Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy

The predictive value of KRAS mutation in metastatic colorectal cancer (MCRC) patients treated with cetuximab plus chemotherapy has recently been suggested. In our study, 59 patients with a chemotherapy-refractory MCRC treated with cetuximab plus chemotherapy were included and clinical response was evaluated according to response evaluation criteria in solid tumours (RECIST). Tumours were screened for KRAS mutations using first direct sequencing, then two sensitive methods based on SNaPshot and PCR-ligase chain reaction (LCR) assays. Clinical response was evaluated according to gene mutations using the Fisher exact test. Times to progression (TTP) were calculated using the Kaplan–Meier method and compared with log-rank test. A KRAS mutation was detected in 22 out of 59 tumours and, in six cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, P=0.015). Our study confirms that KRAS mutation is highly predictive of a non-response to cetuximab plus chemotherapy in MCRC and highlights the need to use sensitive molecular methods, such as SNaPshot or PCR-LCR assays, to ensure an efficient mutation detection

‘A phase II study of oral uracil/ftorafur (UFT®) plus leucovorin combined with oxaliplatin (TEGAFOX) as first-line treatment in patients with metastatic colorectal cancer'

This phase II trial was performed to evaluate the efficacy and tolerability of a new combination of Uracil/Ftorafur (UFT®)/leucovorin (LV) and oxaliplatin in patients (pts) with metastatic colorectal cancer (MCRC) who had not received prior chemotherapy for metastatic disease. Between February 2002 and October 2002, 64 patients received UFT® 300 mg m−2 day−1 and LV 90 mg day−1 from day 1 to day 14 combined with oxaliplatin 130 mg m−2 on day 1, every 3 weeks. All patients were evaluable for safety analysis and 58 of 64 patients were eligible for efficacy. Responses were reviewed by an independent review committee. Of the 58 per-protocol defined assessable patients, 1 complete response and 20 partial responses were observed yielding a response rate of 34% (95% CI: 22–47). The median response duration was 8.74 months (range 1.6–14). The median time to progression and the median survival were 5.88 months (95% CI: 4.34–8.21) and 18.2 months (95% CI: 10–20.7), respectively. Diarrhoea and peripheral neuropathy were the most frequent and predictable toxicities. These events were reversible, noncumulative and manageable. Grade 3 diarrhoea occurred in only 11% of the patients. No grade 4 gastrointestinal toxicity was reported in the study. The incidence of grade 3/4 (National Cancer Institute Common Toxicity Criteria 2: NCI-CTC 2) peripheral neuropathy was 15%. Haematological toxicity was of mild to moderate intensity with 10% of the patients with Grade 3/4 neutropenia without any episode of complication. The TEGAFOX regimen, a new combination using UFT®/LV and oxaliplatin every 3 weeks is feasible on an outpatient basis. The combination is safe and active and may offer a promising alternative to the intravenous route. Nevertheless this efficacy results should be confirmed by randomized phase III trials

Induction cisplatin–irinotecan followed by concurrent cisplatin–irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial

A recent phase I study showed that weekly cisplatin, irinotecan and concurrent radiotherapy can be administered with moderate toxicity in patients with oesophageal cancer. Patients with no prior treatment and oesophageal cancer stage I to III, performance status <3, caloric intake >1500 kcal day−1 were included. Chemotherapy, with cisplatin 30 mg m−2 and irinotecan 60 mg m−2, was administered at days 1, 8, 22, 29, and concurrently with radiotherapy at days 43, 50, 64 and 71. Radiotherapy was delivered with 50 or 50.4 Gy in 25 fractions/5 weeks. Forty-three patients were included, 10 stage I, 19 stage II and 14 stage III. Mean age was 59.2 years (range 44–79). A total of 30 out of 43 (69.8%) patients underwent all planned treatment. During induction chemotherapy, 14 severe toxicities of grade 3 or 4 in 10 patients (23.3%) were reported with 57.1% due to haematoxicity. During chemoradiotherapy, 31 severe toxicities of grade 3 or 4 with 64.5% due to haematotoxicity were reported in 18 patients. One toxic death occurred (diarrhoea grade 4). The complete clinical response rate was 58.1% (95% CI: 43.4–72.8%). Overall survival rate at 1 and 2 years was 62.8%, (95% CI, 58.3–77.3%) and 27.9% (95% CI, 13.4–41.3%), respectively. In conclusion, cisplatin–irinotecan–radiotherapy is an active and well-tolerated regimen feasible in out-patients

The Influence of Meteorology on the Spread of Influenza: Survival Analysis of an Equine Influenza (A/H3N8) Outbreak

The influences of relative humidity and ambient temperature on the transmission of influenza A viruses have recently been established under controlled laboratory conditions. The interplay of meteorological factors during an actual influenza epidemic is less clear, and research into the contribution of wind to epidemic spread is scarce. By applying geostatistics and survival analysis to data from a large outbreak of equine influenza (A/H3N8), we quantified the association between hazard of infection and air temperature, relative humidity, rainfall, and wind velocity, whilst controlling for premises-level covariates. The pattern of disease spread in space and time was described using extraction mapping and instantaneous hazard curves. Meteorological conditions at each premises location were estimated by kriging daily meteorological data and analysed as time-lagged time-varying predictors using generalised Cox regression. Meteorological covariates time-lagged by three days were strongly associated with hazard of influenza infection, corresponding closely with the incubation period of equine influenza. Hazard of equine influenza infection was higher when relative humidity was <60% and lowest on days when daily maximum air temperature was 20–25°C. Wind speeds >30 km hour−1 from the direction of nearby infected premises were associated with increased hazard of infection. Through combining detailed influenza outbreak and meteorological data, we provide empirical evidence for the underlying environmental mechanisms that influenced the local spread of an outbreak of influenza A. Our analysis supports, and extends, the findings of studies into influenza A transmission conducted under laboratory conditions. The relationships described are of direct importance for managing disease risk during influenza outbreaks in horses, and more generally, advance our understanding of the transmission of influenza A viruses under field conditions

Safety and outcome of definitive chemoradiotherapy in elderly patients with oesophageal cancer

Little is known about chemoradiotherapy (CRT) in elderly patients with a locally advanced oesophageal cancer (OC). The aim of our study was to evaluate the tolerance and the outcome of elderly patients older than 70 years treated with CRT for a non-metastatic OC. Chemoradiotherapy was based on radiotherapy combined with a cisplatin-based chemotherapy. Clinical complete response (CCR) to CRT was evaluated on upper digestive endoscopy and computed tomography scan 6–8 weeks after CRT completion. One hundred and nine consecutive patients were included. A CCR was observed in 63 patients (57.8%) and 2-year survival was 35.5%. Adverse events ⩾grade 3 were observed in 26 (23.8%) patients. Chemotherapy dose reduction, chemotherapy delays more than 1 week, and treatment discontinuation were observed in 33 (30.3%), 45 (41.3%), and 17 patients (15.6%), respectively. Comorbidity index according to Charlson score was significantly associated with treatment tolerance. In multivariate analysis, a CCR to CRT (P<0.01), a dose of radiotherapy ⩾80% (P=0.02), and a Charlson score ⩽2 (P=0.046) were identified as independent prognostic factors of overall survival. These results suggest that CRT could be considered as an effective treatment without major toxicity in elderly patients with OC

Equine dendritic cells generated with horse serum have enhanced functionality in comparison to dendritic cells generated with fetal bovine serum

BACKGROUND: Dendritic cells are professional antigen-presenting cells that play an essential role in the initiation and modulation of T cell responses. They have been studied widely for their potential clinical applications, but for clinical use to be successful, alternatives to xenogeneic substances like fetal bovine serum (FBS) in cell culture need to be found. Protocols for the generation of dendritic cells ex vivo from monocytes are well established for several species, including horses. Currently, the gold standard protocol for generating dendritic cells from monocytes across various species relies upon a combination of GM-CSF and IL-4 added to cell culture medium which is supplemented with FBS. The aim of this study was to substitute FBS with heterologous horse serum. For this purpose, equine monocyte-derived dendritic cells (eqMoDC) were generated in the presence of horse serum or FBS and analysed for the effect on morphology, phenotype and immunological properties. Changes in the expression of phenotypic markers (CD14, CD86, CD206) were assessed during dendritic cell maturation by flow cytometry. To obtain a more complete picture of the eqMoDC differentiation and assess possible differences between FBS- and horse serum-driven cultures, a transcriptomic microarray analysis was performed. Lastly, immature eqMoDC were primed with a primary antigen (ovalbumin) or a recall antigen (tetanus toxoid) and, after maturation, were co-cultured with freshly isolated autologous CD5+ T lymphocytes to assess their T cell stimulatory capacity. RESULTS: The microarray analysis demonstrated that eqMoDC generated with horse serum were indistinguishable from those generated with FBS. However, eqMoDC incubated with horse serum-supplemented medium exhibited a more characteristic dendritic cell morphology during differentiation from monocytes. A significant increase in cell viability was also observed in eqMoDC cultured with horse serum. Furthermore, eqMoDC generated in the presence of horse serum were found to be superior in their functional T lymphocyte priming capacity and to elicit significantly less non-specific proliferation. CONCLUSIONS: EqMoDC generated with horse serum-supplemented medium showed improved morphological characteristics, higher cell viability and exhibited a more robust performance in the functional T cell assays. Therefore, horse serum was found to be superior to FBS for generating equine monocyte-derived dendritic cells

The role of motion platform on postural instability and head vibration exposure at driving simulators

This paper explains the effect of a motion platform for driving simulators on postural instability and head vibration exposure. The sensed head level-vehicle (visual cues) level longitudinal and lateral accelerations (ax,sensed = ax_head and ay,sensed = ay_head, ayv = ay_veh and ayv = ay_veh) were saved by using a motion tracking sensor and a simulation software respectively. Then, associated vibration dose values (VDVs) were computed at head level during the driving sessions. Furthermore, the postural instabilities of the participants were measured as longitudinal and lateral subject body centre of pressure (XCP and YCP, respectively) displacements just after each driving session via a balance platform. The results revealed that the optic-head inertial level longitudinal accelerations indicated a negative non-significant correlation (r = −.203, p = .154 > .05) for the static case, whereas the optic-head inertial longitudinal accelerations depicted a so small negative non-significant correlation (r = −.066, p = .643 > .05) that can be negligible for the dynamic condition. The XCP for the dynamic case indicated a significant higher value than the static situation (t(47), p < .0001). The VDVx for the dynamic case yielded a significant higher value than the static situation (U(47), p < .0001). The optic-head inertial lateral accelerations resulted a negative significant correlation (r = −.376, p = .007 < .05) for the static platform, whereas the optic-head inertial lateral accelerations showed a positive significant correlation (r = .418, p = .002 < .05) at dynamic platform condition. The VDVy for the static case indicated a significant higher value rather than the dynamic situation (U(47), p < .0001). The YCP for the static case yielded significantly higher than the dynamic situation (t(47), p = .001 < 0.05)