Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

A novel antibacterial peptide derived from Crocodylus siamensis haemoglobin hydrolysate induces membrane permeabilization causing iron dysregulation, oxidative stress and bacterial death.

AIMS: A novel antibacterial peptide from Crocodylus siamensis haemoglobin hydrolysate (CHH) was characterized for antimicrobial activity. METHODS AND RESULTS: CHHs were hydrolysed for 2 h (2 h-CHH), 4 h (4h-CHH), 6 h (6 h-CHH) and 8 h (8 h-CHH). The 8 h-CHH showed antibacterial activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa at concentrations of 20, 20, 20 and 10 mg ml-1 (w/v) respectively. Fluorescent microscopy revealed that the 8 h-CHH had bactericidal activity against E. coli and P. aeruginosa. ß-galactosidase assay supported by RT-qPCR demonstrated that the 8 h-CHH resulted in differential expression of genes involved in iron homeostasis (ftnA and bfd) and oxidative stress (sodA, soxR and oxyR). Siderophore assay indicated that the 8 h-CHH also impaired siderophore production with diminished expression of pvdF. This pattern of gene expression suggests that the 8 h-CHH triggers the release of free ferric ions in the cytoplasm. However, decreased expression of genes associated with the SOS response (recA and lexA) in combination with neutral comet revealed that no DNA damage was caused by 8 h-CHH. Membrane permeabilization assay indicated that 8 h-CHH caused membrane leakage thought to mediate the antibacterial and iron-stress responses observed, due to loss of regulated iron transport. The novel active peptide from 8 h-CHH was determined as QAIIHNEKVQAHGKKVL (QL17), with 41% hydrophobicity and +2 net charge. CONCLUSIONS: The QAIIHNEKVQAHGKKVL fragment of C. siamensis haemoglobin is antibacterial via a mechanism that likely relies on iron dysregulation and oxidative stress which results in bacterial death. SIGNIFICANCE AND IMPACT OF THE STUDY: We have described for the first time, a novel peptide derived from C. siamensis haemoglobin hydrolysate that has the potential to be developed as a novel antimicrobial peptide.

FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases.

BACKGROUND: Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM. MATERIAL AND METHODS: An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care. RESULTS: 78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all >20months from initial treatment. CONCLUSIONS: In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

BACKGROUND: Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS: Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS: Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS: Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges.

BACKGROUND: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. AIMS: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. METHODS: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. RESULTS: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. CONCLUSIONS: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy.

BACKGROUND: This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS: Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS). RESULTS: The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients. CONCLUSION: Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.

The anti-leukemic effect and molecular mechanisms of novel hydroxamate and benzamide histone deacetylase inhibitors with 5-aza-cytidine.

Histone deacetylase inhibitors (HDACi) demonstrate considerable in vitro and in vivo activity and clinical efficacy in the treatment of hematological malignancies. Pre-clinical and early phase clinical trials identify therapeutic activity using a combination of HDACi and demethylating agents which may be more efficacious than single agent treatment. Our studies aimed to determine the effects and molecular mechanisms of action of novel hydroxamate (MCT-3) and benzamide [MGCD0103 (MG)] HDACi's in the HL-60 cell line alone and in combination with the demethylating agent 5-aza-cytidine (AZA). MG, MCT-3 and AZA treatment significantly inhibited HL-60 cell growth in vitro with MG being the most potent agent. MG in combination with AZA demonstrated no significant increase in inhibition of cell growth over MG treatment alone whilst MCT-3 in combination with AZA demonstrated increased inhibition of cell growth over either agent alone although no more significant than MG alone. MG alone or MCT-3 in combination with AZA significantly increased p15 and caspase-3 expression. MG and MCT-3 significantly attenuated AZA-induced MMP-9 mRNA expression and proteolytic activity. Interestingly, MCT-3, MG and AZA alone and in combination increased expression of the novel tumour suppressor gene Nur77, important in leukemogenesis, with MG a more potent inducer as a single agent. These observations suggest the enhanced anti-leukemia activity of the combination of AZA and HDACi may only reside with certain HDACi classes and may be in-part explained by regulation of genes associated with cell cycle arrest, apoptosis and tumour suppression.

PEGylated amyloid peptide nanocontainer delivery and release system.

A micellar nanocontainer delivery and release system is designed on the basis of a peptide-polymer conjugate. The hybrid molecules self-assemble into micelles comprising a modified amyloid peptide core surrounded by a PEG corona. The modified amyloid peptide previously studied in our group forms helical ribbons based on a beta-sheet motif and contains beta-amino acids that are excluded from the beta-sheet structure, thus being potentially useful as fibrillization inhibitors. In the model peptide-PEG hybrid system studied, enzymatic degradation using alpha-chymotrypsin leads to selective cleavage close to the PEG-peptide linkage, break up of the micelles, and release of peptides in unassociated form. The release of monomeric peptide is useful because aggregation of the released peptide into beta-sheet amyloid fibrils is not observed. This concept has considerable potential in the targeted delivery of peptides for therapeutic applications.

The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression.

A combination of demethylating agents and histone deacetylase inhibitors (HDACi) has been proposed as a novel therapy in leukemia and myelodysplasia. In HL-60 cells azacytidine (AZA) and Metacept-1 (MCT-1), a novel HDACi augmented inhibition of cell growth and increased apoptosis. In identifying a molecular mechanism responsible for these effects MCT-1 alone and in combination with AZA induced p15INK4b, p21WAF1/CIP1 and Caspase-3 whilst attenuating Bcl-XL expression. Interestingly, MCT-1 in combination with AZA significantly induced the recently identified suppressor of leukemogenesis Nur77 and attenuated AZA-induced MMP-9 expression. The combination of MCT-1 and AZA is more effective in inhibiting leukemic cell growth and induction of apoptosis. Regulation of a recently identified tumour suppressor gene together with cell cycle, apoptosis and matrix degrading proteases may underpin the molecular mechanism responsible for these effects.

Self-assembly of Peptide nanotubes in an organic solvent.

The self-assembly of a modified fragment of the amyloid beta peptide, based on sequence Abeta(16-20), KLVFF, extended to give AAKLVFF is studied in methanol. Self-assembly into peptide nanotubes is observed, as confirmed by electron microscopy and small-angle X-ray scattering. The secondary structure of the peptide is probed by FTIR and circular dichroism, and UV/visible spectroscopy provides evidence for the important role of aromatic interactions between phenylalanine residues in driving beta-sheet self-assembly. The beta-sheets wrap helically to form the nanotubes, the nanotube wall comprising four wrapped beta-sheets. At higher concentration, the peptide nanotubes form a nematic phase that exhibits spontaneous flow alignment as observed by small-angle neutron scattering.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

Cost effectiveness of olanzapine in prevention of affective episodes in bipolar disorder in the United Kingdom.

This study evaluated the cost effectiveness of olanzapine compared with lithium as maintenance therapy for patients with bipolar I disorder (BP1) in the UK. A Markov model was developed to assess costs and outcomes from the perspective of the UK National Health Service over a 1-year period. Patients enter the model after stabilization of a manic episode and are then treated with olanzapine or lithium. Using the findings of a recent randomized clinical trial, the model considers the monthly risk of manic or depressive episodes and of dropping out from allocated therapy. health care resources associated with acute episodes were derived primarily from a recent UK chart review. Costs of maintenance therapy and monitoring were also considered. Key factors influencing cost effectiveness were identified and included in a stochastic sensitivity analysis. The model estimated that, compared to lithium, olanzapine significantly reduced the annual number of acute mood episodes per patient from 0.81 to 0.58 (difference -0.23; 95% CI: -0.34, -0.12). Per patient average annual care costs fell by 799 UK pounds (95% CI: - 1,824 UK pounds, 59 UK pounds) driven by reduced inpatient days--but the cost difference was not statistically significant. Sensitivity analysis found the results to be robust to plausible variation in the model's parameters. The model estimated that using olanzapine instead of lithium as maintenance therapy for BP1 would significantly reduce the rate of acute mood events resulting in reduced hospital costs. Based on available evidence, there is a high likelihood that olanzapine would reduce costs of care compared to lithium.

Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage?

BACKGROUND: In a phase III trial, 3-weekly capecitabine (1250 mg/m(2) twice daily days 1-14) plus docetaxel (75 mg/m(2) day 1) demonstrated significantly superior overall survival to 3-weekly docetaxel (100 mg/m(2) day 1). We report a retrospective analysis of the impact of capecitabine/docetaxel dose reduction on safety and efficacy. PATIENTS AND METHODS: Safety and efficacy data were analyzed retrospectively according to the actual doses of capecitabine and docetaxel administered. RESULTS: More patients receiving capecitabine/docetaxel (65%) had dose reductions for adverse events than docetaxel alone (35%). In most patients requiring dose reduction with the combination (80%), capecitabine and docetaxel were simultaneously reduced to 950 mg/m(2) and 55 mg/m(2), respectively. Subsequently, there were fewer cycles (17%) with grade 3/4 adverse events than with the full doses (34%). Time to progression and overall survival appeared to be similar in patients starting the second cycle with reduced doses of capecitabine/docetaxel and those who continued to receive full doses of capecitabine/docetaxel for at least the first four cycles. CONCLUSIONS: Capecitabine/docetaxel dosing flexibility allows management of side-effects without compromising efficacy. This retrospective analysis, as well as multiple phase II studies of taxanes with reduced-dose capecitabine, shows that reducing the starting dose of capecitabine with docetaxel is a reasonable strategy for the treatment of patients with metastatic breast cancer. In addition, reducing the dose of both agents may be appropriate.

Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial.

Oral capecitabine (Xeloda) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.

The cardiovascular and respiratory health of people with schizophrenia.

OBJECTIVE: To examine the cardiovascular and respiratory health of people with severe mental illness (SMI) and compare findings with the Health Surveys for England. METHOD: A prospective, multi-centre observational prevalence study of 602 patients with schizophrenia-related psychoses carried out in six locations across the UK over 24 months. RESULTS: Compared with general population subjects, people with SMI reported higher rates of angina and respiratory symptoms and had poor lung function. Much of this increased risk could be explained by lifestyle risk factors; there were increased levels of obesity among younger people with SMI. CONCLUSION: Key indicators of the cardiovascular and respiratory health of people with SMI are poor compared with those of the general population. Care plans should prioritize interventions to attenuate lifestyle risk factors. Evidence of increasing obesity in younger patients is of particular concern, predicting even greater health needs in the future.

Lack of evidence of disease contamination in ovarian tissue harvested for cryopreservation from patients with Hodgkin lymphoma and analysis of factors predictive of oocyte yield.

Ovarian cryopreservation is a promising technique to preserve fertility in women with Hodgkin lymphoma (HL) treated with chemotherapy. Thus, the aim of this study was to examine harvested ovarian tissue for subclinical involvement by HL by morphology/immunohistochemistry, and to define patient and treatment factors predictive of oocyte yield. This was a retrospective analysis of 26 ovarian tissue samples harvested for cryopreservation from women with HL. Histology, immunohistochemistry and follicle density (number mm(-3)) was examined. Disease status and preharvest chemotherapy details were obtained on 24 patients. The median age was 22 years (range 13-29). Seven of 24 patients had infradiaphragmatic disease at time of harvest. Nine of 20 patients had received chemotherapy preharvest (ABVD (Adriamycin), Bleomycin, Vinblastine and Dacarbazine) = 7, other regimens = 2). The seven receiving ABVD showed no difference in follicle density compared to patients not receiving treatment (n = 14); (median = 1555 vs 1620 mm3 P = 0.97). Follicle density measurement showed no correlation with patient age (R2 = 0.0001, P = 0.99). There was no evidence of HL involvement in the 26 samples examined (95% CI = 0-11%). In conclusion, subclinical involvement of HL has not been identified in ovarian tissue, even when patients have infradiaphragmatic disease. Furthermore, the quality of tissue harvested does not appear to be adversely affected by patient's age or prior ABVD chemotherapy.

The impact of intellectual functioning on symptoms and service use in schizophrenia.

BACKGROUND: This study aims to evaluate differences in the clinical profiles and use of psychiatric services by people with schizophrenia with and without borderline intellectual functioning. Both groups in this study were receiving standard community psychiatric care. METHODS: A naturalistic sample of 372 people with schizophrenia completed the National Adult Reading Test. Data were collected prospectively over 18 months on psychiatric symptoms and service use. Three hundred and thirteen had normal intellectual functioning (mean age 43, range 20-76 years) and 59 had borderline or lower intellectual functioning (mean age 45, range 21-81 years). This was defined by a National Adult Reading Test error score of more than 40. RESULTS: People with borderline or lower intellectual functioning had a lower quality of life, more severe psychotic symptoms, reduced functioning and fewer antidepressant prescriptions. There were no significant differences in service use including hospital admission. CONCLUSIONS: People with schizophrenia and borderline or lower intellectual functioning are a more disabled group within general adult psychiatric services who should be the focus of initiatives for improved service delivery.

Maintenance antipsychotic medication patterns in outpatient schizophrenia patients: a naturalistic cohort study.

OBJECTIVE: Newer antipsychotics are increasingly used in schizophrenia maintenance. The UK change has been slow with little known on switching patterns. We aimed to investigate antipsychotic prescribing patterns in schizophrenia patients. METHOD: A naturalistic six-site cohort sample of 600 patients were interviewed by researchers at 6-monthly intervals for 2 years to record their clinical and social functioning; use of services and medication for the preceding 6 months was obtained by structured extraction from clinical case notes. RESULTS: Alterations in antipsychotic medication were frequent in this group, mainly during periods of inpatient care. Atypical prescribing increased steadily, though slowly, across the period. Polypharmacy was less than anticipated. CONCLUSION: Inpatient care remains the main forum for switching of antipsychotics. The UK maintains a slow shift to atypical antipsychotics.

A phase I trial of high-dose palliative radiotherapy plus concurrent weekly Vinorelbine and Cisplatin in patients with locally advanced and metastatic NSCLC.

The role of concurrent chemoradiotherapy (CRT) in patients with non-small-cell lung cancer (NSCLC) unsuitable for radical therapy but who require locoregional treatment has not been defined. The aims of this phase I trial were thus to develop a novel regimen of weekly chemotherapy concurrent with high-dose palliative RT (40 Gy/20 fractions) and assess its tolerability, objective and symptomatic response rates. Eligible patients had stage I-IIIB NSCLC unsuitable for radical RT or limited stage IV disease, ECOG PS