Purpose
PM00104 (Zalypsis
®
) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting ...toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).
Methods
Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis.
Results
DLTs comprised severe neutropenia lasting >5 days (
n
= 4 patients), vomiting, thrombocytopenia, transaminase increases (
n
= 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (
n
= 1 each). The RD was 4.0 mg/m
2
. Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months.
Conclusions
PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.
Control of carcinoid syndrome with everolimus Capdevila, J.; Díez Miranda, I.; Obiols, G. ...
Annals of oncology,
January 2011, 2011, 2011-Jan, 2011-01-00, Letnik:
22, Številka:
1
Journal Article
Cytochromes P450 of the CYP2C and CYP4A gene subfamilies metabolize arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and to 19-
and 20-hydroxyeicosatetraenoic acids ...(HETEs), respectively. Abundant functional studies indicate that EETs and HETEs display
powerful and often opposing biological activities as mediators of ion channel activity and regulators of vascular tone and
systemic blood pressures. Incubation of 8,9-, 11,12-, and 14,15-EETs with microsomal and purified forms of rat CYP4A isoforms
led to rapid NADPH-dependent metabolism to the corresponding 19- and 20-hydroxylated EETs. Comparisons of reaction rates and
catalytic efficiency with those of arachidonic and lauric acids showed that EETs are one of the best endogenous substrates
so far described for rat CYP4A isoforms. CYP4A1 exhibited a preference for 8,9-EET, whereas CYP4A2, CYP4A3, and CYP4A8 preferred
11,12-EET. In general, the closer the oxido ring is to the carboxylic acid functionality, the higher the rate of EET metabolism
and the lower the regiospecificity for the EET Ï-carbon. Analysis of cis -parinaric acid displacement from the ligand-binding domain of the human peroxisome proliferator-activated receptor-α showed
that Ï-hydroxylated 14,15-EET bound to this receptor with high affinity ( K
i = 3 ± 1 n m ). Moreover, at 1 μ m , the Ï-alcohol of 14,15-EET or a 1:4 mixture of the Ï-alcohols of 8,9- and 11,12-EETs activated human and mouse peroxisome
proliferator-activated receptor-α in transient transfection assays, suggesting a role for them as endogenous ligands for these
orphan nuclear receptors.
Neuroendocrine tumors are of great scientific interest, given that they are difficult to diagnose and treat. Despite being relatively rare (<1/100,000 individuals, 1-2% of the gastrointestinal ...neoplasias) and indolent, their potential malignancy must not be forgotten. An increase in the number of diagnosed tumors has been observed in recent years. The aim of the present study was to update a published case series of 19 patients suspected of presenting with pancreatic neuroendocrine tumor with 51 current cases, to study and compare the new results with those of the previous case series, as well as with other recent publications from Spain, the United States, China, and India.
A retrospective, multicenter case series was conducted on 70 patients (19 cases published in 2011), whose data has been collected over a period of 23 years. The variables analyzed were: age, sex, symptomatology, tumor size, location, metastasis, final diagnosis, and surgery, among others.
Mean patient age was 55 years and 60% of the patients were men. Disease location was the pancreatic head in 28.5% of the patients and the tail in 27.1%, mean tumor size was 3.9cm (0.2-10cm), 71.4% of the patients had non-functioning tumors, 32.8% had metastases (100% to the liver), 74.2% of the patients were operated on, and actuarial survival was 75%.
Differences were observed between the previously published case series and the current results. There was an increase in incidentalomas and non-functioning tumors, but no variation in the overall survival rate. The differences with other case series (age, sex, and tumor location) were dependent on the country where the cases were compiled. The increase in tumors could be related to a higher number of diagnoses made through imaging studies and to the greater sensitivity of the devices employed.
Los tumores neuroendocrinos generan un gran interés científico, dada la dificultad de su diagnóstico y tratamiento. A pesar de ser relativamente raros (<1/100,000 individuos, 1-2% de las neoplasias digestivas) e indolentes, no se debe olvidar que, en última instancia, son potencialmente malignos. En los últimos años, se ha observado un incremento en el número de tumores diagnosticados.
El objetivo del estudio fue la actualización de una serie publicada de 19 casos con sospecha de tumor neuroendocrino pancreático, con otros 51 casos actuales, para el estudio y comparación de los nuevos resultados tanto con la serie anterior como con otras publicadas recientemente en España, Estados Unidos, China e India.
Serie retrospectiva, multicéntrica de 70 pacientes (19 publicados en 2011) recopilados a lo largo de 23 años. Variables analizadas: edad, sexo, sintomatología, tamaño, localización, metástasis, diagnóstico final y cirugía, entre otras.
Edad media de 55 años; 60% hombres; localización: cabeza (28.5%) y cola (27.1%); tamaño medio 3,9cm (0,2-10cm); no funcionantes el 71.4%; metástasis en el 32.8% (100% hepáticas), operados el 74.2% y supervivencia actuarial del 75%.
Se observan diferencias entre la serie anteriormente publicada y los resultados actuales, con un incremento del porcentaje de incidentalomas y de tumores no funcionantes, pero sin variación en la tasa de supervivencia global. Con otras series actuales, las diferencias (edad, sexo y localización tumoral) dependen del país donde se han recopilado los casos. Este incremento podría relacionarse con el aumento del diagnóstico por la imagen y con la mayor la sensibilidad de los dispositivos.
The present study compares the risk factors, presentation and outcome of community-acquired Legionella pneumophila pneumonia in 138 sporadic-case patients (1994-2004) and 113 outbreak-case patients ...(2002) treated in two hospitals in Catalonia (Spain) since urinary antigen assays were adopted. Univariate and multivariate analysis were performed to compare epidemiological and clinical features, blood chemistry values, radiological findings and outcome of sporadic and epidemic legionnaires' disease. Univariate analysis showed that male sex, chronic lung disease, HIV infection and immunosuppressive therapy prevailed in sporadic cases. Presentation with respiratory symptoms, confusion and blood chemistry alterations, such as hyponatraemia, aspartate aminotransferase and blood urea nitrogen elevation, and partial pressure of oxygen P(O)(2) <7.98 KPa (60 mmHg) were also more frequent in sporadic cases, while headache prevailed in outbreak cases. Sporadic cases had a greater delay in treatment, were more severe and had a worse outcome than epidemic cases. Multivariate analysis showed significant differences in sex, chronic lung disease, HIV infection and headache. The clinical and outcome differences between the two groups may be explained by the detection of milder forms of legionnaires' disease, the earlier treatment and the lower severity of underlying disease in the outbreak cases.
Background
Of all thyroid cancers, <5 % are medullary (MTC). It is a well-characterized neuroendocrine tumor arising from calcitonin-secreting C cells, and
RET
gene plays a central role on its ...pathogeny.
Methods
The electronic search was conducted using MEDLINE (PubMed), EMBASE and Cochrane Central Register of Controlled Trials. Quality assessments of selected current articles, guidelines and reviews of MTC were performed.
Results
This consensus updates and summarizes biology, treatment and prognostic considerations of MTC.
Conclusions
Multidisciplinary teams and specialized centers are recommended for the management of MTC patients. In the metastatic setting, those patients with large volume of disease are candidates to start systemic treatment mainly if they are symptomatic and the tumor has progressed in the last 12–14 months. Wait and see strategy should be offered to patients with: disseminated disease with only high levels of calcitonin and no macroscopic structural disease, low burden and absence of progression.
PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II ...dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.
Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.
A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months.
PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.
PDF
