Impact of Biopsy Attempts, Race, and Access on Time to Initiation of Treatment for Pancreatic Cancer.

BACKGROUND: Biopsy of suspected pancreatic cancer (PDAC) in surgical candidates is informative however not always necessary. Biopsies impact treatment options as histological diagnosis are presently required for neo-adjuvant therapy, but not surgical resection. We explored the impact of pursuing tissue diagnosis by endoscopic ultrasound (EUS) biopsy on time to treatment in patients with resectable and borderline resectable PDAC. METHODS: A retrospective review of surgical patients with ultimately proven PDAC was performed (2011-2021). Milestone dates (cancer suspected, biopsy(ies), surgical or neo-adjuvant treatment) were collected. Mann-Whitney-Wilcoxon tests, Pearson's chi-squared tests, Fisher's exact tests, linear regressions, and Cox proportional hazard models were used for data analysis. RESULTS: Among 131 resectable and 58 borderline resectable patients, the borderline resectable group underwent more biopsies (1.2 vs 0.7, p < 0.0001), were more likely to undergo biopsy at tertiary care centers (67.2% vs 30.5%, p < 0.0001), and trended toward longer time to treatment (49 vs 44 days, p = 0.070). Significant increases in days to treatment were seen in patients with Black race (29 days, p = 0.0002) and Medicare insurance (22 days, p = 0.038) and no biopsies at a tertiary care center (10 days, p = 0.039). After adjusting for covariates, additional biopsies significantly delayed treatment (1 biopsy: 21 days, p = 0.0001; 2 biopsies: 44 days, p < 0.0001; 3 biopsies: 68 days, p < 0.0001). CONCLUSIONS: EUS biopsy significantly impacts time between suspicion and treatment of PDAC. This may be exacerbated by clinical practices increasingly favoring neo-adjuvant therapy that necessitates biopsy-proven disease. Time to treatment may also be impacted by access to tertiary centers and racial disparities.

Ethical Considerations of Biopsies in Early-Stage Pancreatic Cancer.

PURPOSE: The standard of care in resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) has evolved to include neoadjuvant treatment before surgical resection. Current guidelines call for obtaining histologic tissue diagnosis via endoscopic ultrasound fine-needle aspiration before administration of neoadjuvant therapy, which differ from guidelines discouraging delay in surgical resection for a biopsy. MATERIALS AND METHODS: Whether to proceed with treatment before a biopsy confirms that malignancy is a nuanced decision and includes considerations of physical and psychological risks entailed in both pursuing and forgoing a biopsy. RESULTS: Accuracy of imaging and biopsy results, the presence of contributing clinical signs/symptoms, and the existing precedents of considering biopsies as waivable such as in scenarios with high clinical suspicion and primary surgical resection. CONCLUSION: When considering the aspects of ethical medical practice including beneficence (doing good), nonmaleficence (avoiding harm), autonomy (allowing patients to make decisions about their care), and utilitarianism (doing the most good for the most people), analysis of whether guidelines guiding biopsies should continue to differ between resection and neoadjuvant treatments in PDAC is prudent.

Weight status and meeting the physical activity, sleep, and screen-time guidelines among Texas children: results from a population based, cross-sectional analysis.

BACKGROUND: Evidence suggests that the interactive effects of physical activity, screen-time and sleep are stronger than independent effects of these behaviors on pediatric obesity. However, this hypothesis has not been fully examined among samples of young school-aged children. The aim of this study is to determine the association of weight status with meeting the physical activity, screen-time, and sleep guidelines, independently and concurrently, among 2nd grade children. METHODS: The Texas School Physical Activity and Nutrition Project collected parent-reported physical activity, screen-time, and sleep, and measured body height and weight on a statewide representative weighted sample (n = 320,005) of children. Weighted multivariable logistic regressions were used to assess associations of weight status (classified using age- and sex-specific body weight [kg]/height [m]2, based on International Obesity Task Force cutoffs) with meeting the physical activity, screen-time, and sleep guidelines, while controlling for relevant covariates (age, sex, race/ethnicity, comorbidities etc.). RESULTS: A greater proportion of healthy weight children (9.9%) met the physical activity, screen-time, and sleep guidelines concurrently compared to children who are thin (3.3%), or children with overweight (5.7%), obese (3.5%), and morbid obesity (1.0%). Children who were thin (adjusted odds ratio [aOR]:0.40, 95% confidence interval [CI]: 0.10, 1.50), overweight (aOR = 0.75, CI: 0.33, 1.70), obese (aOR = 0.53, CI: 0.15, 1.81), and morbidly obese (aOR = 0.10, CI: 0.02, 0.28) had lower odds of concurrently meeting the guidelines compared to children with healthy weight. CONCLUSIONS: Among this representative sample of Texas children, weight status was associated with meeting physical activity, screen-time, and sleep guidelines. Future studies should aim to evaluate causal relations between these behaviors and weight status.

The interleukin-1 axis and the tumor immune microenvironment in pancreatic ductal adenocarcinoma.

Interleukin-1 (IL-1) plays a key role in carcinogenesis and several IL-1-targeted therapeutics are under investigation for the treatment of pancreatic ductal adenocarcinoma (PDAC). We sought to broaden our understanding of how the family of IL-1 ligands and receptors impact the tumor immune landscape and patient survival in PDAC. Gene expression data and DNA methylation data for IL1A, IL1B, IL1RN, IL1R1, IL1R2, and IL1RAP was attained from The Cancer Genome Atlas (TCGA) database and cross validated using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Immune cell-type abundance was estimated using CIBERSORTx. Further confirmatory soluble protein analysis and peripheral blood immunophenotyping were performed on available tissue samples from our institution. 169 PDAC patients and 50 benign pancreatic TCGA-based samples were analyzed. IL1A (p < 0.001), IL1RN (p < 0.001), IL1R2 (p < 0.001), and IL1RAP (p = 0.006) were markedly increased in PDAC tumor tissue compared to benign pancreatic tissue. Furthermore, expression of IL1A, IL1B and IL1R1 were positively correlated with gene expression of immune checkpoints PVR, CD274, CD47, CD80, and HLA-A/B/C (p < 0.001). IL1B and IL1R1 were correlated to expression of PDCD1, CD86, CTLA4 and IDO1 (<0.001). Low expression of IL1RN (p = 0.020), IL1R2 (p = 0.015), and IL1RAP (p = 0.003) and high expression of IL1B (p = 0.031) were correlated with increased patient survival. At the protein level, IL-1ß was correlated with increased peripheral central memory CD4+ and CD8+ T-cells as well as decreased Th2 cells. These findings suggest that the IL-1 axis plays a complex and pivotal role in the host immune response to PDAC.

Outcomes following mycophenolate mofetil versus cyclophosphamide induction treatment for proliferative juvenile-onset lupus nephritis.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) is more severe than adult-onset disease, including more lupus nephritis (LN). Despite differences in phenotype/pathogenesis, treatment is based upon adult trials. This study aimed to compare treatment response, damage accrual, time to inactive LN and subsequent flare, in JSLE LN patients treated with mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVCYC). METHODS: UK JSLE Cohort Study participants, ≤16 years at diagnosis, with ≥4 American College of Rheumatology criteria for SLE, with class III or IV LN, were eligible. Mann-Whitney U tests, Fisher's exact test and Chi-squared tests were utilized for statistical analysis. RESULTS: Of the patients, 34/51 (67%) received MMF, and 17/51 (33%) received IVCYC. No significant differences were identified at 4-8 and 10-14 months post-renal biopsy and last follow-up, in terms of renal British Isles Lupus Assessment Grade scores, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores. Standardized Damage Index scores did not differ between groups at 13 months or at last follow-up. Inactive LN was attained 262 (141-390) days after MMF treatment, and 151 (117-305) days following IVCYC ( p = 0.17). Time to renal flare was 451 (157-1266) days for MMF, and 343 (198-635) days for IVCYC ( p = 0.47). CONCLUSION: This is the largest study to date investigating induction treatments for proliferative LN in children, demonstrating comparability of MMF and IVCYC.

Developing the radiation protection safety culture in the UK.

In the UK, as elsewhere, there is potential to improve how radiological challenges are addressed through improvement in, or development of, a strong radiation protection (RP) safety culture. In preliminary work in the UK, two areas have been identified as having a strong influence on UK society: the healthcare and nuclear industry sectors. Each has specific challenges, but with many overlapping common factors. Other sectors will benefit from further consideration.In order to make meaningful comparisons between these two principal sectors, this paper is primarily concerned with cultural aspects of RP in the working environment and occupational exposures rather than patient doses.The healthcare sector delivers a large collective dose to patients each year, particularly for diagnostic purposes, which continues to increase. Although patient dose is not the focus, it must be recognised that collective patient dose is inevitably linked to collective occupational exposure, especially in interventional procedures.The nuclear industry faces major challenges as work moves from operations to decommissioning on many sites. This involves restarting work in the plants responsible for the much higher radiation doses of the 1960/70s, but also performing tasks that are considerably more difficult and hazardous than those original performed in these plants.Factors which influence RP safety culture in the workplace are examined, and proposals are considered for a series of actions that may lead to an improvement in RP culture with an associated reduction in dose in many work areas. These actions include methods to improve knowledge and awareness of radiation safety, plus ways to influence management and colleagues in the workplace. The exchange of knowledge about safety culture between the nuclear industry and medical areas may act to develop RP culture in both sectors, and have a wider impact in other sectors where exposures to ionising radiations can occur.

Continuing utilisation of specialised health services in extremely preterm infants.

OBJECTIVE: To compare healthcare use from neonatal discharge to 18 months corrected age (CA) of two groups of extremely preterm neonates (23-25 vs 26-28 weeks). DESIGN: Cohort study. PATIENTS: Infants born at < or =28 weeks and admitted in three hospital centres in Quebec, Canada (n=254). MAIN OUTCOME MEASURES: Neurodevelopmental outcomes and healthcare use from neonatal discharge to 18 months CA. RESULTS: Re-hospitalisation rates occurred in 57% of children born at 23-25 weeks and in 49% of those born at 26-28 weeks. In these two age groups, by 18 months, 61% vs 59% were followed in physical or occupational therapy, 29% vs 17% were enrolled in a long-term rehabilitation program, 38% vs 28% used prescribed medication, and 59% vs 33% required medical assistive devices, respectively. Risk of re-hospitalisation was related to bronchopulmonary dysplasia (BPD), severe brain injury, use of home oxygen or an apnoea monitor and older age at neonatal discharge. Multiple births, BPD, severe brain injury, older age at neonatal discharge and single parenthood were associated with risk of using out-patient health services above average (>2 services). CONCLUSION: Extremely preterm children are frequently re-hospitalised during infancy and use a substantial amount of healthcare resources. These results highlight the importance of resource allocation to preterm infants for medical and rehabilitation services after discharge from the neonatal intensive care unit.

Prospective assessment of two-stage testing for Clostridium difficile.

Commonly used immunoassays have limitations as stand-alone tests for the diagnosis of Clostridium difficile infection (CDI). In particular, the specificity of these assays means that these tests generate a relatively large number of false-positive results. We introduced a two-stage regimen for CDI as routine. Unformed stool samples received in our laboratory were initially tested with a Meridian Premier enzyme immunoassay (EIA) and positive samples were retested with reference testing methods (toxigenic culture and cell cytotoxicity assay). Clinicians received diagnostically useful information on the day that the sample arrived in the laboratory, with definitive negative and provisional positive results made available. We reviewed the first 3643 unformed stool specimens of which 158/3643 (4.3%) were provisionally positive by EIA. Of the 158 samples that were EIA positive, 119 were confirmed as being positive by at least one of the reference methods, giving a positive predictive value in this population of 75% (95% confidence interval: 67.6-81.7%). Comparison of the optical density values of the EIA lying between true and false-positive results suggests that the introduction of a second cut-off value would improve diagnostics. A test with two cut-offs would give the following results: 'positive', 'negative' and 'indeterminate result, please perform confirmatory test'. This algorithm was a simple and cost-effective method to immediately improve diagnostics, but there is an urgent need for further research in laboratory diagnosis for CDI.

STEP: simplified treatment of the enlarged prostate.

We propose a simple and practical approach to the identification, evaluation and treatment of lower urinary tract symptoms (LUTS) resulting from an enlarging and obstructive prostate. The proposed Simplified Treatment for Enlarged Prostate (STEP) plan is a logical guide to patient management by the primary care provider (PCP). Symptoms of enlarged prostate (EP) are common and may frequently progress into a condition with profound adverse effects on quality of life. Despite the high prevalence, EP is underdiagnosed and undertreated. This situation may result from patient- and provider-related issues. Assessment of symptoms of EP should be initiated with a discussion of LUTS. Evaluation includes a focused history, physical examination and selected laboratory tests. Certain factors put the symptomatic patient at risk for disease progression; however, not all factors can be readily evaluated in the PCP setting. The serum prostate-specific antigen (PSA) level acts both as an indicator of prostatic size and a screening tool for prostatic cancer, and thereby provides an important tool for PCPs. The STEP plan is a logical guide to patient management. Step 1, watchful waiting, is appropriate in patients with symptoms that are not bothersome. If symptoms cause bother, the initiation of an alpha-blocker (AB) in step 2, provides relatively rapid symptom improvement. Patients with bothersome symptoms and a PSA > or = 1.5 ng/ml are at risk for progression and consideration should be given to combination treatment with an AB and a 5alpha-reductase inhibitor (step 3). Patients with refractory symptoms should be referred to a urologist (step 4). Identification, evaluation and management of EP are within the domain of the primary care setting. The STEP approach provides a simple and practical framework for PCPs to manage most men with symptoms of EP.

A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting.

In response to increasing pressure on inpatient services and a meta-analysis indicating that cisplatin (C) is superior to carboplatin, we report a phase II trial of gemcitabine (G) and split-dose C in advanced non-small cell lung cancer (NSCLC) in an outpatient setting. Patients with stage IIIB/IV NSCLC received: G/C 1250/40 mg/m(2); G and C were given on day (d) 1 and d8 in a 21d cycle. Patients with performance status 0-2, adequate bone marrow function and calculated glomerular filtration rate (GFR) >50 ml/min were eligible. Forty-two patients were enrolled: 25 male; median age 62 (range 37-78) years. There were 26 patients (62%) with stage IV disease. One hundred and thirty-eight cycles of chemotherapy were delivered. Chemotherapy was well tolerated, allowing maintenance of planned dose intensity (DI) with mean dose delivered of 780.1 mg/m(2) (93%) and 25.6 mg/m(2) (96%) for G and C, respectively. The overall response rate was 43%. Median survival was 12.5 months with a median follow-up of 13.5 months. One year survival rate was 51%. G plus C both given on d1 and d8 (q21d) is a very active, well tolerated and convenient outpatient schedule, which maintains DI.

Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis.

OBJECTIVES: Some juvenile dermatomyositis (JDM) patients have a disease course which is refractory to multiple drug treatments. Prolonged disease activity is associated with increased mortality and morbidity. TNF-alpha has been identified in high levels in JDM patients who have a long disease course and calcinosis. We assessed the response of five refractory JDM patients to the anti-TNF-alpha monoclonal antibody, infliximab. METHODS: For all five patients intravenous infliximab was initially given at a dose of 3 mg/kg. Further doses were then given at weeks 2, 6 and every 8 weeks thereafter. The dose and frequency were tailored in accordance with clinical response. Clinical and laboratory data were collected prospectively. RESULTS: We report results between 8 and 30 months after starting infliximab. Improvements were seen in all five patients as shown by positive changes in physician visual analogue scale (VAS), Childhood Myositis Assessment Score (CMAS), Childhood Health Assessment Questionnaire (CHAQ), joint range of movement and, in some, regression of calcinosis and skin signs. There were no major side effects observed with addition of infliximab to the therapeutic regime. CONCLUSIONS: Major clinical benefit was demonstrated after the initiation of infliximab in all five cases of refractory JDM.

Internal iliac artery pseudoaneurysm following renal transplant biopsy successfully treated with endovascular stenting and thrombosis: a case report.

A 49-year-old man underwent living donor renal transplantation in November 2005. The transplant renal artery was anastomosed to the right internal iliac artery with an end-to-end anastomosis. The patient achieved immediate graft function and the allograft was normally perfused. Seven weeks later, renal allograft function deteriorated with a serum creatinine level increased to 244 micromol/L. An ultrasound scan revealed adequate perfusion to the kidney and the absence of hydronephrosis. A transplant biopsy revealed Banff IB rejection, which was treated with high-dose prednisolone. Following biopsy, the patient's renal function rapidly deteriorated with a serum creatinine level increased to 627 micromol/L, requiring hemodialysis. A computed tomography (CT) angiogram demonstrated a 6-cm diameter pseudoaneurysm arising from the internal iliac artery with absence of kidney perfusion. The aneurysm was accessed percutaneously with a 4-F catheter and 1000 U of human thrombin injected, resulting in partial thrombosis of the pseudoaneurysm. A balloon expandable covered metal stent was then placed across the site of the transplant renal artery anastomosis, resulting in successful occlusion of the aneurysm. Intrarenal blood flow was established by dilating 2 intrarenal branches with 3-mm diameter balloons. The serum creatinine level started to decrease within 24 hours of the procedure and renal function improved rapidly to a level achieved immediately after transplantation. Three months later the patient had a well-functioning allograft with a serum creatinine level of 176 micromol/L, follow-up CT scan demonstrated good perfusion of the transplanted kidney with no further change in the pseudoaneurysm. At 12 months follow-up the patient remains with a well-functioning allograft.

CT colonography: interpretative performance in a non-academic environment.

AIM: To investigate interpretative accuracy and reporting time for radiologists performing computed tomography (CT) colonography in day-to-day non-academic clinical practice. MATERIALS AND METHODS: Thirteen radiologists from seven centres, who were reporting CT colonography in non-academic daily clinical practice, interpreted a dataset of 15 colonoscopically validated cases in a controlled environment. Ten cases had either a cancer or polyp >10mm; one case had a medium polyp and four were normal. Correct case categorization and interpretation times were compared using analysis of variance to aggregated results obtained from both experienced observers and observers recently trained using 50 cases, working in an academic environment. The effect of experience was determined using Spearman's rank correlation. RESULTS: Individual accuracy was highly variable, range 53% (95% CI 27-79%) to 93% (95% CI 68-100%). Mean accuracy overall was significantly inferior to experienced radiologists (mean 75 versus 88%, p=0.04) but not significantly different from recently trained radiologists (p=0.48). Interpretation time was not significantly different to experienced readers (mean 12.4 min versus 11.7, p=0.74), but shorter than recently trained radiologists (p=0.05). There was a significant, positive, linear correlation between prior experience and accuracy (p<0.001) with no plateau. CONCLUSION: Accuracy for sub-specialist radiologists working in a non-academic environment is, on average, equivalent to radiologists trained using 50 cases. However, there is wide variability in individual performance, which generally falls short of the average performance suggested by meta-analysis of published data. Experience improves accuracy, but alone is insufficient to determine competence.

Frequency and impact of extracolonic findings detected at computed tomographic colonography in a symptomatic population.

BACKGROUND: Extracolonic findings are frequently recognized alongside colonic pathology at computed tomographic colonography (CTC). This study assessed the clinical impact of extracolonic findings in a symptomatic population at high risk of colorectal cancer. METHODS: CTC was performed in a consecutive cohort of patients assessed in a fast-track colorectal cancer clinic as being at high risk of colorectal cancer. A review of CTC findings and case notes was undertaken. Patients with extracolonic findings were followed up for at least 12 months. RESULTS: Thirty-one (13.8 per cent) of 225 patients investigated by CTC had colorectal cancer. Extracolonic findings were identified in 81 (53.3 per cent) of 152 patients with normal or non-neoplastic bowel findings, compared with 27 (37 per cent) of 73 patients with colorectal neoplasia (P = 0.025). Twenty-four patients (10.7 per cent) with extracolonic findings underwent further investigation or treatment. The median duration of investigation was 19.5 weeks. Seventy-five clinical events were recorded, including 14 surgical procedures. CONCLUSION: A prospective cost-benefit analysis of diagnostic CTC should be performed before it is established as a first-line investigation for colonic symptoms.

Dopaquinone redox exchange with dihydroxyindole and dihydroxyindole carboxylic acid.

A pulse radiolytic investigation has been conducted to establish whether a redox reaction takes place between dopaquinone and 5,6-dihydroxyindole (DHI) and its 2-carboxylic acid (DHICA) and to measure the rate constants of the interactions. To obviate possible confounding reactions, such as nucleophilic addition, the method employed to generate dopaquinone used the dibromide radical anion acting on dopa to form the semiquinone which rapidly disproportionates to dopaquinone. In the presence of DHI the corresponding indole-5,6-quinone (and/or tautomers) was also formed directly but, by judicious selection of suitable relative concentrations of initial reactants, we were able to detect the formation of additional indolequinone from the redox exchange reaction of DHI with dopaquinone which exhibited a linear dependency on the concentration of DHI. Computer simulation of the experimental time profiles of the absorption changes showed that, under the conditions chosen, redox exchange does proceed but not quite to completion, a forward rate constant of 1.4 x 10(6)/M/s being obtained. This is in the same range as the rate constants previously established for reactions of dopaquinone with cyclodopa and cysteinyldopa. In similar experiments carried out with DHICA, the reaction more obviously does not go to completion and is much slower, k (forward) =1.6 x 10(5)/M/s. We conclude that, in the eumelanogenic pathway, DHI oxidation may take place by redox exchange with dopaquinone, although such a reaction is likely to be less efficient for DHICA.

An outbreak of wound infection in cardiac surgery patients caused by Enterobacter cloacae arising from cardioplegia ice.

This paper describes an outbreak of postoperative sternal wound infections. A cardiac surgeon noted a cluster of serious infections leading to wound dehiscence, despite the fact that none of his colleagues had noticed a rise in infection rates. The infections were predominantly with Enterobacter cloacae, and molecular typing and serotyping showed these isolates to be indistinguishable. Observation of the surgeon's practice revealed nothing untoward, and there were no infections among his patients operated on in another hospital. There appeared to be no significant difference between the modes of operation of the different surgeons. The operating theatres were screened to exclude an environmental source, with samples cultured on CHROMagar Orientation, a selective/differential medium designed for urine samples. Further questioning revealed one difference between the practices of the different surgeons; this surgeon used semi-frozen Hartmann's solution to achieve cardioplegia. The freezer used for this was swabbed and yielded E. cloacae, indistinguishable from the clinical isolates. It is hypothesized that this organism contaminated the freezer, and that the contamination was passed on to the ice/slush solution, thus infecting the patients. There have been no more cases since the freezer was replaced, a rigorous cleaning schedule instituted, and steps taken to reduce the possibility of any further contamination.

Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.

AIMS/HYPOTHESIS: Neonatal diabetes is a rare disease with several identified molecular aetiologies. Despite associations with other malformations, neonatal diabetes with intestinal and biliary anomalies has not been described. The current study aims to describe a new syndrome, and to examine a possible link with one of three genes known to cause neonatal diabetes. METHODS: Five clinical cases are described. Immunohistochemical staining for pancreatic islet hormones was performed on three of the infants. DNA from one infant was analysed for abnormalities of the PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes. RESULTS: Five infants (two sibling pairs from two families, and an isolated case) presented with neonatal diabetes, hypoplastic or annular pancreas, jejunal atresia, duodenal atresia and gall bladder aplasia or hypoaplasia. One sibling pair was born to consanguineous parents. One patient with a milder form is surviving free of insulin. Four children died in the first year of life despite aggressive medical management. Pancreatic immunohistochemistry revealed few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon and somatostatin. Exocrine histology was variable. In one case from the consanguineous family, molecular analysis showed no duplication or uniparental isodisomy of PLAGL-1 at 6q24, no contiguous gene deletion involving the glucokinase gene, and no mutation in the coding sequences or splice sites of PDX-1. CONCLUSIONS/INTERPRETATION: This combination of multiple congenital abnormalities has not been previously described and probably represents a new autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development and whose aetiology is as yet unknown.

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer.

A randomised phase III trial of MVAC (methotrexate, vincristine, doxorubicin, cisplatin) vs gemcitabine and cisplatin (GC) (G 1000 mg m(-2) days 1, 8, and 15 plus C 70 mg m(-2) day 2, q 4 wks) indicated GC had similar efficacy and lower toxicity (JCO 2000). Significant haematologic toxicities in the GC arm occurred on day 15, necessitating dose adjustments in 37% of cycles. We conducted a phase I/II dose escalation trial using GC on a 21-day cycle, with G and C split between days 1 and 8. The objective of the study to define maximum-tolerated dose and dose-limiting toxicity (DLT), objective response rate, and overall survival. In all, 32 patients with locally advanced, relapsed, or metastatic disease received: dose level 1, G/C 1000/35; level 2, 1100/35; level 3, 1200/35; level 4, 1200/45 mg m(-2) (G and C given on days 1 and 8 every 3 wks). A total of 19 patients had glomerular filtration rate <60 ml min(-1) and 19 patients had metastatic disease. Dose-limiting toxicity was haematologic (grade 4 thrombocytopenia) at dose level 2. Of 151 cycles, at day 15, platelets were <100 in 61 cycles; neutrophils <0.5, platelets <50 in 26 cycles. Only seven cycles were deferred due to haematological toxicity; four for renal toxicity (chemotherapy instituted posthydration). Overall response rate was 65.5% on an intention-to-treat analysis (75% [21/28] for assessable patients), with four complete responses (12.5%) and 17 partial responses (53%). After the median follow-up of 17.2 months (range 13.1-32.4 months), 12 patients remain alive. The overall median survival was 16 months (range 10.1-26.6 months). G plus C every 3 weeks is active and well tolerated in an outpatient setting, even in patients receiving prior platinum-based regimens and with poor renal reserve.

The use of self-expandable metal stents in the palliation of malignant bowel obstruction.

Palliation of malignant gastrointestinal obstruction is a major aspect of oncology. We assessed the efficacy of stents in the palliation of gastric outlet, duodenal and colonic obstruction. We undertook a retrospective study of 35 consecutive patients who were referred for stent insertion with palliative intent from June, 1999 to March, 2003. Thirty-two stents were successfully placed in 30 patients. Technical success rate was 86% (30/35 patients). Of the patients who had successful insertion, 83% had complete relief of symptoms. In 1 patient the stent failed to expand. There was no procedure related mortality. Median survival was 1.6 months (range, 0-14.8). The conclusion was that self-expandable metal stents provide an effective method of palliation in malignant gastrointestinal obstruction, with high clinical and technical success rates and low complication rates.