Bariatric Surgery for Congestive Heart Failure Patients Improves Access to Transplantation and Long-term Survival.

INTRODUCTION: Obese patients with congestive heart failure (CHF) are often denied access to heart transplantation until they obtain significant weight loss to achieve a certain BMI threshold, often less than 35 kg/m2. It is unknown whether the rapid weight loss associated with bariatric surgery leads to improved waitlist placement, and as such improved survival for morbidly obese patients with CHF. METHODS: A decision analytic Markov state transition model was created to simulate the life of morbidly obese patients with CHF who were deemed ineligible to be waitlisted for heart transplantation unless they achieved a BMI less than 35 kg/m2. Life expectancy following medical weight management (MWM), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) was estimated. Base case patients were defined as having a pre-intervention BMI of 45 kg/m2. Sensitivity analysis of initial BMI was performed. Markov parameters were extracted from literature review. RESULTS: RYGB improved survival compared with both SG and MWM. RYGB patients had higher rates of transplantation, leading to improved mean long-term survival. Base case patients who underwent RYGB gained 2.1 additional years of life compared with patient's who underwent SG and 7.4 additional years of life compared with MWM. SG patients gained 5.3 years of life compared with MWM. CONCLUSIONS: When strict waitlist criteria were applied, bariatric surgery improved access to heart transplantation and thereby increased long-term survival compared with MWM. Morbidly obese CHF patients who anticipate need for heart transplantation should be encouraged to pursue surgical weight management strategies, necessitating discussion between bariatric surgeons, cardiologists, and cardiac surgeons for appropriate perioperative risk management.

Impact of body mass index on minimally invasive ventral hernia repair: an ACS-NSQIP analysis.

PURPOSE: Body mass index (BMI) ≥ 35 kg/m2 is a known independent risk factor for complications following open ventral hernia repair (VHR). We sought to examine the relationship between BMI and minimally invasive VHR. METHODS: The ACS-NSQIP database was queried for all patients age ≥ 18 years undergoing minimally invasive VHR (2005-2015). Patients were stratified into seven BMI classes: underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (25-29.9), obese (30-34.5), severely obese (35-39.9), morbidly obese (40-49.9), and super obese (BMI ≥ 50), as well as by hernia type (reducible vs. strangulated) and time of repair (initial vs. recurrent). Multivariate logistic regression was employed to assess the risk of complication by BMI class. RESULTS: A total of 55,180 patients met inclusion criteria, and 61.4% had a BMI > 30 kg/m2. When stratified by BMI class, we found significant differences in age, gender, race, comorbidities, and pre-operative characteristics across groups. The overall complication rate was 4.0%, ranging from 3.0% for normal BMI patients, to 6.9% for patients with a BMI ≥ 50 kg/m2. Recurrent repairs and strangulated hernias both demonstrated higher complication rates. All complications (surgical and medical) were significantly associated with BMI class after adjustment (p < 0.0001). Patients with a BMI ≥ 50 kg/m2 had a 1.4 times greater risk for complications than patients with normal BMIs (18-24.9 kg/m2, p = 0.01). CONCLUSION: BMI ≥ 50 kg/m2 was determined to be an independent risk factor for surgical and medical complications after minimally invasive VHR.

Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

BACKGROUND: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). METHODS: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. RESULTS: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. CONCLUSIONS: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Utility of barium studies for patients with recurrent weight gain after Roux-en-Y gastric bypass.

AIM: To determine the utility of barium studies for detecting abnormalities responsible for recurrent weight gain after gastric bypass surgery. METHODS: A computerized search identified 42 patients who had undergone barium studies for recurrent weight gain after gastric bypass and 42 controls. The images were reviewed to determine the frequency of staple-line breakdown and measure the length/width of the pouch and gastrojejunal anastomosis. A large pouch exceeded 6 cm in length or 5 cm in width and a wide anastomosis exceeded 2 cm. Records were reviewed for the amount of recurrent weight gain and subsequent weight loss after additional treatment. RESULTS: Staple-line breakdown was present in 6/42 patients (14%) with recurrent weight gain. When measurements were obtained, 13/35 patients (37%) with recurrent weight gain had a large pouch, three (9%) had a wide anastomosis, and four (11%) had both, whereas 22/42 controls (52%) had a large pouch, one (2%) had a wide anastomosis, and two (5%) had both. Ten patients (24%) with recurrent weight gain underwent staple-line repair (n = 3) or pouch/anastomosis revision (n = 7). These 10 patients had a mean weight loss of 38.1 lbs versus a mean loss of 8.6 lbs in 19 patients managed medically. CONCLUSION: Only 14% of patients with recurrent weight gain after gastric bypass had staple-line breakdown, whereas 57% had a large pouch, wide anastomosis, or both. Not all patients with abnormal anatomy had recurrent weight gain, but those who did were more likely to benefit from surgical intervention than from medical management.

Re-examining the BMI threshold for bariatric surgery in the USA.

BACKGROUND: The optimal BMI threshold above which gastric bypass surgery should be offered to obese patients is controversial. The objective of this study was to compare the impact of Roux-en-Y gastric bypass (RYGB) vs. diet and exercise (D&E) on life expectancy to find the BMI at which patients experience an improvement in their life expectancy by undergoing surgery. METHODS: A Markov state transition model was designed to implement a decision tree that simulated the lives of obese patients. Life expectancies following RYGB and 2 years of D&E were estimated and compared. Ten thousand patients' lives were simulated in each weight-loss intervention group in the model. In addition to base case analysis (45 kg/m(2) BMI pre-intervention), sensitivity analysis of initial BMI at the start of the study was completed. Markov model parameters were extracted from the literature. RESULTS: The impact of RYGB on survival relative to D&E depended on the patient's initial BMI. Compared to patients who underwent 2 years of "optimal" diet and exercise (7 % total body weight loss/year), RYGB improved long-term survival for patients above a BMI of 31.3 kg/m(2). CONCLUSIONS: Roux-en-Y gastric bypass can improve long-term survival for patients with class I obesity. This study suggests that RYGB should not be reserved solely for patients with class II or III obesity.

Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies.

CONTEXT: The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Deletion and inactivation of FHIT have been seen in a number of human premalignant and malignant lesions. OBJECTIVE: To review and evaluate preclinical studies of cancer therapy using the FHIT tumor suppressor gene and related studies involving Fhit protein expression. DATA SOURCES: A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional relevant articles. STUDY SELECTION: Immunohistochemical studies of primary tumors or relevant lesions were selected to evaluate Fhit expression in premalignant or malignant stages. Preclinical studies on antitumorigenic or therapeutic introduction of FHIT were reviewed for the effects of exogenous Fhit expression. For the immunohistochemical analyses, 26 studies were included that analyzed at least 15 cases of a single type of tumor. For precancerous lesions, 9 studies were included that analyzed at least 4 cases. For studies of FHIT introduction, 9 published studies were included. DATA EXTRACTION: Using primary data from each of the studies, we assessed the rationale and potential contribution of FHIT cancer therapy. Data was independently abstracted by 2 authors and study quality was assessed by 2 other authors. DATA SYNTHESIS: Overall, 60% (1162/1948 cases) of primary tumors showed absent or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduction of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/408 cases]). Preclinical studies using 26 cancer-derived cell lines from human lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidney cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo tumorigenicity in 17 (57%) of 30 cell line experiments. Model systems for human preventive cancer therapy suggested that oral introduction of viral vector-mediated FHIT into Fhit-deficient mice may prevent carcinogen-induced tumor development in some cases. CONCLUSION: These findings show that FHIT gene therapy may potentially be clinically useful for treatment of cancer and also prevention of carcinogen-induced tumor development, suggesting a rationale for further research involving FHIT introduction.

Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.

The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease.

FHIT gene therapy prevents tumor development in Fhit-deficient mice.

The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral or adenoassociated viral vectors expressing the human FHIT gene, in heterozygous Fhit(+/-) knockout mice, that are prone to tumor development after carcinogen exposure. We therefore suggest that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.

Reintroduction of a tumor suppressor gene product in cancer cells is a promising strategy for cancer gene therapy. The fragile histidine triad (FHIT) gene has been identified in a region at chromosome 3p14.2, which is deleted in many tumors, including esophageal cancer. Previous studies have shown frequent biallelic alterations of the FHIT gene in numerous tumors, and have demonstrated a tumor suppressor function of Fhit. We have studied the biological effects of adenoviral-FHIT transduction in esophageal cancer cell lines. Results showed suppression of cell growth in vitro in three of seven esophageal cancer cell lines, all seven of which showed abundant expression of the transgene. Adenoviral-FHIT expression, but not control adenoviral infections, induced caspase-dependent apoptosis in two esophageal cancer cell lines, TE14 and TE4, which express no or very little Fhit, respectively. Treatment of TE14 cells with adenoviral-FHIT vectors resulted in abrogation of tumorigenicity in nude mice. A third esophageal cancer cell line, TE12, without detectable endogenous Fhit, showed accumulation of cells at S to G2-M and a small apoptotic cell fraction after adenoviral-FHIT transduction. Thus, adenoviral-FHIT expression can inhibit the growth of esophageal cancer cells, at least in part through caspase-dependent apoptosis, suggesting that adenoviral-FHIT infection should be explored as a therapeutic strategy.

[Tumor necrosis factor-alpha (TNF-alpha) gene polymorphism in surgical intensive care patients with SIRS]. / Tumornekrosefaktor-alpha (TNF-alpha) Gen-Polymorphismus bei chirurgischen Intensivpatienten mit SIRS.

Biallelic polymorphism in the promotor region of the TNF-alpha gene have been associated with variation in TNF-alpha production. We determined the TNFA polymorphism (position--308) and related these data to plasma cytokine levels of TNF alpha, IL6, IL6R and IL8 in patients with SIRS and sepsis. Although there seems to be a different cytokine secretion pattern for both allelic groups (TNFA1 and TNFA2), a clear risk group could not be determined. It still remains unclear whether there is a genetic factor that influences the development of sepsis and multi organ failure.

Granulocyte colony-stimulating factor (G-CSF) serum levels in surgical intensive care patients.

The granulocyte colony-stimulating factor (G-CSF) regulates neutrophil differentiation and function. Serum levels of G-CSF increase during acute infectious processes. The levels of G-CSF were measured in 59 surgical intensive care unit (ICU) patients. In general, G-CSF was only elevated during the first 2 days after admission to the ICU. Higher G-CSF levels were more frequently observed in patients without infectious complications and in patients who survived. Later on, G-CSF levels were below 100 pg/ml in almost all patients studied. The highest G-CSF level (20,000 pg/ml) was observed in one patient with septic shock 36 h after leukopenia. The patient recovered from septic shock and multiple organ failure and was discharged. It is proposed that surgical ICU patients with low or undetectable G-CSF serum levels may benefit from exogenous G-CSF substitution protocols.

Safety of a low-dosage Filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inflammatory process.

OBJECTIVE: To evaluate the effect and safety of a low dose Filgrastim treatment in surgical intensive care patients. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: Ten patients with the systemic inflammatory response syndrome (SIRS) and ten patients with sepsis were included in the study. INTERVENTIONS: Filgrastim was given intravenously at 1.0 microgram/kg for 3 days, followed by 0.5 microgram/kg for 4 days. MEASUREMENTS AND RESULTS: Filgrastim treatment increased leukocyte counts and plasma levels of G-CSF. Cytokine levels (IL-6 and IL-8) decreased in the first 3 days of treatment. None of the SIRS patients developed sepsis or multiple organ failure and none of the patients died. In the sepsis group four patients died. No adverse side effects were observed, especially no attenuation of lung injury. CONCLUSIONS: Low-dosage Filgrastim treatment in ICU patients is safe. Whether the observed changes of the inflammatory response can be attributed to Filgrastim has to be clarified in further randomized trials.

Effect of hyperthermia 42.5 degrees C/120 min on 3H-thymidine incorporation in different tissue components of Wilms' tumors: an in vitro study.

BACKGROUND: Survival rates of Wilms' tumors are correlated to tumor histology. Clinical studies and histological investigations have shown that different histological tumor components of Wilms' tumors also reveal different sensitivities to cytostatic agents and ionizing radiation. The aim of this study is to examine the effect of hyperthermia to Wilms' tumors, generally, and to the different tumor tissues composing nephroblastomas. MATERIAL AND METHOD: The 3H-thymidine labelling indices (LI) of 23 Wilms' tumors and one renal rhabdomyosarcoma were studied by an autoradiographic in vitro method at temperatures of 37.5 degrees C/120 min and 42.5 degrees C/120 min. The LI of each tumor was measured and likewise the LI of all histological tumor components defining standard risk and high risk. The effect of hyperthermia was calculated as the percentage of inhibition of 3H-thymidine incorporation. RESULTS: Labelling indices between 22.4% and 46.3% (mean 33.2%) characterized Wilms' tumors as highly malignant and fast growing tumors. The LI of Wilms' tumors of standard risk and high risk did not differ significantly (33.8% vs. 30.4%). Also, epithelium and blastema of the same groups showed comparable high LI of 31.4% and 34.4%, respectively, and of 32.1% and 26.8%, respectively. The LI of stroma was significantly lower (11.9% and 10.9%). The mean LI of fetal-like rhabdomyoblastic cell elements of ten tumors was 24.5%. These tumor cells revealed a significantly higher LI than rhabdomyosarcomatous cells in one Wilms' tumor and one renal rhabdomyosarcoma (10.2% and 9.0%, respectively). The LI of anaplastic structures of one tumor was more than twice as high as the LI of surrounding tumor tissue. In vitro hyperthermia significantly inhibited 3H-thymidine incorporation into all nephroblastomas. Inhibition ranged between 13.7% and 84.6%, at an average of 47.3%. Four high risk tumors, as well as the single anaplastic and rhabdomyosarcomatous cells responded significantly stronger to heat than standard risk tumors (mean inhibition of 62.6% vs. 42.1%). Hyperthermia was more effective for blastema compared to epithelium and stroma. There was no correlation between the effect of hyperthermia and the amount of the 3H-thymidine LI at normothermia. CONCLUSION: The tremendous inhibition of DNA synthesis by hyperthermia particularly in high risk tumors and highly malignant tumor components is of clinical interest for children with Wilms' tumors resistant to conventional therapy.

A modified PCR-based method for rapid non-radioactive detection of clinically important pathogens.

We have devised a sensitive and rapid method for the detection of several bacterial pathogens in clinical specimens using PCR. This method has been named Direct Labeling and Detection Procedure (DLDP) and is based on the direct incorporation of a nonradioactive digoxigenin label (DIG-11-dUTP) into a microbial species-specific gene fragment during amplification. Following amplification, the resulting PCR products are cleansed of nonincorporated DIG-11-dUTP, spotted onto a nylon membrane, fixed by UV-crosslinking and the labeled DNA is visualized by digoxigenin detection reagents. Using cultivated reference bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa) we were able to demonstrate a rapid and sensitive detection of < 20 CFU of bacteria in human secretions (sputum, urine, mucous). The present study suggests that DLDP can be used as a reliable method for indication of bacteria in clinical or environmental specimens with the proviso that the selected corresponding oligonucleotide primers provide amplification of strong species-specific genes.

[In vitro studies of DNA synthesis inhibition by hyperthermia (42.5 degrees C, 120 min) and cytostatic drugs in embryonal tumors and sarcomas in childhood]. / In vitro-Untersuchungen der DNA-Synthesehemmung durch Hyperthermie (42.5 degrees C, 120 min) und Zytostatika bei embryonalen Tumoren und Sarkomen des Kindesalters.

The effect of hyperthermia (HT), (42.5 degrees C, 120 min), cytostatic agents and the simultaneous application of HT and cytostatics on embryonal tumors and sarcomas in children was studied using an autoradiographic in vitro method. The 3H-thymidine and 3H-uridine incorporation inhibition was measured. HT inhibits DNA and RNA synthesis in a range of 42.0%-51.0% and 45.6%-58.3%. HT enhances the effect of the cytostatic agents ADM, CPM, cis-PL, BLM and BCNU highly significantly. In each case and without exception the simultaneous application of HT and cytostatics overcomes primary resistance to HT or the cytostatic concerned.

Overexpression of Gs alpha subunit in thyroid tumors bearing a mutated Gs alpha gene.

Point mutations occurring at codon 201 of the gene coding for the alpha subunit of the stimulatory G protein impair intrinsic GTPase activity and lead to a constitutive activation of adenylate cyclase. We have examined thyroid follicular and papillary carcinomas and follicular adenomas and found samples that bear this mutation at codon 201 of the Gs alpha gene. Both mutation-positive and mutation-negative tissue samples were investigated for the level of Gs alpha expression relative to a pool of normal thyroid tissue, using immunoblotting against two (mid-region-specific and C-end-specific) antipeptide antibodies. Using 8000 g and 100,000 g membrane fractions of homogenized tissues we have demonstrated that the Gs alpha proteins in normal ad neoplastic thyroid tissues are represented by three isoforms: 43 kDa, 45 kDa and 52 kDa. We have quantified and compared the amount of Gs alpha protein and find it is overexpressed in mutation-bearing tissue samples.