Ultra-high temperature Soret effect in a silicate melt: SiO2 migration to cold side.

The Soret effect, temperature gradient driven diffusion, in silicate melts has been investigated intensively in the earth sciences from the 1980s. The SiO2 component is generally concentrated in the hotter region of silicate melts under a temperature gradient. Here, we report that at ultra-high temperatures above ∼3000 K, SiO2 becomes concentrated in the colder region of the silicate melts under a temperature gradient. The interior of an aluminosilicate glass [63.3SiO2-16.3Al2O3-20.4CaO (mol. %)] was irradiated with a 250 kHz femtosecond laser pulse for local heating. SiO2 migrated to the colder region during irradiation with an 800 pulse (3.2 ms irradiation). The temperature analysis indicated that migration to the colder region occurred above 3060 K. In the non-equilibrium molecular dynamics (NEMD) simulation, SiO2 migrated to the colder region under a temperature gradient, which had an average temperature of 4000 K; this result supports the experimental result. On the other hand, SiO2 exhibited a tendency to migrate to the hotter region at 2400 K in both the NEMD and experimental study. The molar volume calculated by molecular dynamics simulation without a temperature gradient indicates two bends at 1650 and 3250 K under 500 MPa. Therefore, the discontinuous (first order) transition with coexistence of two phases of different composition could be related to the migration of SiO2 to colder region. However, the detailed mechanism has not been elucidated.

Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain.

There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.

Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study).

BACKGROUND: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. METHODS: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. RESULTS: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). CONCLUSION: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.

Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807.

BACKGROUND: We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer. METHODS: ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates. RESULTS: Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS < 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR < 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS. CONCLUSIONS: ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF.

A Single-Arm Confirmatory Study of Definitive Chemoradiation Therapy Including Salvage Treatment for Clinical Stage II/III Esophageal Squamous Cell Carcinoma (JCOG0909 Study).

PURPOSE: Definitive chemoradiotherapy (CRT) is the standard treatment for patients with locally advanced esophageal cancer (EC) who refuse surgery as the initial therapy. However, poor survival, a high incidence of late toxicities, and severe complications after salvage surgery remain issues to be resolved. This single-arm multicenter trial (JCOG0909) aimed to confirm the efficacy of CRT modifications, including salvage treatment for reducing CRT-related toxicities and facilitating salvage treatment for improved survival. METHODS AND MATERIALS: Patients with clinical stage II/III EC (International Union Against Cancer sixth edition, non-T4) were eligible. Chemotherapy comprised cisplatin (75 mg/m2 on days 1 and 29) and 5-fluorouracil (1000 mg/m2/d on days 1-4 and 29-32). Radiation therapy was administered at a total dose of 50.4 Gy. Good responders received 1 to 2 additional cycles of chemotherapy. For residual or recurrent disease, salvage endoscopic resection or salvage surgery was performed based on specific criteria. The primary endpoint was 3-year overall survival (OS). The calculated sample size was 95 patients, with a 1-sided alpha of 5% and a power of 80%. The expected and threshold 3-year OS were 55% and 42%, respectively. RESULTS: Overall, 96 patients were enrolled, and 94 were included in the efficacy analysis. A complete response was achieved in 55 patients (59%). Salvage endoscopic resection and salvage surgery were performed in 5 (5%) and 25 patients (27%), respectively. R0 resection by salvage surgery was achieved in 19 patients (76%). Five patients (20%) showed grade 3 or 4 early operative complications, and 9 patients (9.6%) showed grade 3 late toxicities during the long-term follow-up. The 3-year OS was 74.2% (90% confidence interval, 65.9%-80.8%). CONCLUSION: The combination of definitive CRT and salvage treatment has lower CRT-related toxicities and yields good OS, thus making it a promising novel treatment option for patients with locally advanced EC.

Randomized phase II study of docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma refractory to fluoropyrimidine- and platinum-based chemotherapy: OGSG1201.

BACKGROUND: There is no standard chemotherapy for esophageal squamous cell carcinoma (ESCC) refractory to first-line fluoropyrimidine- and platinum-based chemotherapy. We therefore performed a randomized, selection-design phase II trial to compare docetaxel (DTX) and paclitaxel (PTX) in this setting. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either DTX (70 mg/m2 on day 1 of each 21-day cycle) or PTX (100 mg/m2 on days 1, 8, 15, 22, 29 and 36 of each 49-day cycle). The primary end-point was overall survival (OS), and secondary end-points included progression-free survival (PFS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: Seventy-eight eligible patients (N = 39 in each group) were included for efficacy analysis. OS was significantly longer in the PTX group than in the DTX group (median, 8.8 versus 7.3 months; hazard ratio [HR], 0.62; P = 0.047). A significant benefit of PTX over DTX was also apparent in PFS (median, 4.4 versus 2.1 months; HR, 0.49; P = 0.002) and TTF (median, 3.8 versus 2.1 months; HR, 0.45; P < 0.001). RR (25.6% versus 7.7%, P = 0.065) were higher in the PTX group than in the DTX group. Compared to the PTX group, neutropenia (28% versus 80%) and leukopenia (28% versus 76%) of grade ≥3 as well as febrile neutropenia (0% vs. 46%, P < 0.0001) occurred more frequently in the DTX group. CONCLUSION: PTX showed a significantly better efficacy as well as a more manageable toxicity compared with DTX. CLINICAL TRIAL REGISTRATION: UMIN000007940.

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.

[Clinical features of intravascular large B-cell lymphoma: a single-institute retrospective analysis].

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of extranodal non-Hodgkin's lymphoma, and the absence of specific findings makes ante-mortem diagnosis difficult. This study was conducted to identify the clinical findings useful for timely diagnosis of IVLBCL. Ten patients who were diagnosed with IVLBCL in our institute between 2005 and 2017 were retrospectively analyzed. Eight of the 10 cases had fever and 7 cases presented with respiratory symptoms, including cough, sputum, and dyspnea. Cytopenias were noted in all patients, and serum lactate dehydrogenase levels were elevated in 9 of the 10 patients. Arterial partial pressures of oxygen were <80 mmHg in 6 of the 7 patients examined. Computed tomography scanning detected hepatosplenomegaly and chest abnormalities in 7 and 9 cases, respectively. These results suggest that IVLBCL has a higher frequency of lung involvement than those reported previously. Physicians must therefore be vigilant in the identification of IVLBCL in patients who demonstrate respiratory symptoms or hypoxemia of uncertain origin, because early diagnosis can decrease the severity and prevent mortality.

Publisher Correction: Defective Epstein-Barr virus in chronic active infection and haematological malignancy.

In the version of this Letter originally published, in the sentence beginning "The major driver role of DDX3X mutations...", the citation "Fig. 2a-f" should have been "Fig. 2". In addition, in the sentence beginning "Another finding of interest was the presence of identical driver mutations...", the citation "Fig. 3a,b and Fig. 4" should have been "Fig. 3". This has now been amended in all versions of the Letter.

Defective Epstein-Barr virus in chronic active infection and haematological malignancy.

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14-7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

[Neoadjuvant Triplet Combination Chemotherapy(UDON Therapy)in Esophageal Cancer Patients with Impaired Renal Function-A Retrospective Study].

BACKGROUND: In Japan, pre-operative 5-FU and cisplatin(CDDP)(FP)combination therapy has been the standard neoadjuvant chemotherapy(NAC)for advanced resectable esophageal cancer(EC); furthermore, the efficacy of the docetaxel (DTX)-containing triplet regimen, FP plus DTX, has been reported. However, patients with impaired renal function should not receive high-dose CDDP. We have been developing a non-CDDP-containing triplet regimen, comprising 5-FU, DTX, and nedaplatin(NED)(UDON), on a phase Ⅰ/Ⅱtrial basis. This retrospective study aimed to investigate the safety and efficacy of NAC with UDON in advanced EC patients with impaired renal function. METHODS: Five patients with advanced resectable EC with impaired renal function were enrolled in this study. Patients received NAC(5-FU, 640mg/m / 2, days 1-5; DTX, 28 mg/m2, days 1 and 15; and NED, 72mg/m2, day 1, q28, 2 courses); following this, they underwent esophagectomy. The primary endpoint was response rate, and the secondary endpoint was adverse event(AE). RESULTS: The median age was 79 years (range: 58-80 years). The ECOG performance status was 1/2 : 3/2. The main tumor locations were Ce/Ut/Mt : 1/1/3 and the cStages were ⅡA/ⅢA/ⅢC : 1/2/2. The RR(CR/PR/SD/PD : 0/4/1/0)was 80%. The pathological response was grade 1a/1b : 2/3. Major grade 3 or 4 AEs included neutropenia(40%), febrile neutropenia(20%), diarrhea(20%), and hyponatremia( 40%). There was no treatment-related death or reoperation. CONCLUSIONS: NAC with UDON might be feasible and effective in patients with advanced resectable EC with impaired renal function, who are ineligible for high-dose CDDP administration. We are planning a phaseⅡclinical study based on the present results.

Phase II Trial of 5-Fluorouracil, Docetaxel, and Nedaplatin (UDON) Combination Therapy for Recurrent or Metastatic Esophageal Cancer.

LESSONS LEARNED: The 5-fluorouracil, docetaxel, and nedaplatin (UDON) regimen was well tolerated and showed promising antitumor activity in terms of both objective response rate and survival for patients with advanced or recurrent esophageal squamous cell carcinoma in the first-line setting.UDON may be an optimal treatment option for patients with advanced esophageal cancer who are unfit for docetaxel, cisplatin, and 5-fluorouracil regimens.The high response rate as well as the rapid and marked tumor shrinkage associated with UDON suggest that further evaluation of this regimen in the neoadjuvant setting is warranted. BACKGROUND: A phase II study was performed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for untreated recurrent or metastatic esophageal cancer. METHODS: Patients received intravenous nedaplatin (90 mg/m2) on day 1, docetaxel (35 mg/m2) on days 1 and 15, and 5-fluorouracil (800 mg/m2) on days 1-5 of a 4-week cycle. The primary endpoint was response rate, with secondary endpoints including overall survival (OS), progression-free survival (PFS), dysphagia score, and adverse events. RESULTS: Between March 2015 and July 2017, 23 patients were enrolled. Of 22 evaluable patients, 16 and 4 individuals experienced a partial response and stable disease, respectively, yielding a response rate of 72.7% (95% confidence interval [CI], 49.8%-89.3%) and disease control rate of 90.9% (95% CI, 70.8%-98.9%). Median OS and PFS were 11.2 months (95% CI, 9.1 months to not reached) and 6.0 months (95% CI, 2.5-10.6 months), respectively. Eleven (64.7%) of the 17 patients with a primary lesion showed amelioration of dysphagia after treatment. Frequent adverse events of grade 3 or 4 included neutropenia (87.0%) and leukopenia (39.1%). Febrile neutropenia was observed in two patients (8.7%). CONCLUSION: This phase II study demonstrated promising antitumor activity and good tolerability of UDON.

Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study.

BACKGROUND: Epithelioid hemangioendothelioma is an exceedingly rare sarcoma often occurring as an indolent angiocentric vascular tumor at various anatomic sites. Few reports have evaluated large case series of epithelioid hemangioendothelioma. METHODS: We conducted a retrospective analysis of the clinical data of 42 consecutive patients with epithelioid hemangioendothelioma who were pathologically diagnosed between 1990 and 2014 at 13 Japanese tertiary hospitals. We analyzed their clinical characteristics, tumor features and prognostic factors. RESULTS: The study included 22 men and 20 women, with a median age of 54 (range, 18-78) years. Pain was the most common symptom, occurring in 15 (68%) of the 22 symptomatic patients. The median maximum tumor diameter was 4.0 (range, 1.0-12.8) cm. The most commonly involved organs were the liver (81%), lungs (57%), and bones (12%). The overall survival rates were 79.5% at 1 year and 72.0% at 5 years. Substantially better survival was observed in asymptomatic patients than in symptomatic patients (P = 0.03), and better survival was also ovserved in patients with Ki-67 index ≤10% than in those with Ki-67 index > 10% (P = 0.04). By multivariate analysis, tumor size > 3.0 cm was associated with decreased survival (P = 0.049, hazard ratio 13.33). CONCLUSIONS: This study showed the clinical characteristics of Japanese patients with epithelioid hemangioendothelioma. Tumor size > 3.0 cm is an independent indicator of a poor prognosis in epithelioid hemangioendothelioma. The presence of symptoms at the time of diagnosis and high Ki-67 index implied poor survival.

First-line chemotherapy with S-1 alone or S-1 plus cisplatin for elderly patients with advanced gastric cancer: a multicenter propensity score matched study.

BACKGROUND: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. METHODS: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210; SP group, 234); the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients' characteristics were comparable between groups, except the male ratio (S-1 group, 64.2%; SP group, 77.1%; p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p < 0.001 each). CONCLUSION: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.

MYRF is associated with encephalopathy with reversible myelin vacuolization.

OBJECTIVE: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. METHODS: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. RESULTS: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. INTERPRETATION: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98-106.

[A Case of Advanced Esophageal Cancer Successfully Treated with Neoadjuvant Chemotherapy Containing 5-FU, Docetaxel. and Nedaplatin Combination Therapy].

A 71-year-old man with a history of hypertension, diabetes mellitus, and cerebral infarction was admitted to our hospital with dysphagia. Gastroduodenoscopy, thoracoabdominal CT, and PET-CT findings showed type 2 advanced esophageal cancer( squamous cell carcinoma)with upper mediastinal and cervical lymph node(LN)metastasis: cT3N2M1(LYM #104L), cStage Ⅳ. Two courses of neoadjuvant UDONchemotherapy containing 5-FU(640mg/m / 2, days 1-5), docetaxel(28mg/m2, days 1 and 15), and nedaplatin(72mg/m2, day 1)were administered every 4 weeks. UDONtherapy caused grade(Gr)3 febrile neutropenia, Gr 2 diarrhea, and Gr 1 thrombopenia; the tumor and LNs partially responded to the therapy. After 2 courses of UDONtherapy, esophagectomy with right thoracotomy, 3-field LNdissection, and reconstruction of the gastric tube were performed. The postoperative course was almost uneventful besides recurrent nerve palsy, aspiration, pneumonia, and delirium, and the patient was discharged 60 days after surgery. The pathological diagnosis was ypT0N0M0, ypStage 0, and the histological response of the primary tumor and LNs were evaluated as Gr 3. Neoadjuvant UDON therapy is feasible for elderly patients with advanced esophageal cancer and renal failure or comorbidities, for whom CDDP could not be administered. We are planning a clinical trial to assess the effectiveness of neoadjuvant UDONtherapy.

Clinical evaluation of palliative chemoradiotherapy for metastatic esophageal cancer.

Platinum-based chemotherapy is considered a standard treatment option for patients with metastatic esophageal carcinoma. However, the overall survival of patients receiving such treatment is <1 year. A common presenting symptom of esophageal cancer is dysphagia, which has a substantial impact on quality of life. We have now retrospectively evaluated the efficacy and safety of palliative chemoradiotherapy for patients with stage IV esophageal cancer, most of whom are unfit for curative chemoradiotherapy. Fifty consecutive patients diagnosed with stage IV esophageal cancer were treated with concurrent chemoradiotherapy at Kindai University Hospital between April 2008 and December 2014. Most (90%) patients received a total radiation dose of at least 50 Gy, and the median number of treatment cycles per patient was four for the combination of 5-fluorouracil and cisplatin. The response of the primary tumor and the overall response were 80% and 44%, respectively. The dysphagia score was improved after chemoradiotherapy in 36 (72%) patients and did not change between before and after treatment in 14 (28%) patients. With a median follow-up time of 9.4 months from the start of chemoradiotherapy, the median progression-free survival and overall survival were 4.7 and 12.3 months, respectively. Three patients (T4b in two, T3 in one) developed esophagobronchial fistula after completion of chemoradiotherapy (n = 2) or after disease progression (n = 1), resulting in death in each case. Our results suggest that palliative chemoradioiotherapy was safe and contributed the improvement of dysphagia in patients with stage IV esophageal cancer.

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes.

We propose a new iterative screening contest method to identify target protein inhibitors. After conducting a compound screening contest in 2014, we report results acquired from a contest held in 2015 in this study. Our aims were to identify target enzyme inhibitors and to benchmark a variety of computer-aided drug discovery methods under identical experimental conditions. In both contests, we employed the tyrosine-protein kinase Yes as an example target protein. Participating groups virtually screened possible inhibitors from a library containing 2.4 million compounds. Compounds were ranked based on functional scores obtained using their respective methods, and the top 181 compounds from each group were selected. Our results from the 2015 contest show an improved hit rate when compared to results from the 2014 contest. In addition, we have successfully identified a statistically-warranted method for identifying target inhibitors. Quantitative analysis of the most successful method gave additional insights into important characteristics of the method used.