Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy.

BACKGROUND: Pancreatoduodenectomy is a surgical procedure used to treat diseases of the pancreatic head and, less often, the duodenum. The most common disease treated is cancer, but pancreatoduodenectomy is also used for people with traumatic lesions and chronic pancreatitis. Following pancreatoduodenectomy, the pancreatic stump must be connected with the small bowel where pancreatic juice can play its role in food digestion. Pancreatojejunostomy (PJ) and pancreatogastrostomy (PG) are surgical procedures commonly used to reconstruct the pancreatic stump after pancreatoduodenectomy. Both of these procedures have a non-negligible rate of postoperative complications. Since it is unclear which procedure is better, there are currently no international guidelines on how to reconstruct the pancreatic stump after pancreatoduodenectomy, and the choice is based on the surgeon's personal preference. OBJECTIVES: To assess the effects of pancreaticogastrostomy compared to pancreaticojejunostomy on postoperative pancreatic fistula in participants undergoing pancreaticoduodenectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 9), Ovid MEDLINE (1946 to 30 September 2016), Ovid Embase (1974 to 30 September 2016) and CINAHL (1982 to 30 September 2016). We also searched clinical trials registers (ClinicalTrials.gov and WHO ICTRP) and screened references of eligible articles and systematic reviews on this subject. There were no language or publication date restrictions. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) assessing the clinical outcomes of PJ compared to PG in people undergoing pancreatoduodenectomy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We performed descriptive analyses of the included RCTs for the primary (rate of postoperative pancreatic fistula and mortality) and secondary outcomes (length of hospital stay, rate of surgical re-intervention, overall rate of surgical complications, rate of postoperative bleeding, rate of intra-abdominal abscess, quality of life, cost analysis). We used a random-effects model for all analyses. We calculated the risk ratio (RR) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes (using PG as the reference) with 95% confidence intervals (CI) as a measure of variability. MAIN RESULTS: We included 10 RCTs that enrolled a total of 1629 participants. The characteristics of all studies matched the requirements to compare the two types of surgical reconstruction following pancreatoduodenectomy. All studies reported incidence of postoperative pancreatic fistula (the main complication) and postoperative mortality.Overall, the risk of bias in included studies was high; only one included study was assessed at low risk of bias.There was little or no difference between PJ and PG in overall risk of postoperative pancreatic fistula (PJ 24.3%; PG 21.4%; RR 1.19, 95% CI 0.88 to 1.62; 7 studies; low-quality evidence). Inclusion of studies that clearly distinguished clinically significant pancreatic fistula resulted in us being uncertain whether PJ improved the risk of pancreatic fistula when compared with PG (19.3% versus 12.8%; RR 1.51, 95% CI 0.92 to 2.47; very low-quality evidence). PJ probably has little or no difference from PG in risk of postoperative mortality (3.9% versus 4.8%; RR 0.84, 95% CI 0.53 to 1.34; moderate-quality evidence).We found low-quality evidence that PJ may differ little from PG in length of hospital stay (MD 1.04 days, 95% CI -1.18 to 3.27; 4 studies, N = 502) or risk of surgical re-intervention (11.6% versus 10.3%; RR 1.18, 95% CI 0.86 to 1.61; 7 studies, N = 1263). We found moderate-quality evidence suggesting little difference between PJ and PG in terms of risk of any surgical complication (46.5% versus 44.5%; RR 1.03, 95% CI 0.90 to 1.18; 9 studies, N = 1513). PJ may slightly improve the risk of postoperative bleeding (9.3% versus 13.8%; RR 0.69, 95% CI: 0.51 to 0.93; low-quality evidence; 8 studies, N = 1386), but may slightly worsen the risk of developing intra-abdominal abscess (14.7% versus 8.0%; RR 1.77, 95% CI 1.11 to 2.81; 7 studies, N = 1121; low quality evidence). Only one study reported quality of life (N = 320); PG may improve some quality of life parameters over PJ (low-quality evidence). No studies reported cost analysis data. AUTHORS' CONCLUSIONS: There is no reliable evidence to support the use of pancreatojejunostomy over pancreatogastrostomy. Future large international studies may shed new light on this field of investigation.

Vitamin B6 and Cancer Risk: A Field Synopsis and Meta-Analysis.

Background: Vitamin B6 is involved in many biochemical reactions and might play a role in carcinogenesis. We summarized the evidence linking vitamin B6 to cancer risk. Methods: We conducted a systematic review of both observational and intervention studies investigating the relationship between vitamin B6 intake or blood levels of its bioactive form pyridoxal-5'-phosphate (PLP) and the risk of any type of cancer. Random-effects meta-analysis was used to calculate pooled relative risks (RRs) and their 95% confidence intervals (CIs) across studies for high vs low categories of vitamin intake or PLP levels. We also performed a random-effects dose-response meta-analysis. Results: We identified 121 observational studies (participants, n = 1 924 506; cases, n = 96 , 436) and nine randomized controlled trials (RCTs; participants, n = 34 911; cases, n = 2539) considering 19 tumor sites. High intake of dietary (food only) vitamin B6 was statistically significantly associated with lower risk of all cancers (relative risk [RR] = 0.78, 95% CI = 0.73 to 0.84) and specific tumors, with special regard to gastrointestinal carcinomas (RR = 0.68, 95% CI = 0.61 to 0.75). An inverse association was also observed between high PLP levels and the risk of all cancers (RR = 0.66, 95% CI = 0.58 to 0.76) and single tumor sites, the most consistent results being those for gastrointestinal tumors (RR = 0.56, 95% CI = 0.48 to 0.65). There was a statistically significant inverse linear relationship between cancer risk and both vitamin B6 dietary intake and PLP levels. When total (food and supplements) intake was considered, the associations were weaker or null. Findings from RCTs did not support a protective effect of vitamin B6 against cancer, although this evidence was graded as low level. Conclusions: Epidemiological evidence supports the potential of vitamin B6 as a cancer risk reduction agent and the role of PLP as a cancer screening biomarker, especially for gastrointestinal tumors. However, inconsistent findings from total intake and intervention studies suggest that vitamin B6 might also be an indicator of other dietary protective micronutrients.

Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake. METHODS: We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided. RESULTS: We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively. CONCLUSIONS: These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease.

Telomere-specific reverse transcriptase (hTERT) and cell-free RNA in plasma as predictors of pathologic tumor response in rectal cancer patients receiving neoadjuvant chemoradiotherapy.

PURPOSE: To investigate whether the plasma levels of cell-free RNA (cfRNA) and telomere-specific reverse transcriptase mRNA (hTERT) are associated with tumor response in rectal cancer patients who received preoperative chemoradiotherapy (pCRT). METHODS: Patients who underwent pCRT for rectal cancer and for whom baseline and paired post-pCRT blood samples were available were studied. On the basis of tumor regression score, patients were classified as having response or having no response. Clinical variables and plasma levels of cfRNA and hTERT before and after the pCRT were evaluated. The association between each predictor and tumor response was assessed by univariate and multivariate analyses. RESULTS: Of 98 eligible patients, 45 were determined to respond to therapy, and 53 did not respond to therapy. In univariate analysis, gender (P = 0.040), baseline levels of cfRNA (P = 0.026), post-pCRT levels of both hTERT and cfRNA (P < 0.0001 and P = 0.001, respectively), and the difference between the post- and pre-pCRT levels of both hTERT and cfRNA (P = 0.009 and P = 0.001, respectively) were found to be significant predictors of tumor response. In multivariate analysis, using variables that were available before pCRT, cfRNA levels and gender independently predicted the tumor response, while in multivariate analysis, which used all of the variables available before the surgical procedure, the post-pCRT levels of cfRNA and the difference between the post- and pre-pCRT levels of cfRNA independently predicted tumor response. CONCLUSIONS: Plasma levels of cfRNA and hTERT are promising markers of tumor response to pCRT for rectal cancer.

APC I1307K mutations and forkhead box gene (FOXO1A): another piece of an interesting correlation.

PURPOSE: Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS). EXPERIMENTAL DESIGN: An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated. RESULTS: Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients. CONCLUSIONS: Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

Prognostic value of putative circulating cancer stem cells in patients undergoing hepatic resection for colorectal liver metastasis.

BACKGROUND: Although surgery is the gold standard treatment of hepatic metastasis from colorectal cancer (CRC), many patients ultimately die of their disease. We tested the hypothesis that the detection of circulating tumor cells (CTC) might identify patients at high risk of dying of disease recurrence after apparently radical liver surgery. METHODS: We considered 50 patients undergoing radical surgery for liver-confined hepatic metastasis from CRC. The expression of a panel of cancer-related genes, as assessed by quantitative real-time PCR, was used to detect CTC in the peripheral blood of these patients immediately before surgery. Survival analysis was performed by the Cox regression model. RESULTS: Univariate analysis of the expression levels of CD133 (a marker of colon cancer stem cells) and survivin (an antiapoptotic factor) resulted in statistically significant association with patient survival [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.9-3.7, P < 0.0001; and hazard ratio 2.1, 95% CI 1.4-3.2, P < 0.0001, respectively]. Remarkably, multivariate analysis found that only the transcriptional amount of CD133 resulted in statistical significance (HR 2.6, 95% CI 1.9-3.6, P < 0.0001), indicating that this biomarker can independently predict the survival of these patients. CONCLUSIONS: CD133-positive CTC may represent a suitable prognostic marker to stratify the risk of patients who undergo liver resection for CRC metastasis, which opens the avenue to identifying and potentially monitoring the patients who are most likely to benefit from adjuvant treatments.

Circulating cell-free DNA: a promising marker of pathologic tumor response in rectal cancer patients receiving preoperative chemoradiotherapy.

PURPOSE: The circulating cell-free DNA (cfDNA) in plasma has been reported to be a marker of cancer detection. The aim of this study was to investigate whether the cfDNA has a role as response biomarker in patients receiving preoperative chemoradiotherapy (CRT) for rectal cancer. METHODS: Sixty-seven patients (median age 61 years; male/female 42/25) who underwent CRT for rectal cancer were evaluated. After tumor regression grade (TRG) classification was made, the patients were classified as having disease that responded (TRG 1-2) and that did not respond (TRG 3-5) to therapy. Plasma samples were obtained from patients before and after CRT. The cfDNA levels were analyzed by quantitative real-time polymerase chain reaction of ß-globin. On the basis of the Alu repeats, the cfDNA was considered as either total (fragments of 115 bp, Alu 115) or tumoral (fragments of 247 bp, Alu 247). The association between the pre- or post-CRT levels and between variations during CRT of the Alu 247, Alu 115 repeat, and Alu 247/115 ratio (cfDNA integrity index) and the pathologic tumor response was analyzed. RESULTS: The baseline levels of cfDNA were not associated with tumor response. The post-CRT levels of the cfDNA integrity index were significantly lower in responsive compared to nonresponsive disease (P = 0.0009). Both the median value of the Alu 247 repeat and the cfDNA integrity index decreased after CRT in disease that responded to therapy (P < 0.005 and P < 0.005, respectively) compared to disease that did not respond to therapy (P = 0.83 and P = 0.726, respectively). The results of the multivariable logistic regression analysis showed that only the cfDNA integrity index was significantly and independently associated with tumor response to treatment. CONCLUSIONS: The plasma levels of the longer fragments (Alu 247) of cfDNA and the cfDNA integrity index are promising markers to predict tumor response after preoperative CRT for rectal cancer.

Targeted Therapy Database (TTD): a model to match patient's molecular profile with current knowledge on cancer biology.

BACKGROUND: The efficacy of current anticancer treatments is far from satisfactory and many patients still die of their disease. A general agreement exists on the urgency of developing molecularly targeted therapies, although their implementation in the clinical setting is in its infancy. In fact, despite the wealth of preclinical studies addressing these issues, the difficulty of testing each targeted therapy hypothesis in the clinical arena represents an intrinsic obstacle. As a consequence, we are witnessing a paradoxical situation where most hypotheses about the molecular and cellular biology of cancer remain clinically untested and therefore do not translate into a therapeutic benefit for patients. OBJECTIVE: To present a computational method aimed to comprehensively exploit the scientific knowledge in order to foster the development of personalized cancer treatment by matching the patient's molecular profile with the available evidence on targeted therapy. METHODS: To this aim we focused on melanoma, an increasingly diagnosed malignancy for which the need for novel therapeutic approaches is paradigmatic since no effective treatment is available in the advanced setting. Relevant data were manually extracted from peer-reviewed full-text original articles describing any type of anti-melanoma targeted therapy tested in any type of experimental or clinical model. To this purpose, Medline, Embase, Cancerlit and the Cochrane databases were searched. RESULTS AND CONCLUSIONS: We created a manually annotated database (Targeted Therapy Database, TTD) where the relevant data are gathered in a formal representation that can be computationally analyzed. Dedicated algorithms were set up for the identification of the prevalent therapeutic hypotheses based on the available evidence and for ranking treatments based on the molecular profile of individual patients. In this essay we describe the principles and computational algorithms of an original method developed to fully exploit the available knowledge on cancer biology with the ultimate goal of fruitfully driving both preclinical and clinical research on anticancer targeted therapy. In the light of its theoretical nature, the prediction performance of this model must be validated before it can be implemented in the clinical setting.