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Background This meta-analysis sought to evaluate the potential benefits and harms of laparoscopic gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer versus open surgery. Methods A comprehensive search for randomized controlled studies that compared laparoscopic versus open gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer published until December 31, 2018, was conducted. Operative outcomes, early postoperative outcomes, and long-term results were analyzed using a random effects model. Results Five randomized controlled trials containing a collective total of 2157 patients were included. In comparison with open surgery, laparoscopic gastrectomy for locally advanced gastric cancer showed similar risks of short-term mortality and serious adverse events within 30 days after surgery. Regarding intraoperative outcomes, operative time was increased for the laparoscopic approach, whereas the estimated intraoperative blood loss tended to be less. However, the amount of evidence was low for most outcomes. In addition, the results for the length of hospital stay and time to first flatus did not show statistically significant differences. The number of harvested lymph nodes and compliance with D2 lymphadenectomy did not significantly differ between the two groups, indicating oncological equivalence of both approaches. However, long-term oncological results could not be evaluated due to a lack of relevant data in four of the trials. Conclusion Laparoscopic gastrectomy with D2 lymphadenectomy can be performed with equivalent overall short-term morbidity and mortality versus the open approach for locally advanced gastric cancer. However, further well-designed randomized controlled trials are necessary to assess the possible advantages and risks of the laparoscopic approach as well as the long-term results.

Background Lymph node staging of ductal adenocarcinoma of the pancreatic head (PDAC) by cross-sectional imaging is limited. The aim of this study was to determine the diagnostic accuracy of expanded criteria in nodal staging in PDAC patients. Methods Sixty-six patients with histologically confirmed PDAC that underwent primary surgery were included in this retrospective IRB-approved study. Cross-sectional imaging studies (CT and/or MRI) were evaluated by a radiologist blinded to histopathology. Number and size of lymph nodes were measured (short-axis diameter) and characterized in terms of expanded morphological criteria of border contour (spiculated, lobulated, and indistinct) and texture (homogeneous or inhomogeneous). Sensitivities and specificities were calculated with histopathology as a reference standard. Results Forty-eight of 66 patients (80%) had histologically confirmed lymph node metastases (pN+). Sensitivity, specificity, and Youden’s Index for the criterion “size” were 44.2%, 82.4%, and 0.27; for “inhomogeneous signal intensity” 25.6%, 94.1%, and 0.20; and for “border contour” 62.7%, 52.9%, and 0.16, respectively. There was a significant association between the number of visible lymph nodes on preoperative CT and lymph node involvement (pN+, p = 0.031). Conclusion Lymph node staging in PDAC is mainly limited due to low sensitivity for detection of metastatic disease. Using expanded morphological criteria instead of size did not improve regional nodal staging due to sensitivity remaining low. Combining specific criteria yields improved sensitivity with specificity and PPV remaining high.

Pancreatic fistula (PF) represents a major complication after distal pancreatectomy. In a consecutive series of 110 patients, risk factors for the incidence of PF and surgical morbidity were identified. Patients having undergone distal pancreatectomy between 2003 and 2007 were identified. Clinicopathologic parameters as well as perioperative data were correlated with the incidence of PF and overall surgical morbidity using univariate and multivariate models. In 72 patients (65%), malignant disease was present. Splenectomy and multivisceral resection were performed in 84 (76%) and 47 (42%) patients, respectively. Overall major surgical morbidity was 18%, and 12 patients (11%) developed PFs. A body mass index > 25 kg/m 2 was the only independent significant predictive factor for PF. Malignancy, splenectomy, multivisceral resection, transfusion, comorbidity, and stapler use did not show statistical significance. For overall surgical morbidity, there was no significant indicator. A body mass index > 25 kg/m 2 contributes to the incidence of PF after distal pancreatectomy. Other parameters did not show a significant influence on PF or on overall surgical morbidity.

Background The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC. Methods Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed. Results Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival. Conclusions In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.

Purpose Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. Methods Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. Results Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3 Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. Conclusions Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC.

One of the most exciting concepts being explored in cancer research today is the idea of cancer stem cells. Evidence for the existence of such cells was first proposed for haematological malignancies and, more recently, for solid tumors, including breast, brain, colon and pancreatic cancer. The cancer stem cell hypothesis states that a minority of transformed stem cells, or progenitors with acquired self-renewal properties, are the source of tumor cell renewal and thereby determine the behaviour of tumors, including proliferation, spreading and response to chemo- and radiotherapy. Indeed, just as somatic stem cells may be resistant to the induction of apoptosis by cytotoxic agents and radiation therapy, cancer stem cells may display increased resistance to these agents as compared with the more differentiated cells that comprise the mass of tumors. More specifically, the reactivation of varied developmental signalling cascades (epidermal growth factor (EGF)/EGFR, stem cell factor (SCF)/KIT, sonic hedgehog, Notch, and/or Wnt/β-catenin) combined with the increased DNA repair mechanisms and ABC transporter-mediated drug efflux in cancer stem cells may be responsible for their resistance to conventional therapies. Furthermore, changes in the local microenvironment of cancer stem cells may also influence their behaviour. Thus, the molecular targeting of such highly tumorigenic cancer cells must be considered for improving the efficacy of the current anti-cancer strategies with the aim to sensitize tumors toward conventional therapies and effectively abrogate tumorigenesis. This review provides a summary of some developments in the field of cancer stem cell targeting and highlights aspects where it could be of help in the drug discovery process.

Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.

Purpose The benefit of elective primary tumor resection for non-curable stage IV colorectal cancer (CRC) remains largely undefined. We wanted to identify risk factors for postoperative complications and short survival. Methods Using a prospective database, we analyzed potential risk factors in 233 patients, who were electively operated for non-curable stage IV CRC between 1996 and 2002. Patients with recurrent tumors, resectable metastases, emergency operations, and non-resective surgery were excluded. Risk factors for increased postoperative morbidity and limited postoperative survival were identified by multivariate analyses. Results Patients with colon cancer (CC = 156) and rectal cancer (RC = 77) were comparable with regard to age, sex, comorbidity, American Society of Anesthesiologists score, carcinoembryonic antigen levels, hepatic spread, tumor grade, resection margins, 30-day mortality (CC 5.1%, RC 3.9%) and postoperative chemotherapy. pT4 tumors, carcinomatosis, and non-anatomical resections were more common in colon cancer patients, whereas enterostomies (CC 1.3%, RC 67.5%, p < 0.0001), anastomotic leaks (CC 7.7%, RC 24.2%, p = 0.002), and total surgical complications (CC 19.9%, RC 40.3%, p = 0.001) were more frequent after rectal surgery. Independent determinants of an increased postoperative morbidity were primary rectal cancer, hepatic tumor load >50%, and comorbidity >1 organ. Prognostic factors for limited postoperative survival were hepatic tumor load >50%, pT4 tumors, lymphatic spread, R1-2 resection, and lack of chemotherapy. Conclusions Palliative resection is associated with a particularly unfavorable outcome in rectal cancer patients presenting with a locally advanced tumor (pT4, expected R2 resection) or an extensive comorbidity, and in all CRC patients who show a hepatic tumor load >50%. For such patients, surgery might be contraindicated unless the tumor is immediately life-threatening.

Telmisartan is an angiotensin I (AT1) receptor blocker used in the treatment of essential hypertension, with partial peroxisome proliferator-activated receptor γ (PPARγ) agonism. In prior studies, PPARγ activation led to apoptosis and cell cycle inhibition in various cancer cells. The aim of the present study was to investigate the potential antiproliferative and apoptotic effects of telmisartan by partially activating PPARγ. HT-29, SW-480 and SW-620 cells were incubated with telmisartan (0.2-5 μM) or the full agonist, pioglitazone (0.2-5.0 μM). The antiproliferative and apoptotic effects of telmisartan in the human colon cancer cells were significant at therapeutic serum concentrations, and telmisartan exhibited a potency at least equivalent to the full PPARγ agonist, pioglitazone. The antiproliferative and apoptotic effects of pioglitazone in the human colon cancer cells were not completely deregulated by PPARγ blockade with GW9662. In the telmisartan-treated cells, PPARγ blockade resulted in an increased antiproliferative and apoptotic effect. These effects are not entirely explained by PPARγ activation, however, possible hypotheses that require further experimental investigation are as follows: i) Ligand-independent PPARγ activation through the activation-function 1 domain; ii) a PPARγ-independent mechanism; or iii) independent antiproliferative and apoptotic effects through GW9662.