Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.     

Inflammatory mechanisms in Alzheimer's disease

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as 1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.     

Antiapoptotic activity of bovine papilloma virus

Transformed fibroblasts have been recently shown to be sensitive for induction of apoptosis by TGF-beta-treated neighbouring untransformed cells. Cells transformed by a variety of different transformation principles were regularly sensitive for intercellular induction of apoptosis, but fibroblasts transformed by bovine papillomavirus (BPV) represented a striking exception. In contrast to chemically transformed C127 cells, BPV-transformed C127 cells showed resistance against intercellular induction of apoptosis. In addition, BPV-transformed cells were resistant against induction of apoptosis by ROS in glutathione depleted cells. The antiapoptotic function of papillomaviruses may be of central importance for papillomavirus-induced tumor formation as it can protect transformed cells from intercellular control of oncogenesis.     

Transformed cells trigger induction of their own apoptosis in coculture with normal cells

In vitro, transforming growth factor type betal triggers normal cells to induce apoptosis in transformed cells. We show that in the absence of exogenous transforming growth factor type betal, induction of apoptosis of transformed cells in coculture with normal cells is dependent on the number of transformed cells per assay and is abrogated by antibodies against TGF-beta 1. Therefore, transforming growth factor type betal produced by transformed cells seems to be responsible for triggering a mechanism that leads to the induction of their apoptosis. This mechanism may be crucial for the control of carcinogenesis in vivo.     

Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer

The management of rectal cancer presents substantial challenges. Patients with T3 and/or node-positive rectal cancers are at high risk for local failure and distant metastases (DM). Adjuvant radiation has been shown to decrease local recurrence (LR) rates; however, this local therapy has not been demonstrated to improve survival when compared to surgery alone. In several prospective randomized trials adjuvant chemoradiation with 5-fluorouracil-(5-FU)-based chemotherapy improved LR rates, DM rates, and overall survival (OS). The optimal chemotherapeutic regimen has not been determined; however, studies comparing standard IV bolus 5-FU administration with continuous infusion (CI) 5-FU demonstrated that CI administration was superior. Preoperative therapy has potential advantages over adjuvant therapy such as less acute bowel toxicity and improved sphincter preservation. Preoperative chemoradiation has been shown in several studies to improve LR rates and OS when compared to surgery alone. Our current approach to patients with resectable T3 or N1 cancer in the distal two-thirds of the rectum on preoperative staging is preoperative chemoradiation with planned postoperative chemotherapy. This regimen offers the best chance for local control and disease-free survival while potentially downstaging the tumor and improving sphincter preservation.     

Hodgkin's disease occurring in a child after liver transplantation

Here we describe the case of a 14-year-old boy who underwent livertransplantation for post-Kasai biliary atresia when aged 4. Antirejectiontreatment consisted of prednisone and cyclosporine. At the age of 11 years thepatient developed left cervical lymphadenopathy; the biopsy showed classicalHodgkin's disease(HD) of the mixed cellularity (MC) type. Neoplastic cellsexpressed CD30 and CD15, and were negative for CD45, CD20, CD3, CD43, andCD79a. Furthermore, they carried the EBV-related products LMP1 and EBER1/2.Treatment consisted of three cycles of adriamycin, bleomycin, vinblastine andDTIC (ABVD), followed by radiotherapy (2,000 cGys) on involved fields. Atpresent, 42 months after the diagnosis of HD, the patient is still in completeremission. This is, to the best of our knowledge, the first reported case ofclassical HD following liver transplantation. The positivity of neoplasticcells for LMP1 and EBER1/2 indicates a possible role for immunosuppression inthe development of the tumor, and whether a reduction in immunosuppressionmight have influenced the course of the disease is open to question.     

Serological response of multiple sclerosis patients and controls to 6/94-parainfluenza virus

Summary The serological responses of 195 multiple sclerosis (MS) patients and 251 controls were tested against 6/94-parainfluenza virus, which was previously isolated from brain tissue of two patients with MS. The hemagglutination-inhibition titers of 1:128 were found more frequently in MS patients (21.5%) than in controls (14.0%). However, the geometric mean titers did not differ between these two groups. The present study concludes that a causal relationship of 6/94-virus to MS, based on a specific immune response, is improbable, although it does not exclude the possibility of a pathogenetic significance of the agent in the cases from which the autopsy material was derived.Supported by Deutsche Forschungsgemeinschaft (Schwerpunkt Ätiologie und Pathogenese der Multiplen Sklerose und verwandter Erkrankungen)     

Isolation and detection of phorbolesters in crotonoil with HPLC.

A HPLC method using reversed-phase columns is described for the determination and isolation of phorbolesters in crotonoil. The identification of the compounds is based on an off-line combination of HPLC-MS, as well as on fatty acid analysis by GC. With this method several new phorbolesters of crotonoil could be detected. This method is also suitable for the determination of phorbol- or similar diterpenesters in other Euphorbiaceae.     

Transformation of rodent fibroblasts by herpes simplex virus: presence of morphological transforming region 1 (MTR 1) is not required for the maintenance of the transformed state.

Studies on the mechanisms of transformation of mammalian cells by herpes simplex virus (HSV) in vitro have been prevented so far by the extremely low transformation frequencies obtained in monolayer culture. Here we present a transformation system that relies on the direct seeding in soft agar of infected single cells, thus avoiding negative interactions between normal and transformed cells. We took advantage of HSV-I temperature-sensitive mutants at the UL9 locus, which codes for a DNA-binding protein necessary for viral DNA replication. At the non-permissive temperature, viral DNA synthesis and late gene expression are prevented. Viral gene expression is restricted to immediate early and early genes. Induction of transformation was highly efficient in our one-step transformation system. It depended on intact viral particles and viral DNA. Immediate early and/or early viral gene expression was sufficient to induce transformation. Colonies were stably transformed and did not show any rescue of viable virus after temperature downshift and co-cultivation with susceptible cells. Transformed cells maintained the transformed state in the absence of viral DNA. Our data therefore support the "hit-and-run" hypothesis for the transforming effect of HSV.