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Anti-tumour necrosis factor (TNF) agents such as infliximab and adalimumab have greatly altered the treatment landscape in inflammatory bowel disease (IBD). However, there are remaining unmet needs and opportunities to optimise their use. Recent data suggest that proactive therapeutic drug monitoring may lead to more efficient usage of these agents, with potential for higher rates of corticosteroid-free clinical remission than with reactive monitoring. Expanded application of faecal calprotectin measurements may also be valuable, given the ease of use of the assay and its proven effectiveness as a diagnostic tool and predictor of relapse risk. From a practical viewpoint, improved multidisciplinary working may be essential to optimise patient care, with IBD nurse specialists playing an increasingly central role within this model. Finally, the availability of biosimilars of the anti-TNF agents allow drug costs to be reduced without compromising safety or efficacy - thereby providing opportunities to improve accessibility. Alongside extensive data on originator to biosimilar infliximab switch, new studies are beginning to demonstrate the safety of biosimilar to biosimilar switch, as well as adalimumab biosimilar transitions. The risk of a nocebo effect when switching to a biosimilar can be reduced through improved patient education and preparation., Competing Interests: Declaration of Competing of interest Prof. Alessandro Armuzzi; Consultancy for: AbbVie, Allergan, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Gilead, Janssen, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda; Lecture fees from: AbbVie, Amgen, AstraZeneca, Biogen, Chiesi, Ferring, Janssen, MSD, Mitsubishi Tanabe, Nikkiso, Pfizer, Samsung Bioepis, Sandoz, Takeda, Tigenix; Research grants from: MSD, Takeda, Pfizer Prof. Yoram Bouhnik; Honoraria from AbbVie, Biogaran, Biogen, Boehringer Ingelheim, Celgene, Ferring, Gilead, Hospira, Janssen, Mayoli Spindler, MSD, Norgine, Pfizer, Roche, Samsung Bioepis, Sandoz, Sanofi, Shire, Takeda, UCB; Grants from Pfizer, Takeda Prof. Fraser Cummings; Ad Boards: Hospira/Pfizer, NAPP, MSD, Abbvie, Biogen, Amgen, Takeda, Janssen, Samsung Bioepis; Speaker Fees: Hospira/Pfizer, NAPP, MSD, Abbvie, Biogen, Takeda, Janssen, Samsung Bioepis; Research Collaboration: Hospira/Pfizer, MSD, Abbvie, Biogen, Amgen, Takeda, Janssen, GSK, Astra Zeneca, Samsung Bioepis Ms. Marion Bettey; Lecture fees and honorarium, advisory board; Abbvie, Dr Falk, Hospira, Janssen, MSD, Napp, Takeda, Pfizer, Samsung Bioepis Dr. Burkhard Pieper; Employee of Biogen Mr. Taegyun Kang; Employee of Samsung Bioepis, (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this data in brief article dataset of plasma-assisted nitrogen doping of a binderless, spin-coated CuO-NiO mixed oxide thin film was presented (Palmer et al., 2020). A comparison of the CuO, N-CuO/Cu 2 O, CuO:NiO and N-CuO/Cu 2 O:NiO are presented. The as prepared films were used for the application of a glucose sensor. The nitrogen doped species, generated during plasma ignition, resulted in a beneficial phase transformation of CuO to Cu 2 O. Characterisation techniques such as XPS, particle size distribution and EIS techniques were utilized to study the morphology, structural features, doping profile and electrical properties of the various developed electrodes. The electrochemical performance of the thin film sensors was tested using cyclic voltammetry and chronoamperometry. The CuO exhibited a sensitivity of 830 µA/mM cm 2 up to 1.65 mM of glucose, N-CuO/Cu 2 O had a linear range up to 1.91 mM with a sensitivity of 873 µA/mM cm 2 and the CuO:NiO electrode had a linear range up to 1.65 mM with a sensitivity of 1103 µA/mM.cm 2 respectively. A detailed description of the methodology used is provided below., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Authors.)

Introduction : The purpose of this review is to highlight the role of biosimilars in early treatment in IBD and introduce ways to facilitate a patient-centric switching process through multidisciplinary approach. Areas covered : We summarize existing scientific literature related to the role of biosimilars in inflammatory bowel disease in terms of early treatment and cost-saving and implementing switching process. Expert opinion : Use of anti-TNF biosimilars in patients has the potential for large drug-acquisition cost-saving, which can be reinvested into early treatment. Managed switched programs for adalimumab can add further benefits in the future.

Background: The UK IBD Audit Programme reported improved inpatient care processes for ulcerative colitis (UC) between 2005 and 2013. There are no independent data describing national or institutional trends in patient outcomes over this period., Aim: To assess the association between the outcome of emergency admission for UC and year of treatment., Methods: Retrospective analysis of hospital administrative data, focused on all emergency admissions to English public hospitals with a discharge diagnosis of UC. We extracted case mix factors (age, sex, co-morbidity, emergency bed days in last year, deprivation status), outcomes of index admission (death and first surgery), 30-day emergency readmissions (all-cause, and selected causes) and outcome of readmission., Results: There were 765 deaths and 3837 unplanned first operations in 44 882 emergency admissions, with 5311 emergency readmissions (with a further 171 deaths and 517 first operations). Case mix adjusted odds of death for any given year were 9% lower (OR 0.91, 95% CI: 0.89-0.94), and that for emergency surgery 3% lower (OR 0.97, 95% CI: 0.95-0.98) than the preceding year. Results were robust to sensitivity analysis (admissions lasting ≥4 days). There was no reduction in odds for all-cause readmission, but rates for venous thromboembolism declined significantly. Analysis of institutional-level metrics across 136 providers showed a stepwise reduction in outliers for mortality and unplanned surgery., Conclusions: Risk of death and unplanned surgery for UC patients admitted as emergencies declined consistently, as did unexplained variation between hospitals. Risk of readmission was unchanged (over 1 in 10). Multiple factors are likely to explain these nationwide trends., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Advanced oxidation processes based on sulphate radical generated by peroxymonosulphate (PMS) activation is a promising area for environmental remediation. One of the biggest drawbacks of heterogeneous PMS activation is catalyst instability and metal ion leaching. In this study, a simple organic binder mediated route was explored to substitute Ti 4+ ions into the Co 3 O 4 host lattice structure to create a Co-O-Ti bond to minimise cobalt leaching during methyl orange degradation. The catalyst was characterised by X-ray diffraction, and scanning and transmission electron microscopy. The as-prepared catalysts with Co 3 O 4 :TiO 2 ratio of 70:30 exhibited minimal leaching (0.9 mg/L) compared to other ratios studied. However, the pristine Co 3 O 4 exhibited highest catalytic activity (rate constant = 0.41 min -1 ) and leaching (26.7 mg/L) compared to composite material (70:30 Co 3 O 4 :TiO 2 ). Interestingly, the morphology of the composite and leaching of Co 2+ ions were found to be temperature dependent, as an optimum temperature ensured strong Co-O-Ti bond for prevention of Co 2+ leaching. The classical quenching test was utilised to determine the presence and role of radical species on methyl orange degradation. The fabricated catalyst also exhibited good catalytic activity in degrading mixed dyes and good recyclability, making it a potential candidate for commercial application.

Results from clinical trials show that vedolizumab is an efficacious treatment for inflammatory bowel disease, namely Crohn's disease (CD) and ulcerative colitis (UC). However, there is limited evidence from real-world clinical practice, especially on early clinical experiences in the UK.To describe real-world early experiences of vedolizumab to treat CD and UC in the UK.A retrospective, chart review study of patients with CD or UC treated with vedolizumab across 5 UK hospitals. All eligible adults (≥18 years at initiation) with a diagnosis of CD and ≥14 weeks of data or UC and ≥10 weeks of data available following vedolizumab initiation were included.Data were analyzed for 112 patients (CD: 66; UC: 46). Patients with CD had a median of 7.4 (interquartile range 5.7-9.4) months follow-up and patients with UC had a median of 7.4 (5.6-10.2) months follow-up post-vedolizumab initiation. Most patients, 80% (53/66) with CD and 89% (41/46) with UC, remained on vedolizumab treatment at the time of data collection. No new safety signals were identified during the study.These results add to the body of evidence supporting vedolizumab as an effective and well-tolerated treatment for CD and UC in real-world clinical practice.

Iron deficiency without anemia and iron deficiency anemia are common and frequently overlooked complications of inflammatory bowel disease. Despite the frequency and impact of iron deficiency in inflammatory bowel disease, there are gaps in our understanding about its incidence, prevalence and natural history and, consequently, patients may be undertreated. Medical registries have a key role in collecting data on the disease's natural history, the safety and effectiveness of drugs in routine clinical practice, and the quality of care delivered by healthcare services. Even though iron deficiency impacts inflammatory bowel disease patients and healthcare systems substantially, none of the established European inflammatory bowel disease registries systematically collects information on iron parameters and related outcomes. Collection of robust iron parameter data from patient registries is one way to heighten awareness about the importance of iron deficiency in this disease and to generate data to improve the quality of patient care, patient outcomes, and thus quality of life. This objective could be achieved through collection of specific laboratory, clinical, and patient-reported measurements that could be incorporated into existing registries. This review describes the status of current European inflammatory bowel disease registries and the data they generate, in order to highlight their potential role in collecting iron data, to discuss how such information gathering could contribute to our understanding of iron deficiency anemia, and to provide practical information in regard to the incorporation of accumulated iron parameter data into registries., Competing Interests: Conflict-of-interest statement: Halfvarson J has received honoraria/grants from Abbvie, Celgene, Hospira, Janssen, Medivir, MSD, Pfizer, Sandoz, Takeda, Tillotts Pharma, and Vifor Pharma; Cummings F has received honoraria/grants from Biogen, Abbvie, Ferring, Hospira, Janssen, Pfizer, MSD, Napp, Pharmacosmos, Shield Therapeutics, Takeda, and Vifor Pharma; Grip O has received honoraria from Abbvie, Ferring, Janssen, Takeda, and Vifor Pharma; and Savoye G has received honoraria from HAC Pharma France, Pharmacosmos, and Vifor Pharma.

Background and Aims: Biosimilar infliximab CT-P13 offers the potential for large drug acquisition cost savings. However, there are limited published data regarding its efficacy, safety, and immunogenicity in inflammatory bowel disease [IBD], particularly in switching IBD patients from originator to biosimilar infliximab. We present the outcomes of a service evaluation of switching IBD patients established on originator infliximab to biosimilar, using a managed switching programme funded via a gain share agreement in a UK teaching hospital., Methods: Evaluation outcomes included drug persistence, changes in drug acquisition costs, patient-reported side effects, adverse events, patient outcomes assessed using the IBD-control Patient-Reported Outcome Measures [PROM] questionnaire, serum drug and antibody levels, and routinely collected biochemical markers., Results: A total of 143 patients with IBD [118 Crohn's disease, 23 ulcerative colitis, 2 IBD unclassified] were switched from originator infliximab to CT-P13. Patients reported a similar incidence of side effects before and after switch. No clinically significant differences were observed in mean C-reactive protein [CRP], albumin, haemoglobin levels, or platelet and white cell counts after the switch to CT-P13, whereas mean IBD-control-8 score improved from 10.4 to 11.2 [p = 0.041]. There was no significant difference in drug persistence between biosimilar and originator infliximab [p = 0.94] and no increase in immunogenicity was found. Drug acquisition costs decreased by £40,000-60,000 per month., Conclusions: A managed switching programme from originator infliximab to biosimilar CT-P13 in IBD, using a gain-share agreement, delivers significant cost savings and investment in clinical services while maintaining similar patient-reported outcomes, biochemical response, drug persistence, and adverse event profile., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

In this work, we have shown that mining waste derived Fe 3+ can be used to enhance the photocatalytic activity of TiO 2 . This will allow us to harness a waste product from the mines, and utilize it to enhance TiO 2 photocatalytic waste water treatment efficiency. An organic linker mediated route was utilized to create a composite of TiO 2 and biogenic jarosite. Evidence of FeOTi bonding in the TiO 2 /jarosite composite was apparent from the FTIR, EFTEM, EELS and ELNEFS analysis. The as prepared material showed enhanced photocatalytic activity compared to pristine TiO 2 , biogenic jarosite and mechanically mixed sample of jarosite and TiO 2 under both simulated and natural solar irradiation. The prepared material can reduce the electrical energy consumption by 4 times compared to pristine P25 for degradation of organic pollutant in water. The material also showed good recyclability. Results obtained from sedimentation experiments showed that the larger sized jarosite material provided the surface to TiO 2 nanoparticles, which increases the settling rate of the materials. This allowed simple and efficient recovery of the catalyst from the reaction system after completion of photocatalysis. Enhanced photocatalytic activity of the composite material was due to effective charge transfer between TiO 2 and jarosite derived Fe 3+ as was shown from the EELS and ELNEFS. Generation of OH was supported by photoluminesence (PL) experiments., (Copyright © 2016. Published by Elsevier B.V.)

Background: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease., Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15)., Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; p interaction =0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group., Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence., Funding: Medical Research Council., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients., Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls., Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1)., Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ruxolitinib, a small molecule JAK-1/2 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in November 2011, as the first therapeutic for the treatment of intermediate and high-risk myelofibrosis. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of the most well-studied intracellular signaling networks. Recent advances in our understanding of the complexities of signal activation and regulation of gene expression has provided opportunities for targeted therapeutic interventions. Although numerous inhibitors of the JAK/STAT pathway are currently being evaluated in clinical trials, ruxolitinib represents the first FDA approved in-class JAK inhibitor. We report a drug eruption associated with ruxolitinib.

A 39-year-old Indian man was diagnosed with ulcerative colitis on colonic biopsy and started on mesalazine, prednisolone and azathioprine. However, the colitis remained active and required antitumour necrosis factor (TNF) treatment with infliximab. Prior to starting infliximab, his chest X-ray was normal and QuantiFERON interferon γ release assay for tuberculosis (TB) was negative. However, his wife had been treated for pulmonary TB 11 years previously when they were cohabiting. On attending for his third dose of infliximab, he was feverish and tachycardic, and was admitted for investigation. Chest X-ray on admission showed changes consistent with miliary TB, and thoracic CT confirmed extensive miliary nodules with supraclavicular and mediastinal lymphadenopathy. Abdominal CT showed multiple mesenteric lymph nodes. Subsequent bronchoalveolar lavage, neck lymph node aspirate and colonic biopsies all cultured Mycobacterium tuberculosis. In retrospect, a clear history of close household TB exposure should have precipitated consideration of TB chemoprophylaxis prior to anti-TNF treatment.

Enteral feeding tube placement has been described in veterinary medicine for several years. Indications include oral, esophageal, gastrointestinal, pancreatic, hepatic, and neurologic diseases. In this paper, endoscopically assisted placement of an esophagojejunostomy (EJ) feeding tube in dogs with pancreatitis and prolonged anorexia is described. To the author's knowledge there are no published reports of this procedure. Esophagojejunostomy feeding tubes provide an alternative to other forms of postgastric feeding tube placement (e.g., nasojejunal, gastrojejunostomy, and jejunostomy tubes) without the associated complications of patient discomfort, sneezing, epistaxis, and peritonitis. Tube occlusion, transient vomiting and loose stool were the most commonly reported complications.

CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number of inflammatory arthritides including the spondyloarthritides. Th17 development is promoted by IL-23. Ankylosing spondylitis, the most common spondyloarthritis (SpA), is genetically associated with both HLA-B27 (B27) and IL-23R polymorphisms; however, the link remains unexplained. We have previously shown that B27 can form H chain dimers (termed B27(2)), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B27(2)-expressing APCs stimulate the survival, proliferation, and IL-17 production of KIR3DL2(+) CD4 T cells. KIR3DL2(+) CD4 T cells are expanded and enriched for IL-17 production in the blood and synovial fluid of patients with SpA. Despite KIR3DL2(+) cells comprising a mean of just 15% of CD4 T in the peripheral blood of SpA patients, this subset accounted for 70% of the observed increase in Th17 numbers in SpA patients compared with control subjects. TCR-stimulated peripheral blood KIR3DL2(+) CD4 T cell lines from SpA patients secreted 4-fold more IL-17 than KIR3DL2(+) lines from controls or KIR3DL2(-) CD4 T cells. Strikingly, KIR3DL2(+) CD4 T cells account for the majority of peripheral blood CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23. Our findings link HLA-B27 with IL-17 production and suggest new therapeutic strategies in ankylosing spondylitis/SpA.

A study of the uncertainty of dosimeter results is required by the national accreditation programs for each dosimeter model for which accreditation is sought. Typically, the methods used to determine uncertainty have included the partial differentiation method described in the U.S. Guide to Uncertainty in Measurements or the use of Monte Carlo techniques and probability distribution functions to generate simulated dose results. Each of these techniques has particular strengths and should be employed when the areas of uncertainty are required to be understood in detail. However, the uncertainty of dosimeter results can also be determined using a Model II One-Way Analysis of Variance technique and accreditation testing data. The strengths of the technique include (1) the method is straightforward and the data are provided under accreditation testing and (2) the method provides additional data for the analysis of long-term uncertainty using Statistical Process Control (SPC) techniques. The use of SPC to compare variances and standard deviations over time is described well in other areas and is not discussed in detail in this paper. The application of Analysis of Variance to historic testing data indicated that the accuracy in a representative dosimetry system (Panasonic® Model UD-802) was 8.2%, 5.1%, and 4.8% and the expanded uncertainties at the 95% confidence level were 10.7%, 14.9%, and 15.2% for the Accident, Protection Level-Shallow, and Protection Level-Deep test categories in the Department of Energy Laboratory Accreditation Program, respectively. The 95% level of confidence ranges were (0.98 to 1.19), (0.90 to 1.20), and (0.90 to 1.20) for the three groupings of test categories, respectively.

Background: The prognosis of acute severe ulcerative colitis (ASC) influences therapeutic decisions, but data on prevalence or long-term outcome are few., Methods: A systematic review of all patients with UC diagnosed in Oxford was performed to assess the prevalence of ASC defined by Truelove and Witts' (TW) criteria and determine whether outcome is related to disease activity on admission, likelihood of recurrence and long-term prognosis., Results: 750 patients (median follow up 12.7 yr, range 0-648 mo) met inclusion criteria out of a total cohort of 1853 patients. 24.8% (186/750) had at least one admission for ASC (294 admissions in 186 patients). Overall, 12% (93/750) had a colectomy, compared to 39.8% (74/186) of patients with one or more episodes of ASC (p<0.0001) and 3.4% (19/564) in those with no admission. The colectomy rate on first admission (37/186, 19.9%) was lower than on the second or subsequent admissions (OR 2.35, 95% CI 1.33-4.14, p=0.003), being 29.0%, 36.6%, 38.2% after two, three, or subsequent episodes respectively. It was 8.5% (11/129) if patients had one TW criterion in addition to ≥6 bloody bowel motions/day, compared to 31% (29/94) if two additional criteria were present and 48% (34/71) if three or more additional criteria were present (p=1.4 × 10⁻⁵; OR 4.35, 95% CI 2.20-8.56 one criterion vs two or more)., Conclusions: A quarter of all patients with ulcerative colitis experience at least one episode of ASC; 20% come to colectomy on first admission, but 40% after two admissions. The likelihood of colectomy is related to biological severity on admission., (Copyright © 2010. Published by Elsevier B.V.)

In 2010, the U.S. Department of Energy will adopt a new set of radiation weighting factors and quality factors to be consistent with values recommended by the International Commission on Radiological Protection. The change will affect the magnitude of occupational exposure assigned to radiation workers exposed to neutron radiation. Understanding the energy response of the dosimeter and the effect of the new quantities is critical to accurately ensuring that occupational exposure remains below the established regulatory limits. Therefore, the factors used to interpret dosimeter readings must be re-evaluated for each irradiation field over the range of neutron energies in which the dosimeter is used. This paper describes one method of determining the neutron response of the dosimeter. A Monte Carlo approach was used to model the energy response of the Panasonic Model 809 dosimeter over the range of energies from 1.0 x 10(-8) to 20 MeV. The response, normalized to the response at 2.1 MeV, ranged from approximately 0.5 at 20 MeV to approximately 26 at 1 eV. The response was then divided at each energy by the appropriate dose conversion coefficient to determine the dose response of the dosimeter. The dose responses, normalized to the response at 2.1 MeV, ranged from approximately 0.4 at 20 MeV to 765 at 1 eV. Dose conversion factors were determined for various reference neutron spectra and plotted on the dose response curve. Good agreement was observed except for the case of D2O-moderated (252)Cf.

Background: Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior., Methods: Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform., Results: In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location., Conclusions: This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.

Background & Aims: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15., Methods: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought., Results: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15., Conclusions: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.

Background: Estramustine phosphate (EMP) and vinblastine have radiosensitizing properties and significant activity against hormone refractory prostate carcinoma. Strontium-89 is a palliative agent that acts as a selective radiation source for bone metastasis. The combination of EMP, vinblastine, and strontium-89 was developed to exploit the potential for radiosynergy. PATIENTS AND METHODS Forty-four patients at the Brown Oncology Group affiliated hospitals were treated with oral EMP 600 mg/m2 daily on Weeks 1-4 and 7-10, vinblastine 4 mg/m2 intravenously once each week on Weeks 1-4 and 7-10, and strontium-89 2.2 MBq/kg on Day 1. Courses were repeated every 12 weeks. Response assessment was based on a change in the serum prostate specific antigen (PSA) levels, correlated with change in measurable disease and bone scan appearance., Results: A greater than or equal to 50% decline in PSA for at least 6 weeks was observed in 21 patients (48%, 95% confidence interval, 33-62%). Median duration of response was 23 weeks (range, 6-70.8 weeks). The median survival was 13 months with 1- and 2-year survival rates of 55% and 25%, respectively. After completion of protocol therapy, a retrospective review showed that only nine patients received subsequent palliative external beam radiation after progression., Conclusions: The addition of strontium-89 to the regimen of EMP and vinblastine can be delivered safely and in repeated doses, provides effective palliation, and may decrease the need for future radiation therapy. A randomized trial is necessary to quantify these effects., (Copyright 2002 American Cancer Society.)

Expressions are given for the Gauss and Mean curvatures of a surface of thickness h. The two curvatures, (K and H), which are given at each point of the middle surface, are adequate to describe the surface. The sheet thickness varies with position in the middle surface bisecting the apical and basal surfaces. The definitions of K and H are in terms of radii of curvature, but such radii are not appropriate variables for determining how morphogens in the surface may couple to the geometry. More suitable expressions are developed here. Two important geometrical constraints must be satisfied, namely the famous Gauss-Bonnet theorem, and an inequality stemming from the definition of the two curvatures. It is argued that these constraints are of great usefulness in determining the form of the coupling of morphogens to the geometry. In particular, when two key morphogens suffice to determine surface geometry, explicit expressions are suggested to determine both Gauss (K) and Mean (H) curvatures as functions of invariant morphogen densities.

A model of pattern formation in the early embryo is presented. It is motivated by the necessary interaction of kinases and phosphatases, and in particular by the family of Wnt kinase and RPTP phosphatase signaling pathways. It is seen as complementary to the more short-range patterning of the Delta/Notch (or juxtacrine) signaling pathway., (Copyright 2000 Academic Press.)

Purpose: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation., Patients and Methods: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years)., Results: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF., Conclusion: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

The model addresses the question of the origin of traveling waves, mimicking waves of the Hh and Dpp proteins such as found in development of the fly eye. These two proteins, which are part of an important signaling pathway to the genome, are found in a diverse array of developmental situations, for example in the formation of the proximal-distal axes in limbs. The complex intracellular biochemistry involved is modeled in the simplest way in both cases, with the intent that concepts be emphasized over biochemical detail., (Copyright 1999 Academic Press)

Signaling pathways to the genome are a common way by which cells communicate with each other and their environment, and are often kineases or phosphatases. Patter formation is the differential spatial specification of gene activity necessary for multicellularity. It has been suspected that signaling pathways are crucial players in pattern formation in metazoans, but exactly how the pattern arise from the signaling systems has not been shown. The model discussed here is based on the protein tyrosine phosphatases, and it is shown how this important signaling system may straightforwardly produce patterns typical of early development. The protein tyrosine phosphatases have architectural characteristics basically different from those of the kinases, with the receptor tyrosine phosphatases displaying structural motifs of cell adhesion molecules. These membrane-spanning phosphatases then have a unique mission in cell growth, cell shape, and differentiation quite apart from that of the kineases. The complex intracellular biochemistry involved is modeled in the simplest way, with the intent that concepts be emphasized over biochemical detail., (Copyright 1999 Academic Press)

The optimal dose and schedule for paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer are not known. Based on our phase I study in non-small cell lung cancer, in which the dose intensity of paclitaxel was successfully escalated by using a weekly schedule, we initiated a phase II study of weekly paclitaxel in previously untreated patients with metastatic breast cancer (MBC) and locally advanced breast cancer (LABC). Treatment consists of weekly paclitaxel 175 mg/m2 intravenously over 3 hours for 6 weeks, followed by a 2-week break. Doses are modified for neutropenia (absolute neutrophil count < 1,500/microL), bilirubin levels greater than 1.5 times normal, or greater than grade 1 neuropathy. Patients with MBC continue treatment until disease progression. Patients with LABC receive one to two cycles before proceeding to surgery if resectable. Thus far, 15 patients, eight with MBC and seven with LABC, are assessable for response and/or toxicity. Most patients have required dose modification, with median delivery of 75% (cycle 1) and 50% (cycle 2) of the planned dose of paclitaxel. Neutropenia has been the most common cause of dose reductions, although only one patient required treatment for neutropenic fever. Six patients have developed grade 2/3 peripheral sensory neuropathy, but with dose reductions many have continued treatment with stable or improving neurologic symptoms. Objective responses have been seen in 12 of 14 assessable patients, including six with MBC (one complete response, five partial responses) and six with LABC (two complete responses, four partial responses), for an overall response rate of 86% (95% confidence interval, 66% to 96%). All responding LABC patients have been rendered free from disease at surgery. These preliminary results are very encouraging. Accrual to the study continues.

Accelerated disease control initiatives, such as polio eradication by the year 2000, may substantially benefit public health programs in general. In Egypt, the control of other vaccine-preventable diseases, most noticeably neonatal tetanus (NT), has been facilitated by the polio eradication initiative. Linking NT reporting with the acute flaccid paralysis (AFP) surveillance system, which had been established for polio eradication, markedly improved the capacity to identify NT high-risk areas and target supplementary immunization activities appropriately. While the close integration of surveillance activities was to the benefit of both programs, mass immunization activities were not conducted simultaneously because of differences in the objectives, target populations, and operational aspects of oral polio vaccine and tetanus toxoid campaigns. In addition to substantial progress toward polio eradication in Egypt since 1988, there has been an 80% reduction in annual NT cases, in part due to the integration of appropriate aspects of these two disease control initiatives.

A model is given for the generation of pattern and form in living systems, based on the assumption of two types of a single adhesion molecule that form homotypic cell-cell contacts. The time dependence of the model is different from that of the Turing models, instead viewing the change in time as being driven by the change in time of the total area A, along with the sequential gene activation which is called into play at discrete times as the organism grows and changes shape. Two equations are derived on the assumption of an energy minimum equilibrium being achieved at all times on a scale that is short compared with the rate of change over time of the total area. The two equations derived from the simple assumptions of the model are the (nonlinear) Helmholtz equation and the Laplace equation. It is argued that a suitable "morphogen" should attempt to satisfy certain rather specific conditions.

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2-14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

Purpose: To investigate the long-term survival of premenopausal women with previously untreated first recurrence or metastases of breast cancer entered on Eastern Cooperative Oncology Group (ECOG) study 2177 (EST 2177), which completed accrual in June 1983., Materials and Methods: One hundred forty-seven premenopausal women with metastatic breast cancer were entered onto the study. Eighty-nine patients with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide (CTX), doxorubicin (ADR), and fluorouracil (FU) (CAF) or surgical oophorectomy plus CAF (O+CAF). Fifty-eight patients with known ER-negative disease were treated with CAF. Survival time was measured from the time of study entry. Randomization was stratified by performance status (PS), dominant metastatic site, and ER status., Results: One hundred thirty patients were eligible. The median survival time of randomized patients was 35 months (90% confidence interval, 28.9 to 54.3), with 28% alive at 5 years. The overall median survival duration, including ER-negative patients, was 30 months. There was no significant difference in survival time between the randomized treatments (median, 42 months for O+CAF and 30 months for CAF). In models of survival time, age > or = 45 years and last menstruation within 1 month were associated with significantly longer survival (P < .004 for each). There were also three significant interactions with treatment (even after correction for multiple comparisons): age (P = .00009; O+CAF associated with longer survival in patients < 45 years, CAF associated with longer survival in patients > 45 years), PS (P = .002; O+CAF associated with consistently better survival in PS O patients), and disease-free interval (DFI)., Conclusion: Long-term follow-up data of premenopausal women with metastatic breast cancer show a longer than expected median survival time at 2.5 years overall and close to 5 years for patients treated with O+CAF who were ER-positive or had a good PS.

Diabetic ketoacidosis occurs more frequently in the young adult population than in any other age group. In a 3-year retrospective casenote review of all patients admitted with ketoacidosis to this hospital, we have defined the clinical characteristics of ketoacidosis in this age group. Young adults (< 25 years) had worse preceding glycaemic control (median HbA1 14.6 vs 10.1%, p = 0.0001) and more frequent episodes of ketoacidosis in the previous 5 years (3 vs 0, p = 0.0001) than older adults (> 25 years); on admission they had lower blood urea concentrations (p = 0.0001) and had a lower incidence of systolic hypotension (6% vs 32%, p = 0.007). There were fewer complications of ketoacidosis in the young adults, and the duration of hospital stay was less than that in the older age group (4 vs 8 days, p = 0.0003). Young adults were less likely to have a proven underlying infective or other organic precipitant for ketoacidosis, but were investigated and treated in a similar way to older adults. Insulin error or manipulation was identified in 42% of young adults; abnormal insulin treatment behaviour is likely to be the major cause of ketoacidosis in this age group.

This phase I trial evaluated a high-dose, short-term infusion of zidovudine (AZT) following oral leucovorin (LV) and bolus 5-fluorouracil (FUra). Thirteen patients with metastatic cancer received 30 cycles of therapy. Plasma monitoring demonstrated a dose-dependent increase in peak plasma levels of AZT through the range of dose levels, from 104.3 +/- 8.7 microM at the 1.5 g/m2 dose of AZT to 1312.6 +/- 165.9 microM at the 11.0 g/m2 dose. While AZT did not potentiate the usual clinical toxicities of LV plus FUra, an unexpected finding of symptomatic hypotension during the AZT infusion was the dose-limiting toxicity in this trial. One partial response was observed in a previously untreated patient with metastatic colorectal cancer. The maximal tolerated dose of AZT, 7.0 g/m2 over 2 hr, is recommended for future phase II evaluation of this novel combination.

53 patients with stage IIIA non-small cell carcinoma of the lung (NSCCL) were treated with multimodality therapy consisting of induction radiotherapy (55.8 Gy) and two cycles of concurrent chemotherapy with cisplatin, 25 mg/m2 for 4 days by continuous infusion and bolus etoposide, 100 mg/m2 on days 2 and 4 of each cycle followed by surgery and adjuvant chemotherapy. Of 53 evaluable patients, 47 achieved clinical responses (9 complete response, 38 partial response) after induction therapy for a response rate of 89%. 47 patients were resectable after induction therapy, but 8 patients refused surgery and 6 patients were not eligible for surgery based on poor pulmonary function (medical contraindications). 33 patients underwent thoracotomy and in 6 patients, resection was technically unfeasible. Thus complete surgical resection was accomplished in 27 patients. After all therapy, 28 patients achieved a complete response (53%) and 19 patients a partial response (36%). Toxicities were mild. At a maximum of 75 months (median, 28 months) of follow-up, the median survival of the entire group is 24 months. The median survival of resected patients has not been reached; their 6-year survival rate is 55%. Unresected patients survived for a median of 11 months. This multimodality regimen is well-tolerated, induces a high response and resectability rate and prolongs survival in resected patients.

Purpose: This study analyzes the long-term results and causes of death in elderly women with node-positive breast cancer who participated in a double-blind adjuvant trial that compared tamoxifen with placebo to determine the benefit of 2 years of treatment., Patients and Methods: One hundred eighty-one women 65 to 84 years old were given 20 mg of tamoxifen or placebo daily for 2 years after stratification by estrogen receptor status, tumor size, and degree of lymph node involvement. Approximately 30% of patients were older than 70 years and 20% were older than 75 years. Eighty-five percent were estrogen receptor-positive. Median follow-up was 10 years., Results: Among the 168 eligible patients, there have been 98 recurrences (59 placebo v 39 tamoxifen), with reduced distant and bone-only first sites in patients treated with tamoxifen. Median time to failure was 4.4 years for placebo versus 7.4 years for tamoxifen (log-rank P = .001). A similar number of new nonbreast cancers occurred in each arm (seven placebo v six tamoxifen), but a reduced number of opposite-breast cancers (five placebo v one tamoxifen) was noted. Overall, there were 102 deaths (57 placebo v 45 tamoxifen). Median survivals were 8.0 years with placebo and 8.5 years with tamoxifen (log-rank P = .063); 50% of the tamoxifen patients and 33% of the placebo patients are still alive. Sixty-one percent of the deaths were reported to have been caused by breast cancer recurrence, 4% by other cancers, and 22% by the sequelae of non-cancer-related illness, with equal distributions for cardiovascular and cerebrovascular disease. There was no increase in the number of endometrial or other types of cancer, or thrombotic or orthopedic complications in this older group., Conclusion: Tamoxifen currently is the treatment of choice for elderly women with breast cancer. It extends the time to treatment failure by 3 years and reduces the number of recurrences, deaths, distant and bone-only first recurrences, and second breast cancers.

Twenty previously untreated patients with advanced colorectal adenocarcinoma were entered on a Phase II trial of 3-day continuous infusion cisplatin (25 mg/m2/day) and 5-fluorouracil (800 mg/M2/day) with oral calcium leucovorin (30 mg/dose) every 6 hours. There were four partial responses (20%) and two complete responses (10%) for a total response rate of 30% (95% confidence limits +/- 20%). Patients received a median of 4.5 cycles of therapy (range 2-9 cycles). Three patients experienced neutropenia; one had a life-threatening infection. One developed neuropathy at 375 mg/M2 cumulative dose. Four patients developed mucositis. Treatment was stopped for one patient with stable disease after 5 cycles because of anorexia and nausea and vomiting; treatment was stopped for four patients because of excessive fatigue. The median duration of responses was 4 months (range 3-6 months). Although this regimen is active, the response rate, cumulative nature of the toxicity, and the requirement for hospitalization led us to conclude that this regimen does not warrant Phase III testing but might be a basis for further Phase II therapeutic trials.

Thirty-seven patients with refractory lymphoma or cutaneous T-cell lymphoma were treated with 2'-deoxycoformycin (pentostatin; dCF), 5 mg/m2 intravenous (IV) bolus for 3 consecutive days of every 3-week cycle in this Eastern Cooperative Oncology Group (ECOG) trial. Included were 25 with the diagnosis of non-Hodgkin's lymphoma, three with Hodgkin's disease, eight with cutaneous T-cell lymphoma (CTCL), and one with unknown subtype, of whom 31 were considered eligible. The majority had failed at least two, but no more, conventional chemotherapy regimens. Ten (32%) of the eligible patients had a partial response (PR), including patients with nodular poorly differentiated lymphocytic (NPDL), nodular mixed (NM), diffuse poorly differentiated lymphocytic (DPDL), or diffuse histiocytic (DH), lymphoma mixed-cellularity (MC), Hodgkin's disease, and unknown subtype, and in four patients with CTCL. The overall median time to treatment failure (TTF) was only 1.3 months, but the range extended to 57.3 months. The overall response duration was 16.0 months, and the range extended to 53.4 months. Overall median survival was 2.7 months, with the range extending to 63.2 months. The majority of patients had no toxicity, but there were some instances of severe or life-threatening events. Four fatal toxicities occurred, in two patients with underlying pulmonary conditions and two with prior cardiac histories. From this study, we conclude that dCF is active in refractory lymphomas and CTCLs, should be avoided in patients with a history of serious pulmonary or cardiac diseases, and warrants consideration for incorporation of a low-dosage schedule into conventional combination chemotherapy regimens, including its use with biologic response modifiers.

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.

Twenty-nine evaluable patients with colorectal adenocarcinoma were treated in a phase I-II trial of combination chemotherapy with a 72-h continuous infusion of cisplatin (CDDP) and 5-fluorouracil (5-FU) with an infusion of VP-16 given at 24 and 48 h after the start of therapy. There were five (17 +/- 14%) partial responses lasting 2-6 months (median, 3). Three of these responses occurred among the 10 previously untreated patients. The toxicity of this regimen was pronounced. Four of eight patients with severe neutropenia required hospitalization for infections, two of which were life-threatening; one of six patients with severe thrombocytopenia had a life-threatening hemorrhagic complication; and four patients experienced severe, dose-limiting fatigue. These complications occurred principally with CDDP and VP-16 at doses above 27.5 mg/m2/day and 110 mg/m2/dose, respectively. Mucositis occurred in six patients and limited the dose of 5-FU to 1,300 mg/m2/day. Although the response rate appeared to be high in previously untreated patients, the minimal palliative benefit of treatment and the brief duration of the responses do not compensate for the toxicity observed.

We examined the relationship between patient age and medical care received by patients diagnosed with the following two common cancers: non-small-cell lung cancer and colorectal cancer. Controlling for the influence of sex, marital status, presence of comorbid disease, and socioeconomic status, we found that age was not related to the diagnostic tests ordered for either cancer type. However, lung cancer patients with local disease who were older than age 74 years underwent definitive surgical treatment less often than did younger patients. Few patients at any age (less than 9%) with colorectal cancer did not undergo definitive surgical treatment. Patients with regional colorectal disease who were older than 74 years of age underwent radiation therapy to the abdomen less often than did younger patients. These results add to the growing body of literature suggesting that older cancer patients are less likely to undergo the same type of care received by younger patients.

A model for the morphogenetic movement of surfaces composed of cellular monolayers is proposed. The cells are presumed joined at their lateral surfaces. An otherwise unspecified substance called a "morphogen" is introduced which is the agent of change in the individual cell (or cell-like region). The distribution of these cellular deformations define a surface (the middle surface, through the middle of the cell heights) via equations given for the Gauss and Mean curvatures of the surface defined at each point. The Gauss curvature as a function of the morphogen level determines the metric of the surface "g(u, v)" in conformal co-ordinates u, v. A unique equation for the morphogen distribution over the survace is presented which has the property of size invariance, that is, the model "regulates" without need of further arguments. The two resulting coupled equations for the metric and the morphogen, eqns (4) and (2), both non-linear equations, are to be solved self-consistently, once the individual cell deformation as a function of morphogen is given. The surface geometry determines the morphogen distribution, and the morphogen distribution in turn affects the surface geometry. Extension of the model to two or more morphogens is straightforward, and the key property of "regulation" or size invariance of the model is retained. Numerical integration of the two coupled equations is carried out in the case of axial symmetry, and the results presented by the case that individual cells deform by changing the ratio of their apical to basal areas, as well as their heights. Gastrulation in small regulating holoblastic eggs (e.g. starfish, sea urchin and amphioxus) is discussed in light of the present model.

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.

Ipsilateral stapedius reflex testing has been evaluated in 166 patients. It proves of value in defining the state of an ear (1) opposite to a unilateral conductive loss; (2) the less hard-of-hearing ear in the presence of bilateral asymmetrical sensorineural hearing losses where the worse ear has sufficiently severe loss to prevent a contralateral reflex from being elicited; (3) in patients with absent contralateral acoustic reflexes at 500, 1000, and 2000 Hz; and (4) in suspected central lesions. The test is still bedevilled by artifacts which are produced in the ear rather than the machine; atypical results must be evaluated with extreme caution.