Successful rechallenge with clozapine after treatment associated eosinophilia.

OBJECTIVE: Eosinophilia has been associated with the use of clozapine. Where clozapine associated eosinophilia develops, and is associated with organ specific damage, clozapine is usually ceased. In cases of treatment associated eosinophilia without evidence of organ specific damage, clozapine would also typically be withdrawn. There are small numbers of reports in the literature describing patients who have had a successful rechallenge of clozapine having previously stopped treatment due to eosinophilia without associated organ specific inflammation. We report the case of a man who underwent a successful retrial of clozapine. METHOD: Case from authors' clinical practice reviewed. RESULTS: We present the case of a young man with treatment resistant schizophrenia who underwent a successful re-challenge of clozapine, having previously ceased treatment due to an eosinophilia associated with treatment. CONCLUSION: We believe that the current report provides further evidence that it may be unnecessary to cease treatment in all patients who develop an eosinophilia without organ dysfunction whilst on clozapine. Furthermore, where clozapine has been ceased due to an eosinophilia without evidence of organ specific inflammation, clozapine rechallenge with increased haematological monitoring should be considered.

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997-2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival.

A prospective study of the role of inflammation in bladder cancer.

INTRODUCTION: To examine the role of inflammation in bladder cancer, we assessed the relationship between a systemic inflammation prognostic score (modified Glasgow Prognostic Score, mGPS), the tumor inflammatory cell infiltrate as measured by the Klintrup-Makinen score and tumor necrosis with cancer specific survival in patients with bladder cancer. MATERIALS AND METHODS: The cohort consisted of 68 bladder cancer patients, 47 with localised disease and 21 with muscle invasive disease. The mGPS response was constructed by measuring C-reactive protein and albumin concentrations and the Klintrup-Makinen score was evaluated histologically for the local inflammatory response. Pathological parameters such as grade, T stage and tumor necrosis were also assessed. RESULTS: Median follow was 47 months and 24 patients died of their disease. On univariate analysis, T stage (p < 0.001), grade (p < 0.001) and mGPS (p = 0.002) were significant predictors of cancer specific survival. On multivariate analysis, T stage (hazard ratio 5.98, 95% confidence interval 3.18-11.24, p < 0.001) and mGPS (hazard ratio 1.78, 95% confidence interval 1.09-2.9, p = 0.02) were significant independent predictors of cancer specific survival. CONCLUSION: A preoperative systemic inflammatory response is an independent predictor of poor cancer specific survival in patients with bladder cancer.

Nuclear factor κB predicts poor outcome in patients with hormone-naive prostate cancer with high nuclear androgen receptor.

Despite recent advances in prostate cancer treatments, disease recurrence is common and associated with significant morbidity and mortality. The need for more effective antitumor agents has led researchers to target signaling pathways that drive tumorigenesis by modulating or bypassing androgen receptor signaling--attenuation or blockade of which current treatments aim to effect. The transcription factor nuclear factor κB/p65 has been implicated in prostate cancer progression; however, few studies have examined the involvement of nuclear factor κB in hormone-naive disease. We used immunohistochemistry to investigate expression of p65, androgen receptor, Ki-67, and phosphorylation status of p65 at serine 536, in 154 tumor samples taken from patients before hormone ablation or radical treatment. Nuclear p65 expression was significantly associated with disease-specific mortality: P = .005; hazard ratio, 2.2. When patients were stratified according to androgen receptor status, this relationship was abolished in low androgen receptor-expressing patients and potentiated in high androgen receptor-expressing patients: P = .002; hazard ratio, 3.1. Ki-67 expression was also prognostic of shorter disease-specific mortality: P = .001; hazard ratio, 2.3. When the cohort was stratified according to androgen receptor status, this relationship held for high androgen receptor expressers but not low expressers: P = .0003; hazard ratio, 3.5. Neither androgen receptor nor p65 phosphorylated at S536 were significantly prognostic when considered individually. These data suggest that future prostate cancer treatments that target nuclear factor κB signaling should be assigned primarily to patients with concomitant high nuclear p65 and androgen receptor expression.

Tumoral C-reactive protein and nuclear factor kappa-B expression are associated with clinical outcome in patients with prostate cancer.

Prostate cancer (Pca) is the most common form of cancer affecting men, despite recent advances in PCa treatments, one third of patients diagnosed each year succumb to this disease. The inflammatory response has been implicated in prostate cancer progression. The pro-inflammatory transcription factor, NFκB/p65 has been implicated in PCa progression. Few studies have examined the involvement of NFκB and inflammatory signalling in PCa.Immunohistochemistry was employed to investigate the expression of NFκB/p65, C-reactive protein and Ki67 in 61 clinical samples. Tumours expressing high levels of p65 (p=0.004), CRP (p=0.011) and Ki67 (p=0.0003) had a shorter disease specific survival. Upon combining p65 and CRP status it was observed that those tumours with low expression of both proteins had a median survival of 11 years compared to 3.9 years for those with tumours with high expression of both (p=0.005). CRP expression was significantly higher in the 21 patients who died of their disease and on multivariate analysis CRP expression retained independent significance (p=0.005). This study suggests CRP and NFκB may function collectively to drive prostate cancer progression in a subset of patients. Tumoral CRP is a significant independent predictor of cancer specific survival. The relationship between tumour CRP and signalling pathways warrants further investigation in a larger cohort.

Systemic inflammatory response and survival in patients with localised prostate cancer: 10-year follow-up.

AIM: To examine the prognostic value of circulating C-reactive protein concentrations at diagnosis in patients with organ-confined prostate cancer. PATIENTS AND METHODS: Ninety-eight patients with histologically proven clinically localised prostate cancer were studied. Clinical stage, tumour grade, circulating PSA and C-reactive protein concentrations at diagnosis were recorded. RESULTS: The majority of patients was under the age of 70 years and had low-grade tumours. Approximately half the patients received radical local treatment. During the follow-up period (median 10 years) 38 patients died, of whom 18 died of prostate cancer, 6 of other cancers and 14 of non-cancer causes. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05), C-reactive protein (p < 0.05) and treatment (p < 0.05) were significant predictors of overall survival. On univariate survival analysis, age (p < 0.001), Gleason score (p < 0.05) and C-reactive protein (p < 0.05) were significant predictors of prostate cancer-specific survival. On multivariate analysis of these significant variables age (HR 4.88, 95% CI 1.79-13.29, p < 0.01), Gleason score (HR 2.16, 95% CI 1.23-3.78, p < 0.01) and C-reactive protein (HR 1.88, 95% CI 1.01-3.52, p < 0.05) remained significant independent predictors of prostate cancer-specific survival. CONCLUSION: The results of the present study show that the presence of a systemic inflammatory response, at diagnosis, independently predicts poor long-term cancer outcome in patients with localised prostate cancer.

Antipsychotic use in the elderly: what doctors say they do, and what they do.

OBJECTIVE: To review psychiatrists' attitudes and actual practice on the use of typical and atypical antipsychotics in the elderly. METHODS: Audit data were collected from 18-old-age psychiatry units across Australia. The attitudes of old age psychiatrists and their perceptions of the efficacy, tolerability and clinical usefulness of antipsychotics were examined. RESULTS: The medications used for 321 patients were audited, and the attitudes of the 57 prescribing doctors were assessed. All available atypicals were prescribed and reported as more efficacious and clinically useful than typicals. Adverse events perceived by doctors as an obstacle to prescribing were more frequent than reported adverse event rates in product information. All diagnostic groups improved. Off-label use comprised almost 22% in this sample. CONCLUSIONS: Adverse events are impediments to prescribing, more so with typical than atypical antipsychotics. All available atypicals were used and appeared effective in this elderly population.

The relationship between the local and systemic inflammatory responses and survival in patients undergoing resection for localized renal cancer.

OBJECTIVE: To examine the relationship between the systemic inflammatory response (C-reactive protein, CRP), tumour interleukin-6 receptor and cyclooxygenase (COX)-2 expression, tumour T-lymphocytic (CD4+, CD8+) infiltration and cancer survival in patients undergoing resection for renal cell carcinoma (RCC), as both the local and systemic inflammatory responses appear to predict the outcome in these patients. PATIENTS AND METHODS: The study included 60 patients undergoing nephrectomy for localized RCC. Pre-operative circulating CRP levels were measured and tumour interleukin-6 receptor and COX-2 expression, tumour CD4+ and CD8+ T lymphocytes were assessed using immunohistochemical analysis. RESULTS: The median follow-up was 78 months, with 14 patients relapsing from their disease and nine cancer-specific deaths. On univariate and multivariate survival analysis, tumour stage and grade and CRP levels were identified as significant factors associated with relapse-free and cancer-specific survival. There was a significant direct relationship between Fuhrman grade and CD4+ T-lymphocytic infiltrate (P < 0.05). An increase in tumour expression of interleukin-6 receptor was weakly associated with an increase in tumour CD8+ T-lymphocytic infiltration (P = 0.057). An increase in tumour CD4+ T-lymphocytic infiltration was associated with an increase in CD8+ T-lymphocytic infiltration (P < 0.01). CONCLUSIONS: The present results suggest that tumour-based factors such as interleukin-6 receptor and COX-2 expression or T-lymphocytic subset infiltration are subordinate to systemic factors such as CRP level in determining survival in patients with localized RCC.

Systemic inflammatory response, prostate-specific antigen and survival in patients with metastatic prostate cancer.

BACKGROUND: It is increasingly recognised that, in cancer patients, disease progression is dependent on a complex interaction of the tumour and the host inflammatory response and that the systemic inflammatory response, as evidenced by an elevated C-reactive protein (CRP) concentration, may be a useful prognostic factor. MATERIALS AND METHODS: The prognostic value of CRP compared with prostate-specific antigen (PSA) was examined in 62 patients with metastatic prostate cancer receiving androgen-deprivation therapy. RESULTS: In all, 41 (66%) of patients died, 38 (61%) of their disease. On univariate survival analysis, PSA (p < 0.05) and CRP (p < 0.05) were significant predictors of cancer-specific survival. On multivariate analysis, both PSA (HR 1.96, 95% CI 1.00-3.83, p = 0.049) and CR (HR 1.97, 95% CI 0.99-3.92, p = 0.052) were independent predictors of cancer-specific survival. PSA concentrations were significantly correlated with those of CRP (r(s) = 0.46, p < 0.001). CONCLUSION: The results of the present study suggest that, in patients with metastatic prostate cancer, the presence of an elevated CRP concentration predicts poor outcome, independent of PSA.

Vitamin antioxidants, lipid peroxidation and the systemic inflammatory response in patients with prostate cancer.

The relationship between lipid soluble antioxidant vitamins, lipid peroxidation, disease stage and the systemic inflammatory response were examined in healthy subjects (n = 14), patients with benign prostate hyperplasia BPH (n = 20), localized (n = 40) and metastatic (n = 38) prostate cancer. Prostate cancer patients had higher concentrations of malondialdehyde (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and beta-carotene (p < 0.05). Patients with metastatic prostate cancer, when compared with patients having localized disease, had a higher Gleason score (p < 0.01) and had more hormonal treatment, but lower concentrations of PSA (p < 0.05), alpha-tocopherol (p < or = 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). In the prostate cancer patients, PSA was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs= 0.353, p = 0.002). C-reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs= -0.263, p = 0.020) and lycopene (rs= -0.269, p = 0.017). These results indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer.

Porcine cytomegalovirus in pigs being bred for xenograft organs: progress towards control.

In human medicine, human cytomegalovirus (HCMV) is readily transmitted by organ transplant causing end-organ disease and triggering graft rejection in recipients. Because of a chronic shortage of human organs, pigs transgenic for human complement control proteins are being considered as potential donors. Such xenotransplantation raises concerns about the potential zoonotic transmission of viruses including porcine cytomegalovirus (PCMV), an endemic infection of pigs. Similar to HCMV and PCMV transmission is thought to occur in utero and perinatally. We used quantitative polymerase chain reaction to examine the prevalence, organ distribution and viral load of PCMV in human decay accelerating factor (CD55) transgenic pigs. In animals reared under conventional farm conditions, virus was identified in a wide range of organs including potential xenografts (liver, kidney and heart). The spleen was PCMV DNA positive in all infected pigs. Examination of foetal spleens failed to identify evidence of transplacental infection and prospective monitoring of two litters showed that infection occurred in the postnatal period. This transmission was prevented by hysterotomy derivation and barrier rearing. Our findings demonstrate that PCMV could be eradicated from pig herds being bred for xenotransplantation and argue that the spleen from donor animals should be examined as part of quality control procedures if clinical trials proceed.

The production of transgenic pigs for potential use in clinical xenotransplantation: baseline clinical pathology and organ size studies.

This report describes the results of hematology, serum biochemistry, growth, and organ weight studies undertaken on pigs from nine cohorts of qualified pathogen free (QPF) pigs reared within a high welfare bioexclusion facility as potential organ source animals. Confirmation of the high health status of the pigs was given through total leukocyte counts and serum globulin concentrations that fell below the expected reference range for conventional pigs. The calculated mean growth rate for QPF pigs was found to exceed target rates set for optimum genotype commercial pig herds. Body weights of QPF pigs were compared with kidney, heart and liver weights at necropsy.

The production of transgenic pigs for potential use in clinical xenotransplantation: microbiological evaluation.

Debate over the infection hazards of pig-to-human xenotransplantation has focused mainly on the porcine endogenous retroviruses (PERV). However, hazards of exogenous infectious agents possibly associated with the xenograft have also been evaluated (Xenotransplantation 2000; 7: 143). We report the results of a health monitoring program demonstrating the exclusion of more than 80 potential pathogens from nine cohorts of pigs reared in a high welfare bioexclusion facility as potential xenograft source animals. A dynamic bacterial flora of pigs reared under barrier conditions was characterized, emphasizing the significance of monitoring for multiresistant antimicrobial sensitivity patterns. Evidence was found for exclusion of two commonly residual exogenous viruses, porcine cytomegalovirus and porcine lymphotropic herpesviruses, among a proportion of the cohorts tested. Finally, there was histopathological evidence for low grade pneumonitis among sentinel pigs, likely to have been associated with the use of quaternary ammonium disinfectants during the production process, indicating a need for review of toxicology data for disinfectant agents used in such bioexclusion systems. Intensive health monitoring programs, based upon regularly updated recommendations from the microbiological research community, will enable significant reductions in the potential hazards associated with pig-to-human xenotransplantation.