression lead to depressed E-cadherin and elevated N-cadherin. QPCR and western blot analysis confirmed that ABCC1, ABCC2 and P-gp1 were induced after HES1 over-expression.Conclusions: HES1 promotes chemoresistance to 5-Fu by prompting EMT and inducing of several ABC transporter genes. HES1 might be a novel therapeutic target in CRC treatment.

We found ETS, a higher BMI, and a family history of RSA to be independent risk factors for RSA in our population.

Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its expression and thus cancer risk. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G and -1044A>T) with the Taqman assay, and we found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a decreased risk of lung cancer [odds ratio (OR) = 0.74; 95% confidence interval (CI) = 0.61-0.90 for TG, and OR = 0.62; 95% CI = 0.41-0.94 for GG] in an allele dose-response manner (adjusted P(trend) = 0.0005). Further stratification analysis showed that the protective role of the -1304G variant allele was more evident in low or normal body mass index (BMI) but restrained in the overweighters and that the -1304G variant genotypes interacted with BMI in reducing cancer risk (adjusted P(interaction) = 0.003). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 protein expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of lung cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to lung cancer.