Small cell lung cancer cell lines were resistant to FasL and TRAIL-induced apoptosis, which could be explained by an absence of Fas and TRAIL-R1 mRNA expression and a deficiency of surface TRAIL-R2 protein. In addition, caspase-8 expression was absent, whereas FADD, FLIP and caspases-3, -7, -9 and -10 could be detected. Analysis of SCLC tumors revealed reduced levels of Fas, TRAIL-R1 and caspase-8 mRNA compared to non-small cell lung cancer (NSCLC) tumors. Methylation-specific PCR demonstrated methylation of CpG islands of the Fas, TRAIL-R1 and caspase-8 genes in SCLC cell lines and tumor samples, whereas NSCLC samples were not methylated. Cotreatment of SCLC cells with the demethylating agent 5 0 -aza-2-deoxycytidine and IFNc partially restored Fas, TRAIL-R1 and caspase-8 expression and increased sensitivity to FasL and TRAIL-induced death. These results suggest that SCLC cells are highly resistant to apoptosis mediated by death receptors and that this resistance can be reduced by a combination of demethylation and treatment with IFNc.

Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several nonliver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. Conclusion: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. (HEPATOLOGY 2011;53:854-864) H epatocellular carcinoma (HCC) is the thirdleading cause of cancer deaths worldwide. 1 Important risk factors for this disease are persistent infections with hepatitis viruses and chronic steatohepatitis due to ethanol abuse and obesity, which contribute to the increasing incidence of HCC in Abbreviations: AHR, aryl hydrocarbon receptor; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; ETS, E twenty-six; FACS, fluorescenceactivated cell sorting; FBS, fetal bovine serum; FCS, fetal colf serum; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GSK3b, glycogen synthase kinase 3b; HCC, hepatocellular carcinoma; HIF, hypoxia inducible factor; MAP, mitogen-activated protein; MF, myofibroblast; mRNA, messenger RNA; MTF, metal-responsive transcription factor; pERK, phosphorylated extracellular signal-regulated kinase; pGSK3b, phosphorylated glycogen synthase kinase 3b; pS6, phosphorylated S6; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; siFGF18, small interfering RNA targeting fibroblast growth factor 18; siRNA, small interfering RNA;...

SummaryBackgroundThe standardized Clavien-Dindo classification of surgical complications is applied as a simple and widely used tool to assess and report postoperative complications in general surgery. However, most documentation uses this classification to report surgery-related morbidity and mortality in a single field of surgery or even particular intervention. The aim of the present study was to present experiences with the Clavien-Dindo classification when applied to all patients on the general surgery ward of a tertiary referral care center.MethodsWe analyzed a period of 6 months of care on a ward with a broad range of general and visceral surgery. Discharge reports and patient charts were analyzed retrospectively and reported complications rated according to the most recent Clavien-Dindo classification version. The complexity of operations was assessed with the Austrian Chamber of Physicians accounting system.ResultsThe study included 517 patients with 817 admissions, of whom 463 had been operated upon. Complications emerged in 12.5%, of which 19% were rated as Clavien I, 20.7% as Clavien II, 13.8% as Clavien IIIa, 27.6% as Clavien IIIb, 8.6% as Clavien IVa, and 10.3% as Clavien V. No Clavien grade IVb complication occurred within the investigation. Patients having undergone more complex surgery or with higher scores experienced significantly longer lengths of hospital stay.ConclusionThe Clavien-Dindo classification can easily be used to document complication rates in general surgery, even though this collective was not included in the original validation studies of Clavien et al. and consisted of more heavily impaired patients.

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BACKGROUND HER‐2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER‐2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER‐2/neu status. METHODS The authors evaluated HER‐2/neu status in 923 consecutive patients with breast carcinoma by immunohistochemical methods. Correlations involving HER‐2/neu status, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade, patient age, lymph node involvement, and tumor size were evaluated using the Mantel–Haenszel chi‐square test and the Spearman correlation. The authors created a simple scoring system (i.e., the diagnostic instrument for validation of HER‐2/neu score) to define subgroups of patients with breast carcinoma and to determine the likelihood of HER‐2/neu positivity. RESULTS HER‐2/neu overexpression was correlated significantly with negative ER (P = 0.0001) and PR status (P = 0.0001), Grade 3 (G3) lesions (P = 0.0001), and young age (P = 0.006). The likelihood of HER‐2/neu positivity in a patient with positive ER and PR status and G1/G2 disease was approximately 6.1%. CONCLUSIONS The authors demonstrated in a large patient series that HER‐2/neu overexpression was associated with negative hormone receptor status, G3, and young age. In a subgroup of patients presenting with hormone‐responsive and G1/G2 tumors, the likelihood of HER‐2/neu overexpression was very small. Therefore, the assessment of HER‐2/neu status in this subgroup of patients with breast carcinoma may be considered unnecessary, unless the role of HER‐2/neu status in adjuvant treatment has been proven. Cancer 2003;98:2547–53. © 2003 American Cancer Society.