Características clínicas y epidemiológicas asociadas con internación en niños con COVID-19 en un hospital pediátrico de alta complejidad: Estudio de cohorte enero-marzo 2022 / Clinical and epidemiologic characteristics associated with hospital admission in children with COVID19 in a tertiary-care pediatric hospital: A January-March 2022 cohort study

Introducción: La proporción de casos reportados de niños y adolescentes con COVID-19 aumenta progresivamente. La hospitalización relacionada con COVID-19 en niños es infrecuente, pero causa morbilidad y sobrecarga al sistema de salud. Objetivos: Describir las características clínicas y evolutivas de los niños con diagnóstico de COVID-19 en un hospital pediátrico de alta complejidad. Comparar los pacientes que requirieron internación y los que no. Material y métodos: Cohorte prospectiva. Se incluyeron todos los pacientes con diagnóstico virológico de COVID-19 desde 1.1.2022 a 1.3.22 en un hospital pediátrico de alta complejidad. Se compararon los antecedentes, características clínicas y evolutivas de los pacientes según requirieran o no internación. Se utilizó STATA 16. Resultados: n: 1764 pacientes, de ellos 958 eran varones (54%). La mediana de edad fue 56 meses (RIC 17-116). Tenían enfermedad de base 789 pacientes (46%). Las más frecuentes fueron: enfermedad oncohematológica 215 (12%), neurológica 103 pacientes (6%) , enfermedad pulmonar crónica 68 (4%), cardiopatías congénitas 65 (4%) y síndrome genético 57 pacientes (3%). Eran inmunosuprimidos: 292 (17%). Presentaron síntomas relacionados con COVID-19 1319 pacientes (79%). Requirieron internación 591 (34%). Tuvieron coinfección con otros virus respiratorios 33 pacientes (2%). Ingresaron a Cuidados intensivos en relación a la COVID-19 22 pacientes (1.3%) y fallecieron en relación con la infección 8 (0.5%). En el análisis univariado, la presencia de comorbilidades, la coinfección viral y la inmunosupresión se asociaron estadísticamente con el requerimiento de internación. El antecedente de 2 o más dosis de vacuna para SARS-CoV-2 fue un factor protector para la internación en los mayores de 3 años. En el modelo multivariado, los pacientes menores de 3 años (OR 6.5, IC95% 1.2-36.8, p 0.03), con comorbilidades (OR 2.04, IC 95% 1.7- 3.3, p 0.00) y los huéspedes inmunocomprometidos (OR 2.89, IC95% 2.1-4.1, p 0.00) tuvieron más riesgo de internación. Ajustado por el resto de las variables, haber recibido dos o más dosis de vacuna fue un factor protector para la internación (OR 0.65, IC 95% 0.49-0.87, p<0.01). Conclusiones: En este estudio de cohorte prospectivo de niños con diagnóstico confirmado de COVID-19 predominó la enfermedad sintomática. Fueron admitidos en relación con el COVID-19, 34% de los pacientes. La vacunación con dos o más dosis fue un factor protector para la internación en el modelo multivariado. Además, se asociaron estadísticamente con la hospitalización, la edad menor de 3 años, las comorbilidades previas y la inmunosupresión (AU)

Introduction: The rate of reported cases of children and adolescents with COVID-19 is progressively increasing. COVID-19-related hospital admission in children is uncommon, but leads to morbidity and places a burden on the healthcare system. Objectives: To describe the clinical characteristics and outcome of children diagnosed with COVID-19 in a pediatric tertiary-care hospital and to compare patients who required hospital admission with those who did not. Material and methods: A prospective cohort study. All patients with a virological diagnosis of COVID-19 seen between 1.1.2022 and 1.3.22 in a tertiary-care pediatric hospital were included. We compared patient history, clinical characteristics, and outcome according to whether or not they required hospital admission. STATA 16 was used. Results: n: 1764 patients, 958 of whom were male (54%). The median age was 56 months (IQR, 17- 116). Overall, 789 patients had an underlying disease (46%), the most frequent of which were hematology-oncology disease in 215 patients (12%), neurological disease in 103 (6%), chronic lung disease in 68 (4%), congenital heart disease in 65 (4%), and a genetic syndrome in 57 (3%); 292 were immunosuppressed (17%). Overall, 1319 patients (79%) had COVID-19-related symptoms and 591 (34%) required hospital admission. A coinfection with other respiratory viruses was observed in 33 patients (2%). Intensive care admission due to COVID-19 was required in 22 patients (1.3%) and 8 (0.5%) died with COVID-19. In univariate analysis, the presence of comorbidities, viral coinfecton, and immunosuppression were statistically significantly associated with the need for hospitalization. A history of two or more doses of the SARSCoV2 vaccine was a protective factor against hospital admission in children older than 3 years. In the multivariate model, patients younger than 3 years (OR 6.5, 95% CI 1.2-36.8, p 0.03), with comorbidities (OR 2.04, 95%CI 1.7-3.3, p 0.00) and immunocompromised hosts (OR 2.89, 95% CI 2.1-4.1, p 0.00) had a higher risk of hospital admission. When adjusting for the remaining variables, having received two or more doses of the vaccine was found to be a protective factor against hospital admission (OR 0.65, 95% CI 0.49-0.87, p<0.01). Conclusions: In this prospective cohort study of children with a confirmed diagnosis of COVID-19, symptomatic disease predominated. Thirty-four percent of the patients were admitted for COVID-19. Vaccination with two or more doses was a protective factor against hospitalization in the multivariate model. In addition, age younger than 3 years, previous comorbidities, and immunosuppression were statistically associated with hospital admission (AU)

Factores de riesgo de bacteriemia en niños con cáncer y neutropenia febril / Risk factors for bacteremia in children with cancer and febrile neutropenia

La bacteriemia representa una importante causa de morbimortalidad en pacientes oncológicos. Durante el episodio de neutropenia inducida por quimioterapia, un 15%­25% de los pacientes tendrá bacteriemia. Objetivo: identificar factores de riesgo asociados con bacteriemia en pacientes oncológicos pediátricos con neutropenia y fiebre. Material y métodos: estudio de cohorte prospectivo. Se incluyeron pacientes con enfermedades hematooncológicas y neutropenia febril, internados en un hospital pediátrico de alta complejidad entre julio de 2018 y mayo de 2019. Se excluyeron receptores de trasplante de médula ósea. Se compararon las características clínicas según se documentara bacteriemia (B) o no. Resultados: Se incluyeron 160 pacientes (p). Eran varones 93 (58%). La mediana de edad fue 81,5 meses (RIC 36-127,5). La enfermedad de base (EB) más frecuente fue: leucemia linfoblástica aguda (LLA) 88 (55%). Se identificaron 20 (12,5%) pacientes con bacteriemia (B). En el análisis univariado hubo asociación entre B y LMA (p=0,003) y la internación en UCI (p=0,0001). En el modelo multivariado, ajustado por el resto de las variables, se identificaron la LMA (OR 8,24, IC95% 2,5-26,4; p<0,001) y la tiflitis (OR 5,86, IC95% 1,2-27,3; p=0,02) como factores relacionados con bacteriemia. Los principales microorganismos identificados fueron: estreptococos del grupo viridans 6 (30%), Escherichia coli 4 (20%) y estafilococos coagulasa negativos 3 (15%). Quince (75%) fueron bacteriemias secundarias a un foco clínico. El foco más frecuente fue el mucocutáneo (n=7, 35%). En esta cohorte de niños con cáncer y neutropenia febril, los factores asociados con bacteriemia fueron: la LMA, la tiflitis y la internación en UCI (AU)

Bacteremia is an important cause of morbidity and mortality in oncology patients. During an episode of chemotherapy-induced neutropenia, 15%-25% of patients will develop bacteremia. Objective: to identify risk factors associated with bacteremia in pediatric oncology patients with neutropenia and fever. Material and methods: prospective cohort study. Patients with hematology-oncology diseases and febrile neutropenia, admitted to a tertiary-care pediatric hospital between July 2018 and May 2019 were included. Bone marrow transplant recipients were excluded. Clinical characteristics were compared according to whether or not bacteremia was recorded. Results: 160 patients were included of whom 93 (58%) were male. Median age was 81.5 months (IQR 36-127.5). The most common underlying disease was acute lymphoblastic leukemia (ALL) in 88 patients (55%). Twenty (12.5%) patients with bacteremia were identified. In univariate analysis, an association was found between bacteremia and acute myeloid leukemia (AML) (p=0.003) and ICU admission (p=0.0001). In the multivariate model, adjusted for the remaining variables, AML (OR 8.24; 95%CI 2.5-26.4; p<0.001) and typhlitis (OR 5.86; 95%CI 1.2-27.3; p=0.02) were identified as factors related to bacteremia. The main microorganisms identified were viridans group streptococci in 6 (30%), Escherichia coli in 4 (20%), and coagulase negative staphylococci in 3 (15%). In 15 cases (75%), bacteremia was secondary to a clinical focus. The most frequent focus was mucocutaneous (n=7, 35%). In this cohort of children with cancer and febrile neutropenia, the factors associated with bacteremia were AML, typhlitis, and ICU admission (AU)

Outcome and technical consideration of conversion total hip arthroplasty after failed fixation of intracapsular and extracapsular hip fractures: Are they really that different?

INTRODUCTION: Conversion Total Hip Arthroplasty (cTHA) is a rescue strategy for proximal femur osteosynthesis failures. However, it is unclear whether cTHAs performed for extra-capsular fracture fixation failures (ECF) or for intra-capsular fracture fixation failures (ICF) share the same complexity and efficacy. The purpose of our study was to compare cTHAs performed on pre-existing ICFs and pre-existing ECFs, focusing on surgical complications and functional outcomes in both groups. METHODS: An observational retrospective study was conducted on cTHA patients, treated between 2014 and 2018, divided into 2 groups: ICF-group and ECF-group. The main outcomes were: type of implant used, duration of surgery, need for transfusions, incidence of complications, functional outcomes. RESULTS: 28 patients were included (15 in the ECF group and 13 in the ICF group); the average follow-up was of 31 ± 17.3 months. No significant differences were identified in terms of the type of implant used and duration of surgery. The number of transfused patients was 4 in the ICF group and 12 in the ECF group (p = 0.02); the average transfused units were 0.4 ± 0.7 in the ICF group and 1.3 ± 0.9 in the ECF group (p = 0.01). The incidence of complications - an infection and a dislocation, both of which occurred in the ICF group - and functional outcomes did not present significant differences. CONCLUSION: The conversion surgery on ECFs patients is technically more difficult for the surgeon and prone to greater blood loss. The outcomes are satisfactory and overlap between the two groups.

Efficacy of mechanical thrombectomy in patients with ischemic stroke and cancer.

Cancer-related coagulopathy is a known cause of stroke and can lead to formation of thrombi with a unique composition. The effectiveness of mechanical thrombectomy in cancer patients is still unknown. The aim of the study was to evaluate the rate of successful reperfusion and the clinical outcome in cancer patients with stroke treated with endovascular therapies, compared to patients without cancer. We performed a retrospective analysis of consecutive patients with ischemic stroke treated with endovascular therapies at our hospital between January 2008 and January 2016. A sub-group analysis was performed including only patients with cryptogenic stroke. We included in the final analysis 14 patients with active cancer and 267 patients without cancer. Successful reperfusion was achieved in 79% of patients without cancer, and 71% of patients with active cancer (P = 0.68). Patients with cryptogenic stroke and active cancer had a lower reperfusion rate compared to patients with cryptogenic stroke without active cancer, although not significantly so (2/4 cancer patients, 50% vs 37/50, 74%, p: 0.31). Mortality rate was higher among cancer patients. Hemorrhagic transformation occurred in similar proportions in the two groups. Endovascular treatment in cancer patients seems, thus, effective.

Características clínicas y evolutivas de niños con infección por SARS-CoV-2 en un hospital de alta complejidad: estudio de cohorte / Clinical and outcome characteristics of children with SARS CoV-2 infection in a tertiary-care hospital: a cohort study

Introducción: Las infecciones por SARS-CoV-2 representan un problema de salud pública a nivel mundial. En los niños se reporta menor incidencia y cuadros clínicos más leves. Se realizó el presente estudio con el objetivo de describir las características clínicas y evolutivas de los niños con diagnóstico de infección por SARS CoV-2 en el Hospital Juan P. Garrahan. Material y métodos: estudio de cohorte prospectivo. Se incluyeron todos los pacientes con diagnóstico confirmado por PCR de COVID-19 desde 20.4.20 hasta el 3.07.21 y con seguimiento en el hospital de Pediatría Juan P. Garrahan. Resultados: n: 1644. Eran varones 836 (51%). La mediana de edad fue 75 meses (RIC 22- 143). Tenían alguna enfermedad de base previa al diagnóstico de COVID-19: 884 pacientes (53,7%), la más frecuente fue la enfermedad oncohematológica. Estaban asintomáticos 423 pacientes (25,7%). De los pacientes sintomáticos, 1071 (65,1%) presentaron cuadro leve, 5 (0,3%) moderado, 69 (4,2%) grave y 76 (4,6%) crítico. La fiebre fue el hallazgo más frecuente n: 782; (47,5%). Se internaron 900 pacientes (54,7%), 33 en UCI (2%). Fallecieron 7 pacientes (0,4%), todos ellos con comorbilidades graves. Conclusiones: En este estudio de cohorte de niños con infección por SARS-CoV-2 confirmada, predominaron los pacientes con enfermedad de base y las formas leves de COVID-19. El ingreso a UCI fue menor al 2%. Fallecieron 7 pacientes (0.4%) todos ellos con comorbilidades y coinfecciones (AU)

Introduction: SARS-CoV-2 infections represent a worldwide public health problem. A lower incidence and milder clinical pictures are reported in children. The aim of this study was to describe clinical and outcome characteristics of children diagnosed with SARS-CoV-2 infection at Hospital de Pediatría Juan P. Garrahan. Methods: A prospective cohort study was conducted. All patients with a PCR-confirmed diagnosis of COVID-19 seen between 20.4.20 and 3.07.21 and followed-up at Hospital de Pediatría Juan P. Garrahan were included. Results: n: 1644; 836 males (51%) were male. Median age was 75 months (IQR, 22-143). Overall, 884 patients (53.7%) had an underlying disease prior to COVID-19 diagnosis, most frequently hematologic/ oncologic disease. 423 patients (25.7%) were asymptomatic. Of the symptomatic patients, 1071 (65.1%) had mild, 5 (0.3%) moderate, 69 (4.2%) severe, and 76 (4.6%) critical disease. Fever was the most frequent finding (n: 782; 47.5%). A total of 900 patients (54.7%) were admitted, 33 of whom to the ICU (2%). Seven patients (0.4%) died, all with severe comorbidities. Conclusions: In this cohort study of children with confirmed SARSCoV-2 infection, patients with underlying disease and mild forms of COVID-19 predominated. ICU admission occurred in less than 2%. Seven patients (0.4%) died, all of them with comorbidities and coinfections. (AU)

Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing-remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients. METHODS: Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6 months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. RESULTS: In all, 476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P = 0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%-40.5% and >40.5%), was observed (P = 0.008). The nadir of ALC drop (-33.6%) and 35% of grade III lymphopaenia cases occurred after 12 months of treatment. CONCLUSION: A higher lymphocyte count drop at 6 months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer.

PURPOSE: The phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy. METHODS: Of 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety. RESULTS: Thirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities. CONCLUSION: A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.

Abdominal scar endometriosis: case report.

Abdominal scar endometriosis, corresponding to the presence of an endometrial tissue near or inside an abdominal surgical incision, is a rare clinical event that can occur in women after gynecological or obstetric surgery. Generally, a triad consisting of underlying mass at the incision, cyclic menstrual scar pain, and history of previous gynecological or obstetric surgery leads to the preoperative diagnosis. In rare cases, the clinical presentation is atypical and the differential diagnosis with incarcerated incisional hernia, granuloma, abscess or other soft tissue tumors can be difficult. The authors describe the case of 39-year-old woman who underwent three previous cesarean sections, with a 20-week history of underlying palpable mass at the Pfannenstiel incision, associated to continuous pain. In this case, a surgical excision followed by the histology definitely clarified the diagnosis.

Chronic telogen effluvium and female pattern hair loss are separate and distinct forms of alopecia: a histomorphometric and immunohistochemical analysis.

BACKGROUND: Chronic telogen effluvium (CTE), a poorly understood condition, can be confused with or may be a prodrome to female pattern hair loss (FPHL). The pathogenesis of both is related to follicle cycle shortening and possibly to blood supply changes. AIM: To analyze a number of histomorphometric and immunohistochemical findings through vascular endothelial growth factor (VEGF), Ki-67, and CD31 immunostaining in scalp biopsies of 20 patients with CTE, 17 patients with mild FPHL and 9 controls. METHODS: Ki-67 index and VEGF optical density were analyzed at the follicular outer sheath using ImageJ software. CD31 microvessel density was assessed by a Chalkley grid. RESULTS: Significant follicle miniaturization and higher density of nonanagen follicles were found in FPHL, compared with patients with CTE and controls. Ki-67+ index correlated positively with FPHL histological features. The FPHL group showed the highest VEGF optical density, followed by the CTE and control groups. No differences were found in CD31 microvessel density between the three groups. CONCLUSIONS: Histomorphometric results establish CTE as a distinct disorder, separate from FPHL from its outset. Its pathogenic mechanisms are also distinct. These findings support the proposed mechanism of 'immediate telogen release' for CTE, leading to cycle synchronization. For FPHL, accelerated anagen follicular mitotic rates and, thus, higher Ki-67 and VEGF values, would leave less time for differentiation, resulting in hair miniaturization.

Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression.

Once stimulated, the epidermal growth factor receptor (EGFR) undergoes self-phosphorylation, which, on the one hand, instigates signaling cascades, and on the other hand, recruits CBL ubiquitin ligases, which mark EGFRs for degradation. Using RNA interference screens, we identified a deubiquitinating enzyme, Cezanne-1, that opposes receptor degradation and enhances EGFR signaling. These functions require the catalytic- and ubiquitin-binding domains of Cezanne-1, and they involve physical interactions and transphosphorylation of Cezanne-1 by EGFR. In line with the ability of Cezanne-1 to augment EGF-induced growth and migration signals, the enzyme is overexpressed in breast cancer. Congruently, the corresponding gene is amplified in approximately one third of mammary tumors, and high transcript levels predict an aggressive disease course. In conclusion, deubiquitination by Cezanne-1 curtails degradation of growth factor receptors, thereby promotes oncogenic growth signals.

Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth.

Monoclonal antibodies (mAbs) to HER2 are currently used to treat breast cancer, but low clinical efficacy, along with primary and acquired resistance to therapy, commonly limit clinical applications. We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects, probably due to accelerated receptor degradation. Here, we extend these observations to three-dimensional mammary cell models, and compare the effects of single mAbs with the effects of antibody combinations. Collectively, our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth. Importantly, while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype, combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids. In conclusion, our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells. Hence, combining mAbs offers a therapeutic strategy, potentially able to enhance clinical efficacy of existing antireceptor immunotherapeutics.

Dimensions of postpartum psychiatric distress: preliminary evidence for broadening clinical scope.

BACKGROUND: Perinatal psychiatric disturbances afflict a significant number of women sometimes with tragic consequence. Yet, the range and characteristics of these disturbances are poorly understood. The goals of this research were to characterize a broader range of postpartum psychiatric symptoms and to identify their inherent structure using exploratory factor analysis (EFA). METHODS: An Internet-based survey with 142 Likert-type questions, covering nine dimensions of postpartum mental health was constructed and posted on women's health websites. Data collected from 215 respondents was analyzed in three steps: (1) inter-item correlations were used to reduce the total number of variables by eliminating items that provided redundant information; (2) an EFA using a principal components extraction and VARIMAX rotation was performed and factors loading with Eigenvalues >1.0 were retained; (3) internal consistency was measured with Cronbach's alpha. RESULTS: The 10 factors retained accounted for 58% of the variance and included: mental status (28%), psychoticism/morbid thoughts (6%), generalized anxiety (6%), panic (3%), guilt/self-criticism (3%), compulsive behavior (3%), hyper-vigilance (2%), contentment (2%), negative body-image (2%), and manic behavior (2%). There was strong (>0.8) internal consistency in all but the mania factor (0.6). LIMITATIONS: The study was retrospective and respondent demographics were homogeneous. CONCLUSION: Postpartum psychiatric disturbances are not limited to depressive symptoms. In the current study, cognitive difficulties, psychotic-morbid thoughts and anxiety symptoms accounted for the preponderance of variance while depressive symptoms did not form a cohesive factor and accounted for minimal variance. These results suggest postpartum screening tools should assess a broader array of symptoms.

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS).

Overexpression of the c-Met/hepatocyte growth factor receptor(HGF-R) proto-oncogene and abnormal generation of intracellular oxygen species (reactive oxygen species (ROS)) have been linked, by independent lines of evidence, to cell transformation and to malignant growth. By comparing two subpopulations of the B16 mouse melanoma (B16-F0 and B16-F10) endowed with different lung metastasis capacities (low and high, respectively) we found that both the expression/phosphorylation of c-Met and the steady-state levels of ROS positively correlated with metastatic growth. shRNA-mediated downregulation of c-Met in F10 cells led to a parallel decrease in the generation of oxygen species and in metastatic capacity, suggesting that oxidants may mediate the pro-metastatic activity of the HGF receptor. c-Met activation by a ligand elicits the formation of oxidant species through the oxidase-coupled small GTPase Rac-1, a relevant downstream target of the HGF-R. Moreover, cell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells, consistent with a critical role for oxygen species in HGF signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c-Met in vivo. Thus, we have outlined a novel cascade triggered by c-Met and mediated by ROS, linked to metastasis and potentially targetable by new antimetastatic, redox-based therapies.

Occult HBV infection and suppression of HCV replication in the early phase of combination therapy for chronic hepatitis C.

BACKGROUND: Occult HBV infection in subjects with chronic hepatitis C is related to more severe disease outcome. It has been suggested that it might reduce sensitivity to antiviral treatment. AIMS: To assess in HBsAg negative subjects with chronic hepatitis C any effect of the presence of HBV genomes in the liver on the early kinetics of HCV-RNA under PEG-IFN plus ribavirin. PATIENTS AND METHODS: Twenty-two anti-HCV and HCV-RNA positive subjects, with biopsy-proven chronic hepatitis C (M/F 15/7; 50 +/- 8.6 years, 16 genotype 1b) were given PEG-IFN alpha 2b 1.0 microg qw plus ribavirin (800 to 1,200 mg daily according to body weight) for an intended 52 week period. Early virological response was assessed over the first 4 weeks of therapy by quantifying HCV-RNA. Occult HBV infection was assessed by testing for HBV-DNA in the liver before therapy. RESULTS: HBV genomes were found in the liver of 7 of 22 (31.4%) patients, unrelated to anti-HBc status. Kinetics of HCV-RNA during the first 4 weeks of antiviral treatment was unaffected by occult HBV infection, both in terms of absolute reduction of viral load and of number of cases with a reduction of > or = 2 log10 on treatment. CONCLUSIONS: Occult HBV infection does not affect the early phase of response to combination therapy. Further follow-up of patients into the maintenance phase of antiviral treatment and after stopping it will clarify if and when occult HBV has a role in reducing sustained virological response.

Occupational head injury and subsequent glioma.

We report the case of a policeman who suffered a severe head injury to the right temporoparietal lobe while driving a police car. Four years later, the patient developed a neoplasm at the precise site of the meningocerebral scar. Histological examination confirmed a glioblastoma multiforme adjacent to the dural scar. Radiological documentation of the absence of tumor at the time of injury, exact localization of the neoplasm in the injured cerebral area, and latency of the cancer supported the hypothesis of a causal relationship with brain trauma. Physicians faced with brain neoplasms in adults should carefully investigate the patient's personal history of head trauma. When a relationship with occupational head injury is probable, reporting of suspect occupational illness is compelling.

Are hepatitis G virus and TT virus involved in cryptogenic chronic liver disease?

BACKGROUND: Hepatitis G virus can cause chronic infection in man but the role of this agent in chronic liver disease is poorly understood. Little is known about the relation of another newly discovered agent, the TT virus, with chronic liver disease. AIM: To investigate the rate of infection with hepatitis G virus and TT virus in patients with cryptogenic chronic liver disease. PATIENTS: A total of 23 subjects with chronically raised alanine transaminase and a liver biopsy in whom all known causes of liver disease had been excluded, and 40 subjects with hepatitis C virus-related chronic liver disease. METHODS: Evaluation of anti-hepatitis G virus by enzyme immunoassay. Hepatitis G virus-RNA by polymerase chain reaction with primers from the 5' NC and NS5a regions. TT virus-DNA by nested polymerase chain reaction with primers from the ORF1 region. Results. Hepatitis G virus-RNA was detected in 4 out of 23 patients with cryptogenic chronic hepatitis and in 6 out of 40 with hepatitis C virus chronic hepatitis (17.4% vs 15% p=ns). At least one marker of hepatitis G virus infection (hepatitis G virus-RNA and/or anti-hepatitis G virus, mostly mutually exclusive) was present in 6 out of 23 patients with cryptogenic hepatitis and 16 out of 40 with hepatitis C virus liver disease (26. 1% vs 40% p=ns). T virus-DNA was present in serum in 3 subjects, 1 with cryptogenic and 2 with hepatitis C virus-related chronic liver disease. Demographic and clinical features, including stage and grade of liver histology, were comparable between hepatitis G virus-infected and uninfected subjects. Severe liver damage [chronic hepatitis with fibrosis or cirrhosis) were significantly more frequent in subjects with hepatitis C virus liver disease. CONCLUSIONS: In Southern Italy, hepatitis G virus infection is widespread among patients with chronic hepatitis, independently of parenteral risk factors. Its frequency in subjects with cryptogenic liver disease parallels that observed in hepatitis C virus chronic liver disease, thus ruling out an aetiologic role of hepatitis G virus. TT virus infection is uncommon in patients with cryptogenic or hepatitis C virus-related liver disease who do not have a history of parenteral exposure.

Response-adjusted alpha-interferon therapy for chronic hepatitis C in HIV-infected patients.

In patients with chronic hepatitis C and HIV infection, responsiveness to the standard schedule of alpha-interferon (IFN) is unsatisfactory. To quantify the effectiveness of tailoring IFN dosage according to HCV viral load under treatment, we enrolled 41 patients (M/F 32/9) chronically coinfected by HCV and HIV with chronic liver disease. All were former i.v. drug addicts, with a mean age of 32+/-4 years, and had clinical and histological evidence of chronic hepatitis (10% with cirrhosis). The CDC stage was A1 in five, A2 in 14, A3 in eight, B2 in eight, B3 in three and C3 in three. Twenty four patients were on triple therapy with protease inhibitors, 11 were on two-drug anti-HIV regimens and three were untreated. IFN (alphan1 interferon) was started at 3 MU tiw and increased at 6 MU tiw at 4 weeks if serum HCV-RNA had not dropped by at least 50%. IFN was stopped at 24 weeks in non-responders. Eleven patients received a dose increase (total IFN dose at 24 weeks 396 MU), while 16 did not increase the initial dose (total IFN dose at 24 weeks 216 MU). Fourteen subjects stopped within the first weeks due to relapse of drug abuse (ten) or subjective intolerance (four). ALT and HCV-RNA levels were markedly decreased at week 4, and this reduction lasted up to 24 weeks. However only one patient had a complete biochemical and virological end-of-treatment response, which was maintained over a 24 weeks post-therapy follow-up. All other patients relapsed to baseline ALT and HCV-RNA values after stopping IFN. HIV viral load was slightly reduced under IFN therapy, while CD4 counts were unaffected. We conclude that raising the dose of IFN dose not eradicate HCV in most HIV-infected patients, even when HIV is well controlled by treatment. HCV viraemia and necroinflammation are temporarily suppressed by IFN, but the relevance of these surrogate endpoints to progression of liver disease and to survival cannot be assessed.