Prognostic Value of Body Mass Index on Short-Term and Long-Term Outcome after Resection of Esophageal Cancer

Introduction: Cachexia and obesity have been suggested to be risk factors for postoperative complications. However, high body mass index (BMI) might result in a higher R0-resection rate because of the presence of more fatty tissue surrounding the tumor. The purpose of this study was to investigate whether BMI is of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer. Methods: In 556 patients who underwent esophagectomy (1991-2007), clinical and pathological outcome were compared between different BMI classes (underweight, normal weight, overweight, obesity). Results: Overall morbidity, mortality, and reoperation rate did not differ in underweight and obese patients. However, severe complications seemed to occur more often in obese patients (p = 0.06), and the risk for anastomotic leakage increased with higher BMI (12.5% in underweight patients compared with 27.6% in obese patients, p = 0.04). Histopathological assessment showed comparable pTNM stages, although an advanced pT stage was seen more often in patients with low/normal BMI (p = 0.02). A linear association between BMI and R0-resection rate was detected (p = 0.02): 60% in underweight patients compared with 81% in obese patients. However, unlike pT-stage (p < 0.001), BMI was not an independent predictor for R0 resection (p = 0.12). There was no significant difference in overall or disease-free 5-year survival between the BMI classes (p = 0.25 and p = 0.6, respectively). Conclusions: BMI is not of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer and is not an independent predictor for radical R0 resection. Patients oncologically eligible for esophagectomy should not be denied surgery on the basis of their BMI class

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l−1, 1=C-reactive protein >10 mg l−1, and 2=C-reactive protein >10 mg l−1 and albumin<35 g l−1) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54–9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29–11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11–4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99–3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05–4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82–3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01–2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

Background: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. Methods: In total, 205 patients received neoadjuvant CT±ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. Results: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5–20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). Conclusion: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies

Preoperative serum carcinoembryonic antigen, albumin and age are supplementary to UICC staging systems in predicting survival for colorectal cancer patients undergoing surgical treatment

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine influence of prognostic factors in addition to UICC staging systems, on cancer-specific and overall survival rates for patients with colorectal cancer (CRC) undergoing surgical treatment.</p> <p>Methods</p> <p>Between January 1996 and December 2006, a total of 1367 CRC patients who underwent surgical treatment in Kaohsiung Medical University Hospital were analyzed. We retrospectively investigated clinicopathologic features of these patients. All patients were followed up intensively, and their outcomes were investigated completely.</p> <p>Results</p> <p>Of 1367 CRC patients, there were seven hundred and fifty-seven males (55.4%) and 610 (44.6%) females. The median follow-up period was 60 months (range, 3–132 months). A multivariate analysis identified that low serum albumin level (<it>P </it>= 0.011), advanced UICC stage (<it>P </it>< 0.001), and high carcinoembryonic antigen (CEA) level (<it>P </it>< 0.001) were independent prognostic factors of cancer-specific survival. Meanwhile, a multivariate analysis showed age over 65 years (<it>P </it>< 0.001), advanced UICC stage (<it>P </it>< 0.001), and high CEA level (<it>P </it>< 0.001) were independent prognostic factors of overall survival. Furthermore, combination of UICC stage, serum CEA and albumin levels as predictors of cancer-specific survival showed that the poorer the prognostic factors involved, the poorer the cancer-specific survival rate. Likewise, combination of UICC stage, age and serum CEA level as predictors of overall survival showed that the poorer the prognostic factors involved, the poorer the overall survival rate. Of these prognostic factors, preoperative serum CEA level was the only significant prognostic factor for patients with stage II and III CRCs in both cancer-specific and overall survival categories.</p> <p>Conclusion</p> <p>Preoperative serum albumin level, CEA level and age could prominently affect postoperative outcome of CRC patients undergoing surgical treatment. In addition to conventional UICC staging system, it might be imperative to take these additional characteristics of factors into account in CRC patients prior to surgical treatment.</p

Alternative methods of follow up in breast cancer: a systematic review of the literature

Regular clinical follow up after breast cancer is a common practice. Evidence from retrospective reviews casts doubt on the efficacy of this practice and the various guidelines for follow up show little concordance. Our aim was to investigate what alternative follow-up methods (including reduced frequency of visits) have been subjected to controlled trial and to establish what evidence exists from controlled trials to advise the guidelines. The study involved systematic review of the literature using MEDLINE, Embase, CancerLit, Web of Sciences and EBM reviews as data sources. Methods included reviewing all randomised controlled trials comparing different follow-up frequencies or comparing an alternative method with clinical follow up after breast cancer. All outcome measures addressed in the trials were analysed. Two trials compared frequency of traditional follow up. Five trials assessed alternative methods. All were of inadequate power or duration to establish ideal frequency of clinic visits or safety of alternative follow-up methods. Alternative follow up had no detrimental effect on satisfaction or outcome. Few trials have been conducted, all of which are underpowered to establish safety of reducing or replacing clinic visits. Alternative methods of follow up are acceptable to patients and may be associated with other benefits. Larger trials are required

New insights into the role of age and carcinoembryonic antigen in the prognosis of colorectal cancer

The aim of this study was to verify through relative survival (an estimate of cancer-specific survival) the true prognostic factors of colorectal cancer. The study involved 506 patients who underwent locally radical resection. All the clinical, histological and laboratory parameters were prognostically analysed for both overall and relative survival. This latter was calculated from the expected survival of the general population with identical age, sex and calendar years of observation. Univariate and multivariate analyses were applied to the proportional hazards model. Liver metastases, age, lymph node involvement and depth of bowel wall involvement were independent prognosticators of both overall and relative survival, whereas carcinoembryonic antigen (CEA) was predictive only of relative survival. Increasing age was unfavourably related to overall survival, but mildly protective with regard to relative survival. Three out of the five prognostic factors identified are the cornerstones of the current staging systems, and were confirmed as adequate by the analysis of relative survival. The results regarding age explain the conflicting findings so far obtained from studies considering overall survival only and advise against the adoption of absolute age limits in therapeutic protocols. Moreover, the prechemotherapy CEA level showed a high clinical value

Low-Load High Volume Resistance Exercise Stimulates Muscle Protein Synthesis More Than High-Load Low Volume Resistance Exercise in Young Men

BACKGROUND: We aimed to determine the effect of resistance exercise intensity (%1 repetition maximum-1RM) and volume on muscle protein synthesis, anabolic signaling, and myogenic gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Fifteen men (21+/-1 years; BMI=24.1+/-0.8 kg/m2) performed 4 sets of unilateral leg extension exercise at different exercise loads and/or volumes: 90% of repetition maximum (1RM) until volitional failure (90FAIL), 30% 1RM work-matched to 90%FAIL (30WM), or 30% 1RM performed until volitional failure (30FAIL). Infusion of [ring-13C6] phenylalanine with biopsies was used to measure rates of mixed (MIX), myofibrillar (MYO), and sarcoplasmic (SARC) protein synthesis at rest, and 4 h and 24 h after exercise. Exercise at 30WM induced a significant increase above rest in MIX (121%) and MYO (87%) protein synthesis at 4 h post-exercise and but at 24 h in the MIX only. The increase in the rate of protein synthesis in MIX and MYO at 4 h post-exercise with 90FAIL and 30FAIL was greater than 30WM, with no difference between these conditions; however, MYO remained elevated (199%) above rest at 24 h only in 30FAIL. There was a significant increase in AktSer473 at 24h in all conditions (P=0.023) and mTORSer2448 phosphorylation at 4 h post-exercise (P=0.025). Phosporylation of Erk1/2Tyr202/204, p70S6KThr389, and 4E-BP1Thr37/46 increased significantly (P<0.05) only in the 30FAIL condition at 4 h post-exercise, whereas, 4E-BP1Thr37/46 phosphorylation was greater 24 h after exercise than at rest in both 90FAIL (237%) and 30FAIL (312%) conditions. Pax7 mRNA expression increased at 24 h post-exercise (P=0.02) regardless of condition. The mRNA expression of MyoD and myogenin were consistently elevated in the 30FAIL condition. CONCLUSIONS/SIGNIFICANCE: These results suggest that low-load high volume resistance exercise is more effective in inducing acute muscle anabolism than high-load low volume or work matched resistance exercise modes

Cataract-Causing Defect of a Mutant γ-Crystallin Proceeds through an Aggregation Pathway Which Bypasses Recognition by the α-Crystallin Chaperone

Background: The transparency of the eye lens depends upon maintenance of the native state of the γ- and β-crystallins, which is aided by the abundant chaperones αA- and αB-crystallin. Mature onset cataract, the leading cause of blindness worldwide, involves the polymerization of covalently damaged or partially unfolded crystallins into light-scattering aggregates. A number of single amino acid substitutions and truncations of γ-crystallins result in congenital cataract in both humans and mice, though in many cases the coupling between the protein alterations and the accumulation of aggregates is poorly defined. Methodology/Principal Findings: We have studied the aggregation properties and chaperone interactions of human γD-crystallin carrying substitutions of two buried core mutants, I90F and V75D, which cause congenital cataract in mice. The in vitro aggregation pathway competing with productive refolding was not altered by either substitution. Furthermore, this aggregation pathway for both mutant proteins–originating from a partially folded intermediate–was efficiently suppressed by αB-crystallin. Thus the cataract pathology was unlikely to be associated with a direct folding defect. The native state of wild-type human γD-crystallin exhibited no tendency to aggregate under physiological conditions. However both I90F and V75D native-like proteins exhibited slow (days) aggregation to high molecular weight aggregates under physiological conditions. The perturbed conformation of I90F was recognized and bound by both αA and αB chaperones. In contrast, the aggregation derived from the perturbed state of V75D was not suppressed by either chaperone, and the aggregating species were not bound by the chaperone. Conclusions/Significance: The cataract phenotype of I90F in mice may be due to premature saturation of the finite α- crystallin pool. The V75D aggregation pathway and its escape from chaperone surveillance and aggregation suppression can account for the congenital cataract pathology of this mutant. Failure of chaperone recognition may be an important source of pathology for many other protein folding defects.National Eye Institute (Grant no. EY015834 )National Institutes of Health (U.S.) (Grant no. GM17980

Altering Chemosensitivity by Modulating Translation Elongation

BACKGROUND: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. METHODOLOGY/PRINCIPAL FINDINGS: Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. CONCLUSION/SIGNIFICANCE: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations