Evidence for cytotoxic T lymphocyte response against human lung cancer: reconstitution of antigenic epitope with peptide eluted from lung adenocarcinoma MHC class I

BACKGROUND: Cancer-associated, major histocompatibility complex (MHC)-restricted peptide antigens have been elucidated in human melanomas and ovarian, breast, and renal carcinomas; but relatively little is known about lung cancer antigens. METHODS: To work toward delineation of lung cancer-associated antigens, we developed tumor infiltrating lymphocytes (TILs), peripheral blood mononuclear cell-derived cytolytic T cell lines (CTL), autologous lung cancer cell lines, and normal lung cell lines from 17 patients undergoing lung cancer resections. The TILs and CTL lines were subsequently evaluated for markers of activation and specific lysis of autologous or allogeneic lung cancer cell lines or both. RESULTS: Freshly isolated TILs contained a more activated T cell population compared with the patients' peripheral blood T cells as evidenced by an increased expression of HLA-DR, CD25, and CD45RO. TILs isolated from 15 patients lysed allogeneic lung cancer lines. TILs lysed autologous lung cancer but not autologous normal lung or Epstein-Barr virus transformed B cell lines (B-LCL) in 4 of 8 cases tested, suggesting tumor specificity. A CTL line (RHPBL57.1) was generated from peripheral blood mononuclear cells of an HLA-A24(+) patient by stimulation against an established HLA-A24(+) allogeneic lung cancer cell line. RHPBL57.1 lysed the lung cancer cell line in an HLA-A24-restricted manner. Moreover, RHPBL57.1 specifically lysed autologous B-LCL pulsed with peptides, eluted from MHC class I and isolated from the HLA-A24(+) lung cancer cell line. CONCLUSIONS: TILs isolated from patients with lung cancer are predominantly an activated population of T cells with evidence of tumor and MHC class I-restricted lysis. Furthermore, we provide evidence for a lung cancer-associated, MHC class I-bound peptide antigen(s) that reconstitutes the epitope recognized by a lung cancer specific CD8(+) T cell line derived from a patient with lung cancer.     

Treatment of restenosis

Carotid restenosis after endarterectomy is observed in up to 24.1% of patients with long-term follow up. Indication for reintervention in asymptomatic patients however should be reserved for greater than 80% stenosis. Treatment options include repeat surgical reconstruction as well as intraoperative or percutaneous balloon angioplasty +/- stenting. We compared our past experience with 66 operative reconstructions in 64 patients with a recent series of 60 patients who underwent intraoperative balloon-dilatation and stenting. After conventional surgery 2 patients (3.1%) suffered a permanent neurological deficit, one patient developed a TIA (1.5%). After intraoperative dilation and stenting 8 patients (13.3%) suffered a stroke; 2 patients died after surgery (one stroke, one myocardial infarction) (mortality 3.3%). When compared to conventional operative repair intraoperative carotid balloon angioplasty and stenting of restenosis is complicated by a substantial increase in morbidity and mortality and cannot be recommended as routine therapy.     

Efficacy of Intravenous Granisetron to Control Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy

The safety and efficacy of granisetron (10 µg/kg and 40 µg/kg) were evaluated during a second (n = 393) and third (n = 200) cycle of chemotherapy in this multicenter, double-blind, randomized, parallel-group study. Granisetron was administered as a single intravenous dose before the start of cisplatin chemotherapy (≥60 mg/m²). Total control (no vomiting, no retching, no nausea, and no use of antiemetic rescue medication) after the first 24 hr following chemotherapy was achieved in 40% and 49% of patients in Cycles 2 and 3, respectively, for the 10 µg/kg group, and in 42% and 38% of patients in Cycles 2 and 3, respectively, for the 40 µg/kg group. Both dose levels of granisetron were well tolerated. The results demonstrate comparable efficacy between the 10 µg/kg and 40 µg/kg doses of granisetron in preventing nausea and vomiting during repeat cycles of high-dose cisplatin-based chemotherapy. The results of this study show that granisetron 10 µg/kg is safe and well tolerated, and remains effective with repeat cycle use.     

"Not unaffected by northern winds"? Swiss psychiatry and eugenics in the period between world warms

On the basis of the publications and meeting reports of the Swiss Society of Psychiatry this essay examines the relationship of Swiss psychiatry and eugenics during the time between the wars. In a democratic country Swiss psychiatry, on the one hand held a leading position in the justification of eugenic measures, on the other hand a majority of Swiss psychiatrists refused coercive measures, and in World War II disassociated from the racialist eugenics and healthpolicy that were established in NS-Germany. Thus, in difference to NS-Germany the practice of eugenic sterilizations in Switzerland wasn't regulated by any specific national law.     

An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity.

Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.     

Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer.

PURPOSE: Cancer-testis genes mapping to the X chromosome have common expression patterns and show similar responses to modulators of epigenetic mechanisms. We asked whether cancer-testis gene expression occurred coordinately, and whether it correlated with variables of disease and clinical outcome of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Tumors from 523 NSCLC patients undergoing surgery were evaluated for the expression of nine cancer-testis genes (NY-ESO-1, LAGE-1, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7/MAGE-C1, SSX2, and SSX4) by semiquantitative PCR. Clinical data available for 447 patients were used to correlate cancer-testis expression to variables of disease and clinical outcome. RESULTS: At least one cancer-testis gene was expressed by 90% of squamous carcinoma, 62% of bronchioloalveolar cancer, and 67% of adenocarcinoma samples. Statistically significant coexpression was observed for 34 of the 36 possible cancer-testis combinations. Cancer-testis gene expression, either cumulatively or individually, showed significant associations with male sex, smoking history, advanced tumor, nodal and pathologic stages, pleural invasion, and the absence of ground glass opacity. Cox regression analysis revealed the expression of NY-ESO-1 and MAGE-A3 as markers of poor prognosis, independent of confounding variables for adenocarcinoma of the lung. CONCLUSIONS: Cancer-testis genes are coordinately expressed in NSCLC, and their expression is associated with advanced disease and poor outcome.     

Is the preoperative radiograph useful in predicting the outcome of a total hip replacement?

The preoperative radiographs of 1015 patients undergoing 1163 total hip replacements for osteoarthritis were evaluated to determine if a relationship exists between the extent of osteoarthritis and the clinical results of a total hip replacement. Preoperative radiographs were graded with respect to the degree of cartilage space loss, direction of cartilage space loss (femoral head migration), and severity of osteophyte formation. Followup averaged 32.1 months (range, 6-93 months). Greater degrees of cartilage space loss correlated with lower hip scores preoperatively but were unrelated to preoperative pain. These patients had statistically less pain at 6 months and 1 year. Patients with superior cartilage space loss before surgery also had statistically less pain at 6 months. However, at 3 years and beyond, pain was independent of degree of preoperative cartilage space loss, osteophyte formation, or femoral head migration. In addition, hip scores at any followup were independent of the degree of osteoarthritis observed on the preoperative radiograph. These findings provide statistical support to the concept that greater degrees of joint space loss correlate with better relief of pain and less severe joint space loss correlates with less relief of pain within the first year after total hip replacement. At 3 years and beyond, hip and pain scores were independent of the degree of preoperative osteoarthritis.     

Concerns of an Itinerant Surgeon: Results of a Guatemalan Surgical Aid Trip

Over the past decade the popularity of foreign medical aid has increased and gained notoriety. Operation Walk is a philanthropic organization dedicated to improving the ambulatory potential of patients in developing countries by providing free surgical treatment for patients who otherwise lack access to care of debilitating bone and joint conditions. During Operation Walk Mooresville's 2013 trip to Guatemala 40 patients prospectively completed a Likert Scale style survey. The 63-question survey assessed patient impressions and concerns regarding the care they receive as part of itinerant surgical aid trips. Mean scores were calculated and then concerns were ranked accordingly. We are aware of no other investigation assessing these sorts of patient centered perspectives for international surgical aid trips.