Undocumented immigrants suffering from inequality of vaccination access in Japan: measuring the institutional barriers and exploring the associated factors.

OBJECTIVES: Undocumented immigrants (UIs) have been reported to suffer from the unequal distribution of COVID-19 vaccination, but this inequality has never been quantified, and the associated factors have not been measured. STUDY DESIGN AND METHODS: We interviewed 190 municipal offices throughout Japan about the access to COVID-19 vaccination for UIs and control group foreigners. Using logistic regression, we investigated the association between assured access and municipal characteristics. RESULTS: Out of the respondent municipalities, 57.5% answered that UIs can apply for a COVID-19 vaccination voucher. Additionally, 31.5% said they had received an inquiry about vaccines from UI individuals. Furthermore, only 23.2% of the municipalities responded that they had issued vouchers for UIs at least once. The control groups were reported to have been given more access to vouchers. Logistic regression showed that the foreign resident ratio, tertiary industry, and university graduation ratio were positively associated with vaccination access. CONCLUSIONS: This study revealed for the first time that UIs are disproportionately marginalized compared with other visitors, implying that "illegality" plays an important role in the context of vaccination eligibility. The street-level vaccination desks of local governments may refuse to supply vaccines. Vaccine equity will be more readily achievable when vaccination access to all populations including UIs is ensured. Such access will also improve overall public health by increasing the vaccination rate.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

Individual response of humans to ionising radiation: governing factors and importance for radiological protection.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

New physician specialty training system impact on distribution of trainees in Japan.

OBJECTIVES: The problem of uneven distribution of medical services and inequitable distribution of physicians is drawing much attention worldwide. Revealing how changes in the specialty training system in Japan have affected the distribution of doctors could help us understand this problem. In 2018, a new and standardized specialty training system was implemented by the Japanese Medical Specialty Board, which is recognized by the Ministry of Health, Labor and Welfare. The purpose of this study was to investigate how this new system has affected the geographical distribution of doctors commencing specialty training (trainees) and choice of specialty in Japan. STUDY DESIGN: Retrospective observational study. METHODS: The change in the number of trainees between the control period (2012-2014) and 2018 was investigated, taking into account the prefecture and specialty selected. Population, the proportion of residents aged 65 years or older (aging rate), and the total number of overall doctors in each prefecture were considered as the background characteristics of each prefecture. We created a Lorenz curve and calculated the Gini coefficient for the distribution of trainees. RESULTS: In 2018, the number of trainees per 100,000 population increased to 6.6 nationwide compared with 5.5 during the control period. The number of trainees per 100,000 population in 2018 increased in prefectures with a large population of ≧ 2,000,000, a low aging rate (<27%), and a high doctor density (≧ 250 doctors per 100,000 population). The Gini coefficient showed an increase to 0.226 in 2018 compared with only 0.160 during the control period. CONCLUSIONS: After the implementation of the new training system, there was an increase in the number of doctors enrolling in specialty programs, and the specialties other than internal medicine and surgery have attracted more trainees. Inequality in the distribution of doctors between urban and rural prefectures worsened. This indicates the need to explore new ways of balancing distribution while maintaining optimal opportunities for specialist training.

Comparative effectiveness of gastric bypass versus gastric banding on acute care use for cardiovascular disease in adults with obesity.

BACKGROUND AND AIMS: Gastric bypass is known to have larger effects on weight and metabolism than gastric banding. However, scarce data exist as to whether the differences are translated into differential risks of cardiovascular disease (CVD)-related morbidities. The objective was to examine whether adults with obesity and CVD who underwent gastric bypass have a lower rate of acute care use (emergency department [ED] visit or unplanned hospitalization) for CVD than those with gastric banding. METHODS AND RESULTS: We performed a comparative effectiveness study of gastric bypass versus banding among adults with obesity and CVD who underwent either surgery, using population-based [ED] and inpatient samples in California, Florida, and Nebraska from 2005 through 2011. The primary outcome was acute care use for CVD during a two-year postoperative period. We constructed negative binomial regression models to compare the event rate during sequential 6-month periods, using gastric banding group as the reference. We identified 11,229 adults with obesity and CVD who underwent gastric bypass and 3896 adults who had gastric banding. Patients with gastric bypass had significantly lower rate of the outcome compared to those with banding in the 7-12 months postoperative period (adjusted rate ratio [aRR] 0.77; 95% confidence interval [CI], 0.61-0.98; P = 0.03). The significant reduction in the rate persisted during 13-18 months (aRR 0.71; 95% CI, 0.57-0.90; P = 0.005) and 19-24 months (aRR 0.66; 95% CI, 0.52-0.82; P < 0.001) after bariatric surgery. CONCLUSION: In this population-based comparative effectiveness study of adults with obesity and CVD, the rate of acute care use for CVD was lower after gastric bypass compared to gastric banding.

The effects of teriparatide on acceleration of bone healing following atypical femoral fracture: comparison between daily and weekly administration.

We compared the effectiveness of promoting bone healing between two teriparatide preparations for atypical femoral fracture (AFF). A total of 45 AFFs were included in this study, and we compared the duration of bone union. Teriparatide administered by daily injection enhanced bone union more than weekly administration in complete AFFs. INTRODUCTION: The efficacy of teriparatide for atypical femoral fracture (AFF) has been recently reported. Although two different teriparatide preparations can be used to treat osteoporosis in Japan, daily or weekly injection, all previous reports on the effectiveness of teriparatide for AFF only examined daily injection formulations. Therefore, we compared the promotion of bone healing between the two teriparatide preparations for AFF. METHODS: A total of 45 consecutive AFFs in 43 Japanese patients were included in this study. They received either a daily 20-µg teriparatide injection (daily group; n = 32) or a once-a-week 56.5-µg teriparatide injection (weekly group; n = 13). We compared the clinical background and duration of bone union between these two groups. RESULTS: When all patents were included, the fracture healing time was not significantly different between the two groups. Only patients with complete AFFs had significantly fewer daily bisphosphonate or denosumab injections than the weekly group (P < 0.05). The fracture healing time in the daily group (6.1 ± 4.1 months) was significantly shorter than that in the weekly group (10.1 ± 4.2 months) (P < 0.05). Even if the influence of bisphosphonate or denosumab usage was excluded, a similar significant difference was observed in the fracture healing time (P < 0.05). There was no significant difference between the two groups among patients with incomplete AFFs. CONCLUSIONS: Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients.

Comparison of spinal alignment, muscular strength, and quality of life between women with postmenopausal osteoporosis and healthy volunteers.

This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. INTRODUCTION: Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. METHODS: Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. RESULTS: BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p < 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (p < 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (p < 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (p < 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (p < 0.05 each). CONCLUSIONS: These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC.

BACKGROUND: The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway. PATIENTS AND METHODS: We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets. RESULTS: Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC, AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC, AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival. CONCLUSIONS: Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.

Improvement of spinal alignment and quality of life after corrective surgery for spinal kyphosis in patients with osteoporosis: a comparative study with non-operated patients.

UNLABELLED: This study evaluated changes in spinal alignment and quality of life (QOL) after corrective spinal surgery for patients with postmenopausal osteoporosis and spinal kyphosis. Spinal global alignment and QOL were significantly improved after corrective spinal surgery but did not reach the level of non-operated controls. INTRODUCTION: With the increased aging of society, the demand for corrective spinal instrumentation for spinal kyphosis in osteoporotic patients is increasing. However, previous studies have not focused on the improvement of quality of life (QOL) after corrective spinal surgery in patients with osteoporosis, compared to non-operated control patients. The purposes of this study were thus to evaluate changes in spinal alignment and QOL after corrective spinal instrumentation for patients with osteoporosis and spinal kyphosis and to compare these results with non-operated patients. METHODS: Participants comprised 39 patients with postmenopausal osteoporosis ≥50 years old who underwent corrective spinal surgery using multilevel posterior lumbar interbody fusion (PLIF) for symptomatic thoracolumbar or lumbar kyphosis, and 82 age-matched patients with postmenopausal osteoporosis without prevalent vertebral fractures. Spinopelvic parameters were evaluated with standing lateral spine radiography, and QOL was evaluated with the Japanese Osteoporosis QOL Questionnaire (JOQOL), SF-36, and Roland-Morris Disability Questionnaire (RDQ). RESULTS: Lumbar kyphosis angle, sagittal vertical axis, and pelvic tilt were significantly improved postoperatively. QOL evaluated with all three questionnaires also significantly improved after 6 months postoperatively, particularly in domain and subscale scores for pain and general/mental health. However, these radiographic parameters, total JOQOL score, SF-36 physical component summary score, and RDQ score were significantly inferior compared with non-operated controls. CONCLUSIONS: The results indicate that spinal global alignment and QOL were significantly improved after corrective spinal surgery using multilevel PLIF for patients with osteoporosis and spinal kyphosis but did not reach the level of non-operated controls.

Abnormal cell proliferation in the p75NTR-positive basal cell compartment of the esophageal epithelium during squamous carcinogenesis.

The low affinity neurotrophin receptor p75NTR is known to be expressed in the mitotically quiescent basal layer (BL) of the normal esophageal epithelium. The aim of the present study was to detect oncogenic changes in the p75NTR-positive BL during esophageal squamous carcinogenesis. The normal epithelium (NE), low-grade intraepithelial neoplasia (LGN), high-grade intraepithelial neoplasia (HGN), and esophageal squamous carcinoma (SCC), in which invasion was limited to the muscularis mucosa, were obtained from surgically removed esophagi. The expression of p75NTR, the proliferation marker ki67, hTERT, p53, and p63 was examined immunohistochemically. The expression of p75NTR was detected in these tissues with average staining indexes (number of stained cells/100 nucleated cells; SI) of 1.00, 0.99, 0.81, and 0.73, respectively. The expression of ki67 in the BL significantly increased with the progression from LGN to HGN. The expression of hTERT and p53 significantly increased with the progression from NE to LGN, and then increased in a stepwise manner in HGN and SCC, with SI (hTERT/p53) of 0.10/0.11, 0.32/0.45, 0.50/0.72, and 0.65/0.61, respectively. The expression of p63 showed no significant difference among NE, LGN, HGN, and SCC, with SI of 0.82, 0.77, 0.85, and 0.87, respectively. A correlation was observed between the expression of ki67 and p53 (P = 0.005), while a negative correlation was found between p75NTR and hTERT (P = 0.01). Our results demonstrated that phenotypic changes from quiescent to active proliferation in the p75NTR-positive BL occurred during the progression from LGN to HGN. The altered expression of hTERT and p53 in the BL was detected in LGN, which suggested that additional oncogenic events that disrupt mitotic regulation in the p75NTR-positive quiescent BL may play a crucial role in malignant transformation. Further investigations using the isolation and tracing of p75NTR-positive cells in precancerous epithelia may provide us with a better understanding of squamous carcinogenesis.

RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis.

BACKGROUND: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors. METHODS: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement. RESULTS: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001). CONCLUSIONS: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing. RESULTS: A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients. CONCLUSIONS: Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Downregulation of Max dimerization protein 3 is involved in decreased visceral adipose tissue by inhibiting adipocyte differentiation in zebrafish and mice.

BACKGROUND: The diet-induced obesity model of zebrafish (DIO-zebrafish) share a common pathophysiological pathway with mammalian obesity. OBJECTIVES: We aimed to investigate the role of Max dimerization protein 3 (MXD3) in visceral fat accumulation and adipocyte differentiation, by conducting knockdown experiments using zebrafish and mouse preadipocytes. METHODS: To identify genes related to visceral adiposity, we conducted transcriptome analyses of human and zebrafish obese populations using the Gene Expression Omnibus and DNA microarray. We then intraperitoneally injected morpholino antisense oligonucleotides (MO-mxd3) to knockdown mxd3 gene expression in DIO-zebrafish and measured several parameters, which reflected human obesity and associated metabolic diseases. Finally, lentiviral Mxd3 shRNA knockdown in mouse 3T3-L1 preadipocytes was conducted. Quantitative PCR analyses of several differentiation markers were conducted during these gene knockdown experiments. RESULTS: We found that MXD3 expression was increased in the obese population in humans and zebrafish. Intraperitoneal MO-mxd3 administration to DIO-zebrafish suppressed the increase in body weight, visceral fat accumulation and the size of mature adipocytes. Subsequently, dyslipidemia and liver steatosis were also ameliorated by MO-mxd3. In mouse adipocytes, Mxd3 expression was drastically increased in the early differentiation stage. Mxd3 shRNA inhibited preadipocyte proliferation and adipocyte maturation. Quantitative PCR analyses showed that the early differentiation marker, CCAAT/enhancer-binding protein delta (Cebpd) and late differentiation markers (CCAAT/enhancer-binding protein, alpha and peroxisome proliferator-activated receptor gamma) were downregulated by Mxd3 knockdown in 3T3-L1 cells and DIO-zebrafish. Subsequently, mature adipocyte markers (adiponectin and caveolin 1 for zebrafish, and fatty acid binding protein 4 and stearoyl-coenzyme A desaturase 1 for mouse adipocytes) were also decreased. CONCLUSION: Mxd3 regulates preadipocyte proliferation and early adipocyte differentiation via Cebpd downregulation in vitro and in vivo. Integrated analysis of human and zebrafish transcriptomes allows identification of a novel therapeutic target against human obesity and further associated metabolic disease.

Visceral fat accumulation is associated with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. METHODS: This study comprised 506 Japanese subjects 35-74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm(2) . Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). RESULTS: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm(2) than those with VFA < 100 cm(2) . A VFA ≥ 100 cm(2) was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. CONCLUSIONS: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.

Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Local failure after definitive chemoradiotherapy (CRT) for stage IB, II, and III esophageal cancer is one of the causes of poor outcome. Endoscopic mucosal resection (EMR) is an effective treatment for superficial esophageal cancer. However, its feasibility as a salvage treatment for local recurrent or residual tumors after definitive CRT for stage IB, II, and III esophageal cancer remains unclear. Between January 2000 and February 2008, 274 patients with stage IB, II, and III esophageal squamous cell cancer excluding T4 received definitive CRT at the National Cancer Center Hospital, Japan. Of these patients, nine patients with local recurrence after achieving complete response and two patients with residual tumor underwent salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively reviewed the 11 patients (13 lesions). Characteristics of all 11 patients were as follows: median age of 69 (range: 45-78); male/female: 10/1; baseline clinical stage (Union for International Cancer Control 7th) IB/IIA/IIB/III: 1/3/7/0. The depth of resected tumor was limited to the mucosal layer in seven lesions and submucosal in six lesions. En bloc resection was performed on six lesions (46%). The vertical margin was free of cancer cells in 11 lesions (84.6%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. At a median follow-up period of 38.9 months (range: 5.3-94 months) after salvage EMR, no recurrence was detected in six patients (54%). Local recurrence was detected in five patients (27%). Of these patients, two had lung metastasis simultaneously, and one was also detected lung metastasis 2 months after the detection of local recurrence. The 5-year survival rate after salvage EMR was 41.6%. Salvage EMR is a feasible treatment option for local recurrent or residual lesions after definitive chemotherapy and/or radiotherapy for stage IB, II, and III esophageal squamous cell cancer.

The Effect of a Deproteinizing Pretreatment on the Bonding Performance and Acid Resistance of a Two-step Self-etch Adhesive on Eroded Dentin.

OBJECTIVES: This study evaluated how deproteinization using sodium hypochlorite (6% NaOCl) or hypochlorous acid (50 ppm HOCl) with or without the subsequent use of an arylsulfinate salt-containing agent (Clearfil DC Activator; DCA; Kuraray Noritake Dental) affects the micro-tensile bond strength (µTBS) and formation of an acid-base resistant zone (ABRZ) of a two-step self-etch adhesive on eroded dentin. METHODS: Coronal dentin surfaces of sound human molars were exposed to 48 cycles of demineralization (1% citric acid; 5 minutes) and remineralization (buffer solution with pH=6.4; 3.5 hours). They were then assigned to experimental groups according to the pretreatment used: none (negative control), NaOCl, NaOCl+DCA, HOCl, and HOCl+DCA. Sound dentin surfaces with no pretreatment were used as a positive control. The dentin surfaces were bonded with Clearfil SE Bond 2 (Kuraray Noritake Dental), and µTBS was measured either after 24 hours or 20,000 thermal cycles (TC). The µTBS data were statistically analyzed using a mixed-model analysis of variance (ANOVA) and t-tests with Bonferroni correction. Failure mode was determined with scanning electron microscopy (SEM), which was also used for the observation of ABRZ. RESULTS: Among experimental groups, there was no significant difference between the negative control, HOCl, and HOCl+DCA after 24 hours, but the HOCl-pretreated groups exhibited significantly higher µTBS than the negative control after TC (p<0.01). Pretreatment with NaOCl and NaOCl+DCA resulted in significantly higher µTBS (p<0.001), but the highest µTBS was measured on sound dentin (p<0.001). TC decreased µTBS significantly in all groups (p<0.001) except for sound dentin and NaOCl+DCA (p>0.05). Adhesive failures prevailed in eroded groups, whereas cohesive failures were predominant on sound dentin. ABRZ was recognized in all groups but marked morphological differences were observed. CONCLUSIONS: The combined use of 6% NaOCl and the arylsulfinate salt-containing agent partially reversed the compromised bonding performance on eroded dentin, while the effect of 50 ppm HOCl was negligible.