Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs. PATIENTS AND METHODS: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over. RESULTS: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients. CONCLUSIONS: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

A Combined test using both cell sediment and supernatant cell-free DNA in pleural effusion shows increased sensitivity in detecting activating EGFR mutation in lung cancer patients.

INTRODUCTION: The aim of this study was to examine whether a combined test using both cell sediment and supernatant cytology cell-free DNA (ccfDNA) is more useful in detecting EGFR mutation than using cell sediment DNA or supernatant ccfDNA alone in pleural effusion of lung cancer patients. METHODS: A total of 74 lung adenocarcinoma patients with paired samples between primary tumour and corresponding metastatic tumour with both cell sediment and supernatant ccfDNA of pleural effusion cytology were enrolled in this study. Cell sediment and supernatant ccfDNA were analysed separately for EGFR mutations by polymerase chain reaction. RESULTS: Out of 45 patients with mutant EGFR in primary tumours, EGFR mutations were detected in 23 cell sediments of corresponding metastases (sensitivity; 51.1%) and 20 supernatant ccfDNA corresponding metastases (sensitivity; 44.4%). By contrast, the combined test detected EGFR mutations in 27 corresponding metastases (sensitivity; 60.0%), and had a higher sensitivity than the cell sediment or the supernatant ccfDNA alone (P < .05). Out of 45 patients with mutant EGFR, 24, three and 18 were cytologically diagnosed as positive, atypical or negative, respectively. The detection rate in the combined test was highest (95.8%) in the positive group, and mutant EGFR was also detected in four of 18 samples (22.2%) in the negative group. CONCLUSIONS: A combined test using both cell sediment DNA and supernatant ccfDNA samples increases the concordance rate of EGFR mutations between primary tumour and corresponding metastases. Our findings indicate that supernatant ccfDNA is useful even in cases where the cytological diagnosis is negative.

SurePath® LBC improves the diagnostic accuracy of intrahepatic and hilar cholangiocarcinoma.

INTRODUCTION: The current study aimed to compare cytology using SurePath® (SP)-LBC and biliary tissue histology (BTH) for the diagnosis of biliary disease. METHODS: Between January 2014 and December 2016, 57 patients underwent endoscopic retrograde cholangiopancreatography for the diagnosis of biliary disease. Biliary cytological samples were processed using SP-LBC and subsequently BTH was performed. A final diagnosis was confirmed by surgery (23 malignant cases) and clinical follow-up (34 benign and malignant cases): 18 extrahepatic cholangiocarcinoma; 17 intrahepatic/hilar cholangiocarcinoma (intra/H-CC); eight other malignant disease; and 14 benign biliary disease. The diagnoses made using SP-LBC and BTH were classified into four categories: (1) benign; (2) indeterminate; (3) suspicious for malignancy/malignant; and (4) inadequate. In addition, diagnostic accuracy was compared between SP-LBC and BTH. RESULTS: Although 23% (13/57) of BTH samples were classified as inadequate, all SP-LBC cases were classified as adequate. Among 43 malignant cases, 11 normal, four indeterminate and 28 suspicious for malignancy/malignant were found using SP-LBC (26%, 9% and 65%, respectively), in contrast to 10 inadequate, nine normal, 10 indeterminate and 14 suspicious for malignancy/malignant observed using BTH (23%, 21%, 23%, and 33%, respectively). The identification of malignant cells was strikingly different between SP-LBC and BTH. Furthermore, limited to intra/H-CC, accuracy was significantly higher using SP-LBC than using BTH (P < .001). CONCLUSIONS: SP-LBC of the biliary tract is a useful and reliable method for diagnosing biliary malignant disease and has an advantage over BTH for detecting malignant cells and accurately diagnosing intra/H-CC.

Patient perceptions of symptoms and concerns during cancer chemotherapy: 'affects my family' is the most important.

BACKGROUND: Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients' concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients' quality of life during chemotherapy. METHODS: Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. RESULTS: The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was 'affects my family or partner,' followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were 'affects my family or partner' and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems. CONCLUSION: Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort 'affects my family or partner' was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.

The influence of preceding dive cycles on the foraging decisions of Antarctic fur seals.

The foraging strategy of many animals is thought to be determined by their past experiences. However, few empirical studies have investigated whether this is true in diving animals. We recorded three-dimensional movements and mouth-opening events from three Antarctic fur seals during their foraging trips to examine how they adapt their behaviour based on past experience--continuing to search for prey in the same area or moving to search in a different place. Each dive cycle was divided into a transit phase and a feeding phase. The linear horizontal distance travelled after feeding phases in each dive was affected by the mouth-opening rate during the previous 244 s, which typically covered two to three dive cycles. The linear distance travelled tended to be shorter when the mouth-opening rate in the previous 244 s was higher, i.e. seals tended to stay in the same areas with high prey-encounter rates. These results indicate that Antarctic fur seals follow decision-making strategies based on the past foraging experience over time periods longer than the immediately preceding dive.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Comparison between the effects of epidural and intravenous patient-controlled analgesia on postoperative disability-free survival in patients undergoing thoracic and abdominal surgery: A post hoc analysis.

BACKGROUND: Thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) are widely used to mitigate immediate postoperative pain; however, their effects on long-term disability-free survival are poorly documented. This study aimed to compare the effects of postoperative TEA and IV-PCA on disability-free survival in patients who underwent thoracic or abdominal surgery. METHODS: This post hoc analysis of a prospective observational study included 845 inpatients aged ≥55 years that underwent elective thoracic and abdominal surgery between 1 April 2016 and 28 December 2018 in a tertiary care hospital. Inverse probability of treatment weighted (IPTW) using stabilized inverse propensity scores was adopted to minimize bias. The primary outcome in this study was disability-free survival, defined as survival with a 12-item World Health Organization Disability Assessment Schedule 2.0 score of <16%, assessed at 3 months and 1 year after surgery. RESULTS: The final analysis included 601 patients who received TEA and 244 who received IV-PCA. After IPTW, the weighted incidence of disability-free survival at 3 months and 1 year was 60.5% and 61.4% in the TEA group and 78.3% and 66.2% in the IV-PCA group, respectively. The adjusted OR for disability-free survival at 3 months and 1 year was 0.84 (95% confidence interval [CI]: 0.50-1.39) and 1.21 (95% CI: 0.72-2.05), respectively, for the TEA group. CONCLUSION: No significant differences were observed in the disability-free survival at 3 months and 1 year after elective thoracic and abdominal surgery in patients aged ≥55 years who received TEA or IV-PCA. SIGNIFICANCE STATEMENT: This study is the first in our setting to document the long-term effects of patient-controlled analgesia. In a post hoc analysis of our prospective cohort study, we show that although differences in chronic postsurgical pain exist at 3 months post-surgery, disability-free survival rates at 1 year do not differ irrespective of the choice of patient-controlled analgesia. The findings of this study highlight the need for shared decision-making between clinicians and patients.

Parallel comparison of apheresis-collected platelet concentrates stored in four different additive solutions.

BACKGROUND AND OBJECTIVES: Partially replacing plasma with additive solutions in platelet (PLT) concentrates (PCs) may help to reduce transfusion reactions. Constituents of PLT additive solutions (PASs) have been revealed to affect the quality of PCs. Previous studies involved pairwise comparison of identical PLTs with two different PASs or multicomparison using random PLTs with three or more PASs. In this study, we performed parallel comparison using PCs from identical donors with four PASs. In addition to traditional parameters, the release of bioactive substances and plasma proteins was assessed. MATERIALS AND METHODS: Platelets collected four times by apheresis from three donors were suspended in Intersol, SSP+, Composol or M-sol with 35% autologous plasma. The PC parameters, including PLT activation markers, glucose consumption, chemokines and plasma proteins, were assessed during 5-day storage. RESULTS: Mean PLT volumes were decreased in SSP+, Composol and M-sol after 5-day storage, with significant differences, whereas the hypertonic shock response (HSR) was decreased only in Intersol. Glucose consumption was faster in Intersol and M-sol than in SSP+ or Composol. PLT activation, determined as CD62P, sCD62P, sCD40L and RANTES, was significantly higher in Intersol than the other three PASs. No marked change was observed in fibrinopeptide A and C3a in any PASs. CONCLUSIONS: M-sol, SSP+ and Composol effectively preserved the quality of PCs. PLT activation was significantly enhanced in Intersol compared with the other three PASs. These effects seem to depend on magnesium and potassium as a constituent. Parallel comparison further verified that the PC quality largely depended on PASs but not donors.

Prophylactic strategies in recurrent vulvovaginal candidiasis: a 2-year study testing a phytonutrient vs itraconazole.

The aim of the present study was to assess the clinical efficacy of a one week/month treatment with a phytocompound with antimycotic properties (K-712, with following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30 percent concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC), as compared to once a week treatment with an azole drug for 24 months follow up. This prospective randomized study involving 122 women (19 to 63 years old) with a history of proven episodes of RVVC in the prior 12 months. Patients were allocated in two treatment groups of 61 patients each and given A) Itraconazole 200 mg orally once a week or B) 1 tab twice a day of K-712 for one week/month. Each treatment schedule was well tolerated with 19 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste), while only 3 patients on K-712 reported slight dyspepsia. The number of relapses was significantly lower in the K-712-treated group as compared to the itraconazole-group (22 vs 39, p less than 0.05). Moreover, the former group showed a significantly decreased number of cases resistant or dose-dependent susceptible as compared to group A (p less than 0.05 vs itraconazole) and the same occurred for the occurrence of non-albicans species (group A 64.1 percent vs group B 31.8 percent, p less than 0.05). The overall mycological cure at the end of the 2-year study showed a comparable benefit between the two groups. From these data it appears that the present antifungal phytonutrient is equally effective as itraconazole in the overall treatment of RVVC over a 2-year follow-up, but yielding a significantly better prophylactic effect and also maintenance benefit with lower relapse rate, antifungal susceptibility and growth of azole-resistant species.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Predictions of the pathological response to neoadjuvant chemotherapy in patients with primary breast cancer using a data mining technique.

Nomogram, a standard technique that utilizes multiple characteristics to predict efficacy of treatment and likelihood of a specific status of an individual patient, has been used for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients. The aim of this study was to develop a novel computational technique to predict the pathological complete response (pCR) to NAC in primary breast cancer patients. A mathematical model using alternating decision trees, an epigone of decision tree, was developed using 28 clinicopathological variables that were retrospectively collected from patients treated with NAC (n = 150), and validated using an independent dataset from a randomized controlled trial (n = 173). The model selected 15 variables to predict the pCR with yielding area under the receiver operating characteristics curve (AUC) values of 0.766 [95 % confidence interval (CI)], 0.671-0.861, P value < 0.0001) in cross-validation using training dataset and 0.787 (95 % CI 0.716-0.858, P value < 0.0001) in the validation dataset. Among three subtypes of breast cancer, the luminal subgroup showed the best discrimination (AUC = 0.779, 95 % CI 0.641-0.917, P value = 0.0059). The developed model (AUC = 0.805, 95 % CI 0.716-0.894, P value < 0.0001) outperformed multivariate logistic regression (AUC = 0.754, 95 % CI 0.651-0.858, P value = 0.00019) of validation datasets without missing values (n = 127). Several analyses, e.g. bootstrap analysis, revealed that the developed model was insensitive to missing values and also tolerant to distribution bias among the datasets. Our model based on clinicopathological variables showed high predictive ability for pCR. This model might improve the prediction of the response to NAC in primary breast cancer patients.

Is there a potential application of a fermented nutraceutical in acute respiratory illnesses? An in-vivo placebo-controlled, cross-over clinical study in different age groups of healthy subjects.

The role of oxidants in viral diseases is fairly complex because it includes metabolic regulation both of host metabolism and viral replication. However, a role for reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of virus-induced lung damage is supported by studies and antioxidants can thus be expected to act at many different levels. The aim of the present pilot study was to test an antioxidant nutraceutical approach on some relevant immunological parameters known to be affected in common seasonal respiratory tract infection. The study population consisted of 90 sedentary healthy patients, previously selected as being GSTM1-positive, divided into three groups: A) 20-40 years; B) 41-65 years; B) over 65 years. Each patients was administered a life style and dietary questionnaire. Subjects were supplemented for 6 weeks with either 9g/day (4.5g twice a day sublingually) of a fermented papaya preparation (Osato Research Institute, Gifu, Japan) or placebo. After a further month period of wash out, subjects were treated again in a crossover manner. Parameters checked were as follows: routine blood tests with WBC formula, saliva flow rate and secretary IgA and lysozyme production and redox gene expression of Phase II enzyme and SOD from upper airways cells (from nasal lavage). Salivary secretion rate showed an age-related decline and was significantly increased by FPP supplementation only in the youngest age-group (p less than 0.05). Subjects treated with FPP showed a significantly higher lever of IgA and lisozyme production., irrespective of age group while their baseline production was significantly lower in the oldest age-group as compared to the youngest one (C vs A, p less than 0.05). FPP treatment brought about a significant upregulation of all phase II enzyme and SOD gene expression tested in nasal lavage cells. In conclusion, FPP supplementation during 1 month resulted in higher salivary IgA and increase in phase II and SOD enzyme expression, i.e the most important antioxidant in the respiratory tract. The biological significance of these effects i.e., whether it will help reducing the whole respiratory oxidative stress in the human airway and, hopefully, the incidence and/or severity of URTI remains to be demonstrated in longer clinical trials.

Recognition of endoscopic diagnosis in differentiated-type early gastric cancer by flexible spectral imaging color enhancement with indigo carmine.

BACKGROUND/AIMS: To evaluate the usefulness of flexible spectral imaging color enhancement with indigo carmine (I-FICE) in early gastric cancer (EGC) demarcation. METHODS: The study participants were 29 patients with differentiated-type EGC. The endoscope was fixed and images of the same area of EGC demarcations in each lesion were obtained using four different methods (WLE, flexible spectral imaging color enhancement (FICE), CE, and I-FICE). FICE mode at R 550 nm (Gain: 2), G 500 nm (Gain: 4), and B 470 nm (Gain: 4) was used. Four endoscopists ranked the images obtained by each method on the basis of the ease of recognition of demarcation using a 4-point system. We calculated the standard deviation of pixel values based on L*, a*, and b* color spaces in the demarcation region (Lab-SD score). RESULTS: The median ranking score for I-FICE images was significantly higher than that obtained from the other methods. Further, the average Lab-SD score was significantly higher for I-FICE images than for images obtained by the other methods. There was a good correlation between the ranking score and Lab-SD score. CONCLUSION: EGC demarcations were most easily recognized both subjectively and objectively using I-FICE image, followed by CE, FICE and WLE images.

Negative predictors of clinical response to triptans in patients with migraine.

Moderate to severe migraine attacks are treated with triptans. However, about 25% of migraineurs fail to respond to triptans. We investigated the involvement of gene polymorphisms, personality traits and characteristics of headache, and made a scoring system for prediction of clinical response to triptans in patients with migraine. Gene polymorphisms including serotonin (5-HT)(1B) receptor G861C and dopamine receptor 2 (DRD2) C939T, personality traits and characteristics of headache were investigated in 46 consistent responders and 14 inconsistent responders to triptans. The multivariate stepwise logistic regression analysis revealed that age, periorbital/deep orbital pain and C/C genotype carrier at DRD2 C939T were significant factors that contributed independently to the negative response to triptans in patients with migraine. Their odds ratios were 6.329 (40-69 vs. 20-39 years, 95% CI 1.441-27.778), 6.772 (no vs. yes, periorbital/deep orbital pain, 95% CI 1.159-39.580) and 14.085 (non-C/C vs. C/C genotype at DRD2 C939T, 95% CI 1.253-166.667), respectively. The predictive index (PI) of clinical response to triptans in patients with migraine was calculated using these three factors. The score in inconsistent responders (1.6 ± 0.6) was significantly higher than that in consistent responders (0.8 ± 0.7, P < 0.001). Sensibility of low-score (RI = 0) group was 100%, and specificity of high-score (PI ≥ 2) group was 87%. The proposed scoring system should in the future be the object of larger studies to confirm its validity.

Detection of feeding behaviour in common carp Cyprinus carpio by using an acceleration data logger to identify mandibular movement.

Miniaturized acceleration data loggers were attached to the lower mandible of common carp Cyprinus carpio to remotely identify feeding behaviour. Whether the acceleration signal could distinguish the quantity and quality of food was also investigated. The frequency and amplitude of the lower mandible stroke, calculated from surging acceleration determined by continuous wavelet transformation, significantly increased during the feeding period compared to that during the non-feeding period. These characteristic movement patterns were maintained for mean ±s.e. 187·3 ± 38·2 s when the fish were fed a single item of food and for mean ±s.e. 419·3 ± 28·6 s when they consumed multiple items. The dominant cycle and amplitude calculated according to feeding event duration, however, did not differ significantly between the two types of diets the fish consumed. Surging acceleration could detect mean ±s.e. 89·8 ± 13·5% of feeding events, although the false detection rate was mean ±s.e. 25·9 ± 10·9%. The results indicate that the mandible acceleration measurement method could be utilized to detect and record the feeding events in fishes that use a suction feeding mode similar to C. carpio.

Protective effect of an oral natural phytonutrient in recurrent vulvovaginal candidiasis: a 12-month study.

The aim of the present study is to assess the clinical efficacy of a phytocompound with antimicotic properties (K-712, with the following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30 percent concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC) as compared to an azole drug during a 12-month period: 6 months of treatment followed by 6 months of observation. This prospective randomized study involved 82 women (19-61 years) with complaints of abnormal vaginal discharge and with a history of at least four proven episodes of RVVC in the previous 12 months. Patients were divided into two groups of treatment of 41 patients each and were given: A) Itraconazole 200 mg orally daily for 4 days, then 200 mg once weekly for 6 months or B) 1 tablet twice a day of a K-712 for 4 weeks and then for the first 2 weeks of each month for a total of 6 months. Both groups were then followed-up for further 6 months. Each treatment schedule was well tolerated with only 4 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste). Itraconazole reached an earlier symptomatic relief during the first two weeks of observation as compared with K-712 (p<0.05) but both treatments enabled a comparable benefit during the entire treatment study period, afterwards with comparable symptom/sign score (itraconazole vs K-712: 9 vs 11). At 6-month observation, mycological cure was reached by 83 percent in the itraconazole group and in 78 percent of the K-712-treated patients. During the further 6-month observation period without treatment, the itraconazole group showed significantly more relapses (65.7 vs 34.2 in K-712, p<0.05) and at the end of the whole 12-month study period the mycological cure was significantly higher in the K-712-treated patients (65.8 vs 34.3 percent, p<0.05). There was a non- significant trend increase of less drug-susceptible species in the itraconazole group. From these preliminary data it would appear that a natural antifungal phytocompound proves to be as good as itraconazole in the maintenance treatment of RVVC. Moreover, this approach seems to maintain a higher mycological success rate afterwards by reducing the number of relapses and probably of the growth of azole-resistant species.

Redox balance signalling in occupational stress: modification by nutraceutical intervention.

There is increasing evidence that psychosocial stress can be viewed as a system-wide derangement of cellular homeostasis, with heightened oxidative stress and triggered proinflammatory mechanisms. The aim of this study is twofold: a) to replicate findings that psychological stress increases oxidative damage and b) to determine whether a fermented papaya preparation known to exert significant protective antioxidant properties could buffer such increases in nuclear DNA damage while also inducing epigenetic protective mechanisms. Twenty-eight sedentary men and women (age range: 28-52), who reported living a stressful lifestyle but with an overall positive attitude, were recruited for this study. Chronic diseases as well as severe burnout and use of drugs for anxiety constituted exclusion criteria. Subjects were supplemented for 1 month with 9 g/day (4.5 g twice a day) of a certified fermented papaya preparation. All subjects were given a stress and sleep quality questionnaire together with a diet and life style assessment. Blood was collected at 2 and 4 week, erythrocyte and leukocyte were separated to assess redox balance and heme oxygenase-1 (HO-1) gene expression while bilirubin oxidized metabolites (BOMs) were tested in the urine. Stressed individuals showed a significant abnormality of redox status with increased MDA of erythrocyte and increased level of 8-0HdG in leukocyte and BOMs excretion (p<0.05). Nutraceutical supplementation brought about a normalization of such values already at the 2 week observation (p<0.05) together with a significant upregulation of HO-1 (p<0.01). Taken together, the results of this study confirm that stressful occupational life per se, without any overt psychiatric illness, may be associated to increased oxidative stress. Supplementation with functional food affecting redox regulation may be part of the therapeutic armamentarium to be considered in this clinical setting.