Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD-1 and IL-10 blockade.

Fibrolamellar carcinoma (FLC) is a rare liver tumor driven by the DNAJ-PKAc fusion protein that affects healthy young patients. Little is known about the immune response to FLC, limiting rational design of immunotherapy. Multiplex immunohistochemistry and gene expression profiling were performed to characterize the FLC tumor immune microenvironment and adjacent non-tumor liver (NTL). Flow cytometry and T cell receptor (TCR) sequencing were performed to determine the phenotype of tumor-infiltrating immune cells and the extent of T cell clonal expansion. Fresh human FLC tumor slice cultures (TSCs) were treated with antibodies blocking programmed cell death protein-1 (PD-1) and interleukin-10 (IL-10), with results measured by cleaved caspase-3 immunohistochemistry. Immune cells were concentrated in fibrous stromal bands, rather than in the carcinoma cell compartment. In FLC, T cells demonstrated decreased activation and regulatory T cells in FLC had more frequent expression of PD-1 and CTLA-4 than in NTL. Furthermore, T cells had relatively low levels of clonal expansion despite high TCR conservation across individuals. Combination PD-1 and IL-10 blockade signficantly increased cell death in human FLC TSCs. Immunosuppresion in the FLC tumor microenvironment is characterized by T cell exclusion and exhaustion, which may be reversible with combination immunotherapy.

Cost effectiveness of zoledronic acid in the management of skeletal metastases in hormone-refractory prostate cancer patients in France, Germany, Portugal, and the Netherlands.

OBJECTIVE: Zoledronic acid (ZOL) reduces the risk of skeletal related events (SREs) in hormone-refractory prostate cancer (HRPC) patients with bone metastases. This study assessed the cost effectiveness of ZOL for SRE management in French, German, Portuguese, and Dutch HRPC patients. METHODS: This analysis was based on the results of a randomized phase III clinical trial wherein HRPC patients received up to 15 months of ZOL (n = 214) or placebo (n = 208). Clinical inputs were obtained from the trial. Costs were estimated using hospital tariffs, published, and internet sources. Quality adjusted life-years (QALYs) gained were estimated from a separate analysis of EQ-5D scores reported in the trial. Uncertainty surrounding outcomes was addressed via univariate sensitivity analyses. RESULTS: ZOL patients experienced an estimated 0.759 fewer SREs and gained an estimated 0.03566 QALYs versus placebo patients. ZOL was associated with reduced SRE-related costs [net costs] (-€2396 [€1284] in France, -€2606 [€841] in Germany, -€3326 [€309] in Portugal and -€3617 [€87] in the Netherlands). Costs per QALY ranged from €2430 (Netherlands) to €36,007 (France). CONCLUSIONS: This analysis is subject to the limitations of most cost-effectiveness analyses: it combines data from multiple sources. Nevertheless, the results strongly suggest that ZOL is cost effective versus placebo in French, German, Portuguese, and Dutch HRPC patients.

Administration of human chorionic gonadotropin at embryo transfer induced ovulation of a first wave dominant follicle, and increased progesterone and transfer pregnancy rates.

We hypothesized that administration of hCG to recipients at embryo transfer (ET) would induce accessory CL, increase serum progesterone concentrations, and reduce early embryonic loss (as measured by increased transfer pregnancy rates). At three locations, purebred and crossbred Angus, Simmental, and Hereford recipients (n = 719) were assigned alternately to receive i.m. 1,000 IU hCG or 1 mL saline (control) at ET. Fresh or frozen-thawed embryos were transferred to recipients with a palpable CL on Days 5.5 to 8.5 (median = Day 7) of the cycle (Locations 1 and 2), or on Day 7 after timed ovulation (Location 3). Pregnancy diagnoses (transrectal ultrasonography) were done 28 to 39 d (median = 35 d) and reconfirmed 58 to 77 d (median = 67 d) post-estrus. At Location 1 (n = 108), ovaries were examined at pregnancy diagnosis to enumerate CL. More (P < 0.001) pregnant hCG-treated cows (69.0%) had multiple CL than pregnant controls (0%). Serum progesterone (ng/mL) determined at Locations 1 and 2 (n = 471) at both pregnancy diagnoses in pregnant cows was greater (P ≤ 0.05) after hCG treatment than in controls (first: 8.1 ± 0.9 vs 6.1 ± 0.8; second: 8.8 ± 0.9 vs 6.6 ± 0.7), respectively. Unadjusted pregnancy rates at the first diagnosis were 61.8 and 53.9% for hCG and controls. At the second diagnosis, pregnancy rates were 58.6 and 51.3%, respectively. Treatment (P = 0.026), embryo type (P = 0.016), and BCS (P = 0.074) affected transfer pregnancy rates. Based on odds ratios, greater pregnancy rates occurred in recipients receiving hCG, a fresh embryo (66.3 vs 55.5%), and having BCS >5 (62.3 vs 55.3%). We concluded that giving hCG at ET increased incidence of accessory CL, serum progesterone in pregnant recipients, and transfer pregnancy rates. Furthermore, we inferred that increased progesterone resulting from hCG-induced ovulation reduced early embryonic losses after transfer of embryos to recipients.

Validity and reliability of the 'Ten Questions' questionnaire for detecting moderate to severe neurological impairment in children aged 6-9 years in rural Kenya.

BACKGROUND: The 'Ten Questions' Questionnaire (TQQ) is used to detect severe neurological impairment in children living in resource-poor countries. Its usefulness has been established in Asia and the Caribbean, but there are a few published studies from Africa. We evaluated the TQQ as part of a larger study of neurological impairment in a rural community, on the coast of Kenya. METHODS: The study was conducted in two phases from June 2001 to May 2002; in phase one, a community household screening of 10,218 children aged 6-9 years using the TQQ was performed. Phase two involved a comprehensive clinical and psychological assessment of all children testing positive on the TQQ (n = 810) and an equivalent number of those testing negative (n = 766). Data were interpreted using the impairment-specific approach. RESULTS: Overall, the sensitivity rates for screening the different impairments were: cognitive (70.0%), motor (71.4%), epilepsy (100%), hearing (87.4%) and visual (77.8%). All the specificity rates were greater than 96%. However, the positive predictive values were low, and ranged from 11 to 33%. CONCLUSIONS: These results are similar to those from other continents and provide evidence that the TQQ can be used to compare the epidemiology of moderate/severe impairment in different parts of the world. Furthermore, the TQQ can be used to screen for moderately/severely impaired children in resource-poor countries; however, the low positive predictive values mean that other assessments are required for confirmation.

Formative evaluation of a multimedia program for patients about the side effects of cancer treatment.

Formative evaluation of multimedia programs can prevent costly and time-consuming revisions and result in more effective programs. Yet systematic formative evaluation is seldom conducted. This paper reviews the basic principles of formative evaluation and describes how we applied those principles to the formative evaluation of a multimedia program for patients about the side effects of cancer treatment. It discusses the challenges of developing multimedia programs for patients and provides guidance to other health professionals interested in developing programs on other topics.

Intubation with propofol: evaluation of pre-treatment with alfentanil or lignocaine.

The effect of lignocaine or alfentanil pre-treatment on conditions at orotracheal intubation following induction with propofol, but without the use of muscle relaxants, were compared in a prospective, controlled, double-blind study. Forty five healthy patients undergoing elective surgery were randomly allocated to receive either 0.9% saline (control), alfentanil 20 micrograms/kg-1, or lignocaine 1.5 mg kg-1 prior to induction with propofol 2.5 mg kg-1. Ease of intubation was scored on a four point scale from 'excellent' = 1 to 'not possible' = 4. Alfentanil pre-treatment allowed intubation in 93% of patients compared to 60% in each of the groups pre-treated with lignocaine or saline. Intubation scores of 1 or 2 were obtained in 14 out of 15 patients (93%) in the alfentanil group and this was significantly better than the lignocaine group (33%) or control group (20%). No difference was detected between the scores of the latter two groups.

Contralateral tension pneumothorax during thoracotomy for lung resection.

A patient underwent right thoracotomy and upper lobectomy for a mass found on routine chest radiography. He became profoundly cyanosed with a bradycardia and severe reduction in oxygen saturation at completion of surgery. The diagnosis of tension pneumothorax on the contralateral side to surgery was made and treatment instituted. The causes, treatment and implications of such an event during general anaesthesia for lung resection are discussed.

The effect of different pre-operative feeding regimens on plasma glucose and gastric volume and pH in infancy.

The effects of four different pre-operative feeding regimens were studied in 123 children below the age of one year presenting for surgery. Plasma glucose concentrations, blood acid-base values, gastric volume and gastric pH were measured before and after induction of anaesthesia. No patient was found to be hypoglycaemic and there were no significant differences in plasma glucose concentration and acid-base values between the groups. No correlation was demonstrated between the age and weight of the patients and the duration of fasting and the plasma glucose concentration. There was a significant elevation of plasma glucose concentration in all four groups after induction of anaesthesia (P less than 0.001) compared with the pre-induction level which is a reflection of the stress of blood sampling and induction of anaesthesia. Infants less than three months of age in the milk-feed group had a significantly higher gastric volume with low pH (P less than 0.05) signifying a potentially greater risk of pulmonary acid aspiration. The practice of timing the last pre-operative feed in infancy according to the infant's normal feeding pattern does not appear to increase the risk factors for pulmonary aspiration, if milk is avoided.

Peri-operative management of carcinoid syndrome using ketanserin.

This report describes the successful use of ketanserin, a 5-HT2 receptor antagonist, for the acute control of systemic blood pressure in a patient with the carcinoid syndrome, undergoing hepatic artery embolisation. Serial measurements of plasma 5-hydroxyindoles, platelet 5-hydroxytryptamine and plasma catecholamines are also given.

Recovery from day-case anaesthesia. The effect of different inhalational anaesthetic agents.

Sixty unpremedicated patients undergoing dilatation and curettage were allocated randomly to receive one of three inhalational agents (halothane, enflurane or isoflurane) to supplement 67% nitrous oxide in oxygen after induction of anaesthesia with methohexitone. Recovery was assessed by the time patients took to open their eyes, to give their correct date of birth, to regain their pre-operative level of manipulative skill with a children's postbox toy, and by comparing pre-operative and postoperative performance of a paper and pencil test (the p-deletion test). There was no difference in the time to open eyes or to regain their pre-operative score with the postbox whether the patients received halothane, enflurane or isoflurane. Patients in the isoflurane group took longer than patients in the enflurane group to give their correct date of birth, but they performed better in the p-deletion test postoperatively, completing more lines with the same number of errors. Patients receiving enflurane committed more errors postoperatively in the p-deletion test. The incidence of complications was low and was not influenced by the choice of inhalational agent.

The practice of self-induced vomiting among high school females.

Thirty-eight high school females who were practicing self-induced vomiting to control their weight were studied. Of these students, 9% practiced self-induced vomiting every time any food was ingested while 40% vomited only after a binge. On standardized measures, 58% of the females had disturbed attitudes toward eating, and 55% met the criteria for being psychologically unhealthy. Of the vomiters identified, 63% indicated that they would stop the practice if another effective method of weight control was available.

An enzymatic method for inosine 5'-monophosphate in the femtomole range.

A method for measuring inosine 5'-monophosphate (IMP) by enzymatic generation of NADPH is described. Procedures are given for direct fluorometric assay in the nanomole range and indirect measurement with amplification by enzymatic cycling in the pico- and femtomole ranges. The most sensitive procedure represents a nearly 50,000-fold increase in sensitivity over enzymatic methods now available. Specificity of the assay was greatly enhanced by the use of the antibiotic coformycin, a potent inhibitor of adenosine deaminase (EC 3.5.4.4). This enzyme was found to be a major contaminant of one of the necessary enzymes, phosphoglucomutase (EC 2.7.5.1). The use of the method is illustrated by measurements of IMP in single stimulated and control rat muscle fibers.