Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Fucosylated TGF-ß receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a major inducer of epithelial-mesenchymal transition (EMT) in different cell types. TGF-ß-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-ß is unclear. METHODS: Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-ß downstream molecules were analysed by western blot. Fucosylation of TGF-ß receptor (TßR) was examined by lectin blot analysis. RESULTS: Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I TßR and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT. CONCLUSION: Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-ß-mediated EMT.

Videoendoscopic assessment of swallowing function to predict the future incidence of pneumonia of the elderly.

The purpose of the present study was to examine what dysphagic signs identified by videoendoscopy (VE) could predict the incidence of pneumonia and body weight loss in elderly patients living in nursing homes. This study was performed at six nursing care facilities in Japan from March 2007 to February 2009. The 148 subjects (85·1 ± 8·0 years, male/female: 43/105) were evaluated for their feeding and swallowing movements by clinical and VE examinations during the consumption of a regular meal. The VE examination items included the existence/absence of pharyngeal residue, laryngeal penetration, and aspiration of food and saliva. The patients were followed-up for 3 months with individualized feeding therapy based on the results of the clinical/VE examination at baseline, and the incidence of pneumonia was examined as the primary outcome. In patients without pneumonia, the body weight change was also measured as a secondary outcome. The risk factors for pneumonia and body weight loss (of 3% or more) were identified among the clinical/VE examination items by a Cox proportional hazard analysis. Even with elaborative feeding therapy, 12 (8·1%) of the 148 patients developed pneumonia during the 3 months follow-up period. The existence of signs of 'silent aspiration of saliva' or 'aspiration of saliva' detected by VE examination was a significant risk factor for both pneumonia and a body weight loss of 3% or more. This study shows that 'aspiration of saliva' detected by VE is a significant risk factor for both pneumonia and body weight loss in elderly patients living in nursing homes.

Lip closing pressure and spoon management in passive spoon feeding.

To determine the sources of lip closing pressure (P(LC) ) generation during passive spoon feeding, we used a fine pressure transducer glued into a wooden spoon, as well as electromyography (EMG) of the upper and lower lips and the submental muscle complex, in normal adult volunteers (average age 24·5 years). An assistant fed a seated subject 0·6 mL of yogurt and then withdrew the spoon from the subject's closed mouth. The spoon was held at an angle of 0° (i.e. in the naso-auricular plane) during serving and at either 0° or 60° during withdrawal. We detected simultaneous increases in P(LC) and in EMG activity in the lips and the submental muscle complex. The maximum P(LC) was significantly higher at 60° [65 ± 11 g cm(-2) (mean ± s.e.m)] than at 0° (42 ± 8 g cm(-2)). The former was correlated with the maximum EMG amplitude, which was analysed by using the mean of the root-mean-square EMG and presented as a percentage of the maximum EMG obtained in the lower lip region and the submental muscle complex during subsequent swallowing in each subject. In conclusion, in healthy adult subjects, perioral muscles of the lower lip region and the submental muscle complex participate in P(LC) generation, particularly at a steep spoon withdrawal angle. The results suggest that a steep withdrawal angle not only increases P(LC) but also promotes these muscles' activities in passive spoon feeding.

An ontogenic study of the behavioral effects of chronic intermittent exposure to ayahuasca in mice.

Ayahuasca is a beverage obtained from decoctions of the Banisteriopsis caapi plus Psychotria viridis. In religious contexts, ayahuasca is used by different age groups. However, little is known of the effects of ayahuasca during ontogenic development, particularly with regard to the functional characteristics of the central nervous system. Animal models are useful for studying the ontogenic effects of ayahuasca because they allow exclusion of the behavioral influence associated with the ritualistic use. We investigated the effects of exposure to ayahuasca (1.5 mL/kg, orally, twice a week) on memory and anxiety in C57BL/6 mice, with the post-natal day (PND) being used as the ontogenic criterion for classification: childhood (PND21 to PND35), adolescence (PND35 to PND63), adulthood (PND90-PND118), childhood-adolescence (PND21 to PND63), childhood-adulthood (PND21 to PND118) and adolescence-adulthood (PND35 to PND118). One day after the last ayahuasca exposure, the mice were subjected to the Morris water maze (MWM), open field and elevated plus maze tasks (EPM). Ayahuasca did not affect locomotion in the open field or open arms exploration in the EPM, but increased the risk assessment behavior in the childhood group. Ayahuasca did not cause any change in acquisition of spatial reference memory in the MWM task, but decreased the time spent on the platform quadrant during the test session in the adolescence group. These results suggest that, in mice, exposure to ayahuasca in childhood and adolescence promoted anxiety and memory impairment, respectively. However, these behavioral changes were not long-lasting since they were not observed in the childhood-adulthood and adolescence-adulthood groups.

Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice.

The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old) received ayahuasca or water (1.5 mL/kg, orally) twice a week for 12 months and were tested in the Morris water maze (MWM), open field and elevated plus maze (EPM) tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition) of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Combination thalidomide and cyclosporine for cardiac allograft rejection. Comparison with combination methylprednisolone and cyclosporine.

Combination CsA with corticosteroids is the most commonly used maintenance immunosuppressive regimen after cardiac transplantation, although their high-toxicity profiles frequently limit their clinical benefit. Immunosuppressive agents that would act synergistically with CsA but without the toxicity profile of corticosteroids would be clinically useful. Thalidomide was removed from the market due to its teratogenic effects, although it has known immunomodulatory activity. The purpose of this study was (1) to determine whether maintenance immunosuppression with thalidomide and subtherapeutic doses of CsA can help prevent rat cardiac allograft rejection; and (2) to compare its synergism with CsA to the commonly used corticosteroid, methylprednisolone. ACI-LEW allografts were all treated with subtherapeutic doses of CsA (10 mg/g/day, s.c.) for 4 days. When CsA was then discontinued, severe rejection developed by posttransplant day 14. Group 1 received CsA alone. Group 2 received in addition oral thalidomide 100 mg/day for 14 days. Groups 3, 4, and 5 received CsA and methylprednisolone (low dose: 0.2 mg/kg/day s.c.; moderate dose: 2.0 mg/kg/day s.c.; and high dose: 20 mg/kg/day s.c. Twelve histologic parameters of rejection were semiquantitatively graded 0-4, and total pathology scores were determined. The combination of thalidomide and subtherapeutic CsA significantly reduced the severity of myocardial necrosis, interstitial inflammation, interstitial edema, and the total pathology score. Thalidomide was found to be equally as effective as low-, moderate-, and high-dose methylprednisolone. The results of this study suggest the potential clinical role of CsA and thalidomide in maintenance immunosuppressive regimens, thereby avoiding the use of corticosteroids.

Donor core-cooling provides improved static preservation for heart-lung transplantation.

Twenty-three dairy calves underwent heart-lung allotransplantation after donor organs were procured using either donor core-cooling through cardiopulmonary bypass (CPB) or pulmonary artery flush (PAF) to assess which method provides optimal graft preservation. In Groups 1 (control) and 2, donors were cooled to 15 degrees C on CPB and organs were either immediately transplanted (Group 1) or stored in saline solution (4 degrees C) for 4 hours (Group 2) prior to transplantation. In Group 3, donors were pretreated with prostaglandin E1 prior to PAF with modified Euro-Collins solution. Organs were stored in saline solution (4 degrees C) for 4 hours and were then transplanted. Acute cardiopulmonary function following transplantation was assessed by the ratio of end-systolic pressure to end-systolic dimension, extravascular lung water (EVLW), lung compliance, arterial oxygenation, and lung biopsy. Cardiac function after the transplantation procedure was similar in all groups, but EVLW values and lung biopsy scores were worse after PAF. Arterial O2 tension appeared lower after PAF, but not significantly so. Core-cooling provides superior static preservation and thus improved graft function in the acute bovine model.

HBV-related fulminant hepatic failure: successful intensive medical therapy in a candidate for liver transplantation.

Fulminant hepatic failure (FHF) usually has a fatal prognosis without liver transplantation. We describe the case of a woman who developed FHF, and was evaluated as a candidate for liver transplantation, but who was cured without transplantation through intensive medical care that included glucagon-insulin therapy, methylprednisolone pulse therapy, interferon beta and lamivudine administration, cyclosporine administration, and high-volume hemodiafiltration and plasma exchange. In a patient with FHF who is a candidate for liver transplantation but for whom the transplantation cannot be performed for some reason, intensive medical therapy, including regeneration-promoting therapy, immunosuppressive therapy, antiviral therapy, and vigorous hepatic support, should be carried out.

An early phase II study of a 3-hour infusion of paclitaxel for advanced gastric cancer.

The purpose of this study was to evaluate the feasibility and efficacy of 3-hour infusional paclitaxel for the treatment of advanced gastric cancer with measurable metastatic diseases. Eligibility criteria included no more than one regimen of prior chemotherapy. Paclitaxel was administered as an intravenous infusion over 3 hours at a dose of 210 mg/m2 every 3 weeks. Premedication of dexamethazone, ranitidine, and diphenhydramine were given to all patients. Sixteen patients were registered in the study. One patient did not receive paclitaxel because of gastrointestinal bleeding before the initiation of drug's administration. Thirteen of the 15 patients had a prior history of chemotherapy. Although 10 patients (67%) developed grade 4 neutropenia, no serious infections occurred during the study. Nonhematologic toxicities were generally mild. Three (20%) patients who showed evidences of resistance to the previous intensive regimen achieved a partial response. In conclusion, a 3-hour infusion of paclitaxel is a safe and promising treatment for advanced gastric cancer. Paclitaxel appears to be non-cross resistant to other agents that are commonly used for gastric cancer. A large-scale phase II study is now underway.

A new technique in echocardiology: B-mode to M-mode transformation.

In conventional two-dimensional Echocardiography with sector scanning, M-mode is simultaneously displayed on TV-monitor as the time based ultrasound signals. With conventional system, one end of the cursor-line in B-mode image which indicates the beam direction of M-mode, is always fixed at the point corresponding to the transducer tip. This system has the capability to transform B-mode to M-mode images in any desired direction. However, the time resolution in M-mode is limited to about 33 milli-seconds.

The development of normal feeding and swallowing: Showa University study of the feeding function.

Since the 1980s the Department of Hygiene and Oral Health at the Showa University School of Dentistry has focused its research efforts on the development of feeding function and disorders. In addition, we have treated dysphagic children and dysphagic elderly using our feeding training program approach. The developmental course of the feeding function includes the following steps: 1) Suckle feeding and prefeeding period; 2) Acquiring the ability to swallow with lips closed; 3) Acquiring the ability to take food with lips closed; 4) Acquiring the ability to push mashed food with the tongue and anterior hard palate; 5) Acquiring the ability to perform mastication; 6) Beginning self-feeding; 7) Beginning finger feeding; 8) Beginning using table ware.

Assessment of the development of hand and mouth coordination when taking food into the oral cavity.

The purpose of this study was to establish an assessment method for evaluation of hand and mouth coordination during self-feeding. The subjects were four normally developed infants. Their feeding behavior was videotaped at two or four week intervals (from age eight months to thirty-six months). The items analyzed were nine viewpoints for finger feeding and eight viewpoints for spoon-feeding. The results obtained included: finger feeding--development of cylinder and pinch grasp, two patterns of hand in relation to neck and trunk, placement of food into the mouth, developmental aspects of neck rotation when taking food with the lips; spoon feeding--holding technique, flexion of elbow and shoulder, taking food from the spoon bowl by the lips, patterns of neck rotation. From the results of these observations, we conclude that the items analyzed in this study can be useful for the assessment of the developmental process of hand and mouth coordination in self-feeding.

[Coronary hemodynamics in a patient developing chest pain in the middle age in congenital coronary-pulmonary fistula].

Recently reports of congenital coronary-pulmonary fistula have been increasing with the wide-spread use of coronary angiography. However, the cause of the angina sometimes seen as a chief complaint in coronary fistula has not been well demonstrated although it has been suggested that coronary steal phenomenon accounts for it. This report documented coronary hemodynamics in a patient who came to develop anterior chest pain in the middle age owing to congenital coronary-pulmonary fistula, measuring coronary flow before and after the fistula-closure operation. A 35-year-old woman suffered from a sudden onset of severe anterior chest pain in April, 1986. She was referred to our hospital on suspicion of ruptured aneurysm of Valsalva. Auscultation disclosed continuous murmur at 3 LSB, but no evidence of ruptured aneurysm of Valsalva was detected by echocardiography nor aortography. Coronary angiography showed both left and right coronary fistula into the stem of pulmonary artery and otherwise normal angiogram. Great cardiac vein flow (GCVF) measured with regional thermodilution method was 25 ml/min at rest (70 bpm) and 30 ml/min during rapid atrial pacing (150 bpm) before the operation, and 30 ml/min (78 bpm) and 58 ml/min (150 bpm) after the operation, respectively. Before the surgery, anterior coronary resistance (CRant) was higher than that in normal subjects at rest and remained almost steady during atrial pacing. After the surgery, CRant was still higher at rest but remarkably reduced during pacing of 150 bpm. These findings suggest that the gradual increase in peripheral coronary resistance for a long time may lead to the inducement of coronary steal in the middle-later age in patients with coronary fistula.

[A case of myocardial infarction due to the left main trunk lesion, in which percutaneous coronary recanalization and emergency coronary-aorto bypass graft, and subsequent percutaneous coronary angioplasty were effective not only from a viewpoint of survival but from comeback to social life].

A case of acute myocardial infarction due to the lesion in the left main coronary artery was reported. A 50-year male was referred to our department for suspected acute myocardial infarction. Physical examination on admission revealed slight cyanosis with cold sweating due to severe chest pain. Pulse was irregular and heart rate was 78 beats/min. Blood pressure was 100/80 mmHg. A series of electrocardiograms (ECG) and laboratory data provided the diagnosis of wide-ranged anterolateral infarction in the left ventricle. Emergency coronary angiograms taken without delay showed a subtotal occlusion (99% stenosis) of the left main coronary trunk (LMT) before the initiation of intracoronary thrombolysis (PTCR). Following the intracoronary infusion of urokinase of 1,200,000 units, symptoms and ECG changes transiently improved but worsened later, and LMT stenotic lesion and delayed filling of myocardium were similar with before PTCR. Emergency coronary-aorto bypass graft (CABG) was undertaken without a significant delay to both the left anterior descending artery (LAD) and left circumflex coronary artery (LCX). With these treatments, the patient could survive despite the wide area of infarction due to LMT lesion. Coronary angiograms performed 37 days after the CABG showed that the graft to LAD was completely occluded and the LCX graft was patent with partial stenosis. Treadmill test at this time induced an anginal episode with ischemic ECG changes on moderate exercise, indicating the presence of significant area of ischemic myocardium. For salvage of the ischemic myocardium, percutaneous transluminal coronary angioplasty (PTCA) was successfully performed for the LMT stenosis, resulting in no episode of angina nor ischemic ECG changes during exercise loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice

The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old) received ayahuasca or water (1.5 mL/kg, orally) twice a week for 12 months and were tested in the Morris water maze (MWM), open field and elevated plus maze (EPM) tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition) of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice.

An ontogenic study of the behavioral effects of chronic intermittent exposure to ayahuasca in mice

Ayahuasca is a beverage obtained from decoctions of the Banisteriopsis caapi plus Psychotria viridis. In religious contexts, ayahuasca is used by different age groups. However, little is known of the effects of ayahuasca during ontogenic development, particularly with regard to the functional characteristics of the central nervous system. Animal models are useful for studying the ontogenic effects of ayahuasca because they allow exclusion of the behavioral influence associated with the ritualistic use. We investigated the effects of exposure to ayahuasca (1.5 mL/kg, orally, twice a week) on memory and anxiety in C57BL/6 mice, with the post-natal day (PND) being used as the ontogenic criterion for classification: childhood (PND21 to PND35), adolescence (PND35 to PND63), adulthood (PND90-PND118), childhood-adolescence (PND21 to PND63), childhood-adulthood (PND21 to PND118) and adolescence-adulthood (PND35 to PND118). One day after the last ayahuasca exposure, the mice were subjected to the Morris water maze (MWM), open field and elevated plus maze tasks (EPM). Ayahuasca did not affect locomotion in the open field or open arms exploration in the EPM, but increased the risk assessment behavior in the childhood group. Ayahuasca did not cause any change in acquisition of spatial reference memory in the MWM task, but decreased the time spent on the platform quadrant during the test session in the adolescence group. These results suggest that, in mice, exposure to ayahuasca in childhood and adolescence promoted anxiety and memory impairment, respectively. However, these behavioral changes were not long-lasting since they were not observed in the childhood-adulthood and adolescence-adulthood groups.