Revisiting the use of the EORTC QLQ-STO22 to assess health-related quality of life of patients with gastric cancer: incorporating updated treatment options and cross-cultural perspectives.

BACKGROUND: The EORTC QLQ-STO22 (QLQ-STO22) is a firmly established and validated measure of health-related quality of life (HRQoL) for people with gastric cancer (GC), developed over two decades ago. Since then there have been dramatic changes in treatment options for GC. Also, East Asian patients were not involved in the development of QLQ-STO22, where GC is most prevalent and the QLQ-STO22 is widely used. A review with appropriate updating of the measure was planned. This study aims to capture HRQoL issues associated with new treatments and the perspectives of patients and health care professionals (HCPs) from different cultural backgrounds, including East Asia. METHODS: A systematic literature review and open-ended interviews were preformed to identify potential new HRQoL issues relating to GC. This was followed by structured interviews where HCPs and patients reviewed the QLQ-STO22 alongside new issues regarding relevance, importance, and acceptability. RESULTS: The review of 267 publications and interviews with 104 patients and 18 HCPs (48 and 9 from East Asia, respectively) generated a list of 58 new issues. Three of these relating to eating small amounts, flatulence, and neuropathy were recommended for inclusion in an updated version of the QLQ-STO22 and covered by five additional questions. CONCLUSIONS: This study supports the content validity of the QLQ-STO22, suggesting its continued relevance to patients with GC, including those from East Asia. The updated version with additional questions and linguistic changes will enhance its specificity, but further testing is required.

Differences in innate fear behaviour in native Japanese chickens.

1. Comprehensive knowledge of innate fear in chickens has important implications for understanding the adaptation of native Japanese chickens in modern production and behavioural changes caused by modern breeding goals. Innate fear behaviour seen in chicks from six native Japanese chicken breeds;, Ingie (IG), Nagoya (NAG), Oh-Shamo (OSM), Tosa-Jidori (TJI), Tosa-Kukin (TKU) and Ukokkei (UK), were compared with those in two lines of White Leghorn (WL-G and WL-T) in tonic immobility (TI) and open field (OF) tests.2. TI and OF tests were conducted for 267 chicks at 0-1 days of age in the eight breeds. Raw data for four TI traits and 13 OF traits were corrected for environmental factors. Breed differences were analysed by the Kruskal-Wallis test followed by the Steel Dwass post hoc test. Principal component (PC) analyses were conducted.3. The results showed that OSM was the least sensitive to fear in both the TI and OF tests. The WL-G birds showed higher sensitivity to TI fear but lower sensitivity to OF fear. The PC analysis of OF traits classified the tested breeds into three groups: least (OSM and WL-G), moderate (IG, WL-T, NAG, TJI and TKU) and most sensitive (UK).

Prognostic factors for survival in patients with pT1 N+ or T2-3 N0 gastric cancer in Japan.

BACKGROUND: The outcome for pT1 N+ or pT2-3 N0 gastric cancer is favourable, but some patients suffer from recurrent disease. The aim of this study was to identify prognostic factors in patients with pT1 N+ or pT2-3 N0 gastric cancer. METHODS: This was a multicentre, retrospective cohort study. All patients with pT1 N+ or pT2-3 N0 gastric cancer who underwent curative gastrectomy at five high-volume, specialized cancer centres in Japan between 2000 and 2008 were included. Demographic, clinical, surgical and pathological data were collected. Independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Some 1442 patients were included. The 5-year overall survival rate for patients with pT1 N+ or pT2-3 N0 gastric cancer was 92·0 per cent. Multivariable analysis for overall survival identified age (hazard ratio (HR) 2·67, 95 per cent c.i. 2·09 to 3·43), sex (HR 0·57, 0·39 to 0·83) and clinical tumour depth (cT) (HR 1·45, 1·06 to 1·98) as independent prognostic factors. CONCLUSION: Survival of patients with pT1 N+ or pT2-3 N0 gastric cancer is good. Age 65 years or above, male sex and cT2-4 category are associated with worse overall survival.

Enhanced recovery after surgery for gastric cancer and an assessment of preoperative carbohydrate loading.

BACKGROUND: We previously reported on the feasibility of enhanced recovery after surgery (ERAS) protocol for gastric cancer with a prospective phase II study, but the superiority of this approach over non-ERAS perioperative management remains unclear. Preoperative carbohydrate loading, an important element of the ERAS protocol, has been shown to reduce insulin resistance, but its effects on clinical endpoints in gastric cancer surgery remain controversial. The aim of this study was to clarify the efficacy of the ERAS protocol for gastric cancer surgery, with particular focus on preoperative carbohydrate loading. METHODS: In this ERAS case-control study, we enrolled 121 patients as a case group and 259 patients undergoing gastrectomy for gastric cancer with our conventional perioperative management as a control group. Matched-pair analysis was performed to balance the patients' characteristics for comparison analysis. RESULTS: After matching, 108 patients were included in each group. Postoperative hospital stay was significantly shorter in the ERAS group than in the control group (8 days vs. 9 days, p < 0.001), while the incidence of Clavien-Dindo classification grade II or more postoperative complication was similar between the groups (11.1% vs. 15.7%, p = 0.325). No significant differences were found in serum albumin level, body weight, or grip strength between the groups before surgery and at 1 week and 1 month after surgery. CONCLUSION: Use of the ERAS protocol for gastric cancer shortened the length of postoperative hospital stay without increasing complications. Preoperative carbohydrate loading didn't improve the postoperative nutritional status or maintain the muscle strength postoperatively.

Multicentre observational study of quality of life after surgical palliation of malignant gastric outlet obstruction for gastric cancer.

BACKGROUND: Quality of life (QoL) is a key component in decision-making for surgical palliation, but QoL data in association with surgical palliation in advanced gastric cancer are scarce. The aim of this multicentre observational study was to examine the impact of surgical palliation on QoL in advanced gastric cancer. METHODS: The study included patients with gastric outlet obstruction caused by incurable advanced primary gastric cancer who had no oral intake or liquid intake only. Patients underwent palliative distal/total gastrectomy or bypass surgery at the physician's discretion. The primary endpoint was change in QoL assessed at baseline, 14 days, 1 month and 3 months following surgical palliation by means of the EuroQoL Five Dimensions (EQ-5D™) questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications. RESULTS: Some 104 patients (23 distal gastrectomy, 9 total gastrectomy, 70 gastrojejunostomy, 2 exploratory laparotomy) were enrolled from 35 institutions. The mean EQ-5D™ utility index scores remained consistent, with a baseline score of 0·74 and the change from baseline within ± 0·05. Gastric-specific symptoms showed statistically significant improvement from baseline. The majority of patients were able to eat solid food 2 weeks after surgery and tolerated it thereafter. The rate of overall morbidity of grade III or more according to the Clavien-Dindo classification was 9·6 per cent (10 patients) and the 30-day postoperative mortality rate was 1·9 per cent (2 patients). CONCLUSION: In patients with gastric outlet obstruction caused by advanced gastric cancer, surgical palliation maintained QoL while improving solid food intake, with acceptable morbidity for at least the first 3 months after surgery. Registration number 000023494 (UMIN Clinical Trials Registry).

Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer.

BACKGROUND: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. PATIENTS AND METHODS: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS). RESULTS: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). CONCLUSIONS: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. CLINICAL TRIAL REGISTRATION: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05).

BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.

A modified anaerobic digestion process with chemical sludge pre-treatment and its modelling.

Activated Sludge Models (ASMs) assume an unbiodegradable organic particulate fraction in the activated sludge, which is derived from the decay of active microorganisms in the sludge and/or introduced from wastewater. In this study, a seasonal change of such activated sludge constituents in a municipal wastewater treatment plant was monitored for 1.5 years. The chemical oxygen demand ratio of the unbiodegradable particulates to the sludge showed a sinusoidal pattern ranging from 40 to 65% along with the change of water temperature in the plant that affected the decay rate. The biogas production in a laboratory-scale anaerobic digestion (AD) process was also affected by the unbiodegradable fraction in the activated sludge fed. Based on the results a chemical pre-treatment using H2O2 was conducted on the digestate to convert the unbiodegradable fraction to a biodegradable one. Once the pre-treated digestate was returned to the digester, the methane conversion increased up to 80% which was about 2.4 times as much as that of the conventional AD process, whilst 96% of volatile solids in the activated sludge was digested. From the experiment, the additional route of the organic conversion processes for the inert fraction at the pre-treatment stage was modelled on the ASM platform with reasonable simulation accuracy.

Modelling clogging and biofilm detachment in sponge carrier media.

Sponge carrier media provide a large surface area for biofilm support; however, little information is known about how to model their dual nature as a moving bed and as porous media. To investigate the interaction of mass transfer and detachment with bio-clogging, a novel biofilm model framework was built based on individual-based modelling, and hydrodynamics were modelled using the lattice Boltzmann method. The combined model structure enabled the simulation of oxygen and biomass distribution inside the porous network as well as inside the biofilm. In order to apply the model to moving bed biofilm reactors (MBBR), biofilm detachment due to abrasion (carrier collisions) was modelled to be dependent on intracarrier distance. In the initial growth stage, biofilm grew homogeneously on the internal skeleton after which a more discontinuous growth developed which significantly increased permeability. Low detachment rates caused clogging in the outer pores which limited growth of biofilm to the surface region of the sponge. High detachment rates on the surface enabled deeper oxygen penetration with higher internal biomass activity. The degree of clogging was also sensitive to the presence of extracellular polymeric substances because of its large spatial occupancy.

Tracer experiment and RTD analysis of DAF separator with bar-type baffles.

This paper describes the development of a new dissolved air flotation (DAF) separator with a flow streamlining baffle to improve solid separation efficiency. The analysis of the RTD (residence time distribution) curves indicated that the parameter θ(10) (dimensionless time at which 10% of tracer has discharged) increased from 0.38 for control reactor to 0.54 for the test reactor, suggesting significant reduction in short circuit flow. The RTD curves were also used to develop a compartment model for white water (rich in micro-bubbles and water flow is turbulent) and clear water (little or no air content and water flow is quiescent) zones in the reactor using a series of CSTR (continuous stirred tank reactors) and plug flow regime respectively. The proportion of the volume occupied by the white water zone was different in control and test configurations. In the test reactor, the fraction of the clear water zone was found to increase from 6 to 37%, resulting in improvement of the suspended solid (SS) removal efficiency from 97 to 99%.

Feasibility study of adjuvant chemotherapy with S-1 plus cisplatin for gastric cancer.

PURPOSE: To evaluate the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for stage III gastric cancer after curative resection. METHODS: Japanese patients with stage III gastric cancer who underwent gastrectomy with D2 lymph node resection were enrolled. Treatment consisted of 3 cycles of S-1 (80 mg/m(2)/day, b.i.d.) for 21 days followed by a 14-day rest, and cisplatin (60 mg/m(2) iv) on day 8. After that, S-1 monotherapy was given on days 1-28 every 6 weeks until 1-year postsurgery. After protocol amendment, the first chemotherapy cycle consisted of S-1 monotherapy; cisplatin was added to cycles 2, 3, and 4, followed by S-1 monotherapy up to 1-year postsurgery. The primary endpoint was the completion rate of three cycles of S-1 plus cisplatin. RESULTS: A total of 63 enrolled patients have been evaluated. Grade 3/4 toxicities included neutropenia (40%), anorexia (28%), and febrile neutropenia (4%) before protocol amendment (n = 25), and neutropenia (37%), anorexia (8%), and febrile neutropenia (3%) after amendment implementation (n = 38). Excluding ineligible cases, treatment completion rates were 57% (12/21) before and 81% (30/37) after the protocol amendment. CONCLUSIONS: The amended S-1 plus cisplatin is more feasible than the original protocol because of early dose reduction of S-1 prior to cisplatin addition and greater recovery time from surgery prior to cisplatin. This treatment should be considered as a feasible experimental arm for the next postoperative adjuvant phase III trial.

Prognostic role of immunosuppressive acidic protein in patients with esophageal cancer.

Immunosuppressive acidic protein (IAP) suppresses several immune responses in vivo and in vitro , and high preoperative IAP levels could predict the impairment of the host's immunity. In this study prognostic significance of preoperative IAP levels was investigated in 68 esophageal cancer patients with curative resection and eight with non-curative resection. The curative group had significantly lower levels than the non-curative group (432 +/- 183 mg/mL vs. 739 +/- 235 mg/mL, P < 0.0001). The IAP levels were associated with T-status (P < 0.0001), lymphatic invasion (P < 0.05), and p-stages (P < 0.0001). When 5-year survival rate of patients with curative resection was compared by setting various cutoff values of IAP between high and low IAP groups, several cutoff points (400-580 mg/mL) were revealed to be significantly associated with survival. Setting cutoff value of IAP to 560 mg/mL resulted in a most significant difference of 5-year survival rate of patients between the high and low IAP groups (13.9% and 61.5%, P < 0.0001). These data indicate that pre-operative IAP level is a useful parameter to predict the prognosis of esophageal cancer patients after curative resection.

Cystatin C expression in ischemic white matter lesions.

OBJECTIVES: To study the involvement of cystatin C in the progression of ischemic white matter lesions (WMLs). MATERIALS AND METHODS: Cystatin C levels in the cerebrospinal fluid (CSF) of patients with cerebrovascular disease, and also in primary and established human neural cell cultures were investigated. For pathologic analysis, cystatin C immunoreactivity was investigated in the white matter of patients with severe WMLs, mild WMLs or controls. RESULTS: Cystatin C levels in the CSF of patients with Fazekas WML grade 3 [14 with hypertension; W/HT(+) and nine without hypertension; W/HT(-)] were lower than those in 38 patients with grade 0-1 (P = 0.0022 and P < 0.0001 respectively). Immunohistochemical study showed that the cystatin C immunoreactivity was found in astrocytes, and the number of astrocytes in the white matter in the severe WML group was decreased when compared with that in controls (P = 0.0027) and in the mild WML group (P = 0.0024). In human neural cell cultures, treatments with thrombin, matrix metalloproteinases and interleukin 1 beta increased the expression of cystatin C mRNA in human astrocytes and hybrid neurons, but an enzyme-linked immunosorbent assay revealed that only thrombin significantly increased the production and secretion of cystatin C in astrocytes. CONCLUSIONS: These results suggest that low levels of CSF cystatin C in ischemic WMLs might be due to the decreased number of astrocytes that secrete cystatin C in response to the stimuli of proteases and inflammatory cytokines.

Chemokine-like factor expression in the idiopathic inflammatory myopathies.

OBJECTIVES: We evaluated the expression of chemokine-like factor (CKLF) in biopsied muscle fibers in inflammatory myopathies, non-inflammatory myopathies and neurologically diseased controls. MATERIALS AND METHODS: We studied the expression of CKLF in 15 polymyositis (PM), five dermatomyositis (DM), 15 non-inflammatory myopathies and nine neurologically diseased patients by immunohistochemistry. RESULTS: Chemokine-like factor was mostly expressed in small diameter muscle fibers surrounded by infiltrated lymphocytes of inflammatory myopathies patients. Parts of them were also positive for the staining of the developmental form of myosin heavy chain, a maker of regenerating muscle fibers. Thrombin immunoreactivity was observed in endomysium in PM and perimysium in DM. In vitro differentiation study showed a constitutive expression of CKLF in myoblasts that was abolished in myotubes during differentiation process and was induced again by thrombin. Thrombin regulates CKLF expression through protease-activated receptor-1 in myotubes. Treatment of a protein kinase C inhibitor partially blocked CKLF expression in myoblasts, while it remarkably inhibited that in myotubes. CONCLUSION: Chemokine-like factor expression is differentially regulated in myoblasts and myotubes. Thrombin could be a strong regulator for its expression. As CKLF is immunohistochemically positive in regenerating muscle fibers, we postulate here that CKLF is a useful marker for regenerating muscle fibers in inflammatory myopathies.

Plaque characterisation by Virtual Histology intravascular ultrasound analysis in patients with type 2 diabetes.

OBJECTIVES: To evaluate the in-vivo plaque composition and characteristics in patients with type 2 diabetes mellitus (DM) using Virtual Histology intravascular ultrasound (VH IVUS). METHODS: In 90 patients with stable angina pectoris, de novo target vessels were studied and plaque components were analysed. Patients were divided into two groups: a diabetic group (36 vessels) and a non-diabetic group (54 vessels). RESULTS: The percentage area of necrotic core and dense calcium were significantly larger in the DM group than the non-DM group (necrotic core: 11.0% (interquartile range (IQR): 7.2-15.2%) vs 7.6% (IQR 5.6-13.2%), p = 0.03; dense calcium: 5.6% (IQR: 2.3-7.3%) vs 2.9% (IQR: 1.7-4.9%), p = 0.01). The DM group presented with a significantly higher presence of at least one VH IVUS-derived thin-cap fibroatheroma (VHD-TCFA) (75% vs 41%, p = 0.001) and VH IVUS-derived fibrocalcific atheroma (VHD-FCA) (75% vs 40%, p = 0.001). In the DM group, 53% of the vessels had both VHD-TCFA and VHD-FCA, which was significantly higher than non-DM group (17%, p = 0.0004). CONCLUSIONS: Coronary plaque characteristics in DM patients showed an increased amount of dense calcium and necrotic core, as well as a higher frequency of VHD-TCFA and VHD-FCA. Atherosclerosis of the target vessel was more advanced in diabetic patients.

Phylogeographic origin of Hokkaido house mice (Mus musculus) as indicated by genetic markers with maternal, paternal and biparental inheritance.

We examined intraspecies genetic variation in house mice (Mus musculus molossinus) from the northern third of the Japanese Islands, in order to obtain evidence of the history of mouse colonization that might have shaped the current genetic diversity. We extended the previous sampling of mitochondrial cytochrome b sequence and added information from the Y-linked Sry gene and ribosomal RNA gene surveys. We distinguish mitochondrial haplotypes characteristic of the North Asian musculus subspecies group (involving M. m. musculus and M. m. molossinus) as 'MUS', and that of the Southeast Asian castaneus subspecies group as 'CAS' (although the mice resemble MUS morphologically). There was a clear geographic partition of MUS and CAS types into southern and northern Hokkaido, respectively. Conversely, on Tohoku, the MUS and CAS types were interspersed without clear geographic subdivision. In contrast to the mtDNA data, all Hokkaido and Tohoku mice examined were found to possess a unique type for the Y-linked Sry gene, specific to Korea and Japan. Restriction site analysis of nuclear rDNA probe showed a consistent distribution of MUS and CAS types, as major and minor components, respectively, in the Hokkaido and Tohoku mice. These data support the previous notion that the Hokkaido and Tohoku mice experienced genetic hybridization between primary residents of CAS origin and MUS newcomers arriving via a southern route. The invasion of the MUS type could correspond with the evidence for arrival of prehistoric peoples. There are, however, alternative interpretations, including genetic admixture between MUS arriving by a southern route and CAS from a northern route.

RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer.

RASSF2, a member of the RASSF1 family, has recently been identified as a potential tumour suppressor. We examined methylation status in multiple regions which included the CpG island and spanned the transcription start site of RASSF2 in 10 gastric cancer cell lines, as well as 78 primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation of RASSF2 in at least one of the regions examined was detected in seven (70%) of the 10 cell lines; two (20%) exhibited hypermethylation in all the regions examined including the transcription start site and lost expression of RASSF2 mRNA, which could, however, be restored by 5-aza-2' deoxycytidine treatment, while the other five (50%) cell lines exhibited hypermethylation at the 5'- and/or 3'- edge, with four of them expressing RASSF2 mRNA. In primary gastric cancers and corresponding non-neoplastic gastric epithelia, frequencies of RASSF2 methylation ranged from 29% (23 out of 78) to 79% (62 out of 78) and 3% (two out of 78) to 60% (47 out of 78), respectively, at different CpG sites examined. Methylation was frequently observed at the 5'- and 3'- edges, and became less frequent near the transcription start site in both the primary gastric cancers and corresponding non-neoplastic gastric epithelia. Hypermethylation near the transcription start site was mostly cancer-specific. We thus showed that RASSF2 is silenced by hypermethylation near the transcription start site in gastric cancer. Hypermethylation was found initially to occur at the 5'- and 3'- furthest regions of the CpG island in non-neoplastic gastric epithelia, to gradually spreads near the transcription start site to shut down RASSF2 expression, and ultimately to constitute a field-defect placing tissue increased risk for development of gastric cancer.