Summary Owing to the need of lifelong immunosuppression, solid-organ transplant recipients are known to have an increased risk of posttransplant malignancies including lung cancer. Posttransplant ...neoplastic transformation of donor-derived cells giving rise to hematopoietic malignancies, Kaposi sarcoma, and basal cell carcinoma in nongraft tissues has been reported. The goal of this study was to assess the cell origin (donor versus recipient derived) of posttransplant non–small cell lung carcinomas (NSCLCs) in kidney and heart transplant recipients. An institutional database search identified 2557 kidney and heart transplant recipients in 8 consecutive years. Among this cohort, 20 (0.8%) renal and 18 (0.7%) heart transplant recipients developed NSCLC. The study cohort comprised 6 of 38 NSCLCs arising in donor-recipient sex-mismatched transplant patients. The tumor cell origin was evaluated by chromogenic in situ hybridization with Y-chromosome probe on formalin-fixed, paraffin-embedded tissues. Y-chromosome was identified in 97% ± 1% (range from 92% to 99%) of all types of nucleated cells in male control tissues. In all 5 NSCLCs from male recipients of female donor organ, Y-chromosome was identified in 97% ± 2% (range from 92% to 100%) of tumor cells, statistically equivalent to normal control ( P < .001). No Y-chromosome was identified in NSCLC cells from a female recipient of male kidney. These findings suggest a recipient derivation of NSCLC arising in kidney and heart transplant recipients. A combination of histologic evaluation and chromogenic in situ hybridization with Y-chromosome analysis allows reliable determination of tissue origin in sex-mismatched solid-organ transplant recipients and may aid in management of posttransplant malignancy in such cases.
Our preclinical studies have shown that acidic and basic fibroblastic growth factors confer broad spectrum chemoresistance and that low concentrations (10-50 microM) of suramin, a nonspecific ...fibroblastic growth factor inhibitor, enhance the antitumor activity of paclitaxel in vivo. The present Phase I study evaluated low-dose suramin in combination with paclitaxel/carboplatin in advanced non-small cell lung cancer patients.
Patients received suramin followed by paclitaxel (175-200 mg/m(2)) and carboplatin area under the concentration-time curve of 6 mg/ml/min, every 3 weeks. The initial suramin dose for the first cycle was 240 mg/m(2), and the doses for subsequent cycles were calculated based on the 72-h pretreatment plasma concentrations. The recommended suramin dose would yield plasma concentrations of 10-20 microM at 48 h in >or=5 of 6 patients.
Fifteen patients (11 stage IV, 4 stage IIIB, 9 chemonaive, and 6 previously treated) received 85 courses. The most common toxicities were neutropenia, nausea/vomiting, malaise/fatigue, and peripheral neuropathy. No treatment-related hospitalizations, adrenal dysfunction, or episodes of sepsis occurred. The initial suramin dose resulted in the targeted concentrations of 10-20 microM at 48 h in 5 of the first 6 patients treated but also resulted in peak concentrations > 50 microM in all patients. Dividing the suramin dose to be administered in two doses, 24 h apart, yielded the target concentrations and avoided undesirable peak concentrations. Discernable antitumor activity occurred in 7 of 10 patients with measurable disease, including 2 with prior chemotherapy. The median time to tumor progression is 8.5 months (range, 3-27+ months) for 12 evaluable patients.
Low-dose suramin does not increase the toxicity of paclitaxel/carboplatin combination. The suramin dose can be calculated based on clinical parameters. Because of the preliminary antitumor activity observed, efficacy studies in chemonaive and chemorefractory patients are under way.
With the evolution of softwarised industrial infrastructures, there is an increasing need for more sophisticated cyber security solutions that can protect industrial processes from a rapidly evolving ...landscape of cyber threats. In this context, we present an agent-based approach that provides process monitoring, predictive process behaviour, and process control to give the organisations appropriate situational awareness in relation to cyber security threats, enabling them to re-actively or pro-actively detect attacks and respond to advanced persistent threats and multi-vector attacks. Our architectural solution is based on four agents: Process Inventory Agent (PIA), Process Monitoring Agent (PMA), Process Forecasting Agent (PFA), and the Process Slicing Control Agent (PSCA), which work together to deliver a novel mitigation tool to secure softwarised industrial environments. The architecture has been designed, prototyped, and validated in order to demonstrate the effectiveness of our solution. Experimental results show that the proposed solution can successfully mitigate different attacks in the concerned context.
...the patients treated with NSAIDs usually did not receive antibiotics, until they reached the hospital. ...NSAIDs may hamper the immune response, thus predisposing those who took them to a more ...severe pneumonia manifestation.
Presentamos el caso de una paciente que sufrió accidente de tráfico con avulsión del plexo braquial izquierdo, y que presentaba dolor muy intenso (escala visual analógica 8) de características ...neuropáticas en la fase aguda postraumática. Dosis altas de remifentanilo fueron inefectivas para control del cuadro álgico, el cual se trato con éxito con una infusión de ropivacaína a través de catéter epidural cervical (C5-6). El dolor es controlado en fase crónica (escala visual analógica 2) con agentes específicos contra dolor neuropático (gabapentina, amitriptilina, clonacepam y tramadol).
Introducción: Los pacientes oncológicos pueden presentar dolor de tipo neuropático, el cual representa un reto difícil, con buena respuesta a la medicación antiepiléptica. Existen diversos estudios ...que confirman los buenos resultados asociados al uso de topiramato en pacientes con cáncer y sintomatología neuropática acompañante. Las diferentes drogas antiepilépticas difieren de forma sustancial en sus efectos sobre el peso corporal. El topiramato conlleva cuadros de anorexia y/o pérdida del peso hasta en un 15% de los casos. Casos clínicos: Tres pacientes oncológicos en los que la pérdida de peso asociada al empleo de topiramato fue vivida como un efecto negativo físico y psíquico, por temor a una posible recidiva tumoral. Conclusiones: Topiramato es un fármaco eficaz en el tratamiento del dolor de tipo neuropático. La pérdida de peso que resulta de su utilización puede ser beneficiosa en pacientes con sobrepeso importante. Este efecto podría ser una contraindicación relativa a su uso en pacientes con clínica de anorexia, desnutrición severa y en pacientes oncológicos. En estos últimos, la aparición de este síndrome constitucional puede conllevar un importante aumento de episodios de ansiedad en la familia y el propio enfermo, así como un exceso de pruebas médicas para descartar una progresión tumoral.
The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. ...infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity.
Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities.
Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that precluded dose escalation. The maximum tolerated dose of ET-743 that could be administered repetitively was 325 microg/m(2)/day. Antitumor activity was noted in three patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas. The pharmacokinetics of ET-743 were dose independent, and drug accumulation over the 5 days of treatment was modest, with the ratio of the area under the plasma-versus-time curve on day 5 to that on day 1 averaging 2.05. The volume of distribution at steady state was large (mean, 1037 liters/m(2)), and the mean terminal half life on day 5 was 26.81 h.
The maximum tolerated dose of ET-743 that can be administered repetitively is 325 microg/m(2)/day daily x 5 every 3 weeks, which is recommended for disease-directed clinical trials. The acceptable toxicity profile of ET-743 on the divided-dose schedule evaluated in this trial, as well as the generally superior antitumor activity associated with divided-dose schedules in preclinical studies, provides a rationale for further evaluation of ET-743 on this administration schedule.
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