Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.

PURPOSE: In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. METHODS: 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. RESULTS: Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. CONCLUSION: Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.

Object exploration in extremely preterm infants between 6 and 9 months and relation to cognitive and language development at 24 months.

Although early object exploration is considered a key ability for subsequent achievements, very few studies have analyzed its development in extremely low gestational age infants (ELGA- GA <28 weeks), whose early motor skills are delayed. Moreover, no studies have examined its developmental relationship with cognitive and language skills. The present study examined developmental change in Motor Object Exploration (MOE) and different types of MOE (Holding, Oral, Manual and Manual Rhythmic Exploration) in 20 ELGA and 20 full term (FT) infants observed during mother-infant play interaction at 6 and 9 months. It also explored whether specific types of MOE were longitudinally related to 24-month language and cognitive abilities (GMDS-R scores). ELGA infants increased MOE duration from 6 to 9 months, eliminating the initial difference with FT infants. In addition, ELGA infants showed a different pattern of Oral Exploration, that did not increase at 6 months and decrease at 9 months. Oral and Manual Exploration durations at 6 months were longitudinally related to 24-month GMDS-R language and cognitive performance scores respectively. We discuss the relevance of assessing early exploratory abilities in ELGA infants in order to implement customized intervention programs for supporting the development of these skills.

Dyadic co-regulation, affective intensity and infant's development at 12 months: A comparison among extremely preterm and full-term dyads.

Extremely low gestational age children (ELGA, born below 28 weeks of GA) represent the most at-risk preterm group in terms of survival, developmental sequelae and rates of impairment and cognitive delays. However, the impact of an extremely preterm birth on mother-infant co-regulation and affective intensity which may affect early infant's development has not been investigated. Based on a relational dynamic system approach, our study aimed to investigate the quality of co-regulation and affective intensity during spontaneous play interaction in 20 mother-infant ELGA dyads compared to 20 full-term (FT) dyads at 12 months (corrected age for ELGA infants). Relationships between the quality of dyadic co-regulation and the infant's level of cognitive, motor and language development were also investigated. The quality of dyadic co-regulation was assessed using the Revised Relational Coding System (R-RCS) by Fogel et al. (2003), the mothers' and infants' affective intensity was coded using a coding system by Lunkenheimer, Olson, Hollenstein, Sameroff, and Winter (2011). Infants' development was assessed using the Bayley Scales (BSID-III, 2006). With respect to FT dyads, ELGA dyads were characterised by less frequent symmetric and more frequent unilateral co-regulation patterns and by less positive and more neutral affective intensity of both infants and mothers. Cognitive, motor and language scores were lower in ELGA infants than in FT infants. Symmetrical co-regulation was related to motor scores in ELGA infants, and to cognitive scores in FT infants. Our findings contribute to the literature by demonstrating the difficulties of ELGA mother-infant dyads at 12 months in sharing the symmetric co-regulation and positive affective intensity and how symmetric co-regulation is strictly related to motor development in ELGA infants. Based on these findings, intervention programmes to foster joint attention, active involvement and positive affective intensity in ELGA dyads and infants' development in the first year of life should be designed.

A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases.

BACKGROUND: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s). METHODS: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria. RESULTS: Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively. CONCLUSIONS: This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study.

BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.

Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer.

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy.

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

Condiciones de intubación, extubación y respuesta hemodinámica a la intubación traqueal: estudio de comparación de dos fármacos para técnicas de anestesia intravenosa total: remifentanilo y ketamina / Intubation and extubation, conditions and haemodynamic response to tracheal intubation. Comparative study of two drugs for total intravenous anaesthesia techniques: remifentanilo and ketamina

Introducción: El objetivo fue comparar dos técnicas, ketamina-fentanilo-midazolam y remifentanilo-midazolam, ambas en goteo y evaluar la dificultad de intubación endotraqueal, los criterios para predecir una extubación exitosa y los efectos sobre la respuesta cardiovascular. Pacientes y Métodos: Fueron estudiados 47 pacientes asignados a dos grupos: Grupo (K) ketamina: n=22, recibieron ketamina 0,1 mg/kg/m durante 10 minutos e Innovan 0,02 ml/kg. Grupo (R) remifentanilo: n=25, recibieron remifentanilo 1 A/kg//m durante 5 minutos. Se utilizó succinilcolina 1,5 mg/kg para la intubación endotraqueal. Variables medidas: Valoración de la dificultad de la intubación (IDS). Parámetros hemodinámicos: Tensión arterial sistólica (TAS), Tensión arterial diastólica (TAD), Frecuencia cardíaca (FC) en los siguientes momentos: MO: antes de las drogas anestésicas; M1: inmediatamente; M2, M3 y M4: 5, 10 y 15 minutos después de la intubación de la tráquea, respectivamente. Análisis estadístico: se consideró significativo p<0.05. Resultados: No se observaron diferencias significativas entre los grupos con relación a los datos demográficos, duración del procedimiento, dificultad para intubación y criterios para predecir una extubación exitosa. Con respecto a los parámetros hemodinámicos, no se detectaron diferencias dentro del grupo K en el estudio a lo largo del tiempo para TAS, TAD, FC y FCxTAS, mientras que el grupo R no se encontraron diferencias significativas entre los TAS (p=0.082), detectándose diferencias significativas para TAD, FC y FCxTAS entre M0 y M1, M2, M3 y M4. Comparación entre los grupos K y R: Se comprobaron diferencias significativas, K>R para TAS, TAD, FC, FCxTAS en M1, M2, M3 y M4. Discusión: El grupo ketamina mostró los valores significativos más elevados; a pesar de esto, no se observaron implicancias fisiológicas o clínicas. Se puede concluir que el remifentanilo provee una estabilidad hemodinámica superior a la ketamina. (AU)

Condiciones de intubación, extubación y respuesta hemodinámica a la intubación traqueal: estudio de comparación de dos fármacos para técnicas de anestesia intravenosa total: remifentanilo y ketamina / Intubation and extubation, conditions and haemodynamic response to tracheal intubation. Comparative study of two drugs for total intravenous anaesthesia techniques: remifentanilo and ketamina

Introducción: El objetivo fue comparar dos técnicas, ketamina-fentanilo-midazolam y remifentanilo-midazolam, ambas en goteo y evaluar la dificultad de intubación endotraqueal, los criterios para predecir una extubación exitosa y los efectos sobre la respuesta cardiovascular. Pacientes y Métodos: Fueron estudiados 47 pacientes asignados a dos grupos: Grupo (K) ketamina: n=22, recibieron ketamina 0,1 mg/kg/m durante 10 minutos e Innovan 0,02 ml/kg. Grupo (R) remifentanilo: n=25, recibieron remifentanilo 1 µ/kg//m durante 5 minutos. Se utilizó succinilcolina 1,5 mg/kg para la intubación endotraqueal. Variables medidas: Valoración de la dificultad de la intubación (IDS). Parámetros hemodinámicos: Tensión arterial sistólica (TAS), Tensión arterial diastólica (TAD), Frecuencia cardíaca (FC) en los siguientes momentos: MO: antes de las drogas anestésicas; M1: inmediatamente; M2, M3 y M4: 5, 10 y 15 minutos después de la intubación de la tráquea, respectivamente. Análisis estadístico: se consideró significativo p<0.05. Resultados: No se observaron diferencias significativas entre los grupos con relación a los datos demográficos, duración del procedimiento, dificultad para intubación y criterios para predecir una extubación exitosa. Con respecto a los parámetros hemodinámicos, no se detectaron diferencias dentro del grupo K en el estudio a lo largo del tiempo para TAS, TAD, FC y FCxTAS, mientras que el grupo R no se encontraron diferencias significativas entre los TAS (p=0.082), detectándose diferencias significativas para TAD, FC y FCxTAS entre M0 y M1, M2, M3 y M4. Comparación entre los grupos K y R: Se comprobaron diferencias significativas, K>R para TAS, TAD, FC, FCxTAS en M1, M2, M3 y M4. Discusión: El grupo ketamina mostró los valores significativos más elevados; a pesar de esto, no se observaron implicancias fisiológicas o clínicas. Se puede concluir que el remifentanilo provee una estabilidad hemodinámica superior a la ketamina.

Cisplatin, epirubicin and cyclophosphamide (PEC) in the treatment of advanced ovarian cancer.

We report the long-term results of a series of patients affected by advanced epithelial ovarian cancer treated with the PEC combination (cisplatin 60 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 750 mg/m2, all at day 1, every 21 days). Response was evaluated after three cycles, and treatment continued in responsive patients. A total of 80 patients with a median follow-up of 55 months were studied. Fifty-eight patients with stage III ovarian cancer and 22 patients with stage IV received PEC as primary treatment (41 patients), or for residual disease after surgery (37 patients), or for relapsed disease after primary surgery (2 patients). The overall response rate was 67.5% (20.0% complete response, 47.5% partial response), with 22.5% stable disease and 3.7% progressive disease. Median progression free survival was 13.0 months, and median survival was 25 months. Grade III-IV toxicity was moderate: leukopenia 20.0% of patients, thrombocytopenia 5.0%, anemia 16.2%. No cardiac toxicity was observed. In conclusion, the PEC combination, an anthracycline-containing platinum-based regimen, proved to be effective in advanced ovarian cancer, in terms of response rate and overall survival. The regimen was devoid of significant toxicity and in particular of cardiac toxicity.

Multimodal biochemical modulation of 5-fluorouracil by leucovorin, methotrexate, and interferon alpha in patients with advanced colorectal cancer.

A total of 26 patients with advanced colorectal cancer received 60 mg/m2 methotrexate i.v. on days 1-4; 400 mg/m2 5-fluorouracil i.v. on days 2, 3, 5, and 6; and 100 mg/m2 6S-leucovorin i.v. on days 2, 3, 5, and 6. Interferon-alpha 2b at a dose of 3 million U was given i.m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2-28%): In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5-fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity.