BACKGROUND & AIMS:Short bowel syndrome (SBS)-intestinal failure (IF) patients have impaired quality of life (QoL) and suffer from the burden of malabsorption and parenteral support (PS). A phase III study demonstrated that treatment with teduglutide, a glucagon-like peptide 2 analogue, reduces PS volumes by 32% while maintaining oral fluid intake constant; placebo-treated patients had reduced PS by 21%, but oral fluid intake increased accordingly. As effects of teduglutide on QoL are unknown, they were investigated here. METHODS:QoL analyses from a double-blind, randomised Phase III study in 86 SBS-IF patients receiving teduglutide (0.05 mg/kg/day s.c.) or placebo over 24 weeks. At baseline and every 4 weeks, QoL was assessed using the validated SBS-QoL™ scale. RESULTS:PS reductions were associated with QoL improvements (ANCOVA, p = 0.0194, SBS-QoL per-protocol). Compared to baseline, teduglutide significantly improved the SBS-QoL™ total score and the score of 9 of 17 items at week 24. These changes were not significant compared to placebo. Teduglutide-treated patients with remaining small intestine >100 cm experienced more gastrointestinal adverse events (GI-AE), unfavourably affecting QoL. CONCLUSIONS:Overall, PS volume reductions were associated with improvements in SBS-QoL™ scores. The short observation period, imbalances in oral fluid intake in relation to PS reductions, large patient and effect heterogeneity and occurrence of GI-AE in a subgroup of teduglutide-treated patients may account for the inability to show statistically significant effects of teduglutide on SBS-QoL™ scores compared to placebo.

Rationale: Animal models have showed that ubiquitinproteasome pathway (UPP) may be the effector of muscle loss during cancer cachexia. However, evidence from clinical studies is still needed to understand mechanisms involved in cancer induced muscle catabolism in patients. Methods: Patients (n = 17, 64±6 years) diagnosed with esophageal cancer were undergoing surgery with intent of resection of the primary tumor. As a control group, weight stable patients undergoing reflux surgery (n = 10, 60±7 years) were included. Vastus lateralis muscle biopsies were taken with a Bergstrom needle. Diaphragm biopsies were obtained by open surgery (cancer group) and by laparoscopic surgery (control group). Proteasome, caspase 3, calpains and lysosomal enzymatic activities were measured by using specific fluorogenic peptide substrates. Differences between the groups were tested with a Student’s t-test. Results: Cathepsin L activity was 115% higher in the vastus lateralis of cancer patients compared to the controls (5.3±0.4 vs 2.5±0.3 pmol/min/mg; p < 0.001). Cathepsin B activity in vastus lateralis was 85% higher in the cancer group compared to the control group (2.4±0.2 vs 1.3±0.2 pmol/min/mg; p < 0.001). This latter activity was correlated to the self-reported body weight loss of cancer patients (R2 = 0.41, p = 0.03). In diaphragm, activities of both cathepsins were 60% higher in cancer patients compared to the controls (p < 0.01). Proteasome, calpain and caspase3 activities did not differ between the two groups neither in vastus lateralis nor in diaphragm. Conclusion: The finding of weight-loss related activation of cathepsins in both skeletal and respiratory muscles in patients with esophageal cancer suggest that the lysosomal pathway might be involved in the development of cancer cachexia. In contrast to animal studies, in our study, UPP seems not to be the main or exclusive system implicated in muscle loss during cachexia.

BACKGROUND & AIMS:Subjects with short bowel syndrome (SBS) have impaired quality of life (QoL). No disease-specific instrument has been available to measure treatment-induced changes in QoL over time. Therefore, the aim was to develop and validate an SBS-specific QoL scale. METHODS:Classical test theory and Food and Drug Administration (FDA) guidance were applied for development and validation of the SBS-QoL™. Procedures included item generation and raw scale construction. Factor analysis, construct validity and internal consistency were assessed in a non-interventional observation, test re-test reliability and responsiveness in a randomised clinical study. RESULTS:The SBS-QoL™ comprises 17 items including two subscales. Subjects assessed the scale as easy to handle and comprehensible. Good construct validity was shown by comparison with the Home Parenteral Nutrition-Quality Of Life questionnaire as an external scale, which yielded moderately high correlation (r ≥ 0.7). High internal consistency was demonstrated (Cronbach's alpha: 0.94). Also the test re-test reliability was high (r ≥ 0.95), indicating reliable reproducibility of results. The Responsiveness Index (1.84) indicated the ability of the scale to detect changes in QoL over time. CONCLUSIONS:The SBS-QoL™ is an easy to handle and comprehensible SBS-specific subject-reported QoL scale. It is valid, reliable and sensitive with excellent psychometric characteristics to measure treatment-induced changes in QoL over time in subjects with SBS.

Rationale: GLP-2 analogues are developed for treatment of SBS. To measure treatment-induced health-related quality of life (HRQoL) changes over time, a patient-reported SBS-specific QoL scale (SBS-QoL™) was developed and validated. Methods: Principles from classical test theory and FDA guidance on patient-reported outcome measurements were applied. Item generation was based on literature, input from experts, physicians, and SBS patients. After item aggregation and raw scale construction, SBS-QoL™ was assessed in international focus groups. A factor analysis was done based on data from a multinational non-interventional observation in 185 SBS patients; construct validity (correlation to HPN-QoL© ) and internal consistency were evaluated. Test re-test reliability and responsiveness were determined in scope of a randomized, double-blind, placebo-controlled, multinational study in 86 SBS patients. Results: The self-administered SBS-QoL™ comprises 17 items measured by visual analogue scales and illustrated by pictograms. SBS patients assessed the scale as easy to handle and comprehensive. Factor analysis resulted in 2 subscales consisting of 11 and 6 items; no item was excluded. Construct validity was shown by a correlation coefficient of 0.74. SBS-QoL™ exhibits high internal consistency (Cronbach’s a: 0.95) and a measurement error of 5.4%. High test re-test reliability (correlation coefficient: 0.95) and responsiveness (responsiveness index: >0.8) of the scale were proven. Conclusion: SBS-QoL™ is a validated scale to measure treatment-induced HRQoL changes over time in SBS patients. Its psychometric properties are excellent.

Fungal infections constitute a serious clinical problem in the group of patients receiving total parenteral nutrition. The majority of species isolated from infections of the total parenteral nutrition patients belong to Candida genus. The most important factors of Candida spp. virulence are the phenomenon of "phenotypic switching," adhesins, dimorphism of fungal cells and the secretion of hydrolytic enzymes such as proteinases and lipases, including aspartyl proteinases. We determined the proteolytic activity of yeast-like fungal strains cultured from the clinical materials of patients receiving total parenteral nutrition and detected genes encoding aspartyl proteinases in predominant species Candida glabrata--YPS2, YPS4, and YPS6, and Candida albicans--SAP1-3, SAP4, SAP5, and SAP6. C. albicans released proteinases on the various activity levels. All C. glabrata strains obtained from the clinical materials of examined and control groups exhibited secretion of the proteinases. All 13 isolates of C. albicans possessed genes SAP1-3. Gene SAP4 was detected in genome of 11 C. albicans strains, SAP5 in 6, and SAP6 in 11. Twenty-six among 31 of C. glabrata isolates contained YPS2 gene, 21 the YPS4 gene, and 28 the YPS6 gene. We observed that clinical isolates of C. albicans and C. glabrata differed in SAPs and YPSs gene profiles, respectively, and displayed differentiated proteolytic activity. We suppose that different sets of aspartyl proteinases genes as well as various proteinase-activity levels would have the influence on strains virulence.

BACKGROUND AND AIMS:Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure.METHODS:In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥ 10%. Responders were subjects who demonstrated reductions of ≥ 20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose.RESULTS:Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 ± 475 and 354 ± 334 ml/day), the trend towards higher baseline parenteral volume (1816 ± 1008 vs 1374 ± 639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo.CONCLUSIONS:Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185.

Placement and care of central venous catheter by qualified personnel and adherence to protocols for care and maintenance of the access site decreases the risk of complications. Adequate hydration, coagulopathy correction, examination of venous anatomy by Doppler scan before and proper patient’s position, reducing PEEP, using small-gauge needle to locate the vein and the use of the Seldinger technique during insertion are also important.

Rationale: Perioperative nutritional support via a surgically placed jejunostomy is commonly used in patients undergoing surgical resection of oesophago-gastric cancer. With the development of laparoscopic resectional techniques, is the use of jejunal feeding as safe as at open surgery? Methods: A prospective, comparative study of patients undergoing 2-stage oesophagectomy prior to and following the instigation of laparoscopic gastric mobilization and jejunostomy formation. End points assessed included major surgical complications, mechanical displacement and dislodgement and days of successful feeding. Results: 50 patients were assessed, 25 before and 25 after the change of practice (M:F ratio was 8:2, median age: 64 years). All had a successful insertion of jejunostomy and none had a significant surgical complication at time of insertion. Mechanical complications were similar between the 2 groups (8% in open surgery vs 12% in laparoscopic surgery) The mean number of days of nutritional support was also similar between the two sets of patients (medians with interquartile range) 39.6±42.35 days for open surgery and 19.6±13.21 days for laparoscopic insertion. Conclusion: Laparoscopically placed jejunostomies are as reliable and safe as those placed at open surgery for peri-operative nutritional support in patients undergoing oesophago-gastric cancer resection.