Recognition of islet-directed peripheral blood lymphocytes in vitro before rejection of allogeneic grafted islets

A co-culture of splenic lymphocytes with allogeneic pancreatic islets [i.e., mixed lymphocyte islet co-culture (MLIC)] for 96 hr leads to reduction of beta-cells and to an allospecific induction of major histocompatibility complex (MHC) class II antigens on beta-cells. The intent of our investigation was to determine whether peripheral blood lymphocytes (PBL) obtained from allogeneic islet-grafted BB/OK rats (=sensitization in vivo) cause similar alterations to donor-specific islet cells. PBL prepared before transplantation, before (at day 7) and after islet rejection were co-cultured for 24 hr with donor-specific islets. PBL obtained at any time before and after transplantation caused reduction of beta-cells and enhancement of intercellular adhesion molecule-1(+)/beta-cells. Induction of MHC class II+ beta-cells was most pronounced with PBL obtained before rejection. Down-regulation of major histocompatibility complex class I+ beta-cells was caused by PBL that had been obtained from grafted animals only; it was most pronounced before islet rejection and has never been observed with lymphocytes from nongrafted normoglycemic rats. The 24-hr MLIC is capable of recognizing functionally active, donor-specific lymphocytes and is able to distinguish between the effects of sensitized and nonsensitized lymphocytes.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.     

Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis.

Tumor progression is characterized by stepwise accumulation of genetic alterations. To identify alterations associated with breast cancer metastasis, an analysis of comparative loss of heterozygosity (LOH) was performed on 38 primary sporadic breast carcinomas and 16 distant metastases. Two loci at 5q21 and 18q21 were chosen because of their reported increased deletion frequency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 was analyzed to determine whether there is a specific involvement of these breast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequency at all loci examined. In both gene locus groups, significantly more distant metastases are affected by combined LOH. Furthermore, a significantly reduced postmetastatic survival time has been observed in patients with brain metastases affected by synchronous allelic loss at the four breast cancer-associated gene loci. Our results suggest that cumulative LOH of breast cancer-related gene loci is associated with a more aggressive phenotype of metastatic breast tumors.     

Efficacy of percutaneous abscess drainage in patients with vancomycin-resistant enterococci

OBJECTIVE: We reviewed a 4-year experience draining fluid collections infected with vancomycin-resistant enterococci to determine the outcome of percutaneous intervention in patients with this highly resistant and increasingly common organism. MATERIALS AND METHODS: Charts of patients from whom vancomycin-resistant enterococci had been isolated during percutaneous drainage were reviewed to determine patient response to drainage, catheter management, and outcome of treatment. RESULTS: Twenty-one patients underwent percutaneous drainage of 28 fluid collections from which vancomycin-resistant enterococci were isolated, including 16 intraabdominal abscesses, seven biliary or urinary obstructions, and five empyemas. The drainage of 27 (96%) of 28 collections were technically successful. In seven patients, drainage provided the first isolation of vancomycin-resistant enterococci from the patient. Five patients also had blood cultures with positive findings for vancomycin-resistant enterococci, and 14 collections were coinfected with other bacteria or with fungi. Twenty collections (71%) or obstructions were successfully treated with percutaneous drainage. Drainage was unsuccessful in treating eight collections in seven patients. CONCLUSION: Despite high-level antibiotic resistance, fluid collections infected with vancomycin-resistant enterococci can be successfully drained percutaneously, resulting in a favorable likelihood of recovery for patients.     

Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer.

OBJECTIVE: A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. PATIENTS AND METHODS: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. RESULTS: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. CONCLUSIONS: Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.     

Detection of pharyngeal perforation: comparison of aqueous and barium-containing contrast agents

OBJECTIVE: We sought to assess the value of aqueous and barium-containing contrast agents in the detection of pharyngeal perforation. SUBJECTS AND METHODS: Visual and objective in vitro comparisons of an iodinated aqueous contrast agent, a 50% weight/volume barium suspension, and a 100% weight/volume barium suspension were performed. Moreover, to exclude pharyngeal perforation after surgery, we prospectively examined 109 patients by pharyngography, using the aqueous contrast agent and the 100% weight/volume barium suspension. All patients with a pharyngeal perforation were followed up clinically to exclude complications due to barium application. RESULTS: As opposed to the 100% weight/volume barium suspension, in vitro comparison between the aqueous contrast agent and the 50% weight/volume barium suspension yielded no substantial differences. Seventeen perforations could be detected with the aqueous contrast agent. Although 10 of 17 perforations could be slightly better visualized with the 100% weight/volume barium suspension, two perforations were missed with this agent. Five perforations were equally well detected with both. CONCLUSION: Because of a higher radiopacity, 100% weight/volume barium suspensions may more sharply delineate perforations. However, in contrast to aqueous contrast media, narrow pharyngeal perforations can be missed. Thus, the use of a 100% weight/volume barium suspension does not improve the detection of pharyngeal perforation.     

Neue Systematik der Epilepsien und aktuelle Therapieempfehlungen

Monatsschrift Kinderheilkunde - Die aktuelle Klassifikation der Epilepsien aus dem Jahr 2017 gleicht stark der Version des Jahres 1989. Die Versuche einer Reklassifikation in den Jahren 2001, 2006...