Insuficiência cardíaca de fração de ejeção reduzida após infarto agudo do miocárdio em atleta de endurance: é possível continuar no esporte? / Heart failure with reduced ejection fraction after acute myocardial infarction in an endurance athlete: is it possible to continue in sport?

Insuficiência cardíaca é das principais doenças resultando em redução da capacidade física, sendo a doença arterial coronariana sua principal causa, especialmente em atletas acima de 35 anos. Será que insuficiência cardíaca com fração de ejeção reduzida após infarto agudo miocárdio teria espaço no esporte? Paciente masculino, 56 anos, com antecedente de hipertensão arterial sistêmica, previamente atleta de corrida de rua desde 38 anos de idade (meia maratona com pace médio de 3:50 min/km) procurou atendimento em pronto socorro em março de 2016 por angina típica em repouso. Ficou em observação e liberado após analgesia. Por manter dispneia iniciou acompanhamento com cardiologista e, 2 meses após episódio de dor torácica, realizou cintilografia de perfusão miocárdica com tecnécio sestamibi associado a teste ergométrico, evidenciando hipocaptação persistente extensa em parede anterosseptal, inferosseptal e ápice de ventrículo esquerdo (VE), sem hipocaptação transitória e com fração de ejeção de VE (FEVE) de 30%. Realizada estratificação invasiva mostrando lesão de 99% em segmento médio de artéria descendente anterior com aspecto de recanalização e fluxo TIMI um com acinesia de parede anterior discinesia de parede apical. Paciente encaminhado ao serviço terciário e optado por realizar cintilografia miocárdica com tálio-201 e estresse com teste ergométrico que resultou em ausência de isquemia e de viabilidade miocárdica. Portanto, paciente foi mantido em tratamento clínico e reabilitação cardiovascular. Em acompanhamento ambulatorial após seis anos do evento, atualmente praticando corrida dois a três vezes por semana (10 a 12 km com pace 6:15 min/km), com ecocardiograma transtorácico com aumento biatrial e discreto de VE, FEVE 38% com acinesia do segmento médio do septo e do segmento apical de todas as paredes, insuficiência mitral discreta a moderada por remodelamento ventricular. Teste ergométrico realizado com protocolo de Ellestad, interrompido após 12'45" por exaustão e atingindo 98% da frequência cardíaca máxima preconizada pela idade, sem alterações sugestivas de isquemia, extrassístoles ventriculares isoladas e raras e consumo máximo estimado de oxigênio de 56 ml/kg/min, em uso de betabloqueador. Apesar do paciente apresentar excelente aptidão cardiorrespiratória, foi orientado manter atividades de leve a moderada intensidade (70% da reserva cronotrópica) devido a FEVE reduzida. Portanto, há espaço para esses pacientes no esporte não competitivo: após reabilitação cardiovascular, estratificação de risco e contínuo acompanhamento médico e multidisciplinar.

Vulnerabilidade de placa coronariana com teste funcional normal contraindica exercício físico de alta intensidade? / Coronary plaque vulnerability with normal functional test contraindicate high-intensity physical exercise?

Doença arterial coronariana (DAC) é a principal causa de morte súbita em atletas com mais de 35 anos. Sedentarismo é um fator de risco para DAC porém há evidências de que atividade física vigorosa aumente o risco de eventos cardiovasculares de forma paradoxal. Segundo diretrizes, pacientes nos quais DAC é detectada em exames de screening devem ser restringidos de esportes de alta intensidade quando houver alteração em testes funcionais ou quando houver evidência de progressão de doença em avaliação seriada. No entanto, será que lesões coronarianas com teste funcional negativo porém com características de vulnerabilidade contraindicam atividade física intensa em esportistas?. Trazemos o caso de J.B., 59 anos feminina, hipertensa, dislipidêmica, história familiar de DAC precoce. Esportista, pratica corrida quatro vezes por semana, musculação três vezes por semana e ciclismo duas vezes por semana, em alta intensidade. Em avaliação pré-participação para maratona em serviço externo foi submetida a angiotomografia de coronárias evidenciando escore de cálcio 1772 (p99) com placas calcificadas e redução luminal importante em terço proximal de descendente anterior (DA) e diagonal (DG), e redução luminal discreta de artéria circunflexa (CX), e oclusão total em terço proximal de artéria coronária direita (CD). Ao cateterismo, confirmadas as lesões de 40% em terço médio CD, 70% em terço proximal de DA, 80% diagonal e 40% CX. Em nosso serviço foi submetida a cintilografia de perfusão miocárdica SPECT 99m-Tc precedida de teste de esforço. Não houve sinais de isquemia à imagem e o teste de esforço teve comportamento normal de PA, FC, ausência de arritmia ou de alteração de segmento ST ou sintomas, e desempenho de 12,9 METS, VO2 de 45. O caso foi discutido com conjunto com o setor de tomografia, coronariopatias, hemodinâmica e cardiologia do esporte, sendo contraindicada exercício físico de alta intensidade devido ao achado de vulnerabilidade de placas à angiotomografia e cateterismo, evidência ainda pouco debatida na literatura mundial.

Miopericardite com arritmia complexa após quadro assintomático de COVID19 em atleta de futebol profissional / Myopericarditis with complex arrhythmia after asymptomatic COVID19 in a professional soccer player

INTRODUÇÃO: A avaliação cardiológica para o retorno da prática de atividade físico- -esportiva ganhou destaque durante a pandemia de sars-cov2, visto que o sistema cardiovascular pode ser acometido em 20-30% dos casos de covid-19, com manifestações clínicas que incluem miocardite, síndrome coronariana aguda, insuficiência cardíaca, dentre outras, podendo aumentar o risco de eventos cardiovasculares, em especial a morte súbita, durante a atividade física. Neste relato explicitamos o papel da avaliação pré-participação em atletas após infecção pelo sars-cov 2. MÉTODOS: Relato de caso de paciente masculino de 36 anos, atleta profissional de futebol, previamente hígido, sem história familiar de evento cardiovascular precoce ou morte súbita, atendido no instituto dante pazzanese de cardiologia em 2021 por perda de capacidade funcional vista no retorno aos treinos, 10 dias após quadro assintomático de covid-19 em janeiro de 2021. RESULTADOS: Em fevereiro de 2021 realizou tais exames: eletrocardiograma (ecg) que apresentou onda t invertida em parede inferior e derivações v3-v6, comparados ao ecg basal, o qual era normal; ecocardiograma transtorácico (eco-tt) que evidenciou fração de ejeção ventricular (feve) de 69% e derrame pericárdico laminar anterior; á ressonância magnética cardíaca apresentou realce tardio epicárdico no segmento inferolateral das porções basal e média do ventrículo esquerdo (ve), sugestivo de fibrose miocárdica. Devido quadro de miopericardite, optado por afastamento das atividades físicas. Em junho de 2021, retornou com eco-tt com queda da feve para 50% e alteração de strain longitudinal global (slg) (17%), teste cardiopulmonar evidenciando taquicardica ventricular não sustentada, apesar de excelente aptidão cardiorrespiratória. Foi então iniciado metoprolol e enalapril por início de disfunção de ve. Já em setembro de 2021 retorna com eco-tt mostrando melhora de feve para 63% e melhora do strain (slg) para 21%, entretanto mantendo ao teste ergométrico ectopias ventriculares polimórficas bigeminadas durante esforço e recuperação. Segue em acompanhamento, afastado das atividades físicas, com dose otimizada de beta bloqueador. CONCLUSÃO: Apresentamos um caso de miopericardite adquirida após covid-19 em atleta, evoluindo com alterações de alto risco para morte súbita arritmogênica. Devido a grande taxa de infecções causadas pelo covid 19, reiteramos a importância da avaliação cardiológica para retorno as atividades físico esportivas após tal infecção, mesmo que assintomática, com objetivo de evitar a morte súbita.

Manutenção do ritmo sinusal após retorno à prática esportiva em paciente com fibrilação atrial tratado com descondicionamento / Maintenance of sinus rhythm after return to sports practice in a patient with atrial fibrillation treated with deconditioning

O exercício físico reduz risco de doenças cardiovasculares, metabólicas e está relacionada a aumento do bem-estar e longevidade. Alguns estudos sugerem redução do risco de arritmias, como a fibrilação atrial, em até 19% em homens e 9% em mulheres. Contudo, observa-se prevalência superior, de até 3,5 vezes, de desenvolvimento de fibrilação atrial em praticantes de exercícios de muito alta intensidade ou competitiva, tornando essa a arritmia mais frequente no atleta. Os indivíduos sob maior risco são homens, praticantes de endurance de alta intensidade e com alto volume. A presença de fibrilação atrial, ainda que paroxística, impacta negativamente sobre a capacidade funcional e performance nesses indivíduos, seja pela redução do débito cardíaco pela perda da contração atrial ou pela perda de controle da frequência cardíaca pelo sistema nervoso autônomo. A evidência atual disponível para guiar o manejo desses pacientes se baseia em estudos randomizados em pacientes portadores de FA não atletas, estudos menores em atletas ou em consenso de especialista e o tratamento se baseia nos pilares de controle de ritmo farmacológico ou intervencionista por meio de ablação por radiofrequência ou destrainamento. Esse relato de caso tem como objetivo apresentar a evolução de paciente atleta com fibrilação atrial tratado de forma não invasiva, com destreinamento, de forma a revisar e ampliar o conhecimento sobre o tema. RELATO DE CASO: Paciente, sexo masculino, 42 anos, sem comorbidades prévias, pratica esporte competitivo desde os 15 anos nas modalidades: mountain bike, triátlon e maratona. Procura atendimento médico, sem queixas, solicitando liberação para realização de prova triathlon ironman. Ao exame físico apresentava ausculta cardíaca com frequência de 50 bpm e ritmo irregular, sem outras alterações. O eletrocardiograma apresentava ritmo de fibrilação atrial com baixa resposta ventricular. Foi realizada investigação de cardiopatia estrutural com ecocardiograma que revelou átrio esquerdo aumentado, com volume indexado de 40ml/ m2. Função biventricular preservada. Sem outros achados. Em teste ergométrico, apresentava resposta adequada da frequência cardíaca ao esforço, com excelente capacidade funcional e sem alterações sugestivas de isquemia. Holter evidenciava apenas presença de fibrilação atrial. Foi optado então por tratamento com destreinamento por 3 meses. Após, paciente realizou holter que apresentava ritmo sinusal. Foi mantido seguimento por um ano, com repetição de holter 24h que se manteve em ritmo sinusal.

Avaliação da prática esportiva em atleta jovem com estenose aórtica subvalvar corrigida / Evaluation of sports practice in a young athlete with corrected subvalvular aortic stenosis

Paciente 18 anos, sexo masculino, sem outras comorbidades, ex-atleta amador praticante de Rugby, interrompeu a prática esportiva por orientação médica após o diagnóstico de estenose subvalvar aórtica grave, com gradiente médio de 81 mmHg e máximo de 158 mmHg em membrana subvalvar. Foi realizada correção cirúrgica com ressecção da membrana subaórtica associada à ressecção muscular da via de saída do ventrículo esquerdo e plastia da valva tricúspide. Após recuperação cirúrgica paciente, mantém-se assintomático e retorna periodicamente para avaliação quanto a prática de atividade física e esportiva competitiva. Três anos após cirurgia, em avaliação complementar, ao ecocardiograma, observava-se persistência de prega ventrículo-infundibular e resquício de membrana, determinando estreitamento da via de saída do ventrículo esquerdo (VE), com aceleração de fluxo gerando gradiente sistólico máximo entre VE e aorta de 42 mmHg e médio de 24 mmHg. Refluxo aórtico discreto a moderado. Função sistólica biventricular preservada, hipertrofia ventricular esquerda discreta. Foi solicitado também ecocardiograma com estresse físico que não mostrou sinais de isquemia miocárdica. Membrana subaórtica gerou obstrução importante com repercussão hemodinâmica ao esforço físico. Por fim, realizou teste ergométrico, que apresentou Infradesnivelamento de segmento ST de 2,5mm horizontam em MC5, sem dor, com comportamento adequado da pressão e da frequência cardíaca durante o esforço e capacidade funcional estimada de 13 METs. Após exames complementares, foi realizado reunião com especialistas em cardiologia do esporte e liberado para a prática de atividade física moderada, com cálculo de frequência máxima até 60% da FC reserva e resistiva com até 50% da força máxima. A estenose subvalvar aórtica é uma cardiopatia congênita relativamente frequente que resulta de uma anormalidade subjacente na arquitetura da via de saída do ventrículo esquerdo (VSVE), com fluxo turbilhonado levando à fibrose progressiva dessa região. Obstrução significativa da VSVE leva à hipertrofia ventricular e função hiperdinâmica. É a segunda causa mais comum de estenose aórtica na população pediátrica e muitos pacientes têm regurgitação aórtica associada. A correção cirúrgica geralmente é indicada a partir da 2ª década de vida e 20 até 30% dos pacientes evoluem com recorrência da obstrução. Em virtude da prevalência dessa condição em indivíduos jovens, além de outras condições de risco, a avaliação médica por especialista antes da prática esportiva competitiva torna-se essencial.

Apoptosis as a specific biomarker of diazinon toxicity in NTera2-D1 cells.

The NTera2/D1 (NT2) cell line, which was derived from a human teratocarcinoma, exhibits properties that are characteristics of a committed neuronal precursor at an early stage of differentiation. Its property to express a whole set of molecules related to the cholinergic neurotransmission system, including active acetylcholinesterase (AChE, EC 3.1.1.7) makes it a good alternative model for testing the effects of neurotoxic compounds, such as organophosphorus (OP) insecticides, whose primary target is the inhibition of AChE activity. Recent findings have elucidated the role of AChE in the modulation of apoptosis, but the mechanisms are still rather obscure. NT2 cells exposed to the OP insecticide diazinon at concentrations ranging between 10(-4) and 10(-5)M showed a time-dependent enhancement of cell death. When exposed at 10(-6)M diazinon showed higher cell viability than control samples up to 72 h, followed by a decreasing phase. The cell death caused by the exposures showed a number of features characteristic of apoptosis, including membrane and mitochondrial potential changes. We suggest the hypothesis that such behaviour is due to a dynamic balance between activated and blocked acetylcholine receptors that in turn trigger electrical events and caspase cascade.

In vitro polydeoxyribonucleotide effects on human pre-adipocytes.

OBJECTIVES: Adipose tissue is the most abundant and accessible source of adult stem cells. Human processed lipoaspirate contains pre-adipocytes that possess one of the a characteristic pathways of multipotent adult stem cells and are able to differentiate in vitro into mesenchymal and also neurogenic lineages. Because stem cells have great potential for use in tissue repair and regeneration, it would be significant to be able to obtain large amounts of these cells in vitro. As demonstrated previously, purine nucleosides and nucleotides mixtures can act as mitogens for several cell types. The aim of this study was to evaluate the effects of polydeoxyribonucleotides (PDRN), at appropriate concentrations, on human pre-adipocytes grown in a controlled medium, also using different passages, so as to investigate the relationship between the effect of this compound and cellular senescence, which is the phenomenon when normal diploid cells lose the ability to divide further. MATERIALS AND METHODS: Human pre-adipocytes were obtained by liposuction. Cells from different culture passages (P6 and P16) were treated with PDRN at different experimental times. Cell number was evaluated for each sample by direct counting after trypan blue treatment. DNA assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test were also carried out in all cases. RESULTS AND CONCLUSIONS: PDRN seemed to promote proliferation of human pre-adipocytes at both passages, but cell population growth increased in pre-adipocyte at P16, after 9 days as compared to control. Our data suggest that PDRN could act as a pre-adipocyte growth stimulator.

Characterization and induction of human pre-adipocytes.

Human processed lipoaspirate is a source of multipotent adult stem cells that are able to differentiate between mesenchymal and neurogenic lineage. We characterized PLA cells by cytometry and then they were cultured to induce differentiation into myogenic and neurogenic lineage. Lipoaspirates were digested with collagenase to obtain the pellet, which was labelled with anti-CD44, anti-CD45, and anti-CD90. We used BD FACS Calibur flow cytometer to acquire cellular events. Some cells were cultured at 37 degrees C and 5% CO(2) in neurogenic or myogenic medium and analysed by immunocytochemistry, using Neuron specific enolase, Vimentin, Glial fibrillary acidic protein, Tau, MAP2 to confirm neurogenic differentiation, MyoD1, Myosin heavy chain, Actin smooth muscle, vimentin to confirm myogenic differentiation. The cytometry results suggest that a part of the cells are of a mesenchymal origin, among which there are progenitor endothelial cells and leucocytes. Microscopy observation already reveals neuronal morphology and longitudinal multinucleated cells compared to control cells. Neurogenic cells only express NSE (early neuronal progenitor marker), but not GFAP, Tau, MAP2 (mature neuron and glial markers); myogenic cells are positive for MyoD1 and Myosin heavy chain. This demonstrates that lipoaspirate cells are capable of differentiating in vitro over a short period of time, and could be employed in biological and clinical research, like mesenchymal adult stem cells.

Characterization of multipotent cells from human adult hair follicles.

Recent works demonstrated the presence of a multipotent epithelial cell population in the bulge region of adult human hair follicles. These cells can be cultured in vitro, thus leading to the preparation of dermal-epidermal substitutes which are applicable in the treatment of burns and ulcers. We evaluated the main marker expression in cells obtained from stripped human hair follicles. A pool of hair follicles were incubated at 37 degrees C and 5% CO(2) in a growth medium. The cells were then labelled with antibodies (anti-CD34, anti-CD38, anti-CD45, anti-CD90, anti-CD133, anti-CD146) and analysed by cytometry. We also used hair follicles for immunohistochemical studies, employing antibodies such as CD34, Actin Smooth Muscle, Filaggrin, Desmin, Vimentin, Glial Fibrillary Acidic Protein, Ki-67, PanCytokeratin, CK15, CK19. The cytometry results revealed that a part of bulge cells were CD34+ (1-2%). CD34+ population comprises both large, CD45-, CD133-, CD146- cells and small, CD45+, CD133+, CD146+ cells. Thus, a part of CD34+ cells present a mature endothelial marker (CD146). An expression of the proliferation marker Ki-67 and the stem cell marker CD34 is present in the follicle bulge region. In conclusion, we observed that the stripped hair follicle has the same multipotent cell population as adult and fetal scalp hair follicles.

Biweekly oxaliplatin, raltitrexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I-II study.

Oxaliplatin (OXA), raltitrexed (RTX), 5-fluorouracil (FU) and folinic acid (FA) have shown activity in metastatic colorectal cancer, radioenhancing effect and synergism when combined. We evaluated a chemotherapy (CT) combination of OXA, RTX and FU/FA during preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC) patients. Fifty-one patients with LARC at high risk of recurrence (T4, N+ or T3N0 < or =5 cm from anal verge and/or circumferential resection margin < or =5 mm) received three biweekly courses of CT during pelvic RT (45 Gy). Surgery was planned 8 weeks after CT-RT. Recommended doses (RDs) determined during phase I were utilised in the subsequent phase II trial, where the rate of tumour regression grade (TRG) 1 or 2 was the main end point. No toxic deaths occurred, and severe toxicity was easily managed. In phase II, RDs delivered in 31 patients were OXA 100 mg m(-2) and RTX 2.5 mg m(-2) on day 1, and FU 900 mg m(-2) and LFA 250 mg m(-2) on day 2. Main severe toxicities by patients were grade 4 neutropenia (23%) and grade 3 diarrhoea (19%). In 71% (95% confidence limits, 52-86%) of patients, TRG1 (13) or TRG2 (9) was obtained. All patients are alive and recurrence-free after a median follow-up of 29 months. Combination of OXA, RTX and FU/FA with pelvic RT has an acceptable toxicity and a high clinical activity in LARC and should be studied further in patients at high risk of recurrence.

In vitro evaluation of trypanocidal activity in plants used in Argentine traditional medicine.

Thirty-two organic and aqueous extracts, belonging to 12 Argentine medicinal plants were tested for their in vitro trypanocidal activity on epimastigote forms of Trypanosoma cruzi. Among the selected species, the organic extracts of Ambrosia scabra, Ambrosia tenuifolia, Baccharis spicata, Eupatorium buniifolium, Lippia integrifolia, Mulinum spinosum and Satureja parvifolia, and the aqueous extracts of E. buniifolium, L. integrifolia, M. spinosum and S. parvifolia showed trypanocidal activity with a percentage of growth inhibition higher than 70% at a concentration of 100 microg/ml.

Multidisciplinary approach to locally advanced rectal cancer: results of a single institution trial.

Locally advanced rectal cancer carries out a dismail prognosis despite optimal surgery in terms of local and distant relapses. Neoadjuvant chemoradiation offers good results with tumor downstaging and downsizing and leads to more radical surgery with conservative intent. Selection of patients and an intensive chemotherapy may improve long term results. Our experience with a combined polichemotherapy and radiotherapy for low advanced rectal cancer is presented.

[Early evaluation using PET-FDG of the efficiency of neoadjuvant radiochemotherapy treatment in locally advanced neoplasia of the lower rectum]. / Valutazione precoce con PET-FDG della efficacia del trattamento radiochemioterapico neoadiuvante nelle neoplasie del retto inferiore localmente avanzate.

BACKGROUND AND PURPOSE: Preoperative chemoradiation allows downstaging of locally advanced rectal cancer and in selected patients also a sufficient downsizing to ensure sphincter preservation. Selection of patients warranting a preoperative approach is improved by magnetic resonance imaging (MRI) which is able to define the involvement of mesorectal circumferential margin. Similarly it would be crucial to define the response to chemoradiation during the treatment but traditional morphologic imaging techniques may fail in differentiating neoplastic tissue from scarring. PET-FDG has been successfully used in the detection of metastatic colorectal cancer allowing imaging of deposits as small as 0.5 cm and may have a role in evaluating early response to chemoradiation. METHODS: In the present study, in patients with T3-T4 rectal cancer undergoing preoperative chemoradiation PET-FDG and flow cytometry analysis on endoscopic biopsy specimen have been performed before, during and after preoperative chemoradiation. RESULTS: Chemoradiation treatment has been successful in terms of downsizing and downstaging of the tumor. PET-FDG was able to demonstrate local response at only ten-fifteen days after the beginning of neoadjuvant therapy, also identifying non responding patients. CONCLUSIONS: FDG-PET may have a role in defining the response to chemoradiation and modulate the treatments strategy in patients with advanced rectal cancer.

[Nephrologists and porphyrias]. / I nefrologi e le porfirie.

As usually occurs for rare diseases, the word "PORPHYRIA" often recalls a confused topic with shaded boundaries, presenting "bullous" skin lesions, rare opportunity of diagnosis in clinical practice, unknown pathogenesis, and almost absent therapeutic options. The goal of this review is to draw attention to this topic, as new diagnostic and therapeutic tools might change the natural history of this disease. Porphyrias are disorders resulting from abnormalities of porphyrin metabolism. Porphyrins are molecules made up of four pyrrol rings, which constitute haeme-proteins, including haemoglobin. Following the "trigger" enzyme delta-aminolevulinic acid (ALA) synthase, which is capable of condensing succynil CoA and glycine, seven additional enzymes are involved in the process that eventually leads to haeme biosynthesis. Porphyrias are the result of total or partial deficiencies in these seven enzymes involved in haeme synthesis. Usually, the final haeme product exerts a negative feed-back on its synthesis. The enzyme deficiency that occurs in porphyrias is responsible for reduced haeme production, which, in turn, allows the cascade to be stimulated by increased activity of the trigger enzyme, ALA-synthase (ALA-s). However, due to the subsequent enzyme defects, notwithstanding increased ALA-s activity, haeme synthesis is blunted and intermediate metabolites accumulate. Clinical manifestations depend on which step the enzymatic defect occurs: if enzymatic defects are in the initial steps of the metabolic cascade, early metabolic intermediates will accumulate [i.e. ALA and porphobilinogen (PBG)] responsible for attacks of neurological dysfunction; if the enzymatic defects are in the final steps, sunlight-induced cutaneous lesions (phtotosensitivity) due to porphyrin accumulation in the skin will develop. The seven major human porphyrias may be classified into "hepatic or erythropoietic porphyrias" depending on the organ/tissue where metabolic alterations are more evident, or "acute or chronic porphyrias" depending on the prevalence of clinical symptoms, if neurologic (acute) or cutaneous (chronic). Only a small number of people with inherited enzyme deficiency will develop overt clinical disease, mainly because of the role of acquired aggravating and precipitating factors, such as drugs, hormonal causes, infection, caloric restriction, alcohol. The biochemical diagnosis of porphyrias relies on the detection of the consequences of increased ALA-s activity in the liver: overproduction, accumulation and increased excretion of early (ALA, PBG) or late (porphyrins) intermediate compounds in plasma, faeces and urine. A major difficulty arises from the knowledge that such abnormalities may be completely absent during the remission phases of the disease. Only in very specialised Centres it is now possible to measure specific haeme synthesis enzyme defects, and to perform molecular diagnosis by DNA analysis. The true prevalence of the diseases is unknown, ranging from 1:500 to 1:50,000. Therapeutic strategies include withdrawal of all common precipitants (drug, alcohol, fasting, infection), use of opiates and chlorpromazine, carbohydrates (300-400 g/day) and infusion of human haemine. Genetic therapies are being studied for the future.

Intraosseous mucoepidermoid carcinoma. Report of a long-term evolution case.

Primary central mucoepidermoid carcinoma (CMC) of the jaws accounts only for 2-3% of all mucoepidermoid carcinomas reported. Bhaskar in 1963 first analysed the criteria for his central origin, histology and pathogenesis. The authors report a long-term evolution case of CMC of the mandible with peculiar clinical features observed at the Department of Maxillo-Facial Surgery of the School of Medicine and Surgery of the "Federico II" University of Naples (Naples, Italy) examining histopathologic and clinical features and problems related to the treatment.

Carboplatin + epirubicin +VP-16 + lenograstim followed by radiotherapy + carboplatin as radiosensitizer in limited small cell lung cancer. A multicenter phase II study.

UNLABELLED: A phase II trial was undertaken to test the activity and toxicity of carboplatin (300 mg/m2, i.v. day 1) + epirubicin (75 mg/m2, i.v. day 1) + VP-16 (100 mg/m2, i.v. days 1 to 3) + lenograstim (5 mcg/kg, s.c. days 6 to 15) administered every 3 weeks for 4 cycles and subsequent chest irradiation (50 Gy) + daily carboplatin (25 mg/m2) in the first-line treatment of adults affected by limited small cell lung cancer (SCLC). PATIENTS AND METHODS: A single-stage phase II design was used; the complete response (CR) rate after chest radiotherapy was the primary end-point. Twenty-three CRs were required out of 38 patients to consider the treatment worthy of further study. Prophylactic cranial irradiation (PCI) was planned in case of CR. Patients aged < or = 70 were eligible if they had limited SCLC, a performance status not worse than 2 by the ECOG scale and no prior chemotherapy or radiotherapy. RESULTS: From January 1995 to April 1999, 33 patients were enrolled; the median age was 60 years. All the patients started chemotherapy; 23 patients received chest irradiation and concurrent daily carboplatin; 11 patients also received PCI. Toxicity was generally mild. Sixteen CRs (48.5%, 95% CI: 30.8-66.5) were recorded; the objective response rate was 72.7% (95% CI: 54.5-86.7). The median time-to-progression was 7.9 months (95% CI: 6.5-10.4). The median-survival was 10.7 months (95% CI: 9.2-16.1). CONCLUSION: Induction chemotherapy with carboplatin + epirubicin + VP-16 followed by chest irradiation plus concurrent daily carboplatin is well-tolerated but not sufficiently active to warrant further study in the treatment of patients with limited SCLC.

MRNA encoding a putative RNA helicase of the DEAD-box gene family is up-regulated in trypomastigotes of Trypanosoma cruzi.

Differential display of mRNAs from Trypanosoma cruzi epimastigote and metacyclic trypomastigote stages showed several mRNA species differing in their expression level. The cDNA corresponding to one of these mRNAs was used as a probe in Northern blots and identified a RNA product of 2.6 kb with an expression level eight or more times higher in trypomastigotes than in epimastigotes. This probe was also used to screen a genomic library of T. cruzi CL Brener clone prepared in lambda FIX. A clone of about 15 kb was selected that, after partial sequencing, revealed an open reading frame of 688 amino acids encoding a deduced protein with similarity to RNA helicases of the DEAD-box gene family. The presence of the eight conserved motifs characteristic of the DEAD protein family was observed in the T. cruzi sequence, indicating that it corresponds to a putative RNA helicase gene, which we named HelTc. Southern blot analysis indicated that HelTc is a single-copy gene. Pulsed-field gel electrophoresis separation of chromosomes of several isolates of T. cruzi showed that this gene was localized in one or two chromosomal bands.

Thoracic radiotherapy and daily vinorelbine as radiosensitizer in locally advanced non small cell lung cancer: a phase I study.

Experimental studies have shown that vinorelbine is a powerful radiosensitizer in vitro. To date, no reports on clinical activity of the single agent vinorelbine as radiosensitizer have been published. The aim of the present phase I study was to determine the maximum tolerated dose (MTD) of vinorelbine administered daily concurrently with thoracic radiotherapy, with or without amifostine support, in the treatment of locally advanced non small cell lung cancer. In vitro studies have shown that vinorelbine can potentiate the antitumor effects of radiation therapy. Amifostine is a sulphydril compound that has shown to protect normal tissues from chemotherapy and radiotherapy-induced toxicities. Radiotherapy lasted 6 weeks and the total dose was 55 Gy. The daily fraction was 1.8 Gy, administered 5 days a week for 5 weeks and increased to 2.0 Gy during the sixth and last week. Concurrent vinorelbine was administered daily with a planned escalation of the dose from 4, to 5 and 6 mg/m(2). Fourteen patients were enrolled in the study. The first dose of vinorelbine was 4 mg/m(2) and it showed to be feasible without dose-limiting toxicity (DLT). Instead, the second dose level of 5 mg/m(2) was unfeasible because three out of six patients had DLT (grade 4 neutropenia, treatment interruption longer than 2 weeks for prolonged grade 2 neutropenia and treatment interruption longer than 2 weeks for prolonged grade 3 esophagitis together with grade 4 dyspnea). At that time, the study continued adding amifostine to vinorelbine in order to increase its MTD. Amifostine was administered by means of subcutaneous injection 15 min before each radiotherapy fraction at the fixed dose of 300 mg/m(2). However, 5 mg/m(2) of vinorelbine were considered unfeasible even with amifostine support because three out of five patients showed DLT (grade 4 neutropenia, febrile grade 4 neutropenia and grade 3 liver toxicity). Among 14 patients enrolled in the study, eight completed the planned treatment because six patients experienced DLT, which determined treatment interruption. Overall, four partial and two complete responses were observed. Two partial and one complete response were observed in those three patients who had been treated with the first dose of vinorelbine. In conclusion, our data show that the MTD of daily vinorelbine is 4 mg/m(2). Therefore, this is the recommended dose of daily vinorelbine to be administered with concurrent thoracic radiotherapy in a phase II trial. Finally, amifostine administered subcutaneously failed to increase the MTD of daily vinorelbine.

Single agent docetaxel plus granulocyte-colony stimulating factor (G-CSF) in previously treated patients with advanced non small cell lung cancer. A phase II study and review of the literature.

The use of salvage chemotherapy in advanced non small cell lung cancer (NSCLC) is controversial. However, many patients need to be treated in order to achieve relief of their symptoms. Docetaxel (taxotere) is one of the most active drugs for the treatment of advanced NSCLC and several studies have also shown its effectiveness in pretreated patients. In the present study, 23 patients were treated in order to evaluate both the effectiveness and toxicity of the single agent docetaxel. Furthermore, granulocyte-colony stimulating (G-CSF) factor was administered in order to reduce neutropenia related to docetaxel. Docetaxel was administered intravenously at a dose of 100 mg/m2, on day 1, and it was repeated every 3 weeks. G-CSF was administered for primary prophylaxis of neutropenia at the standard dose of 30 mg/day from day 4 to day 10 of each cycle. The treatment was tolerated well and 5 (21.7%) partial responses were obtained. The median time to progression and the median survival time were 3 and 5 months, respectively. The main side effect noted was fatigue, the intensity of which was grade 2 in 43.4% of cases and grade 3 in 8.7% of patients, respectively. One patient (4.3%) had grade 4 cutaneous toxicity. No cases of grade 4 neutropenia were reported. In conclusion, docetaxel is active when used for salvage chemotherapy in advanced NSCLC whilst concurrent primary prophylactic administration of granulocyte-colony stimulating factor seems to decrease severe neutropenia.