Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

Influence of tumor size on outcomes following pelvic exenteration.

OBJECTIVE: Pelvic exenteration (PE) is often the only curative option for locally advanced or recurrent pelvic malignancies. Despite radical surgery, recurrence risk and morbidity remain high. In this study, we sought to determine tumor size effect on perioperative outcomes and subsequent survival in patients undergoing PE. METHODS: Retrospective chart review was performed for female patients who underwent PE at two comprehensive cancer centers from 2000 to 2015. Demographics, complications and outcomes were recorded. Statistical analyses were performed using chi-square, student's t-test, logistic regression, non-parametric tests, log-rank test, and Cox proportional hazards. RESULTS: Of 151 women who underwent PE, 144 had available pathologic tumor size. Gynecologic oncology, surgical oncology, and urology performed 84, 29, and 31 exenterations, respectively. Tumor dimensions ranged from 0 to 25.5cm. Perioperative complications, 30-day mortality, reoperation, and readmission rates were not associated with tumor size. Obesity and prior radiation increased risk for major perioperative complication while anterior exenterations decreased risk. Larger tumors were more likely to undergo total pelvic exenteration (OR 1.14; 95%CI 1.03-1.27), have positive margins (OR 1.11; 95%CI 1.02-1.22), and recur (65%, 42% and 20% for tumors >4cm, ≤4cm and no residual tumor respectively, p=0.016). Tumor size >4cm and positive margins were associated with worse overall survival amongst gynecologic oncology patients. CONCLUSION: Tumor size was not associated with perioperative morbidity. Larger tumors were associated with positive margins, more extensive resection, and worse survival in gynecologic oncology patients. Larger studies are needed to further understand tumor size impact on PE outcomes within specific tumor types.

Prognostic significance of the prognostic nutritional index in esophageal cancer patients undergoing neoadjuvant chemotherapy.

Nutritional status is one of the most important issues faced by cancer patients. Several studies have shown that a low preoperative nutritional status is associated with a worse prognosis in patients with various types of cancer, including esophageal cancer (EC). Recently, neoadjuvant chemotherapy (NAC) and/or radiotherapy have been accepted as the standard treatment for resectable advanced EC. However, NAC has the potential to deteriorate the nutritional status of a patient. This study aimed to evaluate the prognostic significance of the nutritional status for EC patients who underwent NAC. We retrospectively reviewed 66 squamous cell EC patients who underwent NAC consisting of docetaxel, cisplatin, and 5-fluorouracil followed by subtotal esophagectomy at Nara Medical University Hospital between January 2009 and August 2015. To assess the patients' nutritional status, the prognostic nutritional index (PNI) before commencing NAC and prior to the operation was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count in the peripheral blood (per mm3). The cutoff value of the PNI was set at 45. A multivariable analysis was performed to identify prognostic factors for overall survival (OS) and relapse-free survival (RFS). The mean pre-NAC and preoperative PNI were 50.2 ± 5.7 and 48.1 ± 4.7, respectively (P = 0.005). The PNI decreased following NAC in 44 (66.7%) patients. Before initiating NAC, 9 (13.6%) patients had a low PNI, and 12 (18.2%) patients had a low PNI prior to the operation. The pre-NAC PNI and preoperative PNI were significantly associated with the OS (P = 0.013 and P = 0.004, respectively) and RFS (P = 0.036 and P = 0.005, respectively) rates. The multivariable analysis identified the preoperative PNI as an independent prognostic factor for poor OS and RFS, although the pre-NAC PNI was not an independent predictor. Our results suggest that the preoperative PNI is a useful marker for predicting the long-term outcomes of EC patients undergoing NAC and subsequent subtotal esophagectomy. Therefore, patients with a low preoperative nutritional status may be at a higher risk of EC recurrence.

Diagnostic performance of plasma biomarkers in patients with acute intestinal ischaemia.

BACKGROUND: The aim of this study was to evaluate the use of intestinal fatty acid binding protein (I-FABP) and traditional biomarkers in the early diagnosis of acute intestinal ischaemia of different causes. METHODS: I-FABP, white blood cell (WBC) count, C-reactive protein, base deficit, lactate, lactate dehydrogenase, aspartate aminotransferase, creatine kinase and D-dimer were measured prospectively in consecutive patients suspected of having acute intestinal ischaemia. Biomarker levels were compared in patients with vascular and non-vascular ischaemia. RESULTS: Two hundred and eight patients with a clinical suspicion of acute intestinal ischaemia were enrolled. Vascular intestinal ischaemia was diagnosed in 24 patients (11·5 per cent), non-vascular ischaemia in 62 (29·8 per cent) and non-ischaemic disease in 122 (58·7 per cent). The levels of most biomarkers (except WBC count and creatine kinase) were significantly higher in the vascular ischaemia group than in the other groups (P < 0·010). However, none of the biomarker levels differed between patients with non-vascular intestinal ischaemia and those with non-ischaemic disease. Receiver operating characteristic (ROC) curve analysis suggested that I-FABP was best at diagnosing vascular intestinal ischaemia (area under the curve 0·88). CONCLUSION: Serum biomarkers may be useful in the diagnosis of vascular, but not non-vascular, intestinal ischaemia. Among them, I-FABP shows promise for detecting vascular ischaemia.

Japanese multicenter experience of endoscopic necrosectomy for infected walled-off pancreatic necrosis: The JENIPaN study.

BACKGROUND AND STUDY AIMS: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. PATIENTS AND METHODS: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. RESULTS: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. CONCLUSIONS: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality.

Helical mode conversion using conical reflector.

In a recent paper, Mansuripur et al. indicated and numerically verified the generation of the helical wavefront of optical beams using a conical-shape reflector. Because the optical reflection is largely free from chromatic aberrations, the conical reflector has an advantage of being able to manipulate the helical wavefront with broadband light such as white light or short light pulses. In this study, we introduce geometrical understanding of the function of the conical reflector using the spatially-dependent geometric phase, or more specifically, the spin redirection phase. We also present a theoretical analysis based on three-dimensional matrix calculus and elucidate relationships of the spin, orbital, and total angular momenta between input and output beams. These analyses are very useful when designing other optical devices that utilize spatially-dependent spin redirection phases. Moreover, we experimentally demonstrate the generation of helical beams from an ordinary Gaussian beam using a metallic conical-shape reflector.

Enhancement of delayed hypersensitivity reaction with varieties of anti-cancer drugs. A common biological phenomenon.

Delayed hypersensitivity reaction in mice was commonly enhanced with various anti-cancer agents administered as single or intermittent high doses but not consecutive divided doses. The effect of anti-cancer agents on the delayed hypersensitivity reaction was thought to be due to elimination of suppressor T cell activity.

The effect of preoperative nutritional status on postoperative complications and overall survival in patients undergoing pelvic exenteration: A multi-disciplinary, multi-institutional cohort study.

INTRODUCTION: Optimization of preoperative nutritional status has been recommended and associated with improved outcomes for other oncologic procedures, but has not been studied in patients undergoing pelvic exenteration. METHODS: A retrospective chart review of 199 patients was conducted. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analysis was performed with Cox proportional hazards. RESULTS: 199 patients underwent PE with 61 (31%), 78 (40%) and 58 (29%) patients having colorectal, gynecologic and urologic histological diagnoses, respectively. Median OS following PE was 25 months. Preoperative serum albumin <3.5 g/dL was associated with worsened OS (HR 1.661; 95% CI 1.052-2.624) as well as increased incidence of any postoperative complication (85.9% vs 72.3%, p = 0.034), but was not associated with 90-day mortality (11.3% vs 7.9%, p = 0.457). CONCLUSION: Poor preoperative nutritional status is associated with increased complications and decreased OS. Surgeons should maximize preoperative nutritional status to improve perioperative outcomes and long-term survival.

An invisible medium for circularly polarized electromagnetic waves.

We study the no reflection condition for a planar boundary between vacuum and an isotropic chiral medium. In general chiral media, elliptically polarized waves incident at a particular angle satisfy the no reflection condition. When the wave impedance and wavenumber of the chiral medium are equal to the corresponding parameters of vacuum, one of the circularly polarized waves is transmitted to the medium without reflection or refraction for all angles of incidence. We propose a circular polarizing beam splitter as a simple application of the no reflection effect.

Genotoxicity studies on licorice flavonoid oil (LFO).

Licorice flavonoid oil (LFO) is a new functional food ingredient. In this study, the genotoxicity of LFO was investigated using a test battery of three different methods. In a reverse mutation assay using four Salmonella typhimurium strains and Escherichia coli, LFO did not increase the number of revertant colonies in any tester strain with or without metabolic activation by rat liver S9 mix. In a chromosomal aberration test using Chinese hamster lung (CHL/IU) cells, LFO did not induce any chromosomal aberrations either in the short period test without rat liver S9 mix or in the continuous treatment (24 h or 48 h) test. However, in the short-period test with rat liver S9 mix, LFO induced structural chromosomal aberrations at concentrations higher than 0.6 mg/mL. A bone marrow micronucleus test using male F344 rats was initially conducted. The animals were dosed by oral gavage at doses up to 5000 mg/kg/day. No significant or dose-dependent increases in the frequency of micronucleated polychromatic erythrocytes (MNPCE) were observed and the high dose suppressed the ratio of polychromatic erythrocytes (PCE) to total erythrocytes. Subsequently, a liver and peripheral blood micronucleus test using male F344 rats was conducted. No micronuclei induction either in hepatocytes or PCE was observed even at the highest dose of 5000 mg/kg/day. From the findings obtained from the genotoxicity assays performed in this study and the published pharmacokinetic studies of LFO, it appears unlikely that dietary consumption of LFO will present any genotoxic hazard to humans.

90-Day repeated-dose toxicity study of licorice flavonoid oil (LFO) in rats.

Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of licorice hydrophobic polyphenols in medium-chain triglycerides (MCT). As part of a safety evaluation, a 90-day oral toxicity study in rats was conducted using an LFO concentrate solution (2.90% glabridin). Male and female animals were assigned to one of 12 groups (10 males or females per group) and received corn oil (negative control), MCT (vehicle control), or 400, 600, 800 or 1600 mg/kg of the LFO concentrate solution. In conclusion, LFO concentrate solution induced an anticoagulation effect in both sexes, although there was a clear sex difference. Based on these findings, it is concluded that the no-observed-adverse-effect level (NOAEL) for the LFO concentrate solution is estimated to be 800 mg/kg/day for female rats, and approximately 400 mg/kg/day for male rats.

Capsule plication as a protective measure against post-operative intracapsular haematoma formation following trans-sphenoidal removal of pituitary macroadenoma.

BACKGROUND: Post-operative haematoma and visual deterioration are rare but serious complications after trans-sphenoidal surgery. For more reliable decompression of the optic nerve, we introduce a new technique for volume reduction of the cavity remaining after trans-sphenoidal resection of macroadenomas. TECHNIQUE: After intracapsular removal of the adenoma, the suprasellar portion of the tumour 'capsule' spontaneously prolapsed into the sella turcica. The lowest part of the prolapsed capsule was sutured and/or clipped to reduce the volume of the residual cavity remaining after tumour resection. FINDINGS: A total of 23 patients with macroadenomas extending to suprasellar area had visual symptoms and were treated by trans-sphenoidal surgery. In seven (30%) patients, computerised tomography scans on the first post-operative day demonstrated haematoma formation in the residual cavity. The magnetic resonance imagings on the seventh post-operative day, however, showed approximately 80% reduction in the tumour size. Visual disturbance improved in 20 patients (87%). No patient had post-operative deterioration of visual function. The complications in this series included transient diabetes insipidus in three patients and panhypopituitarism in one patient. CONCLUSIONS: Capsule plication is a useful measure for volume reduction of the large residual cavity after trans-sphenoidal surgery for macroadenoma. It may prevent an acute post-operative complication due to intracapsular haematoma, and improve surgical outcome in well selected cases.

[Giant mediastinal thyroid follicular carcinoma with tracheal stenosis].

A 76-year-old female was admitted to the hospital with dyspnea and hypertention. She had the giant thyroid tumor which had been awared but not treated for 40 years. On a computed tomography (CT) scan and magnetic resonance imaging (MRI), the tumor was 14 x 10 cm and the tracheal stenosis was completely intrathoracic, which was 5 x 7 mm. Tracheal incubation was performed safety by using percutaneous cardiopulmonary support. A subtotal thyroidectomy was performed by midsternotomy with cervical incision. The weight of the resected specimen was 340 g and the pathological diagnosis was follicular thyroid carcinoma. The postoperative course was uneventful and the patient suffered no hoarseness and dyspnea.

[Isolated intracavitary metastatic hepatocellular carcinoma of the right atrium without inferior vena cava involvement; report of a case].

A 63-year-old female had been treated for liver cirrhosis and hepatocellular carcinoma (HCC) since 3 years before. She developed symptoms of dyspnea and echocardiography revealed a large tumor in the right atrium. The stalk of tumor was attached to the intraatrial septum just above the tricuspid valve and the tumor was floating between the right atrium and the right ventricle according to cardiac rhythm. The size of tumor was 30 x 15 mm in diameter. She was admitted to our hospital for emergency operation. She was operated for cardiac tumor under cardiopulmonary bypass successfully and the postoperative course was uneventful. But the pathology reported direct intracavitary metastasis of HCC without intravascular involvement. She was discharged on the 7th postoperative day for the treatment of HCC.

[Perioperative coronary spasm in the modified Bentall's operation for localized dissecting aneurysm of Valsalva sinuses].

A 55-year-old man had suffered from chest oppression while asleep for 1 to 2 years. Moderate aortic regurgitation and aneurysm of Valsalva sinuses were revealed by echocardiography. It was diagnosed as chronic localized dissecting aneurysm of Valsalva sinuses during the operation, and modified Bentall's operation was performed. The patient was extubated 2 hours after the operation. ST segment depression in leads I, aV(L) and V3-V6, and elevation in leads III and aV(R) suddenly occurred 5 hours after the operation. However, hemodynamics was very stable, and he complained of no chest pain. Cardiac asystole was detected 7 hours after the operation, and percutaneous cardiopulmonary support as well as intraaortic balloon pumping (IABP) was immediately started. Emergency coronary angiography revealed acute myocardial infarction due to severe coronary spasm in the left coronary artery. The patient expired on the 3rd postoperative day.

[The saccular coronary aneurysm associated with coronary artery to pulmonary artery fistulae].

Coronary artery fistulae are relatively rare congenital anomalies. Those associated with saccular coronary artery aneurysms are even rarer. Including the current case, only 65 such cases have been reported in Japan. A 62-year-old female was admitted to our hospital for evaluation of abnormal shadow on the chest X-ray. The enhanced chest computed tomography (CT) scan demonstrated a giant saccular coronary aneurysm on the left side of the pulmonary artery. Multi-detector row CT (MDCT) scan demonstrated the coronary artery aneurysm was connected to the left anterior descending artery. Coronary angiography revealed 2 aneurysms with bilateral coronary artery to pulmonary artery fistulae. The patient underwent aneurysmectomy and ligation of fistulae under cardiopulomonary bypass. The postoperative course was uneventful and postoperative coronary angiography revealed complete resection of the aneurysms and only slight blood flow through the fistulae. She was discharged on the 10th postoperative day.

Evaluation of the mutagenic potential of ubidecarenone using three short-term assays.

Addition of ubidecarenone, coenzyme Q(10) (CoQ(10)), to foods has been proposed for its nutritive value. Ubidecarenone is present naturally in a number of foods, including meats (e.g., beef, chicken) and fish (e.g., herring, rainbow trout), and on average, people are estimated to consume 2-20 mg/day of this metabolically important substance. Currently, relatively little formal evidence regarding the safety of ubidecarenone has been identified in the toxicology literature, despite its consumption by humans for centuries without reported notable adverse effects. As such, a series of toxicological studies, including mouse bone marrow micronucleus, chromosomal aberration, and bacterial reverse mutation tests, were conducted to evaluate the in vivo and in vitro mutagenic potential of CoQ(10). The test article, ubidecarenone, was devoid of clastogenic activity when administered orally to mice at doses up to 2000 mg/kg/day. In addition, the test article did not induce chromosomal aberration in CHL/IU cells exposed to concentrations as great as 5.0 mg/ml, nor did it induce reverse mutations in Salmonella typhimurium and Escherichia coli at concentrations as great as 5000 microg/plate.

Light and electron microscopic studies of perineural invasion by esophageal carcinoma.

Light and electron microscopic findings on perineural invasion by human esophageal squamous cell carcinoma are reported. Perineural invasion was observed histologically in 30 of a total of 129 cases (23%) of esophageal squamous cell carcinoma and in 11 of the 24 cases (46%) in which tumors infiltrated other organs by passing through the esophageal adventitial layer. Electron microscopic observation showed that the perineurium of peripheral nerves was completely surrounded by carcinoma cells and that marked degeneration and loss of perineural cells occurred. Irregularly thickened basal laminae were detected in the perineurium. For nerves incompletely surrounded by carcinoma tissue, the free portion of the perineurium revealed degenerative findings similar to those for completely surrounded nerves. Cytoplasmic projections of the leading margin of the invading cancer tissue were located in the degenerated perineurium, contained many lysosomes, and were not always surrounded by basal laminae. These observations suggest that invading carcinoma tissue actively contributes to the degeneration of the perineural sheath and that the special pattern of carcinoma tissue surrounding the peripheral nerves results from infiltration along the degenerated sheath of the perineurium.