Treatment of small cell lung cancer with a combination of VP16-213 and cyclophosphamide with cisplatin or radiotherapy

Summary Fifty five patients with small cell lung cancer were treated with a VP16-213 combination chemotherapy regimen in two consectutive series. The first series included 24 patients; 10 with limited and 14 with extensive disease were treated with VP16-213, 120 mg/m² p.o. daily for 5 consecutive days, Cyclophosphamide 600 mg/m² i.v. and Cisplatin 80 mg/m² i.v. with hydratation and manitol induced diuresis. The cycle was repeated every 3 weeks. The second series included 31 similar patients, 16 limited, and 15 extensive disease, treated with VP16-213 at the same dose and Cyclophosphamide at 1,200 mg/m² i.v. also repeated every 3 weeks; after three cycles the patients were treated with radiotherapy to the primary tumor and regional lymph nodes with 4,000 rads in a split course of three weeks interval, followed by the same combination chemotherapy. Response rate was 75% for the first series with 6 of 24 (25%) of complete responses in four limited and two extensive disease and a median survival time of 24 weeks. In the second series of patients there were 26 of 31 (83.8%) responses with 10 of 31 (32%) complete responses in nine limited and one extensive disease and a median survival time of 33 weeks for responders. Duration of response for complete responders was 36.8 weeks for the first series and 51 weeks for the second. Toxicity was mild and includes nausea and vomiting, myelosupression, alopecia in both series, with one toxic death in the second series.Both regimens are active with a low complete response rate, which was increased in the second series by the addition of radiotherapy, which did not increase overall survival. Send offprint requests to H. Cortés Funes, Section Oncologia Medica, Servicio de Radioterapia y Oncologia     

Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506) is a safe and effective treatment for the prevention of rejection of renal allografts. Mycophenolate mofetil (MMF) has been used as adjunct immunosuppressive therapy with cyclosporine and corticosteroids for the same purpose. The objective of this study was to investigate the safety and efficacy of FK506 and MMF in renal transplant recipients. METHODS: After cadaveric renal transplant, patients were randomized to receive tacrolimus in combination with either azathioprine (AZA, n=59), MMF 1 g/day (n=59), or MMF 2 g/day group (n=58). Patients were followed for 1 yr posttransplant for the incidence of biopsy-confirmed acute rejection, patient and graft survival, and adverse events. RESULTS: Tacrolimus doses and trough concentrations were similar between treatment groups at all time points; 80% of patients were maintained within a range of 5.0-13.9 ng/ml at 12 months posttransplant. The mean dose of MMF decreased in the 2 g/day group to 1.5 g/day by 6 months posttransplant, primarily due to gastrointestinal GI-related disorders. The incidence of biopsy-confirmed acute rejection at 1 year was 32.2%, 32.2%, and 8.6% in the AZA, MMF 1 g/day, and MMF 2 g/day groups, respectively (P<0.01). The use of antilymphocyte antibodies for the treatment of rejection was comparable across treatment groups. The incidence of most adverse events was similar across treatment groups and comparable with previous reports. The overall incidence of posttransplant diabetes mellitus was 11.9%, with the lowest rate observed in the MMF 2 g/day group (4.7%), and was reversible in 40% of patients. The incidence of malignancies and opportunistic infections was low and not different across treatment groups. CONCLUSION: Tacrolimus in combination with an initial dose of MMF 2 g/day is a very effective and safe regimen in cadaveric kidney transplant recipients.     

Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome

BACKGROUND: Select pancreatic enzymes, primarily elastase, precipitate pulmonary injury similar to pancreatitis-associated adult respiratory distress syndrome and stimulate leukocyte cytokine production in vitro via nuclear factor kappa B (NF-kappaB) activation. This study explores the effect of systemic pancreatic enzymes on pulmonary NF-kappaB and inhibitory kappa B (IkappaB) proteins and their role in enzyme-induced pulmonary injury. METHODS: Mice received pancreatic elastase, amylase, lipase, or trypsin intraperitoneally. Bronchoalveolar lavage IkappaBalpha/IkappaBbeta proteins were measured by immunoblot. Pulmonary NF-kappaB activation, tumor necrosis factor (TNF) gene expression, and neutrophil infiltration (myeloperoxidase) were determined and myeloperoxidase experiments repeated in p55 TNF receptor-deficient (TNF KO) animals. Additional animals received pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB activation, and TNF protein and pulmonary microvascular permeability were measured after elastase administration. RESULTS: Pancreatic elastase induced pulmonary IkappaBalpha/IkappaBbeta degradation (30 minutes), NF-kappaB activation (60 minutes), and TNF gene expression (60 minutes) with subsequent neutrophilic inflammation (4 hours) and microvascular leakage (24 hours), whereas amylase, lipase, and trypsin did not. Furthermore, lung injury was markedly reduced in TNF KO animals and PDTC significantly attenuated TNF production and pulmonary microvascular leakage. CONCLUSIONS: Pancreatic elastase induces cytokine-mediated lung injury and this pathway involves the NF-kappaB second messenger system, further supporting elastase as a factor linking pancreatic inflammation to systemic illness during severe acute pancreatitis.     

Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft

The current transplantation strategy in experimental and clinical Parkinson's disease (PD) has been to place nigral dopaminergic grafts not in their ontogenic site (substantia nigra) but in their target area (striatum). Although intrastriatal dopaminergic grafts are capable of reinnervating the striatum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patients. We have previously shown that simultaneous intrastriatal and intranigral dopaminergic grafts (double grafts) may provide a more complete restoration of the nigrostriatal circuitry (Mendez et al. [1996] J Neurosci 16:7216-7227; Mendez and Hong [1997] Brain Res 778:194-205). In the present study, we investigated the contribution of the intranigral graft to functional recovery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were divided into two groups and received either double grafts (n = 10) or intrastriatal grafts alone (n = 10). Following transplantation, both intrastriatally and double-grafted animals had a significant decrease in rotational behavior. However, only animals with double grafts exhibited a significant increase in contralateral adjusting step performance. The intranigral graft was subsequently lesioned by a second 6-OHDA injection. Following the second lesion, animals with double grafts exhibited a significant reversal of rotational behavior and a 51% reduction in contralateral adjusting step performance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest that the intranigral graft has an important role in the functional recovery of double-grafted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a superior strategy in neural transplantation for PD.     

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line--derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.     

Energy density,diet quality,and central body fat in a nationwide survey of young Spaniards

ObjectivesTo determine the impact of energy density on diet quality and anthropometric proxy measures for central body fat in young Spaniards.MethodsData were obtained from a representative national sample of 2513 young Spaniards aged 10 to 24 y. Dietary assessment was performed with a 24-h recall. Adherence to the Mediterranean diet was measured by the KIDMED index. Reduced rank regression analysis was used to identify energy-density dietary patterns. Waist circumferences and height were measured.ResultsPastries and sausages showed the strongest loading for the dietary energy density factor score (DED-FS), with fruits and vegetables at the opposite end of the scale. Multiple linear regression analysis showed a positive association (P < 0.01) of dietary energy density (DED) and the DED-FS with waist circumferences regressed on height and age (WC_height+age) and waist-to-height ratio (WHtR). The adjusted odds ratio for elevated WC_height+age and WHtR increased across quartile distribution of DED (P < 0.001) and DED-FS (P < 0.05). Diet quality characterized by the KIDMED index was negatively associated (P < 0.001) with DED and the DED-FS.ConclusionsHigher DED is a risk for increased central fat distribution and is associated with low adherence to the Mediterranean diet.     

Preoperative Management of Endocrine,Hormonal, and Urologic Medications: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement

Perioperative medical management is challenging due to the rising complexity of patients presenting for surgical procedures. A key part of preoperative optimization is appropriate management of long-term medications, yet guidelines and consensus statements for perioperative medication management are lacking. Available resources utilize the recommendations derived from individual studies and do not include a multidisciplinary focus or formal consensus. The Society for Perioperative Assessment and Quality Improvement (SPAQI) identified a lack of authoritative clinical guidance as an opportunity to utilize its multidisciplinary membership to improve evidence-based perioperative care. SPAQI seeks to provide guidance on perioperative medication management that synthesizes available literature with expert consensus. The aim of this Consensus Statement is to provide practical guidance on the preoperative management of endocrine, hormonal, and urologic medications. A panel of experts with anesthesiology, perioperative medicine, hospital medicine, general internal medicine, and medical specialty experience was drawn together and identified the common medications in each of these categories. The authors then utilized a modified Delphi approach to critically review the literature and generate consensus recommendations.