Alterations in Tumor DNA Are Related to Short Postoperative Survival in Patients Resected for Pancreatic Carcinoma Aimed at Cure.

OBJECTIVES: Pancreatic ductal adenocarcinomas (PDACs) are found in more than 85% of patients with pancreatic cancer and with 5-year survival of less than 10%. Effective treatment may be radical surgery, which is hampered by rapid relapse. Therefore, our aim was to compare DNA sequence alterations in patients with short and long survival to evaluate if confirmed DNA alterations predict short postoperative survival. METHODS: DNA was extracted from tumor tissue from 59 PDAC patients, analyzed for KRAS mutations, and hybridized to 180 K CGH + SNP microarrays and 450 K methylation arrays. Analyses were based on postoperative survival where less than 12 months was considered to be short survival and more than 18 months was considered long survival. RESULTS: Ninety-three percent of the patients had KRAS mutations in tumor DNA. Great heterogeneity of whole genome DNA sequence alterations were observed among chromosomes within the patient materials. Specific DNA sequence alterations did not directly predict postoperative survival, although short survivors had significantly more and larger DNA amplifications (P < 0.006). Amplifications on chromosome 11 and 21 and deletions on chromosome 2 predicted short postoperative survival (P < 0.03). DNA methylation was not related to survival. CONCLUSIONS: Highly variable genetic differences among DNA regions in PDAC tumors were demonstrated. Postoperative short survival was related to tumor sequence DNA alterations on chromosome 2, 11, and 21.

Proteomic mucin profiling for the identification of cystic precursors of pancreatic cancer.

BACKGROUND: Pancreatic cystic lesions (PCLs) are increasingly frequent radiological incidentalomas, with a considerable proportion representing precursors of pancreatic cancer. Better diagnostic tools are required for patients to benefit from this development. METHODS: To evaluate whether cyst fluid mucin expression could predict malignant potential and/or transformation in PCLs, a proteomic method was devised and prospectively evaluated in consecutive patients referred to our tertiary center for endoscopic ultrasound-guided aspiration of cystic lesions from May 2007 through November 2008 (discovery cohort) and from December 2008 through October 2012 (validation cohort). Cytology and cyst fluid carcinoembryonic antigen (CEA; premalignancy > 192 ng/mL, malignancy > 1000 ng/mL) were routinely analyzed, and samples were further processed as follows: one-dimensional gel electrophoresis, excision of high-mass areas, tryptic digestion and nano-liquid chromatography-tandem mass spectrometry, with peptide identification by Mascot software and an in-house mucin database. All diagnostic evaluations were blinded to proteomics results. Histology was required to confirm the presence/absence of malignant transformation. All statistical tests were two-sided. RESULTS: Proteomic mucin profiling proved statistically significantly more accurate (97.5%; 95% confidence interval [CI] = 90.3% to 99.6%) than cytology (71.4%; 95% CI = 59.8% to 80.9%; P < .001) and cyst fluid CEA (78.0%; 95% CI = 65.0% to 87.3%; P < .001) in identifying the 37 (out of 79; 46.8%) lesions with malignant potential (ie, premalignant or malignant tumors). The accuracy of proteomics was nearly identical (96.6% vs 98.0%) between the discovery (n = 29) and validation (n = 50) cohorts. Furthermore, mucin profiling predicted malignant transformation, present in 16 out of 29 (discovery cohort: 9, validation cohort: 20) lesions with available histology, with 89.7% accuracy (95% CI = 71.5% to 97.3%) (for the validation cohort only: 95.0%; 95% CI = 73.1% to 99.7%). This markedly exceeded corresponding results for cytology (51.7%; 95% CI = 32.9% to 70.1%; P = .003) and CEA (57.1%; 95% CI = 34.4% to 77.4%; P = .02). CONCLUSIONS: Proteomic cyst fluid mucin profiling robustly discriminates benign, premalignant, and malignant PCLs. Consequently, it may improve pancreatic cancer prevention and reduce the morbidity burden of unwarranted pancreatic surgery.

Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.

Cost-utility estimations of palliative care in patients with pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: We earlier reported cost-utility estimates in patients who undergo resection aimed at cure for pancreatic carcinoma. The present study describes similar information on patients with unresectable tumors who experienced palliative care only. METHODS: A population-based cohort of patients with exocrine pancreatic adenocarcinoma during 1998-2005 was evaluated retrospectively (n = 444). Total direct health care costs at departments of surgery and oncology, for primary health care, and at hospice were achieved. Self-estimated health-related quality of life (HRQL) was assessed by the SF-36. A single preference-based utility index, SF-6D, was derived from SF-36 items to estimate quality-adjusted life years (QALYs). Results were compared to similar findings in a previously reported group of patients with pancreatic carcinoma resected for cure (n = 31). RESULTS: Palliative care patients (n = 305) had impaired HRQL particularly related to physical domains. The mean preference-based health utility index at diagnosis was 0.65 ± 0.02 [95 % confidence interval (CI) 0.61-0.69] compared to 0.77 ± 0.02 (95 % CI 0.75-0.79) in healthy reference individuals. Total direct health care costs were 50 % in patients on palliative care compared to costs for surgical R0 resections (23,701 and 50,950, respectively). QALYs for 1 year from diagnosis were 0.2 (95 % CI 0.17-0.23) in patients on palliative care and 0.48 (95 % CI 0.44-0.54) in resection patients. Costs per QALY were 118,418 and 106,146, respectively (95 % CI 103,048-139,418 and 94,352-115,795). CONCLUSIONS: Optimized palliative care of patients with exocrine pancreatic carcinoma had costs per achieved utility similar to those for surgical resections aimed at cure.

European consensus on a competency-based virtual reality training program for basic endoscopic surgical psychomotor skills.

BACKGROUND: Virtual reality (VR) simulators have been demonstrated to improve basic psychomotor skills in endoscopic surgery. The exercise configuration settings used for validation in studies published so far are default settings or are based on the personal choice of the tutors. The purpose of this study was to establish consensus on exercise configurations and on a validated training program for a virtual reality simulator, based on the experience of international experts to set criterion levels to construct a proficiency-based training program. METHODS: A consensus meeting was held with eight European teams, all extensively experienced in using the VR simulator. Construct validity of the training program was tested by 20 experts and 60 novices. The data were analyzed by using the t test for equality of means. RESULTS: Consensus was achieved on training designs, exercise configuration, and examination. Almost all exercises (7/8) showed construct validity. In total, 50 of 94 parameters (53%) showed significant difference. CONCLUSIONS: A European, multicenter, validated, training program was constructed according to the general consensus of a large international team with extended experience in virtual reality simulation. Therefore, a proficiency-based training program can be offered to training centers that use this simulator for training in basic psychomotor skills in endoscopic surgery.

Cost-utility estimation of surgical treatment of pancreatic carcinoma aimed at cure.

BACKGROUND: Little is reported on costs for radical tumor resections of pancreatic carcinoma in relationship to adjusted quality of life survival postoperatively. Therefore, the aim of the present study was to estimate the cost utility of surgical treatment aimed at cure. METHODS: A population-based cohort of patients with exocrine or ampullary pancreatic adenocarcinoma resected for cure in Gothenburg University Hospitals during 1998-2005 were evaluated retrospectively (n = 139). Total inpatient and outpatient healthcare costs were available for 103 patients, and health-related quality of life (HRQL) (based on the SF-36 Health Survey) were assessed preoperatively and postoperataively in 119 patients. Survival and utility index (SF-36-6D) across 5 years of postoperative follow-up were used to achieve quality adjusted life years. RESULTS: Mean survival after resection was 977 days for patients with exocrine pancreatic carcinoma, with expected differences among subgroups as related to disease stage (p < 0.01), in agreement with international reports. The HRQL index was 0.65 ± 0.06 preoperatively, 0.63 ± 0.04 early postoperatively (<1 year) and 0.69 ± 0.06 at long-term follow-up (1-5 years) compared to 0.77 ± 0.02 in age-matched healthy reference individuals from the Swedish population (p < 0.05). Total lifetime costs for treatments including surgery and adjuvant chemotherapy were 39,000 euro per patient, with a mean of 1.13 (95% Confidence Interval [CI] 0.93-1.40) QALYs across 5 years follow-up. The cost per QALY was 35,000 euro (95% CI 28,026 euro-41,947 euro). CONCLUSIONS: Resection aimed at cure of pancreatic exocrine ductal carcinoma provided costs for one quality adjusted year of survival comparable to other complex surgical treatments within cost limits regarded as reasonable to bear by the Swedish health care system, as well as in several other Western countries.

Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study.

BACKGROUND: The short-term provision of ghrelin to patients with cancer indicates that there may be benefits from long-term provision of ghrelin for the palliative treatment of weight-losing cancer patients. This hypothesis was evaluated in a randomized, double-blind, phase 2 study. METHODS: Weight-losing cancer patients with solid gastrointestinal tumors were randomized to receive either high-dose ghrelin treatment (13 microg/kg daily; n = 17 patients) or low-dose ghrelin treatment (0.7 microg/kg daily; n = 14 patients) for 8 weeks as a once-daily, subcutaneous injections. Appetite was scored on a visual analog scale; and food intake, resting energy expenditure, and body composition (dual x-ray absorpitometry) were measured before the start of treatment and during follow-up. Serum levels of ghrelin, insulin, insulin-like growth factor 1, growth hormone (GH), triglycerides, free fatty acids, and glucose were measured. Health-related quality of life, anxiety, and depression were assessed by using standardized methods (the 36-item Short Form Health Survey and the Hospital Anxiety and Depression Scale). Physical activity, rest, and sleep were measured by using a multisensor body monitor. RESULTS: Treatment groups were comparable at inclusion. Appetite scores were increased significantly by high-dose ghrelin analyzed both on an intent-to-treat basis and according to the protocol. High-dose ghrelin reduced the loss of whole body fat (P < .04) and serum GH (P < .05). There was a trend for high-dose ghrelin to improve energy balance (P < .07; per protocol). Otherwise, no statistically significant differences in outcome variables were observed between the high-dose and low-dose groups. Adverse effects were not observed by high-dose ghrelin, such as serum levels of tumor markers (cancer antigen 125 [CA 125], carcinoembryonic antigen, and CA 19-9). CONCLUSIONS: The current results suggested that daily, long-term provision of ghrelin to weight-losing cancer patients with solid tumors supports host metabolism, improves appetite, and attenuates catabolism.

Initiation factors for translation of proteins in the rectus abdominis muscle from patients on overnight standard parenteral nutrition before surgery.

Previous studies have provided conflicting conclusions concerning the efficacy of improving protein balance in patients by standard intravenous nutrition [TPN (total parenteral nutrition)], which is either explained by suboptimal nutritional regimens or insensitive clinical methods. The aim of the present study was therefore to evaluate the effects on the initiation of translation of skeletal muscle proteins by standard overnight TPN. A total of 12 patients who underwent standard surgery were included. TPN was provided as an all-in-one treatment by constant infusion [0.16 gN.kg(-1) of body weight.day(-1) (30 kcal.kg(-1) of body weight.day(-1))]. Saline-infused patients served as controls. Rectus abdominis muscle biopsies were taken at the time of the operation. The phosphorylation state of the proteins for initiation of translation was quantified. Plasma glucose, and serum insulin, glycerol, triacylglycerols (triglycerides) and NEFAs (non-esterified fatty acids; 'free fatty acids') were not significantly altered during TPN infusion, whereas total plasma amino acids increased, as shown by increases in methionine, phenylalanine, threonine, alanine, arginine, aspartic acid, glycine and histidine (P<0.05). Overnight TPN increased the formation of active eIF4G-eIF4E (where eIF is eukaryotic-initiation factor) complexes (P<0.05), whereas the inhibitory complex 4E-BP1 (eIF4E-binding protein)-eIF4E was moderately decreased (P<0.06). TPN increased the amount of the most phosphorylated form of 4E-BP1 (P<0.05), and increased the amount (P<0.04) and phosphorylation (P<0.01) of p70(S6K) (70 kDa ribosomal protein S6 kinase). In conclusion, an overnight pre-operative constant infusion of standard TPN altered initiation factor complexes, indicating activation of the initiation of protein translation in rectus abdominis muscle in the presence of increased plasma amino acid levels, but without a concomitant increase in energy substrates and insulin. In contrast with our results from previous studies, the methodology used in the present study appears to be more sensitive in reflecting directional changes in human muscle protein synthesis compared with traditional methods, particularly based on measurements of amino acid flux.

Supportive nutrition on recovery of metabolism, nutritional state, health-related quality of life, and exercise capacity after major surgery: a randomized study.

BACKGROUND & AIMS: The aim of this study was to investigate whether specialized supportive enteral and parenteral feeding have superior effects compared to oral nutrition on recovery during long-term postoperative treatment of cancer patients with preoperative weight loss and reduced maximum exercise capacity. METHODS: One hundred twenty-six patients referred for resection of the esophagus (n = 48), stomach (n = 28), or pancreas (n = 50) were considered to be included before operation. Included patients (n = 80) received supportive enteral or parenteral nutrition postoperatively at home corresponding to 1000 kcal/d until the patients did not wish to continue with artificial nutrition for any reason. Patients randomized to oral nutrition only served as control subjects. Caloric intake, body composition (dual-energy x-ray absorptiometry), and respiratory gas exchanges at rest and during exercise were measured including health-related quality of life. RESULTS: Survival and hospital stay did not differ among the groups, whereas overall complications were higher on artificial nutrition (P < .05). Changes in resting energy expenditure and biochemical tests did not differ during follow-up among the groups. Body weight and whole body fat declined similarly over time in all groups (P < .005), whereas lean body mass was unchanged during follow-up compared to preoperative values. Maximum exercise capacity and maximum oxygen consumption were normalized within 6 months postoperatively in all groups. There was no difference in recovery of food intake among the groups. Parenteral feeding was associated with the highest rate of nutrition-related complications, whereas enteral feeding reduced quality of life most extensively. CONCLUSION: After major surgery, specialized supportive enteral and parenteral nutrition are not superior to oral nutrition only when guided by a dietitian.

Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones.

BACKGROUND: Several investigations that yielded different results in terms of net changes in body composition of weight-losing cancer patients have been reported that employed a variety of methods based on fundamentally different technology. Most of those reports were cross-sectional, whereas to the authors' knowledge there is sparse information available on longitudinal follow-up measurements in relation to other independent methods for the assessment of metabolism and performance. METHODS: For the current report, the authors evaluated time course changes in body composition (dual-energy X-ray absorptiometry) with measurements of whole body and regional distribution of fat and lean tissue in relation to food and dietary intake, host metabolism (indirect calorimetry), maximum exercise capacity (walking test), and circulating hormones in cancer patients who were receiving palliative care during 4-62 months of follow-up. The entire cohort comprised 311 patients, ages 68 years +/- 3 years who were diagnosed with solid gastrointestinal tumors (84 colorectal tumors, 74 pancreatic tumors, 73 upper gastrointestinal tumors, 51 liver-biliary tumors, 3 breast tumors, 5 melanomas, and 21 other tumor types). RESULTS: Decreased body weight was explained by loss of body fat, preferentially from the trunk, followed by leg tissue and arm tissue, respectively. Lean tissue (fat-free mass) was lost from arm tissue, whereas trunk and leg tissue compartments increased, all concomitant with declines in serum albumin, increased systemic inflammation (C-reactive protein, erythrocyte sedimentation rate), increased serum insulin, and elevated daily caloric intake; whereas serum insulin-like growth factor 1 (IGF-1), resting energy expenditure, and maximum exercise capacity remained unchanged in the same patients. Serum albumin levels (P < 0.001), whole body fat (P < 0.02), and caloric intake (P < 0.001) predicted survival, whereas lean tissue mass did not. Daily intake of fat and carbohydrate was more important for predicting survival than protein intake. Survival also was predicted by serum IGF-1, insulin, leptin, and ghrelin levels (P < 0.02 - P < 0.001). Serum insulin, leptin, and ghrelin (total) levels predicted body fat (P < 0.001), whereas IGF-1 and thyroid hormone levels (T3, free T3) predicted lean tissue mass (P < 0.01). Systemic inflammation primarily explained variation in lean tissue and secondarily explained loss in body fat. Depletion of lean arm tissue was related most to short survival compared with the depletion of lean leg and trunk tissue. CONCLUSIONS: The current results demonstrated that body fat was lost more rapidly than lean tissue in progressive cancer cachexia, a phenomenon that was related highly to alterations in the levels of circulating classic hormones and food intake, including both caloric amount and diet composition. The results showed importance in the planning of efficient palliative treatment for cancer patients.

Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients.

PURPOSE: The purpose is to evaluate relationships between objectively assessed exercise capacity and subjectively assessed scoring of physical functioning and well-being after erythropoietin treatment in cancer patients on palliative care. EXPERIMENTAL DESIGN: Unselected cancer patients (n = 108) who experienced progressive cachexia were randomized to receive either anti-inflammatory treatment alone (indomethacin) or recombinant erythropoietin plus indomethacin to prevent the appearance of disease-induced anemia and thereby protect patients' exercise capacity. Follow-up investigations of nutritional status, exercise capacity, and health-related quality of life assessed by SF-36 and the European Organization for Research and Treatment of Cancer QLQ-C30 were compared. RESULTS: Effective treatment by erythropoietin on top of basal whole body anti-inflammatory treatment was confirmed and indicated by time course changes of biochemical, physiologic, and nutritional objectives, whereas individual self-reported scoring of physical functioning and general health did not indicate a clear-cut effectiveness, particularly at moderately subnormal hemoglobin levels. CONCLUSIONS: Discrepancies between objective and subjective self-reported measures may be either fundamental or indicate scoring limitations for evaluation of therapeutic results. Present results demonstrate a clinical benefit of erythropoietin treatment in cancer patients with subnormal to normal hemoglobin levels, whereas the patients' own subjective scoring was insufficient to sense such improvements. The discrepancy may be either fundamental or methodological but emphasizes the importance to document therapeutic outcome in both subjective and objective perspectives in palliative care of cancer patients.

Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia.

Cancer patients lose weight due to negative energy balance because of insufficient appetite and inappropriately high energy expenditure. Host and tumor derived cytokines and more recently eicosanoids have been held responsible as mediators. Accordingly, observations in animal experiments and short-term clinical trials in selected groups of cancer patients, have implied that cyclo-oxygenase (COX) blockade can improve host metabolism and well-being, and long-term COX-treatment of unselected groups have implied improved survival. The aim of this study was to search for evidence that long-term COX-treatment improves energy and cardiovascular homeostasis in unselected weight-losing cancer patients. A retrospective case control analysis was performed on a data-base material collected consecutively. Weight-losing untreated cancer patients had elevated resting energy expenditure compared to undernourished non-cancer patients (23.3+/-0.1, n=702 vs 20.9+/-0.3 kcal/kg/day, n=132, p<0.001). This difference became significantly reduced by long-term indomethacin treatment (p<0.003). Heart rate was correspondingly decreased, while systolic blood pressure increased following indomethacin treatment of cancer patients (p<0.006-0.008). Total body fat was more preserved (p<0.005), while lean body mass was uninfluenced by long-term indomethacin to cancer patients. All these beneficial effects were parallel to a decrease in systemic inflammation (C-reactive protein, erythrocyte sedimentation rate) in cancer patients on indomethacin (p<0.0004). Systemic inflammation and resting energy metabolism predicted weight loss in progressive cancer (p<0.0001). Our data support the concept that COX-treatment may offer beneficial metabolic effects to weight-losing cancer patients by attenuation of resting metabolism and improved appetite due to decreased systemic inflammation.