Jan Kulig

CANVAS 2: the second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections

OBJECTIVES New therapies for complicated skin and skin structure infections (cSSSIs) are needed because of significant morbidity and increasing antimicrobial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of cSSSIs. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a multinational Phase III study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate of ceftaroline fosamil monotherapy to that achieved with vancomycin plus aztreonam combination therapy in the clinically evaluable (CE) and modified intent-to-treat (MITT) analysis populations. METHODS Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00423657 (http://clinicaltrials.gov/ct2/show/NCT00423657). RESULTS The study enrolled 694 patients, 348 of whom received ceftaroline fosamil and 346 of whom received vancomycin plus aztreonam. The treatment groups had comparable baseline characteristics. Clinical cure rates for the ceftaroline fosamil and vancomycin plus aztreonam groups were similar in the CE (92.2%, 271/294 versus 92.1%, 269/292; 95% CI, -4.4, 4.5) and MITT (85.1%, 291/342 versus 85.5%, 289/338; 95% CI, -5.8, 5.0) populations, respectively. MRSA cSSSIs were cured in 91.4% (64/70) of patients in the ceftaroline fosamil group and 93.3% (56/60) of patients in the vancomycin plus aztreonam group. The microbiological success rate in the microbiologically evaluable population was 92.9% and 95.0% for ceftaroline fosamil and vancomycin plus aztreonam, respectively. Ceftaroline fosamil and vancomycin plus aztreonam had similar rates of AEs, serious AEs and discontinuations because of an AE. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam included diarrhoea (6.5% versus 4.4%), nausea (6.2% versus 5.6%), headache (5.3% versus 5.3%) and pruritus (3.8% versus 8.3%), respectively. CONCLUSIONS Ceftaroline fosamil demonstrated high clinical cure and microbiological success rates, was efficacious against cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Monotherapy with ceftaroline fosamil has the potential to provide an alternative treatment for cSSSIs.

Impact of anastomotic leakage on long‐term survival after total gastrectomy for carcinoma of the stomach

Recent studies suggest that anastomotic leak may adversely affect long‐term survival in patients undergoing surgery for gastrointestinal malignancies. Data relating to total gastrectomy for gastric cancer are scarce.

The ratio of metastatic/resected lymph nodes is an independent prognostic factor in patients with node-positive pancreatic head cancer.

Objectives: The aim of this study was to evaluate the prognostic value of nodal involvement in resected adenocarcinoma of the pancreatic head. Methods: For the period between 1980 and 2002, 96 patients underwent pancreaticoduodenectomy for pancreatic cancer. Lymph nodes were numbered and classified into groups according to the Japan Pancreatic Society rules. Metastatic lymph nodes were identified based on hematoxylin and eosin staining. Results: Sixty-four (66.7%) patients had positive lymph nodes. The median number of metastatic nodes was 2 (95% confidence interval [CI], 1.0-3.0) and the median ratio of metastatic/resected nodes was 9.7% (95% CI, 7.1%-14.4%). The median survival was 14.2 months (95% CI, 10.7-17.7) and was significantly higher for node-negative than node-positive patients (27.9; 95% CI, 20.9-34.9 vs. 10.6; 95% CI, 8.7-12.5; P < 0.001). The Cox proportional hazards model, including all patients, demonstrated that nodal involvement (hazard ratio [HR], 1.461; 95% CI, 1.177-12.024), moderate or poor tumor differentiation (HR, 2.330; 95% CI, 1.181-6.949), and positive resection margins (HR, 3.838; 95% CI, 1.390-10.597) were independent negative prognostic factors. If the analysis was limited to node-positive patients, lymph node ratio of more than 20% (HR, 1.364; 95% CI, 1.116-2.599), moderate or poor tumor differentiation (HR, 3.393; 95% CI, 1.041-11.061), and positive resection margins (HR, 9.400; 95% CI, 2.235-39.536) significantly correlated with a poorer survival. Conclusions: Lymph node ratio seems to be a new promising prognostic factor in patients with respectable node-positive pancreatic head cancer.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders: A prospective multicentre study

PURPOSE To assess local control after preoperative radiation and local excision and to determine an optimal radiotherapy regimen. METHODS Eighty-nine patients with G1-2 rectal adenocarcinoma <3-4 cm; unfavourable cT1N0 (23.6%), cT2N0 (62.9%) or borderline cT2/cT3N0 (13.5%) received 5 × 5 Gy plus 4 Gy boost (71.9%) or 55.8 Gy in 31 fractions with 5-FU and leucovorin (28.1%). Local excision (traditional technique 56.2%, transanal endoscopic microsurgery 41.6%, Kraske procedure 2.2%) was performed 6-8 weeks later. If patients were downstaged to ypT0-1 without unfavourable factors (good responders), this was deemed definitive treatment. Immediate conversion to radical surgery was recommended for remaining patients. RESULTS Good response to radiation was seen in 67.2% of patients in the short-course group and in 80.0% in the chemoradiation group, p = 0.30. Local recurrence at 2 years (median follow-up) in good responders was 11.8% in the short-course group and 6.2% in the chemoradiation group, p = 0.53. In the total group, a lower rate of local recurrence at 2 years was observed in elderly patients (>69 years, median value) when compared to the younger patients; 8.3% vs. 27.7%, Cox analysis hazard ratio 0.232, p = 0.016. A total of 18 patients initially managed with local excision required conversion to abdominal surgery but either refused it or were unfit. In this group, local recurrence at 2 years was 37.1%. CONCLUSIONS This study suggests an acceptable local recurrence rate after preoperative radiotherapy and local excision of small, radiosensitive tumours in elderly patients.

The impact of immunostimulating nutrition on infectious complications after upper gastrointestinal surgery: a prospective, randomized, clinical trial.

Background and Aim:Immunomodulating nutrition is supposed to reduce the number of complications and lengthen of hospital stay during the postoperative period in patients after major gastrointestinal surgery. The aim of the study was to assess the clinical effect of immunostimulatory enteral and parenteral nutrition in patients undergoing resection for gastrointestinal cancer in the group of well-nourished patients. Material and Methods:Between June 1, 2001, and December 31, 2005, a group of 214 well-nourished patients was initially assessed (150 men, 64 women, mean age 61.2 years) to participate in the study. Nine patients were subsequently excluded and the remaining 205 subjects were randomly assigned in a 2 × 2 factorial design into 4 study groups, ie, standard enteral nutrition (n = 53), immunomodulating enteral nutrition (n = 52), standard parenteral nutrition (n = 49), and immunomodulating enteral nutrition (n = 51). The study was designed to test the hypothesis that immunonutrition and enteral nutrition would reduce the incidence of infectious complications after upper gastrointestinal surgery; the secondary objective of the study was to evaluate the effect of nutritional intervention on overall morbidity and mortality rates, and hospital stay. The study was registered in the Clinical Trials Database–number NCT 00558155. Results:The overall morbidity rate was 33% and the incidence of individual complications was comparable between all groups. Infectious complications occurred in 26 of 102 patients given standard diets and in 22 of 103 patients receiving immunomodulatory formulas (odds ratio 0.81; 95% CI, 0.43–1.50). There were no significant differences between infectious complications in patients using parenteral nutrition (22 of 100 patients) and parenteral formulas (26 of 105, odds ratio 1.14; 95% CI, 0.61–2.14). Neither immunostimulating formulas nor enteral feeding significantly affected secondary outcome measures, including overall morbidity and mortality rates, and hospital stay. Conclusions:Our study failed to demonstrate any clear advantage of routine postoperative immunonutrition in patients undergoing elective upper gastrointestinal surgery. Both enteral and parenteral treatment options showed similar efficacy, tolerance, and effects on protein synthesis. Parenteral nutrition composed according to contemporary rules showed similar efficiency to enteral nutrition. However, because of its cost-efficiency, enteral therapy should be considered as the treatment of choice in all patients requiring nutritional therapy.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders

BACKGROUND AND PURPOSE To report an early analysis of prospective study exploring preoperative radiotherapy and local excision in rectal cancer. MATERIALS AND METHODS Mucosa at tumour edges was tattooed. Patients with cT1-3N0 tumour <3-4 cm were treated with either 5x5Gy+4Gy boost (N=31) or chemoradiation (50.4Gy+5.4Gy boost, 1.8Gy per fraction+5-fluorouracyl and leucovorin; N=13). Thirteen patients from the short-course group were unfit for chemotherapy. The interval from radiation to full-thickness local excision was 6 weeks. The protocol called for conversion to a transabdominal surgery in case of ypT2-3 disease or positive margin. RESULTS The postoperative complications requiring hospitalization were recorded in 9% of patients. The rate of pathological complete response was 41%. The rate of patients requiring conversion was 34%; however, 18% actually underwent conversion and the remaining 16% refused or were unfit. During the 14 months of median follow-up, local recurrence was detected in 7% of patients and all underwent salvage surgery. Of 19 patients in whom initially anterior resection was likely, 16% had abdominoperineal resection performed for a conversion or as a rescue procedure. CONCLUSION Our study suggests that the short-course radiation prior to local excision is a treatment option for high-risk patients.

The clinical value of parenteral immunonutrition in surgical patients

Abstract Background & Aim: to analyze the clinical impact and cost-effectiveness of parenteral immunonutrition (PN). Methods: prospective clinical trial of a group of 105 patients operated on for gastric carcinoma between 2001-2003. During the postoperative period, patients were randomly allocated to one of three groups: standard PN (A), PN + glu-tamine (B) and PN + omega-3-FA (C). The rate and type of complications, hepatic and renal function, cost and treatment tolerance in all groups were analyzed. Results: postoperative complications were observed in 11 patients (36,6%) in group A, in 7 (23,3%) in B and in 8 (26,6%) in C. The most common complication was pneumonia. Prealbumin concentration and TLC increased faster in groups B and C. The length of hospital stay was significantly shorter in the immunonutrition groups. The cost of PN was highest in C group, while cost of hospital stay was longer in A. Conclusions: immunostimulating parenteral nutrition helps to reduce the number of infectious complications, improves the function of the immune system, and has no influence on surgical complications, hepatic and renal function and protein synthesis. The cost of immunostimulating treatment based on omega-3-unsaturated fatty acids is higher than standard.

Enteral and Parenteral Nutrition in the Conservative Treatment of Pancreatic Fistula: A Randomized Clinical Trial

BACKGROUND & AIMS Postoperative pancreatic fistula is the most common and potentially life-threatening complication after pancreatic surgery. Although nutritional support is a key component of conservative therapy in such cases, there have been no well-designed clinical trials substantiating the superiority of either total parenteral nutrition or enteral nutrition. This study was conducted to compare the efficacy and safety of both routes of nutritional intervention. METHODS A randomized clinical trial was conducted in a tertiary surgical center of pancreatic and gastrointestinal surgery. Seventy-eight patients with postoperative pancreatic fistula were treated conservatively and randomly assigned to groups receiving for 30 days either enteral nutrition or total parenteral nutrition. The primary end point was the 30-day fistula closure rate. RESULTS After 30 days, closure rates in patients receiving enteral and parenteral nutrition were 60% (24 of 40) and 37% (14 of 38), respectively (P=.043). The odds ratio for the probability that fistula closes on enteral nutrition compared to total parenteral nutrition was 2.571 (95% confidence interval [CI]: 1.031-6.411). Median time to closure was 27 days (95% CI: 21-33) for enteral nutrition, and no median time was reached in total parenteral nutrition (P=.047). A logistic regression analysis identified only 2 factors significantly associated with fistula closure, ie, enteral nutrition (odds ratio=6.136; 95% CI: 1.204-41.623; P=.043) and initial fistula output of ≤200 mL/day (odds ratio=12.701; 95% CI: 9.102-47.241; P<.001). CONCLUSIONS Enteral nutrition is associated with significantly higher closure rates and shorter time to closure of postoperative pancreatic fistula.

The immunomodulating enteral nutrition in malnourished surgical patients - a prospective, randomized, double-blind clinical trial.

BACKGROUND & AIM The immunomodulating nutrition was supposed to reduce the incidence of complications in surgical patients, but many authors have questioned its value recently. The aim of the study was to assess the impact of enteral immunonutrition in postoperative period. METHODS Between January 2003 and December 2009, 305 malnourished patients (123 F, 182 M, m. age 60.8) undergoing resection for pancreatic or gastric cancer, after preoperative 14 days of parenteral feeding, were randomized in double-blind manner to receive either postoperative immunomodulating enteral diet (IMEN) or standard oligopeptide diet (SEN). Outcome measures of the intend-to-treat analysis were: number and type of complications, length of hospitalization, mortality, and vital organ function. RESULTS Median postoperative hospital stay was 17.1 days in SEN and 13.1 days in IMEN group (p = 0.006). Infectious complications were observed in 60 patients (39.2%) in SEN and 43 (28.3%) in IMEN group (p = 0.04). Differences were also observed in overall morbidity (47.1 vs 33.5%, p = 0.01) and mortality (5.9 vs 1.3%, p = 0.03), but the ratio of surgical complications, organ function, and treatment tolerance did not differ. CONCLUSIONS The study proved that postoperative immunomodulating enteral nutrition should be the treatment of choice in malnourished surgical cancer patients. The Clinical Trials Database registry number: NCT00576940.

Telocytes: new insight into the pathogenesis of gallstone disease

The major mechanisms of gallstone formation include biliary cholesterol hypersecretion, supersaturation and crystallization, mucus hypersecretion, gel formation and bile stasis. Gallbladder hypomotility seems to be a key event that triggers the precipitation of cholesterol microcrystals from supersaturated lithogenic bile. Telocytes, a new type of interstitial cells, have been recently identified in many organs, including gallbladder. Considering telocyte functions, it is presumed that these cells might be involved in the signalling processes. The purpose of this study was to correlate the quantity of telocytes in the gallbladder with the lithogenicity of bile. Gallbladder specimens were collected from 24 patients who underwent elective laparoscopic cholecystectomy for symptomatic gallstone disease. The control group consisted of 25 consecutive patients who received elective treatment for pancreatic head tumours. Telocytes were visualized in paraffin sections of gallbladders with double immunofluorescence using primary antibodies against c‐Kit (anti‐CD117) and anti‐mast cell tryptase. Cholesterol, phospholipid and bile acid levels were measured in gallbladder bile. The number of telocytes in the gallbladder wall was significantly lower in the study group than that in the control group (3.03 ± 1.43 versus 6.34 ± 1.66 cell/field of view in the muscularis propria, P < 0.001) and correlated with a significant increase in the cholesterol saturation index. The glycocholic and taurocholic acid levels were significantly elevated in the control subjects compared with the study group. The results suggest that bile composition may play an important role in the reduction in telocytes density in the gallbladder.