Development in the treatment of malignant mesothelioma

For many years there has been a search for an effective treatment of malignant pleural mesothelioma. Surgery is of limited applicability and is reserved for special cases, in which it is combined with radiation therapy. In the previous century, many cytostatic agents have been tested, alone or in combination, but the response was limited, the median survival time was unchanged and the toxicity was high. New drugs, including the new antifolates, are being used much more often in the treatment of malignant pleural mesothelioma in combination with a platinum derivative. Cytostatics such as pemetrexed, an antifolate, and to a lesser extent raltitrexed, have shown good response rates and increased survival in phase III studies, but the survival benefit evaporates within 2 years. Inhibitors of angiogenesis and of epidermal growth factor are being tested, but they have shown only limited activity until now. The current studies focus on the use of chemotherapy and biological agents as part of a more complex treatment schedule.     

Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath

BACKGROUND: Multiple drug immunosuppression has allowed the near elimination of rejection, but without commensurate improvements in longterm graft survival and at the cost of quality of life. We have suggested that transplantation outcomes can be improved by modifying the timing and dosage of immunosuppression to facilitate natural mechanisms of alloengraftment and acquired tolerance. STUDY DESIGN: Two therapeutic principles were applied for kidney transplantation: pretransplant recipient conditioning with antilymphoid antibody preparations (Thymoglobulin [Sangstat] or Campath [ILEX Pharmaceuticals]), and minimal posttransplant immunosuppression with tacrolimus monotherapy including "spaced weaning" of maintenance doses when possible. The results in Thymoglobulin- (n = 101) and Campath-pretreated renal transplantation recipients (n = 90) were compared with those in 152 conventionally immunosuppressed recipients in the immediately preceding era. RESULTS: Spaced weaning was attempted in more than 90% of the kidney transplant recipients after pretreatment with both lymphoid-depleting agents, and is currently in effect in two-thirds of the survivors. Although there was a much higher rate of acute rejection in the Thymoglobulin-pretreated recipients than in either the Campath-pretreated or historic control recipients, patient and graft survival in both lymphoid depletion groups is at least equivalent to that of historic control patients. In the Thymoglobulin-conditioned patients for whom followups are now 24 to 40 months, chronic allograft nephropathy (CAN) progressed at the same rate as in historic control patients. Selected patients on weaning developed donor-specific nonreactivity. CONCLUSIONS: After lymphoid depletion, kidney transplantation can be readily accomplished under minimal immunosuppression with less dependence on late maintenance immunosuppression and a better quality of life. Campath was the more effective agent for pretreatment. Guidelines for spaced weaning need additional refinement.     

Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched control study

BACKGROUND: Liver transplant recipients are at high risk for multi-drug resistant infections because of broad-spectrum antibiotic and immunosuppression. This study evaluates the clinical and financial impact of vancomycin resistant Enterococcus (VRE) in liver transplant recipients. METHODS: Liver transplant recipients with VRE from 1995 to 2002 were identified and matched (age, gender, UNOS status, liver disease and transplant date) to controls. Demographics, clinical factors, co-infections, antibiotic use, length of stay, abdominal surgeries, biliary complications, survival and resource utilization were compared with matched controls. RESULTS: Nineteen patients were found to have 28 VRE infections via evaluation of microbiologic culture results of all liver transplant patients in the transplant registry. Thirty-eight non-VRE patients served as matched controls. The four most common sites VRE was cultured from included blood (35%), peritoneal fluid (35%), bile (20%), and urine (12%). Median time from transplant to infection was 48 d (range of 4-348). No significant differences in demographics were observed. The VRE group had a higher incidence of prior antibiotic use than the non-VRE group (95% vs. 34%; p < 0.05). The VRE group also experienced more abdominal surgery (20/19 vs. 3/38; p = 0.029), biliary complications (9/19 vs. 9/38; p = 0.018) and a longer length of stay (42.5 vs. 21.7 d; p = .005). Survival in the VRE group was lower (52% vs. 82%; p = 0.048). Six of the 19 VRE patients were treated with linezolid for eight infection episodes, and four of six patients survived. Eight patients were treated with quinupristin/dalfopristin for nine infections, and two of eight survived. Increased cost of care was observed in the VRE group. Laboratory costs were higher in the VRE group (6500 dollars vs. 1750; p = 0.02) as well. CONCLUSION: VRE was associated with prior antibiotic use, multiple abdominal surgeries, biliary complications and resulted in decreased survival compared to non-VRE control patients. VRE patients also utilized more hospital resources. Linezolid showed a trend toward improved survival.     

Prediction of nephrotoxicant action and identification of candidate toxicity-related biomarkers

A vast majority of pharmacological compounds and their metabolites are excreted via the urine, and within the complex structure of the kidney,the proximal tubules are a main target site of nephrotoxic compounds. We used the model nephrotoxicants mercuric chloride, 2-bromoethylamine hydrobromide, hexachlorobutadiene, mitomycin, amphotericin, and puromycin to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. Male Sprague-Dawley rats were dosed via intraperitoneal injection once daily for mercuric chloride and amphotericin (up to 7 doses), while a single dose was given for all other compounds. Animals were exposed to 2 different doses of these compounds and kidney tissues were collected on day 1, 3, and 7 postdosing. Gene expression profiles were generated from kidney RNA using 17K rat cDNA dual dye microarray and analyzed in conjunction with histopathology. Analysis of gene expression profiles showed that the profiles clustered based on similarities in the severity and type of pathology of individual animals. Further, the expression changes were indicative of tubular toxicity showing hallmarks of tubular degeneration/regeneration and necrosis. Use of gene expression data in predicting the type of nephrotoxicity was then tested with a support vector machine (SVM)-based approach. A SVM prediction module was trained using 120 profiles of total profiles divided into four classes based on the severity of pathology and clustering. Although mitomycin C and amphotericin B treatments did not cause toxicity, their expression profiles were included in the SVM prediction module to increase the sample size. Using this classifier, the SVM predicted the type of pathology of 28 test profiles with 100% selectivity and 82% sensitivity. These data indicate that valid predictions could be made based on gene expression changes from a small set of expression profiles. A set of potential biomarkers showing a time- and dose-response with respect to the progression of proximal tubular toxicity were identified. These include several transporters (Slc21a2, Slc15, Slc34a2), Kim 1, IGFbp-1, osteopontin, alpha-fibrinogen, and Gstalpha.     

Ill-health retirement: national rates and updated guidance for occupational physicians

BACKGROUND: Advising on ill-health retirement is an important role of most practising occupational physicians. In recent years, the eligibility criteria and process for gaining early retirement benefits have changed in many pension schemes in the UK. AIM: To investigate the variation in rates of retirement due to ill-health in National Health Service (NHS) Trusts and Local Authorities and to update previously published guidance on ill-health retirement with specific reference to pension schemes with eligibility criteria that include permanence of incapacity due to ill-health. METHODS: Rates of retirement were calculated for 222 NHS Trusts and 132 Local Authorities with more than 1500 employees. Literature searches and consensus statements by the authors. RESULTS: Rates of retirement were widely distributed in the NHS Trusts and Local Authorities. The median rates of retirement were 2.11 (IQR 1.37-2.91)/1000 active members and 4.10 (IQR 3.01-6.10)/1000 employees, respectively (P<0.001). Difficulties in the doctor-patient relationship and in ascertaining the true functional ability of some patients were identified. CONCLUSION: There continues to be marked variation in rates of early retirement due to ill-health within and between organizations that warrants further investigation. The general and specific guidance that appears as an appendix in Supplementary data to this paper should help occupational physicians to make equitable recommendations when assessing applications for early retirement benefits and fitness to work.     

Video-assisted thoracoscopic surgery using single-lumen endotracheal tube anesthesia

BACKGROUND: Most general thoracic surgeons use double-lumen endotracheal tube (DLET) anesthesia for all video-assisted thoracoscopic surgery (VATS). We evaluated a single-lumen endotracheal tube (SLET) for VATS for drainage of pleural effusions and pleural biopsies. METHODS: A consecutive series of patients with recurrent pleural effusions underwent VATS using an SLET and only one incision. Operations were accomplished via one 2-cm incision using a 5-mm rigid thoracoscope and mediastinoscopic biopsy forceps for directed pleural biopsies. A working area was accomplished with low tidal volumes. RESULTS: There were 376 patients (191 women). The indications for VATS were a nondiagnosed or benign pleural effusion in 294 patients, and a malignant effusion in 82 patients. Two hundred eight patients underwent biopsy of the parietal pleura, and mean operative time was 17 min. Adequate visibility was obtained in all. When compared to preoperative cytology, VATS was more sensitive (45% compared to 99%, p < 0.001), had a higher negative predictive value (56% compared to 99%, p < 0.001), and was more accurate (67% compared to 99%, p < 0.001). Forty-seven percent of patients with a history of cancer had false-negative preoperative cytology results. Complications occurred in seven patients (2%), and there were three operative deaths (none related to the operative procedure). CONCLUSION: VATS using SLET and only one incision is possible, and it affords excellent visualization of the pleural space, allowing pleural biopsies and talc insufflation. It avoids the risk, time, and cost of a DLET. It is significantly more sensitive and accurate than preoperative cytology, and it should be considered as the diagnostic and therapeutic procedure of choice in patients with recurrent pleural effusions.     

The potyviral suppressor of RNA silencing confers enhanced resistance to multiple pathogens

Helper component-protease (HC-Pro) is a plant viral suppressor of RNA silencing, and transgenic tobacco expressing HC-Pro has increased susceptibility to a broad range of viral pathogens. Here we report that these plants also exhibit enhanced resistance to unrelated heterologous pathogens. Tobacco mosaic virus (TMV) infection of HC-Pro-expressing plants carrying the N resistance gene results in fewer and smaller lesions compared to controls without HC-Pro. The resistance to TMV is compromised but not eliminated by expression of nahG, which prevents accumulation of salicylic acid (SA), an important defense signaling molecule. HC-Pro-expressing plants are also more resistant to tomato black ring nepovirus (TBRV) and to the oomycete Peronospora tabacina. Enhanced TBRV resistance is SA-independent, whereas the response to P. tabacina is associated with early induction of markers characteristic of SA-dependent defense. Thus, a plant viral suppressor of RNA silencing enhances resistance to multiple pathogens via both SA-dependent and SA-independent mechanisms.