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.

The clinical significance of serum procalcitonin levels following direct hemoperfusion with polymyxin B-immobilized fiber column in septic patients with colorectal perforation.

BACKGROUND: The efficacy of direct hemoperfusion with polymyxin B-immobilized fiber columns (PMX) has already been demonstrated in clinical studies for the treatment of septic shock. However, serum procalcitonin levels following PMX remain unknown. METHODS: This prospective, multicenter, nonrandomized clinical study was performed at 12 institutions. Forty-five patients with severe sepsis or septic shock due to colorectal perforation underwent PMX. Patients' outcome as well as circulating levels of endotoxin, procalcitonin and IL-6 were monitored. RESULTS: Before surgery, procalcitonin level, but not endotoxin and IL-6 levels, was elevated according to patients' septic conditions. Procalcitonin was significantly and positively correlated with sequential organ failure assessment score. Circulating levels of procalcitonin peaked 24 h after PMX treatment. Change in serum procalcitonin level was significantly higher in nonsurvivors than survivors. Nine mortalities were observed within 28 days. The best predictor for 28-day mortality was procalcitonin >85.7 ng/ml at 24 h after PMX (area under the receiver operating characteristic curve: 0.808 +/- 0.105). CONCLUSIONS: Procalcitonin may be a good indicator of severity of sepsis secondary to colorectal perforation. Furthermore, procalcitonin level at 24 h after PMX appears to predict outcome after PMX. Therefore, procalcitonin may be a useful diagnostic marker to evaluate patients' condition in candidates for PMX treatment.

Effects of 15-deoxy-delta(12,14) prostaglandin J(2) and interleukin-4 in Toll-like receptor-4-mutant glial cells.

15-Deoxy-Delta(12,14) prostaglandin J(2) and interleukin-4 are endogenous anti-inflammatory substances. In this study, we examined the effects of 15-deoxy-Delta(12,14) prostaglandin J(2) and interleukin-4 in glial cells from the Toll-like receptor-4-mutant (C3H/HeJ) and wild-type (C3H/HeN) mouse brains. The lipopolysaccharide-induced expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2 in the Toll-like receptor-4-mutant glial cells have significantly lower levels (about half and quarter, respectively) than those in the wild-type cells. Treatment with both interleukin-4 (at 10 ng/ml, for 48 h) and 15-deoxy-Delta(12,14) prostaglandin J(2) (at 3 microM, for 30 min) completely inhibited the lipopolysaccharide-induced expression of inducible NO synthase and cyclooxygenase-2. In contrast, heme oxygenase-1 was induced by 15-deoxy-Delta(12,14) prostaglandin J(2) alone, but was not changed by interleukin-4 or lipopolysaccharide. The inhibitory protein of nuclear factor-kappa B was degraded by lipopolysaccharide in both mutant and wild-type glial cells, and this degradation was not inhibited by either 15-deoxy-Delta(12,14) prostaglandin J(2) or interleukin-4. These results suggest that the response to lipopolysaccharide is partially dependent on Toll-like receptor-4 in mouse glial cells, and that 15-deoxy-Delta(12,14) prostaglandin J(2) and interleukin-4 differently regulate the expression of inducible NO synthase and cyclooxygenase-2, and heme oxygenase-1.

Aryl hydrocarbon receptor nuclear translocator is induced by kainic acid in rat hippocampal glial cells.

The localization and function of aryl hydrocarbon receptor nuclear translocator (ARNT) in the brain are still unclear. In this study, we examined changes of ARNT protein in rat hippocampus, by immunoblotting and immunohistochemical analysis using anti-ARNT antibody. Treatment of kainic acid (KA) induced marked increase in ARNT protein in both cytosolic and organellar fractions. ARNT immunoreactivity was markedly increased, predominantly in microglia and partly in astrocytes, similar to the immunoreactivity of heme oxygenase-1. In contrast, protein level of dioxin receptor did not change and hypoxia-inducible factor-1alpha protein was undetectable. These results suggest that ARNT expression in glial cells may participate in KA-induced episodes in the hippocampus.

Scattering of dislocated wave fronts by vertical vorticity and the Aharonov-Bohm effect. I. Shallow water.

When a surface wave interacts with a vertical vortex in shallow water the latter induces a dislocation in the incident wave fronts that is analogous to what happens in the Aharonov-Bohm effect for the scattering of electrons by a confined magnetic field. In addition to this global similarity between these two physical systems there is scattering. This paper reports a detailed calculation of this scattering, which is quantitatively different from the electronic case in that a surface wave penetrates the inside of a vortex while electrons do not penetrate a solenoid. This difference, together with an additional difference in the equations that govern both physical systems, lead to a quite different scattering in the case of surface waves, whose main characteristic is a strong asymmetry in the scattering cross section. The assumptions and approximations under which these effects happen are carefully considered, and their applicability to the case of the scattering of acoustic waves by vorticity is noted.

[Lung laceration caused by penetrating chest wall injury in Hanshin & Awaji earthquake: a case report].

A 36-year-old man having a left lower lobe laceration caused by penetrating chest wall injury was operated on 5 hours after Hanshin & Awaji Earthquake. At thoracotomy, significant destruction of the left lower lobe was observed. Therefore, we gave up repairing a lung, and performed left lower lobectomy, with a satisfactory outcome. Our hospital is located on 30 km south of seismic center, but the function of our hospital was not completely paralyzed. In Awaji island, emergent treatments were done satisfactorily.

[Nineteen multiple primary cancer cases of 100 patients undergoing lung cancer resection].

In our department, half of 100 consecutive lung cancer resection cases were over the age of 70 years. In the same 100 patients, nineteen cases had multiple primary cancers. Sixteen cases had double, two cases had triple, one case had quadruple primary cancers. The incidence rate of multiple primary cancers involving the lung was 19%. This incidence of 19% is higher than the others ever reported in Japan. It was concluded, when lung cancer patients were elder, that there was increasment in the frequency of multiple cancer cases involving lung, and there was a high possibility of the occurrence of 2nd and 3rd primary cancers.

[Clinical characteristics of impacted bile duct stone in the elderly].

Acute cholangitis due to impacted bile duct stone is sometimes fatal and require prompt bile duct decompression. Particularly, AOSC (acute obstructive suppurative cholangitis) is the most serious form of bacterial cholangitis and its prognosis is usually very poor when treated conservatively. We have been treated impacted bile duct stones by decompressing the duct endoscopically. Here, we report the characteristics of our elderly patients with impacted bile duct stones who received urgent decompression treatment mainly by endoscopic techniques. In the endoscopical treatment group, the number of patients with AOSC was 5 out of 46 AC (acute cholangitis) patients (11%) under 69 years old, 14 out of 52 (27%) from 70 to 79 years old, and 12 out of 28 (43%) over 80 years old. Obviously, the severity of acute cholangitis (ratio of AOSC to AC) was higher in the elderly. This tendency was similar to the patients who received urgent transhepatic decompression treatment, although they were small in number. In all the patients treated, 7 were classified into the most serious AOSC category with Reynolds' sign, and notably 6 out of 7 were over 70 years old. More strikingly, 5 of 7 patients were over 80, and their mortality rate was indeed high. Thus, in the elderly, bacterial cholangitis by impacted bile stones was a very serious condition. Especially, the outcome of AOSC over 80 years old with Reynolds' sign was very poor, in spite of emergency endoscopic treatment.