Analysis of the natural killer mediated immune response in metastatic renal cell carcinoma patients

Metastatic renal cell carcinomas (MRCC) are considered as immunogeneic tumors on the basis of the clinical responses observed in patients treated by IL-2. However, renal cell carcinoma patients are also characterized by alterations of the immune response that may compromise the immunotherapeutic approaches. In our study, we have studied the phenotype and the functional capacities of peripheral NK cells in a panel of neprectomized metastatic renal cell carcinoma patients. NK cells were harvested by negative immunoselection from fresh peripheral blood samples. In most of MRCC patients analysed (23/28), the expression of NCR (NKp46 and NKp30) was similar to that of donors. Lytic capacities by activated immunoselected NK cells from MRCC patients assessed against K562 and 3 renal tumor cell lines were in the range of that observed in NK cells from normal donors. HLA-I- renal tumor cells UOK23 were killed with a good efficiency, whereas HLA-I renal tumor cells were more resistant. Although LFA-1/ICAM-1 interaction potentiates RCC cell lysis, HLA-I/NKR interaction clearly decreased RCC cell susceptibility to NK cells. In addition, proliferation of NK cells from MRCC patients in response to cytokines was altered.     

Cognitive sequelae of brain radiation in adults

Radiotherapy (RT) is a proven curative and palliative therapeutic tool in the treatment of a wide variety of primary and metastatic brain tumors in adults. Recent advances in multimodality therapy have led to improvement in survival for many cancer patients. As survival has improved, more attention has been directed toward long-term treatment-related morbidity. Specifically, the effect of RT on the long-term cognitive performance of these patients is a major concern. This article reviews the neurocognitive effects of cranial RT on adult patients with brain tumors. Analyses of neurocognitive function are confounded by factors such as surgery, chemotherapy, tumor characteristics, tumor progression, concurrent medical illnesses, neurologic comorbidity, and medications that can contribute to neurocognitive deficits. Risk of deficits after cranial RT is associated with high RT dose, large fraction size, larger field size, and extremes of age at time of treatment. Using modern techniques with moderate total doses (50 to 54 Gy), conformal RT, conventional fractionation, and advanced planning imaging and software, the risks of neurocognitive deficits are quite small and greatly overshadowed by deficits caused by the tumor itself. Further studies need to be undertaken to elucidate the degree and cause of cognitive decline in adult patients undergoing multimodality therapy for cranial tumors.     

Evaluation of the clinical significance of HER2 amplification by chromogenic in situ hybridisation in patients with primary breast cancer

BACKGROUND: The purpose of this study was to assess the clinical relevance of HER2 amplification by a novel chromogenic in situ hybridisation (CISH) technique in patients with primary breast cancer and to determine its relationship with other prognostic markers. MATERIALS AND METHODS: One hundred and seventy-three breast cancer patients with a mean follow-up duration of 75 months were reanalysed in this retrospective study. Expression of HER2 in tumour tissue samples was assessed by immunohistochemistry (IHC) and CISH. Discrepant cases and tumours presenting a HER2 2+ and 3+ staining with IHC were additionally analysed by fluorescence in situ hybridisation (FISH) to exclude false-positive results. RESULTS: HER2 overexpression and amplification was found in 24.3% and 19.1%, respectively. The clinico-pathological correlations revealed a significant association between positive HER2 status and standard prognostic factors including high tumour grade, large tumour size and absence of steroid hormone receptors. Univariate analysis indicated that HER2 overexpression and amplification were predictive for poor overall (OS) and disease-free survival (DFS). The same effect was also seen in the patient groups with node-negative as well as node-positive breast cancer. By multivariate analysis, HER2 alteration proved to be an indicator of poor prognosis, independent of tumour size, tumour grade, hormone receptor expression, nodal involvement and adjuvant therapy. CONCLUSION. HER2 expression, as assessed by CISH, is an independent marker for unfavourable prognosis in primary breast cancers.     

In vitro screening for antiplasmodial activity of isoquinoline alkaloids from Brazilian plant species

In the search for new antimalarial agents, nine Brazilian plant species were selected, from the Annonaceae (6), Menispermaceae (2) and Siparunaceae (1) families naturally occurring at the cerrado and Atlantic rainforest regions, in order to investigate their in vitro antiplasmodial activity. The ethanol and the alkaloid extracts were tested against K1, chloroquine-resistant, and Palo Alto, chloroquine-sensitive, strains of Plasmodium falciparum. The majority of the alkaloid extracts were more active than the ethanol ones, with IC(50) ranging 0.3-8.2 microg/mL. The crude Guatteria australis alkaloids were the most active against K1 with an IC(50) = 0.3 microg/mL. The most promising total alkaloid fractions for further bioguided isolation are those with the IC(50) < or = 5 microg/mL: G. australis, Cissampelos ovalifolia and Duguetia lanceolata.     

Age, risk-benefit trade-offs, and the projected effects of evidence-based therapies

BACKGROUND: Physicians underutilize evidence-based therapies in the elderly, perhaps because of concerns about the generalizability of clinical trial results in elderly patients given that the relative efficacy of therapies may vary with age. We compared the estimated effects of age and efficacy of treatment on survival among patients with acute coronary syndromes. METHODS: Baseline risk, defined as mortality in the year after hospitalization for acute coronary syndromes, was determined for different age strata among 81,584 patients who had been discharged between April 1, 1997, and March 31, 2000, in Ontario, Canada. We calculated the relative efficacy (relative risk reduction) needed to achieve a clinically meaningful absolute survival benefit, using a number needed to treat of 50 patients for the different age strata. We also evaluated risk-benefit trade-offs in the elderly versus the young by modeling different levels of the relative efficacy and rates of fatal complication by age. RESULTS: Baseline risk (1-year all-cause mortality) was 12-fold lower in the youngest patients (age <50 years) than in oldest patients (age > or = 75 years). Given this gradient, a therapy would have to have a relative efficacy of 88% (i.e., a relative risk of 0.12) in the youngest age group, and 7% (a relative risk of 0.93) in the oldest age group, to generate a number needed to treat 50 patients. For a therapy whose relative efficacy was 25%, the fatal complication rate would have to be sevenfold greater in the oldest compared with the youngest age group to outweigh the survival benefits associated with treatment. CONCLUSION: For acute coronary syndromes, baseline mortality is so much higher for elderly patients that neither sharp reductions in the relative efficacy of therapies nor increases in the rates of serious complications are likely to negate the benefits of therapy. More attention should be paid to overall trial results and less to age-specific subgroup data, unless the latter provide very clear evidence for substantial reductions in absolute efficacy or net harm.     

A global index representing the stability of malaria transmission

To relate stability of malaria transmission to biologic characteristics of vector mosquitoes throughout the world, we derived an index representing the contribution of regionally dominant vector mosquitoes to the force of transmission. This construct incorporated published estimates describing the proportion of blood meals taken from human hosts, daily survival of the vector, and duration of the transmission season and of extrinsic incubation. The result of the calculation was displayed globally on a 0.5 degrees grid. We found that these biologic characteristics of diverse vector mosquitoes interact with climate to explain much of the regional variation in the intensity of transmission. Due to the superior capacity of many tropical mosquitoes as vectors of malaria, particularly those in sub-Saharan Africa, antimalaria interventions conducted in the tropics face greater challenges than were faced by formerly endemic nations in more temperate climes.     

Long-term follow-up of empirical treatment or prompt endoscopy for patients with persistent dyspeptic symptoms?

BACKGROUND: There are concerns about the safety and possible high costs of ongoing proton pump inhibitor therapy of empirical management strategies for patients with persistent dyspeptic symptoms. AIM: To compare the long-term results of two treatment strategies: empirical treatment followed by the Helicobacter pylori test and treat strategy (treat and test group) and prompt upper gastrointestinal endoscopy followed by directed medical treatment (endoscopy group). METHODS: In this study we describe the long-term follow-up data from a previously published randomized clinical trial. At least 6 years after randomization all participating general practitioners and patients were asked to give information about medication use, diagnostic testing, symptoms and quality of life by questionnaire. RESULTS: Information about a total of 77 out of the 80 patients initially included (96%) was retrieved. Overall, 16 patients from the treat and test group (41%) underwent 18 diagnostic investigations. The 34 patients (100%) from the endoscopy group underwent 38 investigations (P < 0.01). The number of patients of the treat and test group and endoscopy group using acid inhibition therapy was 15 (38%) and 19 (56%), respectively (P = 0.14). There were also no differences in symptom prevalence and quality of life between the groups. CONCLUSIONS: Treat and test management for patients with dyspeptic symptoms is safe and does not lead to additional diagnostic testing or use of medication when compared to prompt endoscopy.