Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

BACKGROUND: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. METHODS: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). RESULTS: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). CONCLUSIONS: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

An evaluation of a surgical telepresence system for an intrahospital local area network.

We evaluated a digital telepresence system in an operating theatre (OR) environment which enabled a consultant to join the surgical team from a remote site by audiovisual communication. The system is based on video transmission using a streaming technique, with a server and a client connected via a local area network (LAN). Two cameras can be remotely controlled: one camera is built into the OR lamp and a second, laparoscopic camera is mounted on a robotic arm. Another feature of the system is teledemonstration, which permits the remote consultant to demonstrate points of particular interest. We evaluated the system clinically in 237 cases. In 28 cases (12%), telepresence could not be established for various reasons, mainly human failure. In 42 cases (18%), the full potential of telepresence was used. Technical evaluation showed that a data rate of 2 Mbit/s provides sufficient audio and video quality, as well as reliable teledemonstration. The data transmission delay was acceptable for clinical purposes (video 0.92 s, audio 0.6 s from OR to client, audio 0.7 s from client to OR). The study showed that telepresence is a promising means of providing highly specialized expertise within the OR.

Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer.

This phase II trial studied the antitumor effect and toxicity of weekly irinotecan (CPT-11, 125 mg/m(2) 60 min iv infusion, weekly for 4 wk plus 2 wk rest) as second-line chemotherapy in patients with advanced colorectal cancer (CRC) resistant or refractory to prior 5-fluorouracil (5-FU) therapy. Sixty-nine patients with adenocarcinoma (57% in the colon and 43% in the rectum) were enrolled. The median number of treatment cycles received per patient was 4 (range, 1-6). Overall response rate was 18% (95% CI, 9-26), with 4 complete responses (6%) and 8 partial responses (12%), and a median duration of response of 8.1 mo (95% CI, 4.2-12.1). Stable disease was observed in 19 patients (28%). The median time to disease progression was 5.2 mo (95% CI, 4.3-6.1), and the median overall survival was 13.3 mo (95% CI, 9.8-16.8 months). The toxicity profile was favorable: grade 3/4 delayed diarrhea was observed in 10 patients (14.5%) in one cycle each, and grade 3/4 neutropenia in 6 patients (8.7%) and 6 cycles (3.3%). No febrile neutropenia or infection was documented. Grade 3/4 nausea and vomiting were reported in 1 (1.4%) and 7 patients (10.1%), respectively. In conclusion, this phase II trial showed a response rate and a toxicity profile of weekly CPT-11 in line with the results of prior phase II studies.

Análisis de la relación (correlación y asociación) entre la p185 y las variables moleculares RE, RP, pS2 y Cat D, en una serie de pacientes con cáncer de mama y ganglias positivos / Analisis of the relationship (correlation and association) between p 185 and the molecular variables RE, RP, pS2, and Cat D in a series of breast cancer patients with positive lymph nodes

Propósito: Analizar los resultados obtenidos de los estudios comparativos entre la sobreexpresión de la oncoproteína p185 determinada cuantitativamente y las variables moleculares RE, RP, pS2 y Cat D. Material y métodos: En una serie de 217 pacientes con cáncer de mama y ganglios positivos, con la oncoproteína p185 determinada cuantitativamente mediante un método ELISA, se llevaron a cabo estudios comparativos de Relación (Correlación y Asociación) del contenido de la p185 con las variables moleculares RE, RP, pS2 y Catepsina D.Resultados: Con una mediana de seguimiento de 50 meses (rango 9-90 meses) en nuestra serie, el estudio de correlación de Pearson entre los transformados logarítmicos de los niveles de p185 y de los receptores estrogénicos y de los receptores de progesterona no mostró correlación alguna, mientras que sí la hubo para la pS2 y la Catepsina D. Resultados similares se obtuvieron en el estudio de correlación de Spearman. Cuando la serie tumoral fue dicotomizada, en el grupo de tumores p185-negativos se observó una correlación positiva para RE, RP, pS2y CD. En el grupo de tumores p185-positivos se encontró una correlación negativa para RE y RP y correlación positiva para la pS2 y CD. La influencia del estado de la p185 sobre el contenido de RE, RP, hS2,CD fue determinada mediante el análisis de Mann-Whitney mostrando que los tumores con la p185 sobreexpresada tenían una mediana de los niveles de RE y RIP muy baja, igual para la pS2 y más alta para la CD que los tumores con concentraciones de p185 inferiores a 260 fmol/mg (35 fmol/mg). Similares resultados se observaron cuando se llevó a cabo el análisis de tabla de contingencia, y cuando los tumores fueron estratificados en cuatro categorías de p185: muy baja (p185 600 fmol/mg).Conclusiones: Nuestros resultados sugieren la identificación de una subpoblación tumoral con un fenotipo más agresivo y, presumiblemente, con un peor comportamiento evolutivo (AU)

Construction and characterization of an isogenic slt-ii deletion mutant of enterohemorrhagic Escherichia coli.

Enterohemorrhagic Escherichia coli (EHEC) produces Shiga-like toxins (SLT), potent protein synthesis inhibitors. To further dissect the role of SLT-II in the course of disease, we have constructed E. coli TUV86-2, an isogenic SLT-II-negative mutant of EHEC strain 86-24. The slt-ii gene was inactivated by suicide vector mutagenesis. We also isolated derivatives of strain 86-24 that were cured of the phage carrying the toxin genes.

[Iodine-131 therapy of autonomous adenoma of the thyroid. 7-year results]. / 131Jod-Therapie des autonomen Adenoms der Schilddrüse. Ergebnisse aus 7 Jahren.

Between 1977 and 1984 a total of 301 patients with autonomous thyroid adenoma were irradiated with an individually calculated one-time dose of 400 Gy units of 131I. Repeated follow-up tests were made in 217 patients (up to 7.2 years, mean of two years). Pre- and post-treatment diagnosis in all patients consisted of determining T3 and T4, one TRH test, one 131I two-phase test to determine treatment, including quantified scintigraphy (under suppression, if necessary), as well as post-treatment scintigraphy and (post-treatment) 99mTc scintigraphy. The treatment was successful in 98% of patients; there was no difference between compensated and decompensated forms. Euthyroid state was achieved in 87% of patients, with typical findings of compensated T3 oversecretion, as is known to occur with endemic goiter in regions of iodine deficiency. The ability of the thyroid for autoregulatory adaptation to such iodine deficiency is thus preserved. Preclinical hypothyroidism occurred in 11% of patients: it could have been avoided in about half of them. Persistent or recurring autonomous adenoma was observed in 2% of patients as a result of under-dosage. One should thus aim at a dose of 400 Gy, to obtain optimal elimination. Radiation-induced carcinogenesis was not observed: radioiodine treatment and operation are thus of equal value in the causal treatment of autonomous adenoma. Radioiodine treatment is indicated in patients aged over 40 years with additional diseases and increased risk of anaesthesia and operation. It is preferred treatment if there are multiple autonomous adenomas.