Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary adults*

OBJECTIVES The physiological role Of growth hormone in adult life has recently attracted increased Interest. We have studied the clinical effects and the effects on body composition of prolonged replacement with biosynthetic human GH In a large number of hypopituitary adults. DESIGN A randomized double blind placebo controlled trial for 6 months followed by an open trial of GH treatment for 12 months. GH dally dose was 0·04 (0·02-0·05) IU/kg s.c. PATIENTS Forty GH deficient hypopituitary patients (19 M, 21 F; aged 19–67 years) on conventional replacement therapy were studied. MEASUREMENTS Serum insulin like growth factor I (IGF-I), skinfold thickness, total body potassium, total body water (TBW), exercise tolerance and muscle strength, and well-being. RESULTS During the 6-month double blind phase, two GH treated patients withdrew because of adverse events. Lean body mass (LBM) increased and percentage body fat (%BF) decreased on GH but not on placebo (P) (LBM: (GH: from 48·5 ± 9·6 to 49·6 ± 9·5kg; P: from 50·9 ± 9·2 to 50·1 ± 9·0kg, P < 0·05 GH vs P) and TBW (OH: from 34·7 ± 11·4 to 34·2 ± 10·7; P: from 37·4 ± 7·6 to 38·7 ± 8·1, P < 0·05 GH vs P). TBW Increased on GH (P < 0·01) but not on P. No change was observed In waist-to-hip ratio or in muscle strength. During longer-term follow-up combining the double blind and open phase components of the study, 34, 27 and 11 patients received OH for 6,12 and 18 months respectively. Patients dropped out because of adverse events or lack of perceived benefit. Skinfold thicknesses decreased significantly at 6 and 12 months and the waist circumference at 6 months. Waist-to-hip ratio decreased significantly on OH at 12 months. LBM increased on GH treatment from 49·6 ± 9·1 to 51·6 ± 9·4kg (P < 0·0006), 51·9 ± 8·9kg (P < 0·07) and 53·1 ± 10·5 kg (P < 0·0001) at 6, 12 and 18 months respectively. Percentage body fat decreased on GH from 37·2 ± 10·7 to 34·7 ± 10·1 (P < 0·005), 35·1 ± 12·8 (NS) and 34·5 ± 86 (P < 0·04) at 6, 12 and 18 months respectively. TBW also increased at 6 and 12 months of GH treatment. Exercise time increased significantly at 6, 12 and 18 months of GH treatment. Muscle strength in selected muscle groups Increased significantly at 6, 12 or 18 months of GH treatment. Randomization resulted in the placebo group having a greater GHQ score (higher morbidity) than the OH group before therapy. Over the controlled phase, GHQ scores improved on placebo but not on OH and CPRS score was unchanged in either group. In the open phase, the GHQ score did not change on GH therapy but CPRS score improved at 6 and 12 months. CONCLUSIONS Growth hormone replacement therapy in adults for 6 months increased lean body mass, total body water and exercise tolerance, and decreased body fat. Growth hormone replacement for longer than 6 months maintains the advantageous effects seen in shorter-term studies and may have additional effects on body fat distribution, muscle strength and psychological well-being.     

Cell-Mediated Immunity in Professional and Voluntary Blood Donors

Cell-mediated immunity (CMI) was compared in professional and voluntary blood donors. Depressed CMI in professional donors was revealed by the presence of significantly lower numbers of positive delayed reactive hypersensitivity responses to Candida albicans, streptokinase and streptodornase, as well as a decrease in lymphoblast transformation response to phytohaemagglutinin. Furthermore, the serum protein and albumin levels in professional donors did not correlate with the depression in CMI. The blood of professional blood donors should be considered to be a poor source of therapeutic immune cell fractions.     

Novel peptidomimetic cysteine protease inhibitors as potential antimalarial agents

The synthesis of a new class of peptidomimetics 1a-j, based on a 1,4-benzodiazepine scaffold and on a C-terminal aspartyl aldehyde building block, is described. Compounds 1a-j provided significant inhibitory activity against falcipains 2A and 2B (FP-2A and FP-2B), two cysteine proteases from Plasmodium falciparum.     

Toxicity of oxidized beta-carotene to cultured human cells

Carotenoids are effective antioxidants in vitro, but they are also susceptible to autoxidation, which generates volatile and biologically active aldehydes and ketones. In a previous study, we showed that autoxidized beta-carotene inhibits Na+-K+-ATPase activity more effectively than aldehydic products derived from lipid peroxidation, such as 4-hydroxynonenal. In this study, we compared mitochondrial dysfunction in cultured human K562 erythroleukaemic and 28 SV4 retinal pigment epithelium (RPE) cells in response to the degradation products of beta-carotene autoxidation using the MTT assay. We found that oxidized beta-carotene is cytotoxic and that mitochondrial function is decreased in both K562 and RPE cells. In addition, the RPE cells were more resistant to this form of oxidative stress, suggesting that its cytotoxicity may depend on cellular antioxidant capacity.     

Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma

PURPOSE: To evaluate pleurectomy/decortication (P/D) and adjuvant radiotherapy (RT) in the treatment of malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: In a retrospective review, we included MPM patients treated with P/D and adjuvant RT at Memorial Sloan-Kettering Cancer Center from 1974 to 2003. When indicated, patients received intraoperative brachytherapy to residual tumor. RESULTS: All 123 patients received external beam RT (median dose, 42.5 Gy; range, 7.2-67.8 Gy) to the ipsilateral hemithorax postoperatively. Fifty-four patients underwent brachytherapy (matched peripheral dose, 160 Gy). The median and 2-year overall survival for all patients was 13.5 months (range, 1-199 months) and 23%, respectively. One-year actuarial local control for all patients was 42%. Multivariate analysis for overall survival revealed radiation dose <40 Gy (p = 0.001), nonepithelioid histology (p = 0.002), left-sided disease (p = 0.01), and the use of an implant (p = 0.02) to be unfavorable. Two patients (1.6%) died from Grade 5 toxicity within 1 month of treatment. CONCLUSIONS: Pleurectomy/decortication with adjuvant radiotherapy is not an effective treatment option for patients with MPM. Our results imply that residual disease cannot be eradicated with external RT with or without brachytherapy and that a more extensive surgery followed by external RT might be required to improve local control and overall survival.     

Chemometrics of differentially expressed proteins from colorectal cancer patients

AIM:To evaluate the usefulness of differentially expressed proteins from colorectal cancer (CRC) tissues for differentiating cancer and normal tissues.METHODS:A Proteomic approach was used to identify the differentially expressed proteins between CRC and normal tissues.The proteins were extracted using Tris buffer and thiourea lysis buffer (TLB) for extraction of aqueous soluble and membrane-associated proteins,respectively.Chemometrics,namely principal component analysis (PCA) and linear discriminant analy...     

The impact of complications on outcomes after resection for esophageal and gastroesophageal junction carcinoma

BACKGROUND: Efforts to improve surgical outcomes have traditionally focused on improving preoperative patient selection and reducing the risk of postoperative medical complications. Strategies to optimize surgical technique have been less well studied. We sought to assess the relation between complications related to surgical technique and outcomes after esophagogastrectomy for cancer. STUDY DESIGN: Medical records of 510 consecutive patients undergoing esophagogastrectomy for invasive squamous cell carcinoma or adenocarcinoma at Memorial Sloan-Kettering Cancer Center from 1996 to 2001 were reviewed. Data on diagnosis, stage of disease, therapies received, surgical approach, patient comorbidities, technical complications, and postoperative medical complications and outcomes including length of stay and overall survival were determined by one reviewer of the medical records. The primary predictor was surgical complications and the primary outcome was survival. RESULTS: Of the 150 patients studied 138 (27%) had complications directly attributable to surgical technique, such as an anastomotic leak, a paralyzed vocal cord, or chylothorax. At 3 years 43 of 138 patients (31%) with technical complications were alive, whereas 179 of 372 patients (48%) without technical complications were alive. Technical complications were associated with increased length of stay (median 23 days versus 11 days, p < 0.001), increased in-hospital mortality (12.3% versus 3.8%, p < 0.001), and a higher rate of medical complications (77.5% versus 47.3%, p < 0.001). After controlling for age, medical comorbidities, use of induction therapy, tumor stage, histology, and location, and completeness of resection the presence of a technical complication was highly predictive of poorer overall survival; the multivariable hazard ratio was 1.41 (1.22 to 1.63, p = 0.008). CONCLUSIONS: Technical complications have a large negative impact on survival after esophagogastrectomy for cancer. Strategies to optimize surgical technique and minimize complications should improve outcomes in this cancer operation.