Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

Efficacy of guselkumab in a subpopulation with pustulotic arthro-osteitis through week 52: an exploratory analysis of a phase 3, randomized, double-blind, placebo-controlled study in Japanese patients with palmoplantar pustulosis.

BACKGROUND: Previous studies of guselkumab have demonstrated clinical benefits in patients with plaque-type psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis (PPP). OBJECTIVE: The aim of this exploratory analysis of a double-blind, multicenter, placebo-controlled, phase 3 study in Japanese patients with PPP was to evaluate the efficacy of guselkumab in the subset of patients with pustulotic arthro-osteitis (PAO). METHODS: Patients were randomized to receive guselkumab 100 or 200 mg at weeks 0, 4, 12 and every 8 weeks, or placebo with cross-over to guselkumab 100 or 200 mg at week 16 (placebo group). Efficacy endpoints were changes from baseline in magnetic resonance imaging (MRI) score, EuroQOL-5 dimensions (EQ-5D) index score, EQ-5D pain/discomfort dimension score and C-reactive protein (CRP, mg/L) level in all PAO patients through week 52. Data from both guselkumab groups were combined and presented as results for a single overall guselkumab group. RESULTS: Among 159 patients with PPP, 66 with PAO were randomized across treatment groups. For patients with MRI data for all regions assessed, the proportion of patients in the guselkumab group with PAO characterized as severe decreased from 23.8% (10/42) at baseline to 5.4% (2/42) at week 52. The mean (SD) change from baseline at week 52 in EQ-5D index score was 0.20 (0.17) among PPP patients with PAO and 0.15 (0.17) among those without PAO in the guselkumab group. Among all PAO patients, the proportions with an EQ-5D pain/discomfort dimension score of no or slight pain/discomfort in the guselkumab group increased from baseline to week 52 [33.3% (7/21) vs. 87.5% (35/40)]. The mean (SD) CRP levels decreased in all PAO patients in the guselkumab group at week 52 compared to baseline [-1.71 (8.16) mg/L]. CONCLUSION: Guselkumab treatment showed beneficial outcomes for PAO signs and symptoms in Japanese patients with PPP.

Minimally invasive oesophagectomy with extended lymph node dissection and thoracic duct resection for early-stage oesophageal squamous cell carcinoma.

BACKGROUND: Oesophageal squamous cell carcinoma is an aggressive disease owing to early and widespread lymph node metastases. Multimodal therapy and radical surgery may improve prognosis. Few studies have investigated the efficacy of radical lymph node and thoracic duct resection. METHODS: Patients with oesophageal squamous cell carcinoma who underwent transthoracic minimally invasive oesophagectomy (TMIE) for cancer at Keio University Hospital between January 2004 and December 2016 were selected. Between 2004 and 2008, TMIE was performed in the lateral decubitus position without thoracic duct resection (standard TMIE). From 2009 onwards, TMIE with extended lymph node and thoracic duct resection was introduced (extended TMIE). Demographics, co-morbidity, number of retrieved lymph nodes, pathology, postoperative complications and recurrence-free survival (RFS) were compared between groups. RESULTS: Forty-four patients underwent standard TMIE and 191 extended TMIE. There were no significant differences in clinical and pathological tumour stage or postoperative complications. The extended-TMIE group had more lymph nodes removed at nodal stations 106recL and 112. Among patients with cT1 N0 disease, RFS was better in the extended-TMIE group (P < 0·001), whereas there was no difference in RFS between groups in patients with advanced disease. CONCLUSION: Extended TMIE including thoracic duct resection increased the number of lymph nodes retrieved and was associated with improved survival in patients with cT1 N0 oesophageal squamous cell carcinoma.

Purification, Rheological Characterization, and Visualization of Viscous, Neutral, Hetero-exopolysaccharide Produced by Lactic Acid Bacteria.

Viscous exopolysaccharide (EPS)-producing lactic acid bacteria (LAB) have received increasing interest in the dairy industry because of their capability to improve the texture and mouthfeel of fermented dairy products. To date, enormous efforts have been made to reveal the relationship between texture and EPS production in fermented milk products such as yogurt. However, the structure-rheology relationship of EPSs themselves is not yet well understood due to their low yields in general and their wide variety of chemical structures. In this chapter, we describe common techniques for the purification, visualization, and rheological analysis of viscous EPSs produced by LAB.

Meta-analysis of the impact of postoperative complications on survival after oesophagectomy for cancer.

BACKGROUND: Oesophagectomy has a high risk of postoperative morbidity. The impact of postoperative complications on overall survival of oesophageal cancer remains unclear. This meta-analysis addressed the impact of complications on long-term survival following oesophagectomy. METHODS: A search of PubMed and Cochrane Library databases was undertaken for systematic review of papers published between January 1995 and August 2016 that analysed the relation between postoperative complications and long-term survival. In the meta-analysis, data were pooled. The main outcome was overall survival (OS). Secondary endpoints included disease-free (DFS) and cancer-specific (CSS) survival. RESULTS: A total of 357 citations was reviewed; 21 studies comprising 11 368 patients were included in the analyses. Overall, postoperative complications were associated with significantly decreased 5-year OS (hazard ratio (HR) 1·16, 95 per cent c.i. 1·06 to 1·26; P = 0·001) and 5-year CSS (HR 1·27, 1·09 to 1·47; P = 0·002). Pulmonary complications were associated with decreased 5-year OS (HR 1·37, 1·16 to 1·62; P < 0·001), CSS (HR 1·60, 1·35 to 1·89; P < 0·001) and 5-year DFS (HR 1·16, 1·00 to 1·33; P = 0·05). Patients with anastomotic leakage had significantly decreased 5-year OS (HR 1·20, 1·10 to 1·30; P < 0·001), 5-year CSS (HR 1·81, 1·11 to 2·95; P = 0·02) and 5-year DFS (HR 1·13, 1·02 to 1·25; P = 0·01). CONCLUSION: Postoperative complications after oesophagectomy, including pulmonary complications and anastomotic leakage, decreased long-term survival.

Thermal and impact histories of 25143 Itokawa recorded in Hayabusa particles.

Understanding the origin and evolution of near-Earth asteroids (NEAs) is an issue of scientific interest and practical importance because NEAs are potentially hazardous to the Earth. However, when and how NEAs formed and their evolutionary history remain enigmas. Here, we report the U-Pb systematics of Itokawa particles for the first time. Ion microprobe analyses of seven phosphate grains from a single particle provide an isochron age of 4.64 ± 0.18 billion years (1σ). This ancient phosphate age is thought to represent the thermal metamorphism of Itokawa's parent body, which is identical to that of typical LL chondrites. In addition, the incorporation of other particles suggests that a significant shock event might have occurred 1.51 ± 0.85 billion years ago (1σ), which is significantly different from the shock ages of 4.2 billion years of the majority of shocked LL chondrites and similar to that of the Chelyabinsk meteorite. Combining these data with recent Ar-Ar studies on particles from a different landing site, we conclude that a globally intense impact, possibly a catastrophic event, occurred ca. 1.4 Ga ago. This conclusion enables us to establish constraints on the timescale of asteroid disruption frequency, the validity of the crater chronology and the mean lifetime of small NEAs.

A retrospective cohort study investigating risk factors for the failure of Thoroughbred racehorses to return to racing after superficial digital flexor tendon injury.

A retrospective cohort study was conducted to investigate risk factors for the failure of Thoroughbred racehorses to return to racing after an injury of the superficial digital flexor tendon (SDFT). Successful return was defined as the completion of five or more races after SDFT injury. The official Japan Racing Association (JRA) medical records of racehorses with a core-type SDFT injury were reviewed for clinical variables related to the characteristics of the horse and the severity of SDFT injuries at the time of diagnosis. Data on racing outcomes were obtained from the official JRA racing database. Risk factors were screened using univariable logistic regression and subsequent multivariable model building. Forty-nine of 346 (14.2%) horses successfully returned to racing after SDFT injuries. Multivariable model building revealed that an increase in the total number of injured zones (defined as the total number of zones in which the injured hypoechoic area was observed at the time of ultrasonographic diagnosis of SDFT injury) was associated with an increased risk of failure to return to racing after SDFT injury. Horse characteristics, such as age, body mass and sex, were not associated with a successful return to racing. In the rehabilitation of cases with larger (longer) lesions, more effective and careful medical management may be needed for an improvement in the athletic outcomes.

Size of recurrent laryngeal nerve as a new risk factor for postoperative vocal cord paralysis.

Recurrent laryngeal nerve paralysis (RLNP) is a frequent and serious complication following esophageal cancer surgery. Therefore, this study aims to evaluate the correlation between recurrent laryngeal nerve (RLN) size and RLNP. This was a retrospective study of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2012 to December 2014. Eighty-four patients were included in the primary analysis. Diameter of the RLN was measured using the digital video recording of surgical procedures by the ratio between scissor and RLN. For evaluation of vocal cord paralysis or paresis, indirect laryngoscopy was performed. Because RLNP more frequently occurs on the left side than the right, we evaluated the correlation between size of the left RLN and left RLNP. The median size of the left RLN was 1.51 mm. We found that the incidence of postoperative left RLNP (Clavien-Dindo classification ≥1) was significantly higher (71% vs. 24%; P < 0.001) in thin RLNs (≤1.5 mm) than in thick RLNs (>1.5 mm). Thin RLN (P < 0.001), female sex (P = 0.025), and being overweight (P = 0.034) were identified as significant independent risk factors for postoperative RLNP. RLNP more easily occurred when the RLN was thin. It is difficult to confirm occurrence of postoperative RLNP before and at extubation. Therefore, it is helpful to know its risk factors including size of RLN.

Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.

Pulmonary arterial hypertension (PAH) is a rare but serious disease with a grave prognosis. Bone morphogenetic protein type 2 receptor (BMPR2) gene is a strong pathogenic factor for PAH. As a collaborative team from Kyorin University and Keio University in Japan, we have analyzed the BMPR2 gene in 356 probands and more than 50 family members, including secondary patients. Importantly, the study population is a racially, ethnically, and socially homogeneous population. In PAH patients, there is a high incidence of unique mutations in BMPR2, and several mutations are frequently observed in the Japanese population, suggesting that these common and recurring mutations may be highly pathogenic or have high penetrance, explaining why they are found frequently throughout the world. We have also mapped each breakpoint of exonic deletions/duplications and found that most break and rejoining points are in the Alu elements. Reviewing the distribution of the reported mutations on each exon of BMPR2 revealed that the number and frequency of mutations are imbalanced among exons. The penetrance of BMPR2 gene mutations was 3-fold higher in females than males. Full elucidation of BMPR2-mediated pathogenic mechanisms in PAH requires persistent efforts to achieve precision or individualized medicine as a therapeutic strategy for PAH.

Enhancing Survival of Human Hepatocytes by Neonatal Thymectomy and Partial Hepatectomy in Micro-miniature Pigs.

BACKGROUND: With the goal of in vivo cultivation of human hepatocytes that have not been sufficient in full differentiation in vitro, the advantage of neonatal thymectomy was verified on expansion of xenogeneic human hepatocyte in the micro-miniature pig (MMP). METHODS: The thymus was excised immediately after the birth of the MMPs via cesarean section. Newborns were fed by artificial feeding under specific pathogen-free conditions. The thymectomized and nonthymectomized littermates were transplanted with human hepatocytes via a portal vein with or without partial hepatectomy at the MMP adult stage. RESULTS: The growth of thymectomized MMPs and the sham operated littermates was not significantly different; the former weighed 1.98 ± 0.30 kg (average ± standard deviation, n = 4) and the latter weighed 2.28 ± 0.39 kg (n = 4) at 1 month of age, and 17.48 ± 1.92 kg and 16.75 ± 2.68 kg at 12 months of age. Blood thymosin α1 concentrations in the thymectomy group were significantly lower than in the control group (0.22 ± 0.05 ng/mL vs 0.46 ± 0.16 ng/mL; n = 4, 12 months old, P = .029). After human hepatocyte transplantation, human albumin levels were detectable on day 28 in the peripheral blood of the thymectomy plus hepatectomy group (14.3 ± 4.9 ng/mL [± range, n = 2]) but were not detectable even on day 21 in the control group. CONCLUSIONS: Neonatal thymectomy was successfully achieved in infantile MMPs born via cesarean section. These pigs were considered to be an ideal in vivo bioreactor for human hepatocytes.

The use of sonoelastography to assess the recovery of stiffness after equine superficial digital flexor tendon injuries: A preliminary prospective longitudinal study of the healing process.

BACKGROUND: The objective assessment of the mechanical properties of the superficial digital flexor tendon (SDFT) could provide useful information for the rehabilitation of horses with SDFT injuries. Assessment of strain ratio (the strain of a standard reference divided by that of lesions) is a quantitative method in sonoelastography for evaluating tissue stiffness in vivo. As yet, no longitudinal studies have used strain ratio to evaluate the progression of stiffness in SDFT injuries. OBJECTIVES: To test the hypothesis that strain ratio can evaluate the recovery of stiffness during the healing of SDFT injuries. STUDY DESIGN: Prospective and longitudinal study with observer-blinded evaluation. METHODS: Ultrasonography, including sonoelastography, was performed in seven Thoroughbred horses with naturally occurring SDFT injuries at five time points: within 20 days of the injury, and at 2, 3, 6 and 9 months after the injury. Blinded sonoelastographic images were independently evaluated by two veterinarians to assess interobserver agreement. The recovery of stiffness and echogenicity in lesions were evaluated using the strain ratio and grey-scale ratio (echogenicity of lesions divided by that of the surrounding area), respectively. RESULTS: Interobserver agreement was assessed as 'almost perfect'. Strain ratios were significantly higher at 9 months after injury than at the other time points (all P<0.05). Strain ratios at 6 months after injury were significantly higher than those at earlier time points (P<0.05). Grey-scale ratios within 20 days of injury were significantly lower than those at the other time points (all P<0.05). MAIN LIMITATIONS: Validations of SDFT status were evaluated only by recovery of the echogenicity in lesions and not by histopathological examination. CONCLUSIONS: Although further studies are needed to validate the relationships between injured SDFT status and sonoelastographic findings, this preliminary study shows that strain ratio may provide a means to monitor the recovery of stiffness in lesions during rehabilitation, even when the grey-scale ratio remains unchanged from a few months after SDFT injury. The Summary is available in Chinese - see Supporting Information.

Application of sonoelastography for evaluating the stiffness of equine superficial digital flexor tendon during healing.

Sonoelastography can assess the inner stiffness of tissues. Sonoelastographic evaluation of injured equine superficial digital flexor tendons (SDFTs) is considered to be useful for assessing the stiffness of a lesion even during late-stage rehabilitation. The purpose of this study was to investigate and compare the sonoelastographic appearance of injured SDFTs over time from the onset of the injury. Eighteen horses were classified into three groups according to the length of time from injury onset: group A, within two weeks after injury; group B, approximately five months after injury; and group C, approximately nine months after injury. Longitudinal and transverse images of all injured SDFTs were obtained using grey-scale ultrasonography and sonoelastography. Grey-scale and sonoelastographic images were evaluated by two observers using echogenicity-grading and colour-grading systems, respectively. The authors evaluated the interobserver agreement and compared the grades among the three groups. The results indicated almost perfect interobserver agreement. Significant differences were found in the sonoelastography among the three groups, whereas no significant difference was found in the grey-scale ultrasonography between groups B and C. Sonoelastography is a feasible and useful modality to evaluate the equine injured SDFTs in vivo and to distinguish between them among the different phases even during the chronic phase.

Oliguria without serum creatinine increase after living donor liver transplantation is associated with adverse post-operative outcomes.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation and is associated with significant morbidity and mortality. Although clinical guidelines recommend defining AKI based on serum creatinine increase and oliguria, the validity and utility of the oliguric component of AKI definition remains largely unexplored. This study examined the incidence and the impact on clinical outcomes of oliguria meeting the urine output criterion of AKI in patients undergoing liver transplantation. The authors hypothesised that oliguria was an independent risk factor for adverse post-operative outcomes. METHODS: This study retrospectively examined 320 patients who underwent living donor liver transplantation at our centre. AKI stages were allocated according to recent guidelines based on serum creatinine or urine output within 7 days of surgery. RESULTS: The incidence of oliguria meeting the urine output criterion of AKI was 50.3%. Compared with creatinine criterion alone, incorporating oliguria into the diagnostic criteria dramatically increased the measured incidence of AKI from 39.7% to 62.2%. Compared with patients diagnosed without AKI using either criterion, oliguric patients without serum creatinine increase had significantly longer intensive care unit stays (median: 5 vs. 4 days, P = 0.016), longer hospital stays (median: 60 vs. 49 days, P = 0.014) and lower chronic kidney disease-free survival rate on post-operative day 90 (54.2% vs. 73.3%, P = 0.008). CONCLUSION: Oliguria is common after liver transplantation, and incorporating oliguria into the diagnostic criteria dramatically increases the measured incidence of AKI. Oliguria without serum creatinine increase was significantly associated with adverse post-operative outcomes.

Analytical approach to the temporal changes in NIRS signals to separate hemodynamic change from brain activity.

In brain function measurements by near-infrared spectroscopy (NIRS), we focus on the temporal changes in the oxygenated and deoxygenated hemoglobin concentrations and propose an analytical approach to the temporal changes of the hemoglobin concentrations' cross-correlation coefficient in the brain functional signals. The cross-correlation coefficient between the oxygenated and deoxygenated hemoglobin concentrations shows negative values for brain activity and positive values for hemodynamic changes. Experiments with a 16-channel functional NIRS system show that our proposed approach clarifies the interpretation of the measured NIRS signals and it can be used to estimate the influence of hemodynamic change on brain activity.

Integrated theory to unify status among schizophrenia and manic depressive illness.

Tryptophan hydroxylase 1 is primarily expressed in the gastrointestinal tract, and has been associated with both schizophrenia and depression. Although decreased serotonin activity has been reported in both depression and mania, it is important to investigate the interaction between serotonin and other neurotransmitter systems. There are competitive relationships between branched-chain amino acids, and tryptophan and tyrosine that relate to physical activity, and between L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP), both highly dependent on intracellular tetrahydrobiopterin concentrations. Here, I propose a chaos theory for schizophrenia, mania, and depression using the competitive interaction between tryptophan and tyrosine with regard to the blood-brain barrier and coenzyme tetrahydrobiopterin. Mania may be due to the initial conditions of physical hyperactivity and hypofunctional 5-HTP-producing cells inducing increased dopamine. Depression may be due to the initial conditions of physical hypoactivity and hypofunctional 5-HTP-producing cells inducing decreased serotonin. Psychomotor excitation may be due to the initial conditions of physical hyperactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and substantially increased dopamine. The hallucinatory-paranoid state may be due to the initial conditions of physical hypoactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and dopamine.