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The Lymph Node Ratio is the Strongest Prognostic Factor after Resection of Pancreatic Cancer

IntroductionSurvival after surgery of pancreatic cancer is still poor, even after curative resection. Some prognostic factors like the status of the resection margin, lymph node (LN) status, or tumor grading have been identified. However, only few data have been published regarding the prognostic influence of the LN ratio (number of LN involved to number of examined LN). We, therefore, evaluated potential prognostic factors in 182 patients after resection of pancreatic cancer including assessment of LN ratio.MethodsSince 1994, 204 patients underwent pancreatic resection for ductal pancreatic adenocarcinoma. Survival was evaluated in 182 patients with complete follow-up evaluations. Of those 182 patients, 88% had cancer of the pancreatic head, 5% of the body, and 7% of the pancreatic tail. Patients underwent pancreatoduodenectomy (85%), distal resection (12%), or total pancreatectomy (3%). Survival was analyzed by the Kaplan–Meier and Cox methods.ResultsIn all 204 resected patients, operative mortality was 3.9% (n = 8). In the 182 patients with follow-up, 70% had free resection margins, 62% had G1- or G2-classified tumors, and 70% positive LN. Median tumor size was 30 (7–80) mm. The median number of examined LN was 16 and median number of involved LN 1 (range 0–22). Median LN ratio was 0.1 (0–0.79). Cumulative 5-year survival (5-year SV) in all patients was 15%. In univariate analysis, a LN ratio ≥ 0.2 (5-year SV 6% vs. 19% with LN ratio < 0.2; p = 0.003), LN ratio ≥ 0.3 (5-year SV 0% vs. 18% with LN ratio < 0.3; p < 0.001), a positive resection margin (p < 0.01) and poor differentiation (G3/G4; p < 0.03) were associated with poorer survival. In multivariate analysis, a LN ratio ≥ 0.2 (p < 0.02; relative risk RR 1.6), LN ratio ≥ 0.3 (p < 0.001; RR 2.2), positive margins (p < 0.02; RR 1.7), and poor differentiation (p < 0.03; RR 1.5) were independent factors predicting a poorer outcome. The conventional nodal status or the number of examined nodes (in all patients and in the subgroups of node positive or negative patients) had no significant influence on survival. Patients with one metastatic LN had the same outcome as patients with negative nodes, but prognosis decreased significantly in patients with two or more LN involved.ConclusionsNot the lymph node involvement per se but especially the LN ratio is an independent prognostic factor after resection of pancreatic cancers. In our series, the LN ratio was even the strongest predictor of survival. The routine estimation of the LN ratio may be helpful not only for the individual prediction of prognosis but also for the indication of adjuvant therapy and herein related outcome and therapy studies.

Impact of different crystalloid volume regimes on intestinal anastomotic stability.

Background:Anastomotic insufficiency still remains an unsolved problem in digestive surgery. Little clinical data, regarding the impact of perioperative volume management exist, which suggest lower complication rates in intestinal surgery under restrictive volume regimens. The aim of our study was to investigate the effect of the extent of intraoperative fluid administration with crystalloids on the stability of intestinal anastomoses. Material and Methods:Twenty-one rats were randomly assigned to 3 experimental groups (n = 7 rats/group): control group CO (9 mL kg−1 h−1 crystalloid infusion), volume restriction group V (−) (3 mL kg−1 h−1), and animals with volume overload V (+) (36 mL kg−1 h−1). After midline incision, all animals received the corresponding infusion for a 30-minute period. Infusion was continued for further 30 minutes whereas an end-to-end small bowel anastomosis was performed 15 cm proximal to the Bauhin valve with 8 nonabsorbable interrupted inverting sutures. At reoperation on the 4th postoperative day, the anastomotic segment was dissected and the bursting pressure [mmHg] was measured. As a second parameter for the quality of anastomotic healing, hydroxyproline concentration was examined with a spectrophotometric method [&mgr;g/g dry tissue]. Histologically, structural changes of the anastomotic segments were assessed by 2 pathologists. Data are given as mean ± SEM. Results:Anastomotic insufficiency was not seen in all animals. Bursting pressure of CO animals was 102 ± 8 mmHg. Bursting pressure was lowest in V (+) with high volume exposure at 77 ± 6 mmHg and significantly lower than V (−) (112 ± 9 mmHg; P = 0.01) whereas the difference compared with the CO group did not reach significant values. Hydroxyproline concentration in V (+) (64.4 &mgr;g/g dry tissue ± 7.7) was significantly lower compared with V (−) (91.7 &mgr;g/g dry tissue ± 9.1) animals (P < 0.05). In all animals with volume overload a marked submucosal edema was found. Conclusion:We could demonstrate for the first time in a systematic investigation, that the quantity of crystalloid infusion, applied intraoperatively, has a significant impact on functional (bursting pressure) and structural (hydroxyproline) stability of intestinal anastomoses in the early postoperative period. Because the stability and quality of an intestinal anastomosis have an impact on insufficiency rates, it should be noted that volume overload may have deleterious effects on anastomotic healing and postoperative complications in digestive surgery, possibly because of a marked bowel wall edema.

Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer.

Targeted therapies have demonstrated clinical benefit with limited impact on long‐term disease specific survival in the treatment of renal cell cancer (RCC). New opportunities for the treatment of tumors that are resistant or have relapsed, are needed. Increased anaerobic glucose fermentation to lactate (aerobic glycolysis), leading to oxygen‐ and mitochondria‐independent ATP generation is a hallmark of aggressive cancer growth. This metabolic shift results in increased lactate production via cycling through the pentose phosphate pathway (PPP), and plays an important role in tumor immune escape, progression and resistance to immune‐, radiation‐ and chemo‐therapy. This study explored the activity and impact of the oxidative and nonoxidative branches of the PPP on RCC to evaluate new therapeutic options. Activity was determined in the oxidative branch by glucose‐6‐phosphate‐dehydrogenase (G6PD) activity, and in the nonoxidative branch by the total transketolase activity and the specific expression of the transketolase‐like‐1 (TKTL1) protein. Transketolase and G6PD activity were intensely elevated in tumor tissues. Transketolase, but not G6PD activity, was more elevated in metastasizing tumors and TKTL1 protein was significantly overexpressed in progressing tumors (p = 0.03). Lethal tumors, where surrogate parameters such as grading and staging had failed to predict progression, showed intensive TKTL1 protein expression. RCC was found to have activated oxidative and nonoxidative glucose metabolism through the PPP, displaying a bioenergetic shift toward nonoxidative glucose fermentation in progressing tumors. The coexistence of cancer cells with differentially regulated energy supplies provides new insights in carcinogenesis and novel anticancer targets.

Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Cancer cells display high rates of aerobic glycolysis, a phenomenon known as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are overproduced by cancer cells even in the presence of oxygen. The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis, glucose degradation to lactate, and regeneration of redox equivalents. The nonoxidative part of the PPP is controlled by transketolase (TKT) enzymes. One TKT isoform, the transketolase‐like protein 1 (TKTL1) is specifically upregulated in different human cancers and its overexpression predicts a poor patients survival. This finding implicates that an increased TKTL1 expression may activate the PPP leading to enhanced cancer cell growth and survival. To analyze the functional role of TKTL1 in malignant progression, we inhibited TKTL1 by RNAi technologies in human HCT116 colon carcinoma cells. TKTL1 suppression resulted in a significantly slowed cell growth, glucose consumption and lactate production. In TKTL1 knockdown‐cells, the intracellular reactive oxygen species levels were not significantly increased, whereas the sensitivity towards oxidative stress‐induced apoptosis was clearly enhanced. These data provide new clues on the importance of TKTL1 dys‐regulation in tumor cells and indicate that TKTL1 overexpression may be considered not only as a new tumor marker but also as a good target for anticancer therapy.

Hepatitis B virus overexpresses suppressor of cytokine signaling-3 (SOCS3) thereby contributing to severity of inflammation in the liver

The mechanism by which hepatitis B virus (HBV) infection causes severe inflammatory liver diseases is multifactorial and related to interactions with cell signaling pathways and the ensuing inflammatory response. Activation of JAK/STAT/SOCS signaling is essential for the induction of cellular antiviral responses, contributes to apoptosis and is negatively regulated by SOCS proteins. Recent reports have shown that SOCS3 activation interferes with viral protein expression and treatment response and thereby plays a major role in hepatitis virus infections. We analyzed the expression of SOCS3 in liver specimens from HBV-infected patients using immunohistochemistry (IHC) and determined the effect of HBV on STAT/SOCS signaling in functional cell culture experiments (HuH-7) using HBV-expressing adenoviral constructs (AdHBV). Increased expression of SOCS3 protein was identified in liver specimens from patients with chronic HBV-infection and this correlated with the severity of liver inflammation. In accordance with the IHC-findings, in vitro analyses demonstrated that HBV infection of HuH7 cells was associated with increased expression of SOCS3 protein. In spite of the over expression of its negative regulator SOCS3 we observed a constitutive activation of STAT3. SOCS1 levels were not increased while pSTAT1 was suppressed in HBV-infected HuH7 cells. Our results demonstrate that STAT/SOCS-signaling is dysregulated in HBV-infected hepatocytes both in vivo and in vitro and this correlated with the severity of liver inflammatory changes. This interference of STAT/SOCS signaling by HBV may result in an ineffective immune response against HBV and potentially contributes to viral pathogenesis, malignant transformation and may represent an important mechanism of viral persistence.