Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study ...investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients.
Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model.
KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019).
Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC.
NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid ...tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.
This paper describes acoustic and visual instruments developed to perform high-resolution surveys of the volumetric distribution of manganese crusts from an underwater vehicle. The instruments ...consist of an acoustic device, developed to perform in situ measurements of manganese crust thickness at depths of up to 3000 m, and a vision-based mapping system that generates 3-D color reconstructions of the seafloor. Methods to process the information obtained by these sensors to automatically identify areas of exposed crust using the 3-D reconstructions, and subsequently determine the thickness of the crusts based on the acoustic measurements, are described. Sea trials were performed at #5 Takuyo seamount with the systems mounted onboard the remotely operated vehicle Hyper-Dolphin during the NT10-11 cruise of the R/V Natsushima. The results are that the first time in situ measurements of manganese crust thickness have been performed, and it is demonstrated that, for the types of substrate dominant in the surveyed area, continuous acoustic measurement of manganese crust thickness is possible. The work described in this paper indicates that the proposed instruments and data processing algorithms can form useful tools to enable more efficient survey of manganese crusts.
Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancers, although there are no reports in pretreated patients.
We ...retrospectively analyzed 242 patients with advanced gastric cancer (AGC) who received weekly paclitaxel (Taxol) as second-line chemotherapy. Background characteristics and neutropenia as time-varying covariates (TVCs) were analyzed as prognostic factors.
Of the 242 patients, mild neutropenia (grades 1–2) occurred in 101 patients (41.7%) and severe neutropenia (grades 3–4) occurred in 63 patients (26.0%). The other 78 patients (32.2%) did not experience neutropenia. According to a multivariate Cox model with neutropenia as a TVC, hazard ratios of death were 0.61 95% confidence interval (CI) 0.43–0.85; P = 0.004 for patients with mild neutropenia and 0.61 (95% CI 0.41–0.88; P = 0.009) for those with severe neutropenia. Among the patients in landmark analysis (landmark of 2.5 months; median time to treatment failure of paclitaxel), mild and severe neutropenia remained significant prognostic factors.
Our results indicate that neutropenia during chemotherapy is associated with improved survival in patients with AGC who received weekly paclitaxel as second-line chemotherapy. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy.
Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene ...expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets.
In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy.
In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34–0.94).
Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP.
•Limited data exist concerning site-specific therapy for carcinoma of unknown primary.•We evaluated prediction rate of primary sites by immunohistochemistry panel.•Site-specific therapy showed survival benefit compared with platinum empirical therapy in carcinoma of unknown primary.
In Japan, there had been no prospective clinical studies conducted in terms of modified FOLFOX6 + bevacizumab therapy. We performed a post-marketing Phase II multicenter clinical study to examine the ...efficacy and safety of this regimen as first-line therapy for Japanese patients with advanced/recurrent colorectal cancer.
Bevacizumab (5 mg/kg) was administered intravenously, and then oxaliplatin (85 mg/m(2)) and levofolinate calcium (200 mg/m(2)) were infused intravenously over 2 h. Subsequently, a bolus dose of 5-fluorouracil (400 mg/m(2)) was injected, followed by infusion of 5-fluorouracil (2400 mg/m(2)) for 46 h. This regimen was repeated every 2 weeks until 24 cycles unless there was disease progression, unacceptable toxicity or patient refusal. The primary end point was the response rate.
Among the 70 patients enrolled, two patients withdrew the study before treatment, and 68 patients were eligible for analysis of efficacy and safety. The response rate was 51.5% (95% confidence interval: 39.0-63.8%). The median progression-free survival and median overall survival time were 12.6 months (95% confidence interval: 10.4-14.5 months) and 28.5 months 95% confidence interval: 23.1 months-(not applicable), respectively. There were no treatment-related deaths observed. The most common Grade 3 and 4 adverse events included neutropenia in 35.3% of the patients, peripheral neuropathy in 16.2% and hypertension in 16.2%. All adverse events were manageable and tolerable. The exploratory analysis of polymorphisms of three genes, ERCC1, XPD and GSTP1, did not show any trends in terms of correlation with the efficacy or safety of modified FOLFOX6 + bevacizumab therapy.
Modified FOLFOX6 + bevacizumab therapy was manageable and tolerable in Japanese patients, achieving a high response rate.
This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation".
Rheumatoid arthritis (RA) is a progressive ...inflammatory disease that causes damage to multiple joints, decline in functional status, and premature mortality. Thus, effective and frequent objective assessments are necessary. Then, we developed a self-assessment system for RA patients based on a smartphone application.
The purpose of this study was to investigate the feasibility of a self-assessment system for RA patients using a smartphone application.
We measured daily disease activity in nine RA patients who used the smartphone application for a period of three months. A disease activity score (DAS28) predictive model was used and feedback comments relating to disease activity were shown to patients via the smartphone application each day. To assess participants' RA disease activity, the DAS28 based on the C-reactive protein level was measured by a rheumatologist during monthly clinical visits.
The disease activity measured by the application correlated well with the patients' actual disease activity during the 3-month period, as assessed by clinical examination. Furthermore, most participants gave favourable responses to a questionnaire administered at the end of the 3-month period containing questions relating to the ease of use and usefulness of the system.
The results of this feasibility study indicated that the DAS28 predictive model can longitudinally predict DAS28 and may be an acceptable and useful tool for assessment of RA disease activity for both patients and healthcare providers.
The "Zero-G" is designated as a new class of underwater robot that is capable of unrestricted attitude control. A novel control scheme based on internal actuation using control moment gyros (CMGs) is ...developed to provide Zero-G class autonomous underwater vehicles (AUVs) with this unique freedom in control. This is implemented in the CMG-actuated Zero-G class internal kinematic underwater robot actuation (IKURA) system that was developed as part of this research. A series of experiments are performed to demonstrate the practical application of CMGs and verify the associated theoretical developments. The ability to actively stabilize the translational dynamics of the robot is assessed and unrestricted attitude control is demonstrated in an experiment that involves vertically pitched diving and surfacing in surge. Finally, potential applications for Zero-G class AUVs are discussed.
Antiretroviral therapy (ART) effectively slows the progression of AIDS. However, drug resistance and/or toxicity can limit the utility of ART in many patients. In this study, we assessed whether a ...viral vector-based vaccine can be used as a therapeutic vaccine in simian immunodeficiency virus (SIV)-infected monkeys. The effect of vaccinating SIVmac239-infected rhesus monkeys with an SIV gag and gp120-expressing adenovirus (Ad) vector vaccine and a modified vaccinia Ankara (MVA) vaccine was explored while being treated with ART. Rhesus monkeys were intravenously infected with 10 and 1000 TCID(50) (50% tissue culture infectious dose) of SIVmac239. Two months after SIV infection, the monkeys received a 4-month treatment with ART. Some of the monkeys were immunized with adenovirus-based vaccine and MVA-based vaccine with 2 months interval during ART. Viral load, CD4 count and SIV-specific immune responses were observed for 7 months after interruption of ART. The vaccinated animals had higher (i) CD4 counts, (ii) SIV-specific cell-mediated immune responses and (iii) anti-SIV-neutralizing antibody (Ab) titers than monkeys treated with ART alone. More importantly, the vaccination significantly reduced the SIV RNA load from animals infected with a low dose of SIV (10 TCID(50)). The anti-SIV cell-mediated and humoral responses induced by the vaccination was inversely correlated with a reduction in SIV viral load and positively correlated with an increase in CD4(+) T cell counts. These results suggest that vaccination can improve antiviral cell-mediated and humoral immunity, which may contribute to controlling viral replication.
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