Determinants of Pouch-Related Symptoms, a Common Outcome of Patients With Adenomatous Polyposis Undergoing Ileoanal Pouch Surgery.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (<20) was also associated with better outcomes: fewer daily bowel movement (58.3% vs 17.9% with ≤5 daily bowel movement, P = 0.011), less watery consistency (8.3% vs 53.8%, P = 0.005), and abdominal pain (8.3% vs 43.6%, P = 0.037). Eighteen patients (35.3%) had endoscopic signs of inflammation, and 22 patients (43.1%) had histologic signs of pouchitis. However, no correlation was found between symptoms and endoscopic or histologic findings. The median pouchitis disease activity index was low (2, interquartile range 1-4) and did not correlate with clinical symptoms. DISCUSSION: Pouch-related symptoms are common in patients with APS after IPAA. One-stage IPAA and younger age at surgery are associated with better clinical outcomes. However, symptoms do not correlate well with endoscopic or histologic findings or with pouchitis disease activity index and might be attributed to a functional pouch disorder.

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

Genetic features of Lynch syndrome in the Israeli population.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

Neutron skin of (208)pb from coherent pion photoproduction.

Information on the size and shape of the neutron skin on (208)Pb is extracted from coherent pion photoproduction cross sections measured using the Crystal Ball detector together with the Glasgow tagger at the MAMI electron beam facility. On exploitation of an interpolated fit of a theoretical model to the measured cross sections, the half-height radius and diffuseness of the neutron distribution are found to be c(n)=6.70±0.03(stat.) fm and a(n)=0.55±0.01(stat.)(-0.03)(+0.02)(sys.) fm, respectively, corresponding to a neutron skin thickness Δr(np)=0.15±0.03(stat.)(-0.03)(+0.01)(sys.) fm. The results give the first successful extraction of a neutron skin thickness with an electromagnetic probe and indicate that the skin of (208)Pb has a halo character. The measurement provides valuable new constraints on both the structure of nuclei and the equation of state for neutron-rich matter.

The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer.

BACKGROUND: PSA doubling time (PSADT) is an attractive intermediate end point for assessing novel therapies in biochemically recurrent prostate cancer (BRPC). This study explores whether PSADT calculations are influenced by frequency/duration of PSA measurements, and whether statistical variability leads investigators to find false significant results. METHODS: In retrospective analyses of two BRPC cohorts: Johns Hopkins Hospital (JHH) patients who deferred therapy and placebo patients on a randomized clinical trial (RCT), we calculated changes in PSADT from early measurements to later measurements using subsets of available PSAs for patients with ≥6 and ≥9 PSAs. We simulated hypothetical single-arm trials using randomly selected, 50-patient subsets and simulated two-arm RCTs. RESULTS: JHH cohort (n=205) had median follow-up 58 months, median age 61 years and median Gleason 7. PSA variability changed with duration of PSA measurement as median within-patient PSADT increases for men with >6 PSAs ranged from 1.0 to 1.4 months by PSA subset while increases for men with ≥9 PSAs ranged from 3.9 to 4.1 months. Frequency of measurement did not change PSA variability as PSADT increase was unchanged when odd values were used instead of all values. Approximately 30% of JHH men experienced >200% increases in PSADT. Up to 62% of 50-patient single-arm simulations detected a significant PSADT change, whereas simulated RCTs did not. Results were supported in the RCT placebo cohort; 46% of patients experienced PSADT increases >200%. CONCLUSIONS: These data suggest that calculated PSADT in BRPC may naturally increase over time in the absence of therapy and may be influenced by duration of PSA follow-up. As a result, single-arm trials could show false significant increases despite the lack of active treatment of these patients. Placebo-controlled RCTs including clinical end points are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.

Induction of high-titer IgG antibodies against multiple leukemia-associated antigens in CML patients with clinical responses to K562/GVAX immunotherapy.

The ability to target myeloid leukemia with immunotherapy would represent a significant therapeutic advance. We report here immunological analysis of clinical trials of primary and secondary vaccination with K562/GM-CSF immunotherapy in adult chronic phase chronic myeloid leukemia patients (CML-CP) with suboptimal responses to imatinib mesylate. Using serological analysis of recombinant cDNA expression libraries of K562 with autologous vaccinated patient serum, we have identified 12 novel chronic myeloid leukemia-associated antigens (LAAs). We show that clinical responses following K562/GM-CSF vaccination are associated with induction of high-titer antibody responses to multiple LAAs. We observe markedly discordant patterns of baseline and induced antibody responses in these identically vaccinated patients. No single antigen was recognized in all responses to vaccination. We demonstrate that an additional 'booster' vaccination series can be given safely to those with inadequate responses to initial vaccination, and is associated with more frequent induction of IgG responses to antigens overexpressed in K562 vaccine compared with primary CML-CP. Finally, those with induced immune responses to the same LAAs often shared HLA subtypes and patients with clinical responses following vaccination recognized a partially shared but non-identical spectrum of antigens; both findings have potentially significant implications for cancer vaccine immunotherapy.

Investigation of the exclusive 3He(e,e' pn)1H reaction.

Cross sections for the 3He(e,e' pn)1H reaction were measured for the first time at energy transfers of 220 and 270 MeV for several momentum transfers ranging from 300 to 450 MeV/c. Cross sections are presented as a function of the momentum of the recoil proton and the momentum transfer. Continuum Faddeev calculations using the Argonne V18 and Bonn-B nucleon-nucleon potentials overestimate the measured cross sections by a factor 5 at low recoil proton momentum with the discrepancy becoming smaller at higher recoil proton momentum.

Beam-helicity asymmetries in double-pion photoproduction off the proton.

Beam-helicity asymmetries have been measured at the MAMI accelerator in Mainz in the three isospin channels gamma[over -->]p-->pi(+)pi(0)n, gamma[over -->]p-->pi(0)pi(0)p, and gamma[over -->]p-->pi(+)pi(-)p. The circularly polarized photons, produced from bremsstrahlung of longitudinally polarized electrons, were tagged with the Glasgow magnetic spectrometer. Charged pions and the decay photons of pi(0) mesons were detected in a 4pi electromagnetic calorimeter which combined the Crystal Ball detector with the TAPS detector. The precisely measured asymmetries are very sensitive to details of the production processes and are thus key observables in the modeling of the reaction dynamics.

Incoherent neutral pion photoproduction on 12C.

We present the first detailed measurement of incoherent photoproduction of neutral pions to a discrete state of a residual nucleus. The 12C(gamma,pi(0))(12)C*(4.4 MeV) reaction has been studied with the Glasgow photon tagger at MAMI employing a new technique which uses the large solid angle Crystal Ball detector both as a pi(0) spectrometer and to detect decay photons from the excited residual nucleus. The technique has potential applications to a broad range of future nuclear measurements with the Crystal Ball and similar detector systems elsewhere. Such data are sensitive to the propagation of the Delta in the nuclear medium and will give the first information on matter transition form factors from measurements with an electromagnetic probe. The incoherent cross sections are compared to two theoretical predictions including a Delta-hole model.

Probing cold dense nuclear matter.

The protons and neutrons in a nucleus can form strongly correlated nucleon pairs. Scattering experiments, in which a proton is knocked out of the nucleus with high-momentum transfer and high missing momentum, show that in carbon-12 the neutron-proton pairs are nearly 20 times as prevalent as proton-proton pairs and, by inference, neutron-neutron pairs. This difference between the types of pairs is due to the nature of the strong force and has implications for understanding cold dense nuclear systems such as neutron stars.

Pharmacogenetic pathway analysis of irinotecan.

Irinotecan, a chemotherapeutic agent against various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics potentially allow for many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fitted a seven-compartment pharmacokinetic model with enterohepatic recirculation (EHR) to concentrations of irinotecan and metabolites SN-38, SN-38 glucuronide (SN-38G), and aminopentanoic acid (APC). Principal component analysis (PCA) of patient-specific parameter estimates produced measures interpretable along pathways. Nine principal components provided good characterization of the overall variation. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and elimination of SN-38G. The component characterizing irinotecan's compartments was associated with HNF1alpha and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis was able to identify known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

Measurement of the Gerasimov-Drell-Hearn Integrand for 2H from 200 to 800 MeV.

A measurement of the helicity dependence of the total inclusive photoabsorption cross section on the deuteron was carried out at MAMI (Mainz) in the energy range 200

Acute hepatitis B in the era of immunisation: pitfalls in the identification of high risk patients.

BACKGROUND: Since the adoption of a universal hepatitis B immunisation strategy, the reported incidence of acute hepatitis B has declined dramatically worldwide including in Israel. However, new cases of acute hepatitis B still occur. The aim of this study was to describe the incidence of acute hepatitis B in a referral area, routes of transmission, and outcome. METHODS: The charts of all new hepatitis B patients, who visited the clinic in the years 2002 and 2003 (January 2002 to December 2003), were reviewed. The main criteria for a diagnosis of acute hepatitis B were transient increase of alanine transaminase activity, and hepatitis B surface antigen seroconversion. RESULTS: Twenty nine men and seven women were diagnosed with acute hepatitis B infection during the study period. Two patients were previously vaccinated with hepatitis B vaccine. One case of hepatitis D coinfection was reported. The incidence of acute hepatitis B in the referral area was estimated as 2.25 per 100,000 adult population. Mean age was 36 years (17-75). Twenty one patients (18 men and 3 women) acquired the virus through unprotected sexual contact, and seven patients through iatrogenic exposure. Thirty three patients underwent spontaneous seroconversion while three patients became chronic carriers. CONCLUSIONS: Despite a universal immunisation policy, frequent cases of acute hepatitis B in Israel are still seen. High risk heterosexual activity and iatrogenic exposure seem to be the commonest routes of transmission. Further recommendations regarding vaccination policy are discussed.

Congestive heart failure in pregnancy: a case of peripartum cardiomyopathy.

A healthy 28-year-old woman developed full-blown pulmonary oedema in the 36th week of gestation. Echocardiography revealed a globally enlarged heart with reduced systolic function. A remarkable dinical response with regain of normal ventricular function was noted with early medical intervention. This case report illustrates peripartum cardiomyopathy, a unique form of dilated cardiomyopathy affecting women during/following gestation. Clinician familiarity with this entity increases the probability of prompt appropriate treatment, offering patients the best possible prognosis.

Measurement of the exclusive 3He(e,e'p) reaction below the quasielastic peak.

New, high-precision measurements of the 3He(e,e(')p) reaction using the A1 Collaboration spectrometers at the Mainz microtron MAMI are presented. These were performed in antiparallel kinematics at energy transfers below the quasielastic peak, and at a central momentum transfer of 685 MeV/c. Cross sections and distorted momentum distributions were extracted and compared to theoretical predictions and existing data. The longitudinal and transverse behavior of the cross section was also studied. Sizable differences in the cross-section behavior from theoretical predictions based on the plane wave impulse approximation were observed in both the two- and three-body breakup channels. Full Faddeev-type calculations account for some of the observed excess cross-section, but significant differences remain.

Lamivudine treatment for acute severe hepatitis B: a pilot study.

BACKGROUND: Experience with lamivudine treatment of immunocompetent patients with acute hepatitis B is limited. AIM OF STUDY: To evaluate the safety and efficacy of lamivudine for the treatment of acute severe hepatitis B virus (HBV) infection in immunocompetent adults. PATIENTS AND METHODS: Fifteen patients (10 men, 5 women, mean age 34.3+/-7.3 years) with severe acute HBV infection were treated with lamivudine 100 mg daily for 3-6 months, starting 3-12 weeks after onset of infection. Prior to treatment, 5 patients had grade 1-4 encephalopathy; all patients had severe coagulopathy (mean INR was 4.5+/-6.4), and all patients had evidence of severe hepatocyte lysis (mean alanine aminotransferase 3738+/-1659 U/L, and mean total serum bilirubin 18+/-6.8 mg/dl). All patients had evidence of highly replicative HBV (mean HBV DNA 13.5 x 10(6)+/-11 x 10(6) copies/ml). RESULTS: Thirteen patients (86.6%) responded to treatment. Encephalopathy disappeared within 3 days of treatment and coagulopathy improved within 1 week. Serum HBV DNA was undetectable (by polymerase chain reaction) within 4 weeks, and serum liver enzyme levels normalized within 8 weeks. Two patients in whom lamivudine therapy was delayed developed fulminant hepatitis and underwent urgent liver transplantation. (One died of vascular complications 1 month later). The 11 patients who were serum HBeAg-positive before treatment seroconverted, and HBeAb developed within 12 weeks in 9 of them; HBsAg was undetectable in all 11 tested patients, and protective titer of HBsAb developed within 12-16 weeks in 9 of them. Therapy was well tolerated in all cases. CONCLUSIONS: These data indicate that lamivudine induces a prompt clinical, biochemical, serological and virological response in immunocompetent patients with de novo HBV infection. Lamivudine may prevent the progression of severe acute disease to fulminant or chronic hepatitis and should be considered for use in selected patients. A large randomized controlled, double-blind prospective study is needed.

Bioavailability of 239+240Pu and 137Cs in aerosols and deposited dusts: a comparative study by fractional extraction.

The bioavailability of (137)Cs and (239+240)Pu in soil, dust and aerosols has been determined by applying a fractional extraction procedure. In aerosols, 47-57% of (137)Cs was found to be easily exchangeable. This differs significantly from soil and deposited dust samples collected on a nearby street as well as on grassland where (137)Cs was quantitatively found in the acid-soluble fraction and the residue. A similar difference was observed for (239+240)Pu: 47% of (239+240)Pu in aerosols was associated with the organic fraction, while in soil and deposited dust from grassland 63-75% of (239+240)Pu was found in the acid-soluble fraction. In deposited street dust, 53% of (239+240)Pu was associated with the oxide fraction.

Monte Carlo simulation of the photoneutron field in linac radiotherapy treatments with different collimation systems.

Bremsstrahlung photon beams produced by linac accelerators are currently the most commonly used method of radiotherapy for tumour treatments. When the photon energy exceeds 10 MeV the patient receives an undesired dose due to photoneutron production in the accelerator head. In the last few decades, new sophisticated techniques such as multileaf collimators have been used for a better definition of the target volume. In this case it is crucial to evaluate the photoneutron dose produced after giant dipole resonance (GDR) excitation of the high Z materials (mainly tungsten and lead) constituting the collimator leaves in view of the optimization of the radiotherapy treatment. A Monte Carlo approach has been used to calculate the photoneutron dose arising from the GDR reaction during radiotherapy with energetic photon beams. The simulation has been performed using the code MCNP4B-GN which is based on MCNP4B, but includes a new routine GAMMAN to model photoneutron production. Results for the facility at IRCC (Istituto per la Ricerca e la Cura del Cancro) Candiolo (Turin), which is based on 18 MV x-rays from a Varian Clinac 2300 C/D, are presented for a variety of different collimator configurations.

A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863.

BACKGROUND: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. PATIENTS AND METHODS: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. RESULTS: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. CONCLUSIONS: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.