Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer.

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1-2 months later and was associated with poor survival. Ten fractionated urines were collected over 2-days in 29 patients. The median value of the rhythm-adjusted mean of urinary nucleoside excretion varied from 64.3 for pseudouridine down to 0.61 for cytidine. The rhythm amplitudes relative to the 24-h mean of 6 nucleoside excretions were associated with rest duration, supporting a tight link between nucleosides turnover and the rest-activity rhythm. Moreover, the amplitude of the 1-methylguanosine rhythm was correlated with the rest-activity dichotomy index, a significant predictor of survival outcome in prior studies. In conclusion, urinary excretion dynamics of modified nucleosides appeared useful for the characterization of the circadian control of cellular proliferation and for tracking early responses to treatments in colorectal cancer patients.

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

[Integrated management of mother and child health in the region of Monastir (Tunisia)]. / Piese en charge intégrér de la santé de la mere et de L'Enfant dans la région de Monastir (Tunisie).

The programme of integrated management of child health (IMCI) was established in Tunisia in 2002 in some health districts. This study evaluated the management of children under 5 years of age and their mothers using the IMCI programme in Zeramdine, a town 20 km south-west of Monastir. A cross-sectional study was conducted on a convenience sample of 526 medical records of children under 5 years attending the Zeramdine maternal and child health centre. The study evaluated preventive and curative aspects of child health. The mean age was 21.9 (SD 16.7) months. On the curative side, respiratory diseases were the leading reason for consultation (71.2%) followed by diarrhoea (15.4%). For preventive services, physicians systematically checked the child's immunization status and height and weight on the growth charts, and screened for strabismus and anaemia. The contribution to child health of IMCI is undeniable; it allows comprehensive care of the child, develops staff skills, upgrades the health system and improves family and community practices.

Integrated management of mother and child health in the region of Monastir [Tunisia]

The programme of integrated management of child health [IMCI] was established in Tunisia in 2002 in some health districts. This study evaluated the management of children under 5 years of age and their mothers using the IMCI programme in Zeramdine, a town 20 km south-west of Monastir. A cross-sectional study was conducted on a convenience sample of 526 medical records of children under 5 years attending the Zeramdine maternal and child health centre. The study evaluated preventive and curative aspects of child health. The mean age was 21.9 [SD 16.7] months. On the curative side, respiratory diseases were the leading reason for consultation [71.2%] followed by diarrhoea [15.4%]. For preventive services, physicians systematically checked the child’s immunization status and height and weight on the growth charts, and screened for strabismus and anaemia. The contribution to child health of IMCI is undeniable; it allows comprehensive care of the child, develops staff skills, upgrades the health system and improves family and community practices

Le programme de la prise en charge intégrée de la Santé de la mère et de l'enfant [PCIME] a été implanté en Tunisie en 2002 dans quelques circonscriptions sanitaires. La présente étude a évalué la prise en charge des enfants de moins de 5 ans et de leurs mères à travers le programme PCIME à Zeramdine, ville située à 20 km au sud-ouest de Monastir. Une étude transversale a été réalisée sur un échantillon représentatif de 526 dossiers médicaux d'enfants de moins de cinq ans consultant dans le centre de protection maternelle et infantile de Zeramdine. L'étude a évalué tous les aspects curatifs et préventifs de la prise en charge de la santé de l'enfant.La moyenne d'âge était de 21,9 mois [ET 16,7]. Sur le plan curatif, les maladies respiratoires dominaient les motifs de consultation [71,2 %], suivies de la diarrhée [15,4 %]. Sur le plan préventif, les médecins vérifiaient systématiquement l'état vaccinal et le développement staturo-pondéral de l'enfant, et assuraient le dépistage de l'anémie et du strabisme. L'apport de la PCIME est indéniable; elle permet une prise en charge globale de l'enfant, le développement des compétences des ressources humaines, la mise a niveau du système de santé et l'amélioration des pratiques familiales et communautaires

Modern insights into hepatic arterial infusion for liver metastases from colorectal cancer.

Hepatic arterial infusion (HAI) selectively achieves high drug exposure of liver metastases from colorectal cancer. Such pharmacologic advantage has doubled the response rate of liver metastases on fluoropyrimidines (FP) delivered as HAI rather than intravenously, in a meta-analysis of randomised clinical trials (RCT). However, the improvement in antitumour efficacy did not consistently translate into any significant survival advantage across all randomised studies. However, the results of this meta-analysis should be cautiously interpreted due to the heterogeneity of the studies, inadequate study designs, obsolete therapy and high rate of early treatment discontinuation due to HAI technical failures or hepato-biliary toxicity. Most studies actually were performed before year 2000 and did not integrate the considerable progresses accomplished in the management of CRC, such as multidrug regimens instead of single agent FP and secondary resection of metastases, a major contributing factor for prolonged survival. Furthermore, the systemic exposure of patients given HAI was low without concomitant IV therapy, facilitating extra-hepatic relapses. The role of HAI in liver metastases from CRC should, therefore, be revisited, using modern multidisciplinary therapeutic approaches and appropriate study designs. Recommendations for the design of future RCTs exploring HAI are provided.

Feasibility of cetuximab given with a simplified schedule every 2 weeks in advanced colorectal cancer: a multicenter, retrospective analysis.

Cetuximab was approved using a weekly schedule, alone or in combination with chemotherapy (CT). However, many CT regimens in metastatic colorectal cancer (CRC) are delivered every 2 weeks (q2wks). Preliminary data suggested that a simplified schedule using cetuximab q2wks, 500 mg/m² would be equivalent to the standard weekly administration. Medical data of all patients with advanced CRC who received cetuximab q2wks were retrospectively collected and checked for consistency by an independent monitor in 4 European centers. Ninety-one patients were treated between 2005 and 2007 when the K-RAS mutational status of tumors was not determined routinely. They received a median of 4 (0-5) previous drugs, including previous weekly cetuximab in 38.5% of patients. Cetuximab q2wks was associated with an irinotecan-based regimen in 85.7% of patients. The median number of cetuximab administrations was 6 (1-23). Skin toxicity was observed in 68.2% of evaluable patients (grade 3 in 15%). Only one grade 1 allergy was reported. In the 84 patients beyond first-line therapy, response rate was 29.3%. The median progression-free survival was 3.0 months (range 2.2-3.8), and median overall survival was 9.0 months (range 6.2-11.8). Cetuximab q2wks appears safe and effective in heavily pretreated patients and convenient in combination with q2wks CT schedules.

Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Few data are available from clinical trials for elderly patients receiving cetuximab. PATIENTS AND METHODS: The clinical data of consecutive patients aged > or =70 years given cetuximab for metastatic CRC were retrospectively captured from hospital pharmacy registries in seven centers. RESULTS: Fifty-six patients received cetuximab+/-with irinotecan. Median age was 76 years (70-84), 86% of patients were pretreated with fluoropyrimidines, irinotecan and oxaliplatin and 69.6% had documented resistance to irinotecan. Objective response rate was 21% (95% CI: 11-32%). The median progression-free survival was 4.4 months (95% CI: 3.0-5.7 months) and the median overall survival was 16.0 months (95% CI: 13.5-18.5 months). Skin rash occurred in 75% of the patients (11% grade 3) and diarrhea in 80% (20% grades 3-4). CONCLUSION: Tolerability of cetuximab was acceptable in elderly patients with pretreated metastatic CRC. Efficacy appeared similar to that observed in younger patients.