Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

A multicenter study of transient global amnesia for the better detection of magnetic resonance imaging abnormalities.

BACKGROUND AND PURPOSE: The detection rate of diffusion-weighted (DWI) hyperintense lesions varies widely in patients with transient global amnesia (TGA). The aim was to examine the association of hyperintense lesions on DWI magnetic resonance imaging (MRI) with patient characteristics, precipitating factors, clinical presentation and MRI settings in patients with TGA. METHODS: In this multicenter retrospective observational study, using the standardized diagnosis entry system of electronic health records of four tertiary medical centers in the Kansai district of Japan, TGA patients (n = 261) who underwent brain MRI within 28 days of onset were examined. When the onset time was unavailable, the discovery time was used. RESULTS: Diffusion-weighted hyperintense lesions were observed in 79 patients (30%). There were no significant differences in age, sex, vascular risk factors, precipitating factors or clinical presentation between patients with and without DWI lesions. The detection rate increased linearly 24 h after onset and then reached a plateau of 60%-80% by 84 h. After 84 h, the detection rate decreased rapidly. In a multivariate logistic regression model, MRI examination 24-84 h after onset (odds ratio 7.00, 95% confidence interval 3.50-13.99) and a thin-slice (≤3 mm) DWI sequence (odds ratio 7.59, 95% confidence interval 3.05-18.88) were independent predictors of DWI lesions. CONCLUSIONS: This study suggests that DWI hyperintense lesions in TGA are not associated with patient characteristics and clinical presentation. Brain MRI examination 24-84 h after onset and thin-slice DWI sequences enhance the detection of DWI lesions in TGA patients.

Matrix-material dependence on the elongation of embedded gold nanoparticles induced by 4 MeV C60 and 200 MeV Xe ion irradiation.

We report the elongation of embedded Au nanoparticles (NPs) in three different matrices, i.e. amorphous carbon (a-C), crystalline indium tin oxide (InxSn1-xOz; ITO) and crystalline calcium fluoride (CaF2), under irradiations of 4 MeV C60 + cluster ions and 200 MeV Xe14+ ions. Under 4 MeV C60 cluster irradiation, strong sputtering is induced in CaF2 layer so that the whole the layer was completely lost at a fluence of 5 × 1013 ions cm-2. Au NPs were partly observed in the SiO2, probably due to the recoil implantation. Amorphous carbon (a-C) layer exhibits low sputtering loss even under 4 MeV C60 irradiation. However, the elongation in a-C layer was low. While the ITO layer showed a certain decrease in thickness under 4 MeV C60 irradiation, large elongation of Au NPs was observed under both 4 MeV C60 and 200 MeV Xe irradiation. The ITO layer preserved the crystallinity even after large elongation was induced. This is the first report of the elongation of metal NPs in a crystalline matrix.

Comamonas sp. 3ah48 is a dibenz[a,h]anthracene-degrading bacterium that is tolerant to heavy metals.

Industrialization often causes polycyclic aromatic hydrocarbon (PAH) and heavy metal contamination of soil and water. In this study, we isolated a bacterium from bottom mud water around a park of Kawasaki Port, Japan, that degrades the 5-ring PAH dibenz[a,h]anthracene (DBA). The strain, Comamonas sp. 3ah48, degraded 29% of DBA (30 µg ml-1 ) in 7 days, and the degradation level increased drastically, to 59%, by the addition of glutamate to the medium. The strain also degraded 40, 14, 15 and 19% of pyrene (Pyr), benzo[b]fluoranthene (BbF), benzo[k]fluoranthene (BkF) and benzo[g,h,i]perylene (BghiP) respectively. Benzo[a]pyrene (BaP) was degraded only when glutamate was added to the medium. Strain 3ah48 retained its degradation levels in the presence of 2 mmol l-1 Co2+ , Zn2+ or Cr2+ , at almost the same level as that without metal, and increased the DBA degradation level to 57% in the presence of 2 mmol l-1 Cu2+ , suggesting the possibility of the presence of laccase. SIGNIFICANCE AND IMPACT OF THE STUDY: Sixteen polycyclic aromatic hydrocarbons (PAHs) are listed as priority pollutants by the United States Environmental Protection Agency (USEPA). Information about the biodegradation of one of those PAHs, dibenz[a,h]anthracene (DBA), is limited. The present study focuses on DBA degradation by Comamonas sp. 3ah48 strain isolated around Kawasaki Port, Japan. Comamonas sp. 3ah48, cultured with the addition of glutamate to the medium, was found to increase the degradation level of DBA and to degrade DBA even in the presence of high concentrations of heavy metals.

Clinical impacts of sun exposures on the faces and hands of Japanese women of different ages.

OBJECTIVE: To assess the impacts of sun exposures on some skin signs on the faces and hands of differently aged Japanese women, according to their distinct behaviours towards vis à vis sun exposure. METHODS: Two comparable cohorts of Japanese women (aged 18-83 years) were created according to their usual behaviour towards sun exposure i.e. non-sun-phobic (N = 495) and sun-phobic (N = 516) and through their regular use(s) of a photo-protective product. Standard photographs (full-face and 45° lateral) allowed to focus on 18 facial signs that were graded by 15 experts, using a referential skin ageing Atlas. From these two cohorts, two sub-cohorts (114 and 122 women) were created with regard to the similar clinical aspects of the dorsal side of their hands (Left vs. Right) that were further graded. Absolute differences in the scores of each sign were used (non-sun-phobic minus sun-phobic), by age-ranges, to better ascertain the impact of sun exposures and photo-protection. RESULTS: Facial signs related to skin wrinkles/texture and pigmentary spots were found significantly more accentuated among non-sun-phobic women and show an early onset (20-30 years). Facial sagging and crow's feet wrinkles appear delayed (30-40 years). The severity of vascular disorders was found to be similar in the two cohorts. The absolute differences in the grading's of almost all signs were unsurprisingly found increased with advancing ages, illustrating the combination of chronological and photo-ageing processes. With regard to hands, differences in skin texture and pigmentary disorders are of a late onset (40-50 years) and were found much increased at older ages. The cutaneous signs of the hands of Japanese women can hardly be taken as reliable markers of their photo-ageing status. CONCLUSION: The present work illustrates, for the first time, some specificities of the impact of sun exposures on the facial skin of Japanese women, pinpointing the fact that some facial signs are of an early onset. Results significantly confirm the importance of both sun avoidance coupled with photo-protective measures.

OBJECTIF: D'évaluer les impacts de l'exposition solaire sur plusieurs signes du visage et des mains de femmes Japonaises d'âge différents, selon leurs différents comportements vis-à-vis de l'exposition solaire. MÉTHODES: Deux cohortes comparables de femmes Japonaises (âgées de 18 à 83 ans) ont été créées selon leur comportement habituel vis à vis de l'exposition solaire, phobique (N = 516) ou non (N = 495) et selon leur utilisation(s) régulière(s) de produits photo-protecteurs. Des photographies standardisées du visage de face et latérales (45°) ont permis de se focaliser sur 18 signes cliniques du visage dont la sévérité a été quantifiée par 15 experts, utilisant un Atlas de référence du vieillissement cutané. De ces deux cohortes, deux sous-cohortes ont été extraites (114 et 122 femmes) par les aspects cliniques similaires de la face dorsale de leurs mains (Gauche vs. Droite) pour être ensuite quantifiées. Les différences absolues de chaque signe (non-phobiques moins phobiques), par tranches d'âges, ont été utilisées pour mieux déterminer l'impact des expositions solaires et des routines de photo-protection. RÉSULTATS: Les signes du visage liés à la texture cutanée/rides et aux taches pigmentaires ont été trouvés significativement aggravés chez les femmes non-phobiques de l'exposition solaire et d'apparition précoce (20-30 ans) tandis que la ptose du visage ou les rides de la patte d'oie apparaissent plus tardivement (30-40 ans). La sévérité des désordres vasculaires du visage a été trouvée similaire dans les deux cohortes. Les différences absolues dans la sévérité de la plupart des signes ont été logiquement trouvées accrues avec l'âge, illustrant la combinaison du vieillissement chronologique et de celui photo-induit. Concernant les mains, les différences dans la texture cutanée et les désordres pigmentaires apparaissent significativement tardives (40-50 ans) et augmentent à des âges plus avancés. Les signes cutanés des mains des femmes Japonaises ne semblent donc pas être des marqueurs fiables du vieillissement photo-induit. CONCLUSION: La présente étude illustre, pour la première fois, quelques spécificités des impacts de l'exposition solaire sur les signes faciaux de femmes Japonaises, pointant le fait que certains sont d'apparition précoce. Les résultats confirment de manière significative l'importance d'éviter les expositions solaires et de recourir à des mesures photo-protectrices.

Element Selectivity in Second-Harmonic Generation of GaFeO_{3} by a Soft-X-Ray Free-Electron Laser.

Nonlinear optical frequency conversion has been challenged to move down to the extreme ultraviolet and x-ray region. However, the extremely low signals have allowed researchers to only perform transmission experiments of the gas phase or ultrathin films. Here, we report second harmonic generation (SHG) of the reflected beam of a soft x-ray free-electron laser from a solid, which is enhanced by the resonant effect. The observation revealed that the double resonance condition can be met by absorption edges for transition metal oxides in the soft x-ray range, and this suggests that the resonant SHG technique can be applicable to a wide range of materials. We discuss the possibility of element-selective SHG spectroscopy measurements in the soft x-ray range.

Observation of self-polarization in BSA protected Au20 clusters.

Bovine serum albumin (BSA)-protected gold clusters (atomicity âˆ¼ 20), prepared using a wet chemical route, show strong dipolar radiative transition with a gap energy of 1.93 eV due to the high oscillator strength, as confirmed by the emission studies. Self-arrangement of the clusters with fixed atomicity yields a low dispersive dielectric and electric self-polarization nature. The electrical hysteresis loop measurements returned a remanent polarization of 0.05 µC cm-2, which can be correlated with the dipolar orientation (activation energy âˆ¼ 45.32 meV), originating from the structure-dependent deformation of the charge density.

Hypoxia-inducible factor-1α inhibits interleukin-6 and -8 production in gingival epithelial cells during hypoxia.

BACKGROUND AND OBJECTIVE: Hypoxia has been widely studied in inflammatory diseases as it can modulate the inflammatory response, mainly via the hypoxia-inducible factor (HIF). However, little is known about the effects of hypoxia and the role of HIF in the inflammatory responses to periodontitis. In this study, we focused on the gingival epithelium that is exposed to relatively low levels of oxygen. We investigated whether hypoxic conditions have an impact on inflammatory responses in human gingival epithelial cells (HGECs). MATERIAL AND METHODS: Pimonidazole HCl, which accumulates in hypoxic cells, was administered intraperitoneally to C57BL/6 mice with or without Porphyromonas gingivalis infection. Immunohistochemistry was then performed to detect the hypoxic cells in periodontal tissue. Immortalized HGECs were cultured under hypoxic conditions with or without interleukin (IL)-1ß, and the expression levels of IL-6 and IL-8 were measured by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. HIF-1α expression was detected by western blotting. The DNA-binding activity of HIF-1α was determined by a DNA-binding enzyme-linked immunosorbent assay. The involvement of HIF-1α in the hypoxic response was examined by transfection with HIF-1α siRNA. RESULTS: Immunohistochemistry revealed pimonidazole HCl accumulation in the gingival epithelium of both normal and P. gingivalis-infected mice, with a slightly stronger signal in the P. gingivalis-infected mice than in the normal mice. The IL-1ß-induced IL-6 and IL-8 production by HGECs was suppressed under hypoxic conditions. HIF-1α accumulated during hypoxia, and this accumulation was further enhanced by IL-1ß treatment. The hypoxia-dependent suppression of IL-6 and IL-8 expression was reversed by treating the cells with HIF-1α siRNA. CONCLUSION: Our results suggest that the gingival epithelium is exposed to low oxygen tension in periodontal tissue and that this hypoxic condition modulates the local inflammatory response of gingival epithelial cells in an HIF-1α-dependent manner.

Evaluation of the Ca ion release, pH and surface apatite formation of a prototype tricalcium silicate cement.

AIM: To evaluate the Ca2+ -releasing, alkalizing and apatite-like surface precipitate-forming abilities of a prototype tricalcium silicate cement, which was mainly composed of synthetically prepared tricalcium silicate and zirconium oxide radiopacifier. METHODOLOGY: The prototype tricalcium silicate cement, white ProRoot MTA (WMTA) and TheraCal LC (a light-cured resin-modified calcium silicate-filled material) were examined. The chemical compositions were analysed with a wavelength-dispersive X-ray spectroscopy electron probe microanalyser with an image observation function (SEM-EPMA). The pH and Ca2+ concentrations of water in which the set materials had been immersed were measured, and the latter was assessed with the EDTA titration method. The surface precipitates formed on the materials immersed in phosphate-buffered saline (PBS) were analysed with SEM-EPMA and X-ray diffraction (XRD). Kruskal-Wallis tests followed by Mann-Whitney U-test with Bonferroni correction were used for statistical analysis (α = 0.05). RESULTS: The prototype cement contained Ca, Si and Zr as major elemental constituents, whereas it did not contain some metal elements that were detected in the other materials. The Ca2+ concentrations and pH of the immersion water samples exhibited the following order: WMTA = prototype cement > TheraCal LC (P < 0.05). All three materials produced Ca- and P-containing surface precipitates after PBS immersion, and the precipitates produced by TheraCal LC displayed lower Ca/P ratios than those formed by the other materials. XRD peaks corresponding to hydroxyapatite were detected in the precipitates produced by the prototype cement and WMTA. CONCLUSION: The prototype tricalcium silicate cement exhibited similar Ca2+ -releasing, alkalizing and apatite-like precipitate-forming abilities to WMTA. The Ca2+ -releasing, alkalizing and apatite-like precipitate-forming abilities of TheraCal LC were lower than those of the other materials.

Cryopreservation of in vitro Shoot Tips of Ulluco (Ullucus tuberosus Cal.) Using D Cryo-Plate Method.

　　BACKGROUND: Maintenance of in vitro collections of ulluco (Ullucus tuberosus Cal.) is cumbersome and costly in an ex-situ genebank. An alternative method for long term preservation which is safe and cost-effective is required. OBJECTIVE: To apply a novel cryopreservation procedure using the cryo-plate system to improve the long-term conservation of ulluco. MATERIALS AND METHODS: Initially V and D cryo-plate methods were tested, subsequently the D cryo-plate method was selected for ulluco cryopreservation. The D cryo-plate procedures were optimized for post-LN regrowth procedures including cold-hardening, sucrose addition in alginate gel, and duration of LS treatment. Optimized procedures were tested with 11 ulluco lines. RESULTS: Shoot tips were isolated from cold-hardened shoots for 3-4 weeks at 5 degree C were excised to 1.0-1.5 mm long and 0.5 mm wide and precultured for 16h at 25 degree C on MS with 0.3 M sucrose. The shoot tips were attached on the cryo-plates by alginate gel with 0.4M sucrose. The cryo-plates with attached shoot tips were treated with 2.0 M glycerol and 1.0 M sucrose solution for 90 min at 25 degree C and dehydrated on filter paper in a Petri dish by air current flow at 25 degree C for 45 min before direct immersion in LN. This optimized procedure was applied to shoot tips of 11 ulluco lines, resulting regrowth ranging from 73 % to 97 %, with an average of 90 % post-LN regrowth. CONCLUSION: D cryo-plate is a practical and simple procedure for cryo-storage of in vitro grown ulluco shoot tips in an ex situ genebank.

Novel pre-therapeutic scoring system using patient and haematological data to predict facial palsy prognosis.

OBJECTIVES: We describe a novel scoring system, the facial Palsy Prognosis Prediction score (PPP score), which we test for reliability in predicting pre-therapeutic prognosis of facial palsy. We aimed to use readily available patient data that all clinicians have access to before starting treatment. DESIGN: Multicenter case series with chart review. SETTING: Three tertiary care hospitals. PARTICIPANTS: We obtained haematological and demographic data from 468 facial palsy patients who were treated between 2010 and 2014 in three tertiary care hospitals. Patients were categorised as having Bell's palsy or Ramsey Hunt's palsy. MAIN OUTCOME MEASURES: We compared the data of recovered and unrecovered patients. PPP scores consisted of combinatorial threshold values of continuous patient data (eg platelet count) and categorical variables (eg gender) that best predicted recovery. We created separate PPP scores for Bell's palsy patients (PPP-B) and for Ramsey Hunt's palsy patients (PPP-H). RESULTS: The PPP-B score included age (≥65 years), gender (male) and neutrophil-to-lymphocyte ratio (≥2.9). The PPP-H score included age (≥50 years), monocyte rate (≥6.0%), mean corpuscular volume (≥95 fl) and platelet count (≤200 000 /µL). Patient recovery rate significantly decreased with increasing PPP scores (both PPP-B and PPP-H) in a step-wise manner. PPP scores (ie PPP-B score and PPP-H score) ≥2 were associated with worse than average prognosis. CONCLUSIONS: Palsy Prognosis Prediction scores are useful for predicting prognosis of facial palsy before beginning treatment.

Use of a Right Lateral Sector Graft in Living Donor Liver Transplantation Is Feasible, but Special Caution Is Needed With Respect to Liver Anatomy.

Right lateral sector (RLS) grafting has been introduced to enlarge the potential donor pool for living donor liver transplantation (LDLT); however, evidence of its feasibility is limited. Data from 437 LDLTs carried out between 2000 and 2013 were analyzed retrospectively. LDLTs using a right liver graft (n = 251) were compared with those using a RLS graft (RLSG; n = 28). No donor mortality occurred, and the major complication rates were similar between the two groups. Postoperative liver function preservation was better in the RLSG donors. Concerning the recipients, the mortality and overall survival rates were similar between the two groups. The complication rate for the recipients was higher when more than two arterial or biliary anastomoses were necessary. A systematic literature search identified four reports on LDLT using RLSGs. Among 66 LDLTs, including the present series, there were no cases of donor death, and the rates of major and minor complications in the donors were 6% and 29%, respectively. The major complication and overall mortality rates in the recipients were 29% and 6%, respectively. LDLT using an RLSG is feasible, with an acceptable survival rate among the recipients.

IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin.

BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Nodules behind the ears: IgG4-related skin disease.

A 53-year-old healthy factory worker consulted our hospital complaining of small nodules of similar size, shape and location on both ears. The nodules revealed focal and massive infiltration of lymphocytes, plasma cells and eosinophils with fibrosis. They had no specific structure on pathological staining with haematoxylin and eosin. Immunostaining for IgG4 revealed that a large majority of the IgG+ cells were positive for IgG4. The ratio of IgG4+ to IgG+ plasma cells was approximately 40%. IgG4+ plasma cells were present at approximately 250 per high-power field. The patient was diagnosed with IgG4-related skin disease without multiple organ involvement in the systemic syndrome of IgG4-related diseases. Because the patient was a factory worker and exposed to an environment of metallic dust, a skin patch test that included a metal series was performed. Zinc and manganese produced positive reactions. Because only skin lesions were observed in this case, not multiple organ involvement, tissue infiltration by IgG4+ plasma cells might have resulted from continuous sensitization to zinc and/or manganese.

High-resolution manometry findings in symptomatic post-Nissen fundoplication patients with normal endoscopic configuration.

The aim of this study was to investigate high-resolution manometry (HRM) findings in symptomatic post-fundoplication patients with normal endoscopic configuration. A retrospective review of a prospectively maintained database was conducted to identify patients who underwent evaluation with HRM and endoscopy for symptom evaluation after previous fundoplication. Study period extends from September 2008 to December 2012. Only patients with complete 360° fundoplication (Nissen) were included, and patients with partial fundoplication were excluded. Patients with endoscopic abnormality or patients who underwent Collis procedure were also excluded. Additionally, contrast study and 24-hour pH study if done were reviewed. Symptoms were graded using a standard questionnaire with symptoms graded on a scale of 0-3. Symptom grade 2 or 3 was considered a significant symptom. One hundred seventy-nine symptomatic patients with previous Nissen fundoplication underwent HRM and endoscopy during the study period. Of these, 136 patients were excluded (51 had recurrent hiatal hernia, 2 had disrupted fundoplication, 68 had slipped fundoplication, 10 had twisted fundoplication, 2 had esophageal stricture, and 3 had Collis procedure). Remaining forty-three patients met inclusion criteria (mean age of 56.0 ± 14.8, 32 females).The most common symptom was dysphagia (67%). Patients with dysphagia had a significantly longer length of distal esophageal high pressure zone (HPZ) and a higher integrated relaxation pressure (IRP) than patients without dysphagia (P = 0.020, 0.049). Especially, patients who had shorter HPZ (≤2 cm) were less likely to have significant dysphagia. Twenty-three patients (53%) had heartburn. There was no significant difference in HRM findings between patients with and without heartburn. Only 4 of 28 patients with concomitant pH study showed abnormal DeMeester score (>14.7), and there was no correlation between results of pH study and lower esophageal sphincter pressure/length and IRP. Longer HPZ complex length and higher IRP as measured with HRM is associated with post-Nissen fundoplication dysphagia in patients with normal endoscopic configuration. No HRM parameters are associated with reported heartburn or a positive pH score.

Effects of bisphosphonates on human esophageal squamous cell carcinoma cell survival.

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers in Japan. Anticancer chemotherapy has been useful for ESCC treatment. However, therapeutic options are limited. Recently, bisphosphonates (BPs), which are osteoporosis drugs, have shown anticancer effects in several cancer cell lines, but the effects against ESCC cell lines are unknown. In this study, we examined the cytotoxic effects of BPs and their mechanisms of cytotoxicity in human ESCC cell lines. A first-generation BP (etidronate), two second-generation BPs (alendronate and pamidronate), and two third-generation BPs (risedronate and zoledronate) were used in this study. All BPs, except etidronate, were cytotoxic, as indicated by increased caspase-3/7 activity and numbers of Annexin-fluorescein isothiocyanate positive cells in ESCC cell lines. From cell cycle analysis, G0/G1-phase arrest was observed upon treatment with second- and third-generation BPs. In addition, Cyclin D1 protein expression levels were decreased by second- and third-generation BP treatment. Although squalene and trans, trans-farnesol minimally affected BP cytotoxicity, treatment with geranylgeraniol inhibited BP cytotoxicity almost completely. We concluded that second- and third-generation BPs are cytotoxic to ESCC cell lines as they induce apoptosis and inhibit the cell cycle through mevalonate pathway inhibition. Therefore, BP treatment may be a beneficial therapy in ESCC patients.

Validation of the distress and impact thermometer and the changes of mood during the first 6 months of treatment in gynecological cancer patients: a Kansai Clinical Oncology Group (KCOG)-G1103 prospective study.

PURPOSE: To verify distress and impact thermometer (DIT) for screening emotional distress in gynecological cancer patients by Hospital Anxiety and Depression Scale total (HADS-T) as gold standard and to assess emotional changes by DIT and HADS-T. METHODS: A prospective study was conducted in newly diagnosed gynecological cancer patients during the peri-treatment period after the cancer diagnosis followed by 6-month. We defined a HADS-T score of ≥11 as being indicative of emotional distress. RESULTS: 117 patients were enrolled between May 1, 2011 and March 31, 2012, and 95 were eligible. The median age was 54 years (range 31-77). (1) From the baseline to 3-month, distress (DIT-D) ≥4 with Impact (DIT-I) ≥2 exhibited sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of 0.776 [95 % confidential interval (CI) 0.688, 0.850], 0.889 (95 % CI 0.824, 0.954), 0.868 (95 % CI 0.792, 0.949), and 0.808 (95 % CI 0.731, 0.886), respectively. (2) At 6-month, DIT-D ≥2 with DIT-I ≥1 exhibited sensitivity, specificity, PPV and NPV of 0.893 (95 % CI 0.778, 1), 0.825 (95 % CI 0.707, 0.942), 0.781 (95 % CI 0.638, 0.928), and 0.917 (95 % CI 0.826, 1). (3) At 6-month, the HADS-T, DIT-D, and DIT-I scores in individual patients were significantly reduced by a mean of 4.57 (p < 0.0001), 2.34 (p < 0.0001), and 1.10 (p = 0.0031), respectively, compared with those scores of baseline (Student's paired t test), but still remained high. CONCLUSIONS: (1) On acute phase within 3-month setting, DIT; DIT-D ≥4 with DIT-I ≥2, is a reliable cut-off to screen emotional distress among gynecological cancer patients. (2) The patients' moods had improved, but not completely recovered at 6-month after the diagnosis.

Molecular identification and characterisation of catalase and catalase-like protein genes in urease-positive thermophilic Campylobacter (UPTC).

BACKGROUND: Thermophilic Campylobacter are important bacterial pathogens of foodborne diseases worldwide. These organisms' physiology requires a microaerophilic atmosphere. To date, little is known about the protective catalase mechanism in urease-positive thermophilic campylobacters (UPTC); hence, it was the aim of this study to identify and characterise catalase and catalase-like protein genes in these organisms. MATERIALS AND METHODS: Catalase (katA) and catalase (Kat)-like protein genes from the Japanese UPTC CF89-12 strain were molecularly analysed and compared with C. lari RM2100 and other C. lari and thermophilic Campylobacter reference isolates. RESULTS: A possible open reading frame of 1,422 base pairs, predicted to encode a peptide of 474 amino acid residues, with calculated molecular weight of 52.7 kilo Daltons for katA, was identified within UPTC CF89-12. A probable ribosome binding site, two putative promoters and a putative ρ-independent transcription terminator were also identified within katA. A similar katA cluster also existed in the C. lari RM2100 strain, except that this strain carries no DcuB genes. However, the Kat-like protein gene or any other homologue(s) were never identified in the C. lari RM2100 strain, or in C. jejuni and C. upsaliensis. CONCLUSIONS: This study demonstrates the presence of catalase/catalase-like protein genes in UPTC organisms. These findings are significant in that they suggest that UPTC organisms have the protective genetic capability of helping protect the organisms from toxic oxygen stress, which may help them to survive in physiologically harsh environments, both within human and animal hosts, as well as in the natural environment.