The relative contributions of carboxylesterase and beta-glucuronidase in the formation of SN-38 in human colorectal tumours

Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is subsequently metabolised to its inactive glucuronide, SN-38G, which can however be reactivated to SN-38 by beta-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and beta-glucuronidase in the in vitro production of SN-38 in human colorectal tumours. The production of SN-38 from CPT-11 and SN-38G was measured by HPLC in human colorectal tumour homogenates. Carboxylesterase and beta-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, beta-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.     

Scheimpflug photographic imaging following implantation of anterior and posterior chamber phakic intraocular lenses: preliminary results

BACKGROUND: For the correction of refractive errors lenticular procedures are increasingly used in addition to corneal refractive surgery. One of those techniques is the implantation of intraocular lenses into phakic eyes (pIOL). Due to the close neighborhood of the implant to delicate intraocular structures, exact positioning and high postoperative stability are required. Scheimpflug photography has been shown to be a suitable instrument for the biometry of the anterior eye segment and the examination of IOL position. PATIENTS AND METHODS: Four anterior chamber phakic IOLs (pIOLs) (Bausch & Lomb NuVita) and 7 posterior chamber pIOLs (Staar ICL) were examined 1 week, 1 month and 3-6 months following implantation. At each examination 1 Scheimpflug slit image and 1 infrared retroillumination image were taken using the anterior eye segment analysis system EAS-1000 (Nidek Co., Gamagori, Japan). Evaluation of the images was performed with a personal computer and the software provided by the manufacturer. The distance of the pIOL to cornea and human lens was calculated and incidence and amount of pIOL rotation around the optical axis and potential crystalline lens opacification were assessed. RESULTS: The distance between the anterior chamber pIOL and the cornea 1 week after implantation was 1.61 +/- 0.10 mm. The distances between the myopic posterior chamber pIOL and the human lens were 0.34 +/- 0.11 mm and between the hyperopic posterior chamber pIOL and the human lens 0.26 and 0.29 mm, respectively. The values were constant over a period of 3-6 months. The pIOL showed no movement or change of position around the optical axis. There was no detectable cataract formation in the human lens. CONCLUSIONS: All implanted phakic anterior and posterior chamber IOLs showed a stable position in the eye within the observation period. Scheimpflug photography is proved to be a useful technique for the postoperative evaluation of the positioning of phakic IOLs.     

Day-clinic treatment of late-life depression

BACKGROUND: There are few studies evaluating treatment in gerontopsychiatric day-clinics. In this paper, data are presented on the outcome of day-clinic treatment in late-life depression. METHOD: Forty-four depressed elderly patients (mean Hamilton Depression Score: 17.6) were examined at admission and discharge for psychopathology, functioning in daily living, social situation, burden with medical disease and quality of life. RESULTS: At discharge, the patients showed a significant reduction in depressive symptoms, improvements in cognitive performance, social activities and contacts. However, a more detailed analysis revealed that only patients responding to treatment (n=20) improved in the respective parameters. Patients, who did not recover fully from depression (n=24), did not improve in any of these parameters. At admission, responders and nonresponders did not differ concerning quality of life. At discharge, responders were significantly more satisfied in 11 of 20 domains of life quality. A shorter life time duration of depressive disease and male sex were predictive for a remission of depression. Thus, it could be shown that a considerable number of patients suffering from late-life depression may be successfully treated in a gerontopsychiatric day-clinic and 45.5% fully recover from depression. CONCLUSIONS: The day-clinic setting meets the specific needs of patients suffering from late-life depression by maintaining them in the community, supporting their abilities for self-care and promoting social contacts. Treatment in a day-clinic may be recommended for many elderly depressed patients.     

Economics of the antithymocyte globulins Thymoglobulin and Atgam in the treatment of acute renal transplant rejection

OBJECTIVE: To evaluate the economic implications for transplant centres, Medicare and society of treatment of corticosteroid-resistant Banff Grades I, II and III acute kidney transplant rejection with the antithymocyte globulins Thymoglobulin or Atgam. DESIGN AND SETTING: This was a cost analysis of a randomised double-blind multicentre clinical trial comparing the safety and efficacy of Thymoglobulin and Atgam that was performed at 25 centres in the US in 1994 to 1996. PATIENTS AND PARTICIPANTS: The study enrolled 163 patients, 82 in the Thymoglobulin arm and 81 in the Atgam arm. METHODS: Estimates of the cost of care from the initiation of rejection therapy to 90 days post-therapy were derived from various publicly available sources and applied to patient-specific clinical events documented in the clinical trial. Patients received either intravenous Thymoglobulin (1.5 mg/kg/day) for an average of 10 days or intravenous Atgam (15 mg/kg/day) for an average of 9.7 days. RESULTS: On average, Thymoglobulin provided significant cost savings compared with Atgam from the perspective of society [$US5977 (1996 values); 95% confidence interval (CI) $US3719 to $US8254], Medicare ($US4967; 95% CI $US3256 to $US6678) and the transplant centre ($US3087; 95% CI $US1512 to $US4667). The overall advantage attributable to Thymoglobulin was primarily due to savings from fewer recurrent rejection treatments and less frequent return to dialysis. CONCLUSIONS: Treatment of acute renal transplant rejection with Thymoglobulin is a cost saving strategy when compared with treatment with Atgam.     

Differential organization of touch and pain in human primary somatosensory cortex

Processing of tactile stimuli within somatosensory cortices has been shown to be complex and hierarchically organized. However, the precise organization of nociceptive processing within these cortices has remained largely unknown. We used whole-head magnetoencephalography to directly compare cortical responses to stimulation of tactile and nociceptive afferents of the dorsum of the hand in humans. Within the primary somatosensory cortex (SI), nociceptive stimuli activated a single source whereas tactile stimuli activated two sequentially peaking sources. Along the postcentral gyrus, the nociceptive SI source was located 10 mm more medially than the early tactile SI response arising from cytoarchitectonical area 3b and corresponded spatially to the later tactile SI response. Considering a mediolateral location difference between the hand representations of cytoarchitectonical areas 3b and 1, the present results suggest generation of the single nociceptive response in area 1, whereas tactile stimuli activate sequentially peaking sources in areas 3b and 1. Thus nociceptive processing apparently does not share the complex and hierarchical organization of tactile processing subserving elaborated sensory capacities. This difference in the organization of both modalities may reflect that pain perception rather requires reactions to and avoidance of harmful stimuli than sophisticated sensory capacities.     

Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients

BACKGROUND: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients, refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largest series of patients treated with caspofungin outside clinical trials. METHODS: Centres in Germany that were known to treat patients with invasive fungal infections were asked to fill out detailed questionnaires for all patients treated with caspofungin. No effort was made to influence the decision to use caspofungin. RESULTS: A total of 118 patients were evaluable (median age 48 years, interquartile range 38-58), out of which 41 (35%) suffered from acute leukaemia, 31 (26%) had allogeneic stem cell transplants, 16 (14%) lymphoma or myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression. One hundred and six patients were evaluable for efficacy out of which 68 (64%) patients achieved a complete or partial remission. A total of 81 out of 115 (70%) patients were alive 30 days after the end of caspofungin therapy. Response rates were similar in proven (20/32, 63%) and probable (27/46, 59%) infections, in neutropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractory to antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24). Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A, no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found. CONCLUSIONS: This open case study of severely ill patients with invasive fungal infections demonstrates both excellent efficacy and very low toxicity of caspofungin.     

Three‐Year Outcomes From BENEFIT‐EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys

Recipients of extended‐criteria donor (ECD) kidneys have poorer long‐term outcomes compared to standard‐criteria donor kidney recipients. We report 3‐year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty‐three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept‐treated versus cyclosporine‐treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine‐treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept‐treated patients (27–30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept‐treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.     

Payment for Living Donor (Vendor) Kidneys: A Cost-Effectiveness Analysis

The supply of kidneys does not meet the demand. As a consequence, the waiting time for a cadaver kidney continues to lengthen, and there is renewed debate about payment for living donors. To facilitate this debate, we studied what amount of payment would be cost-effective for society, i.e. what costs would be saved (if any) by removing a patient from the waiting list using a paid (living unrelated: LURD) donor-vendor. A Markov model was developed to calculate the expected average cost and outcome benefits of increasing the organ supply and reducing waiting times by adding paid LURD organs to the available pool. We found that a LURD transplant saved $94,579 (US dollars, 2002), and 3.5 quality-adjusted life years (QALYs) were gained. Adding the value of QALYs, a LURD transplant saved $269 319, assuming society values additional QALYs from transplantation at the rate paid per QALY while on dialysis. At a minimum, a vendor program would save society >$90,000 per transplant and provides QALYs for the ESRD population. Thus, society could break even while paying $90,000/kidney vendor.     

Antidepressant medication use before and after kidney transplant: implications for outcomes – a retrospective study

We examined a novel database wherein national US transplant registry identifiers were linked to records from a large pharmaceutical claims warehouse (2008–2015) to characterize antidepressant use before and after kidney transplantation, and associations [adjusted hazard ratio (aHR) 95% CI] with death and graft failure. Among 72 054 recipients, 12.6% filled antidepressant medications in the year before transplant, and use was more common among women and patients who were white, unemployed, and had limited functional status. Pre‐transplant antidepressant use was associated with 39% higher 1‐year mortality (aHR 1.39, 95% CI 1.18–1.64) and 15% higher all‐cause graft loss risk (aHR 1.15, 95% CI 1.02–1.30). More than 50% of patients who filled antidepressants pre‐transplant continued fill post‐transplant. Antidepressant use in the first year after transplant was associated with twofold higher risk of death (aHR 1.94, 95% CI 1.60–2.35), 38% higher risk of death‐censored graft failure, and 61% higher risk of all‐cause graft failure in the subsequent year. Pre‐listing antidepressant use was also associated with increased mortality, but transplantation conferred a survival benefit regardless of prelisting antidepressant use status. While associations may in part reflect underlying behaviors or comorbidities, kidney transplant candidates and recipients treated with antidepressant medications should be monitored and supported to reduce the risk of adverse outcomes.