Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients.

BACKGROUND: The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT). PATIENTS AND METHODS: EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4-6 weeks after EBRT-CT. RESULTS: Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3-80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504-1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106-1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures. CONCLUSIONS: This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Late recurrence of cervical cancer: a report of 16 cases.

PURPOSE: To analyze the clinical characteristics and outcome of cervical cancer patients presenting late recurrence. MATERIALS AND METHODS: The medical records of 16 patients who were treated between 1974 and 1999 at the Institution and whose cancer recurred after a five-year disease-free interval were reviewed. RESULTS: Mean time from initial therapy to recurrence was 162.5 months (60-360 mean). Smear abnormalities, atypical genital bleeding, abdominal and lumbar pain, and respiratory findings were the most common symptoms and signs associated with late recurrence. Fourteen patients were diagnosed by physical examination. Three of the six patients with local recurrence who were re-irradiated developed a vesico-vaginal fistula. At a median follow-up time of 12.5 months (4-38 mean), 12 patients were alive and the median survival time was 30 months. CONCLUSIONS: Cervical cancer patients surviving free of disease after the fifth year post-treatment are still at risk for relapse and in most of them, the recurrence is suspected by clinical examination alone.

Development of an automated MODS plate reader to detect early growth of Mycobacterium tuberculosis.

In this work, an automated microscopic observation drug susceptibility (MODS) plate reader has been developed. The reader automatically handles MODS plates and after autofocussing digital images are acquired of the characteristic microscopic cording structures of Mycobacterium tuberculosis, which are the identification method utilized in the MODS technique to detect tuberculosis and multidrug resistant tuberculosis. In conventional MODS, trained technicians manually move the MODS plate on the stage of an inverted microscope while trying to locate and focus upon the characteristic microscopic cording colonies. In centres with high tuberculosis diagnostic demand, sufficient time may not be available to adequately examine all cultures. An automated reader would reduce labour time and the handling of M. tuberculosis cultures by laboratory personnel. Two hundred MODS culture images (100 from tuberculosis positive and 100 from tuberculosis negative sputum samples confirmed by a standard MODS reading using a commercial microscope) were acquired randomly using the automated MODS plate reader. A specialist analysed these digital images with the help of a personal computer and designated them as M. tuberculosis present or absent. The specialist considered four images insufficiently clear to permit a definitive reading. The readings from the 196 valid images resulted in a 100% agreement with the conventional nonautomated standard reading. The automated MODS plate reader combined with open-source MODS pattern recognition software provides a novel platform for high throughput automated tuberculosis diagnosis.

Point of care HbA1c level for diabetes mellitus management and its accuracy among tuberculosis patients: a study in four countries.

BACKGROUND: Diabetes mellitus (DM) is common among tuberculosis (TB) patients and often undiagnosed or poorly controlled. We compared point of care (POC) with laboratory glycated haemoglobin (HbA1c) testing among newly diagnosed TB patients to assess POC test accuracy, safety and acceptability in settings in which immediate access to DM services may be difficult. METHODS: We measured POC and accredited laboratory HbA1c (using high-performance liquid chromatography) in 1942 TB patients aged 18 years recruited from Peru, Romania, Indonesia and South Africa. We calculated overall agreement and individual variation (mean ± 2 standard deviations) stratified by country, age, sex, body mass index (BMI), HbA1c level and comorbidities (anaemia, human immunodeficiency virus [HIV]). We used an error grid approach to identify disagreement that could raise significant concerns. RESULTS: Overall mean POC HbA1c values were modestly higher than laboratory HbA1c levels by 0.1% units (95%CI 0.1-0.2); however, there was a substantial discrepancy for those with severe anaemia (1.1% HbA1c, 95%CI 0.7-1.5). For 89.6% of 1942 patients, both values indicated the same DM status (no DM, HbA1c <6.5%) or had acceptable deviation (relative difference <6%). Individual agreement was variable, with POC values up to 1.8% units higher or 1.6% lower. For a minority, use of POC HbA1c alone could result in error leading to potential overtreatment (n = 40, 2.1%) or undertreatment (n = 1, 0.1%). The remainder had moderate disagreement, which was less likely to influence clinical decisions. CONCLUSION: POC HbA1c is pragmatic and sufficiently accurate to screen for hyperglycaemia and DM risk among TB patients.

Reducing the string test intra-gastric downtime for detection of Mycobacterium tuberculosis.

OBJECTIVES: To explore the potential for reducing the procedural duration of the string test for the diagnosis of tuberculosis (TB) using microscopic observation drug susceptibility (MODS) culture. METHODS: Twelve patients already diagnosed with pulmonary TB, four each with sputum smear acid-fast bacilli grade 1+, 2+ and 3+, underwent four consecutive string tests of varying intra-gastric downtime (IGDT) of 30 min, 1, 2 and 4 h. Each retrieved string was cut into three-one oesophageal and two gastric sections. Eluates from one of the gastric sections and the oesophageal section were cultured in MODS after a decontamination procedure; eluate from the other gastric section was cultured in MODS with no decontamination. RESULTS: No significant difference was observed in the retrieval efficacy of Mycobacterium tuberculosis (P = 0.29) or time to positive MODS culture (P = 0.80) among string tests of varying IGDTs. Every patient with a sample that was positive after a 4-h IGDT also had positive culture of a 1-h IGDT sample. A pre-inoculation sample decontamination step significantly reduced culture contamination (P < 0.001). CONCLUSION: In smear-positive patients, reducing the IGDT to 1 h did not affect the M. tuberculosis retrieval efficacy of the string test. Future evaluations in non-expectorating human immunodeficiency virus and paediatric populations should include a 1-h IGDT.

Concurrent chemoradiation with carboplatin for elderly, diabetic and hypertensive patients with locally advanced cervical cancer.

INTRODUCTION: Chemoradiation based on cisplatin is the standard treatment of locally advanced cervical cancer, however, a subset of patients are either elderly and/or have comorbidities such as diabetes and hypertension. These conditions may compromise the administration of cisplatin. We report our Institution experience with weekly carboplatin as a radiosensitizer for the management of this subset of patients. PATIENTS AND METHODS: We reviewed the files of 59 patients with locally advanced cervical cancer who were treated with primary chemoradiation with weekly carboplatin. Response rate, toxicity and survival were analyzed. RESULTS: Mean age was 62 years (range, 36-83 years). The majority of cases were squamous cell carcinoma (88.14%), and distribution according to FIGO Stage was IB2 8.4%, IIA 13.5%, IIB 52.5%, IIIA 3.3% and IIIB 18.6%; Overall, 100% and 91% of patients completed external beam and intracavitary therapy. Seventy-nine percent received from five to six planned cycles of weekly carboplatin. Complete responses were achieved in 49 (83.05 %) patients, whereas ten patients (16.95%) had either persistent or progressive disease. The most common toxicities were grades 1 and 2 hematological and gastrointestinal. At median follow-up (20 months; range 2-48 months), 16 patients (32.65%) have relapsed. Estimated 30-month overall survival is 63%. CONCLUSIONS: Weekly carboplatin concurrent with pelvic radiation is well tolerated in patients with locally advanced carcinoma of the cervix who are older than 70 years and/or have diabetes mellitus and/or high blood pressure, however, the apparently slighty lower survival observed cautions against its routine use.

[Abdominal epilepsy in the adult]. / Epilepsia abdominal en el adulto.

Abdominal epilepsy is a rare cause of abdominal pain. We report an adult patient with intermittent, paroxysmal epigastric abdominal pain, accompanied by nausea, vomiting, restlessness and anxiety. Physical examination was normal. Blood analysis disclosed only leucocytosis with neutrophilia. X ray examinations, ultrasound and CT abdominal scan, mesenteric arteriography and exploratory laparotomy did not show evidence of pathology. The electroencephalogram (EEG) showed bilateral theta slow activity during hyperventilation. We started treatment with carbamazepine and the patient remained asymptomatic for nine months. However he had a relapse because he did'nt take his medication regularly. At that time the serum levels of carbamazepine were low. The EEG showed bursts of diffuse paroxysmal acute waves. Once therapeutic serum levels of carbamazepine were achieved the pain disappeared. He has remained asymptomatic during the last twelve months, while taking his treatment regularly.

Validation of microscopic observation drug susceptibility testing for rapid, direct rifampicin and isoniazid drug susceptibility testing in patients receiving tuberculosis treatment.

Drug susceptibility testing (DST) is often needed in patients clinically failing tuberculosis (TB) therapy. Most studies of phenotypic direct drug susceptibility tests, such as microscopic observation drug susceptibility (MODS) tests, have been performed in patients not receiving TB treatment. The effect of ongoing TB treatment on the performance of MODS direct DST has not been previously explored, but patients failing such therapy constitute an important target group. The aim of this study was to determine the performance of MODS direct rifampicin and isoniazid DST in patients clinically failing first-line TB treatment, and to compare MODS direct DST with indirect proportion method DST. Sputa from 264 TB patients were cultured in parallel in Lowenstein-Jensen (LJ) and MODS assays; strains were tested for rifampicin and isoniazid susceptibility by the proportion method at the national reference laboratory. Ninety-three samples were culture-positive by LJ and MODS (concordance of 96%; kappa 0.92). With conventional MODS plate DST reading (performed on the same day as the sample is classified as culture-positive), the isoniazid DST concordance was 96.8% (kappa 0.89), and the concordance for rifampicin susceptibility testing was 92.6% (kappa 0.80). Reading of MODS DST plates 1 week after cultures had been determined to be culture-positive improved overall performance marginally-the isoniazid DST concordance was 95.7% (kappa 0.85); and the rifampicin DST concordance was 96.8% (kappa 0.91). Sensitivity for detection of multidrug-resistant TB was 95.8%. MODS testing provided reliable rifampicin and isoniazid DST results for samples obtained from patients receiving TB therapy. A modified DST reading schedule for such samples, with a final reading 1 week after a MODS culture turns positive, marginally improves the concordance with reference DST.

Second-line drug susceptibility breakpoints for Mycobacterium tuberculosis using the MODS assay.

OBJECTIVE: To establish breakpoint concentrations for the fluoroquinolones (moxifloxacin [MFX] and ofloxacin [OFX]) and injectable second-line drugs (amikacin [AMK], kanamycin [KM] and capreomycin [CPM]) using the microscopic observation drug susceptibility (MODS) assay. SETTING: A multinational study conducted between February 2011 and August 2012 in Peru, India, Moldova and South Africa. DESIGN: In the first phase, breakpoints for the fluoroquinolones and injectable second-line drugs (n = 58) were determined. In the second phase, MODS second-line drug susceptibility testing (DST) as an indirect test was compared to MGIT™ DST (n = 89). In the third (n = 30) and fourth (n = 156) phases, we determined the reproducibility and concordance of MODS second-line DST directly from sputum. RESULTS: Breakpoints for MFX (0.5 µg/ml), OFX (1 µg/ml), AMK (2 µg/ml), KM (5 µg/ml) and CPM (2.5 µg/ml) were determined. In all phases, MODS results were highly concordant with MGIT DST. The few discrepancies suggest that the MODS breakpoint concentrations for some drugs may be too low. CONCLUSION: MODS second-line DST yielded comparable results to MGIT second-line DST, and is thus a promising alternative. Further studies are needed to confirm the accuracy of the drug breakpoints and the reliability of MODS second-line DST as a direct test.

Reliability of the MODS assay decentralisation process in three health regions in Peru.

OBJECTIVE: To deliver rapid isoniazid (INH) and rifampicin (RMP) drug susceptibility testing (DST) close to the patient, we designed a decentralisation process for the microscopic observation drug susceptibility (MODS) assay in Peru and evaluated its reliability. METHODS: After 2 weeks of training, laboratory staff processed ≥ 120 consecutive sputum samples each in three regional laboratories. Samples were processed in parallel with MODS testing at an expert laboratory. Blinded paired results were independently analysed by the Instituto Nacional de Salud (INS) according to pre-determined criteria: concordance for culture, DST against INH and RMP and diagnosis of multidrug-resistant tuberculosis (MDR-TB) ≥ 95%, McNemar's P > 0.05, kappa index (κ) ≥ 0.75 and contamination 1-4%. Sensitivity and specificity for MDR-TB were calculated. RESULTS: The accreditation process for Callao (126 samples, 79.4% smear-positive), Lima Sur (n = 130, 84%) and Arequipa (n = 126, 80%) took respectively 94, 97 and 173 days. Pre-determined criteria in all regional laboratories were above expected values. The sensitivity and specificity for detecting MDR-TB in regional laboratories were >95%, except for sensitivity in Lima Sur, which was 91.7%. Contamination was 1.0-2.3%. Mean delay to positive MODS results was 9.9-12.9 days. CONCLUSION: Technology transfer of MODS was reliable, effective and fast, enabling the INS to accredit regional laboratories swiftly.

MODS accreditation process for regional reference laboratories in Peru: validation by GenoType® MTBDRplus.

SETTING: Although considerable effort has been put into the development and evaluation of new diagnostics for tuberculosis (TB) and multidrug-resistant TB (MDR-TB), little attention has thus far been paid to the technical aspects of initiating quality-assured routine service use. For implementation of the microscopic-observation drug susceptibility (MODS) methodology in the Peruvian reference laboratory network, a laboratory accreditation process was devised; MODS results from an expert reference laboratory (Universidad Peruana Cayetano Heredia [UPCH]) were used as the standard against which implementing laboratory MODS results were judged to ensure that, prior to use for patient care, implementing laboratories achieved the same high performance with MODS as previously demonstrated in the research laboratory. OBJECTIVE: To evaluate the validity of MODS-based accreditation and the concordance of MODS drug susceptibility testing (DST) with molecular testing. DESIGN: Head-to-head comparison of MODS DST results from implementing Peruvian regional reference laboratories and the accrediting expert MODS laboratory (UPCH) with GenoType® MTBDRplus DST. RESULTS: The concordance of phenotypic MODS rifampicin (RMP) DST with GenoType MTBDRplus was respectively 97.4%, 97.9% and 97.1% for the two implementing regional laboratories and UPCH, and respectively 94.7%, 95.7% and 94.6% for isoniazid (INH) DST. CONCLUSION: High and consistent levels of MODS/MTBDRplus concordance for INH and RMP DST confirm the validity of the use of rapid methods as reference standards for accreditation.

Daily rhythms in blood and milk lead toxicokinetics following intravenous administration of lead acetate to dairy cows in summer.

The objective of this study was to investigate circadian variations of blood and milk lead toxicokinetics in dairy cows in summer. Twenty lactating Holstein animals were randomly assigned to four treatments corresponding to different hours after onset of light (HALO): 2, 8, 14, and 20. Cows received a single intravenous administration of 2.5 mg/kg lead as lead acetate. Blood and milk samples were taken and analyzed by atomic absorption spectrophotometry. For each toxicokinetic parameter, a one-way analysis of variance (ANOVA) was performed to outline the existence of daily variations. Significant blood differences as a function of HALO were found for the hybrid constant of distribution (alpha), hybrid constant of elimination (beta), elimination half-life (t(1/2)beta), area under the curve (AUC), volume of distribution at steady state (V(ss)) and clearance (Cl(B)) (p<0.05). Half-life of elimination presented two peaks at 2 and 14 HALO. Milk data showed significant differences for maximum concentration and AUC (p<0.05). The ratio AUC(milk)/AUC(blood) was utilized to estimate penetration of lead in milk. It differed significantly throughout the day (p<0.05). Milk data for the significant parameters could be fitted to circadian rhythms. No circadian rhythms were detected in blood parameters or in the ratio AUC(milk)/AUC(blood).

Leptospirosis en pediatría: a propósito de un caso / Leptospirosis in pediatric medicine: a case report

La leptospirosis es una enfermedad que se presenta sobre todo en países tropicales, asociada a inundaciones. Sus formas clínicas van de leve a severa, siendo esta última potencialmente letal para el individuo. Se presenta el caso de una paciente de sexo femenino de 4 años de edad con diagnóstico de leptospirosis, forma leve, su evolución y tratamiento.

Leptospirosis is a disease that presents generally in tropical countries and is associated with flooding. Its clinical forms range from mild to severe, with the latter form being potentially fatal. We present the case of a 4-year old female patient diagnosed with mild-form leptospirosis and the patients’ evolution and treatment.

Síndrome de HOLT-ORAM

Estudio a lactante menor de 5 meses, de sexo femenino, que ingresa con dificultad respiratoria, rechazo alimentario, fiebre de 24 horas de evolución, con miembros superiores deformes, hiperfonético en área pulmonar, soplo sistólico regurgitativo

Introducción al estudio del receptor al N-Metil-D-Aspartato / Introduction to the study of the N-Methyl-D-Aspartate receptor

Objetivos: Analizar toda la información publicada en los últimos diez años sobre el receptor al N-Metil-D-Aspartato (NMDA). Establecer una correlación farmaco-clínica con respecto a la modulación del dolor y determinar su importancia en anestesiología. Lugar: Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo. Base de datos: Base electrónica Medline de donde se seleccionaron todos los trabajos publicados en idioma inglés sobre el tema y búsqueda de información en castellano de lo publicado en los últimos 10 años. Estrategia de búsqueda: NMDA, dolor, modulación del dolor, protección cerebral. Discusión: Los receptores celulares son estructuras que permiten comandar el metabolismo íntimo de las células que los poseen. Estos interactúan en forma directa a través de un segundo mensajero citoplasmático. En el neuroeje de los mamíferos, se encuentran numerosas neuronas que contienen en su membrana el receptor al NMDA. El bloqueo de éste por drogas que actúan en forma competitiva o no competitiva, produciría analgesia, permitiría la modulación del estímulo doloroso y algunos trabajos demuestran su importancia como protectores cerebrales ante la isquemia. Conclusión: Los inhibidores de los receptores al NMDA como la dizocilpina, actualmente en fase experimental, o la ketamina, adquirirían un rol muy importante en nuestra especialidad en el manejo del dolor y la protección cerebral.

Comparacion de las pruebas horarias de depuracion renal contra las de 24 horas en adultos jovenes sanos. / Comparison of the hourly renal clearance tests against the tests performed 24 hours in healthy young adults

Se estudiaron 22 personas sanas a las cuales se les determinaron depuracion de creatinina, relacion osmolar urinaria y plasmatica depuracion osmolar depuracion de agua libre y fraccion de excrecion de sodio cada dos horas durante las primeras ocho horas, cada cuatro horas durante las siguientes 16, y finalmente a las 24 horas; con la finalidad de determinar si los resultados de las pruebas practicadas en forma horaria se correlacionan con los valores normales y con los de 24 horas, asi como para buscar la variabilidad de estas pruebas en cuanto a edad, sexo y ciclo circadiano del individuo. Se concluyo que los resultados de dos horas fueron iguales a los valores normales de 24 horas que tienen la misma significancia, y que no hubo variaciones en cuanto a edad, sexo y ciclo circadiano del grupo estudiado