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Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Without a current standard of care, patients with rare malignancy are subjected to precision oncology with next-generation sequencing to identify a course of treatment. We sought to establish the clinical relevance of comprehensive genomic profiling (CGP) among patients with rare malignancy. Rare malignancy was defined using the Rare Cancers in Europe definition (6 cases per 100,000 individuals). We analyzed gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Level A gene alterations, categorized using Clinical Interpretations of Variants in Cancer and MD Anderson Knowledge Base for Precision Oncology, were considered druggable. Rare malignancy accounted for 149 (45%) cases, with female genital cancers (32%) most common. Among the rare malignancy cases, we identified a lower frequency of mutation in TP53 (41% vs. 60%, P0.001), KRAS (13% vs. 43%, P0.001) and APC (3% vs. 25%, P0.001), and a higher frequency of ARID1A mutation (14% vs. 6%, P=0.03), as compared with common malignancies. TMB-high and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 37 patients with rare malignancy; this percentage tended to be higher than that for patients with common malignancies (25% vs. 17%, P=0.08). Common druggable alterations were BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variant. Five of the 37 patients with druggable alterations received genome-driven treatment. There was no significant difference in overall survival between the rare and common malignancy groups. Our results provide clues for future clinical development and treatment success among Japanese patients with rare cancers.

Background Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment option for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the oral opioids used most at our hospital. Methods During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 100) and the second group didn’t receive (group B, n = 117) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical recode retrospectively. Results The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and the median dose of maximum Oxycodone dose of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference (Mann-Whitney U test, P Conclusions Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Patients with sensitive gene mutations could achieve better overall survival by taking targeted drugs. Many trials have shown that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EFGR) mutation responded to PD-1/PD-L1 inhibitors worse than EGFR wild-type. And subgroups of trials have also reported the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with other sensitive gene mutations. So, we conducted a complementary systematic review and meta-analysis to compare efficacy of PD-1/PD-L1 inhibitors for NSCLC patients with sensitive gene mutations. Methods PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials (Central) databases were searched for all clinical trials in NSCLC until 5th of January 2019. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients with sensitive gene mutations. The hazard ratio (HR) and 95% confidence intervals (CIs) of overall survival (OS) or progression-free survival (PFS) were used. Results We analyzed 193 patients in this study. Among cumulative total of 210 patients, 197 were treated with PD-1 or PD-L1 inhibitors. Another 8 and 5 patients were treated with CTLA-4 inhibitor alone and combination with PD-1 inhibitor, respectively. This study included non-small cell lung cancer (n = 106; 50.5%), kidney (n = 23; 10.9%), melanoma (n = 30; 14.3%), gastric (n = 19; 9.0%), Hodgkin lymphoma (n = 11; 5.2%), urothelial carcinoma (n = 10; 4.8%) and others (n = 10; 4.8%). Any grade of irAEs occurred in 73 (34.8%) cumulative patients, and among them, 28 (13.3%) were classified as grade 3-5. The most common irAEs in any grade were skin disorders (n = 29) and endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 28). Eosinophilia occurred in 57 cumulative patients (27.1%), and 21 patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.010) and multivariate (p = 0.0463) analyses. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure Y. Miura: Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Chugai. T. Takano: Honoraria (self): Daiichi Sankyo; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Eisai; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Taiho; Research grant / Funding (self): Novartis; Research grant / Funding (self): Chugai. All other authors have declared no conflicts of interest.

Background The aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods Patients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. Results A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p = 0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p Conclusions CAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification 000012535 (09/December/2013). Legal entity responsible for the study Yasuhiro Kodera (Chubu Clinical Oncology Group, Japan). Funding Chubu Clinical Oncology Group. Disclosure All authors have declared no conflicts of interest.

Background According to the results of the randomized phase III study, G-SOX, the combination of S-1 and oxaliplatin (SOX) is as effective as the combination of S-1 and cisplatin for the treatment of HER2-negative advanced gastric cancer (AGC), and also has a favorable safety profile. In this trial, the dose of oxaliplatin tested was 100 mg/m2; however, the dose of 130 mg/m2 is covered by insurance in Japan, based on the results of the pivotal global study. Therefore, the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) remains to be elucidated. In this study, we conducted the final analysis of the survival outcomes in a phase II trial to assess the efficacy and safety of SOX130 in HER2-negative AGC. Methods Patients with HER2-negative AGC or recurrent gastric cancer received 80 mg/m2 S-1 per day orally on days 1-14, and 130 mg/m2 oxaliplatin intravenously, on day 1 of each 21-day cycle, until criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were recorded according to CTCAE version 4.0. Results In this study, 71 patients were enrolled from June 2015 to November 2016, but 8 patients were excluded owing to ineligibility. Therefore, the efficacy and safety analyses were finally conducted among 63 patients. The confirmed RR, assessed by an independent review committee, was 46.0% (95% confidence interval [CI]: 34.3-58.2), and the disease control rate was 77.8% (95% CI: 66.1-86.3). The median PFS and OS were 4.9 months (95% CI: 4.2-7.1) and 14.8 months (95% CI: 11.1-18.9), respectively. The incidence rates of grade 3 or 4 AE were as follows: neutropenia, 9.5%; thrombocytopenia, 11.1%; anemia, 6.3%; sensory neuropathy, 12.7%; anorexia, 19.0%; and diarrhea, 6.3%. Conclusions SOX130 showed favorable survival outcomes and an acceptable safety profile in the treatment of HER2-negative AGC.

3D printing technology holds promise for application to personalized pharmaceuticals. Mold fabrication is a common technique in industrial 3D printing to produce objects with complex structures and could be used in new applications in pharmaceutical production. The aim of the current study is the fabrication of unique suppository shell molds composed of a water-soluble polymer (polyvinylalcohol) using a fused deposition modeling-type 3D printer so that hospital pharmacists can prepare tailored suppository formulations containing progesterone (a model drug for vaginal suppository formulations) in future clinical settings. Suppository formulations with holes in the shells were prepared. The drug release profiles related well to the positions of the holes (upper, middle, lower), the number of holes (0–2 holes), and the diameters of the holes (0–5 mm) in the suppositories. Matryoshka-type suppository formulations composed of 3D-printed multilayered shells were then prepared. The drug release profiles showed pulsed release, and the volumes of the inner/outer spaces in the suppository shells (1/1, 1/3) and the drug concentration (3/1, 1/1) were reflected in the observed drug release profiles. Our study indicates that a 3D printer can produce not only unique and complex suppository formulations, but also provides flexibility and expands possible applications for the development of tailored medicine.

Effective dog training involves reinforcement of the dog's correct actions in response to specific cues given by the trainer. Food is usually selected as the primary reinforcer (reward), although this selection does not necessarily account for the learning preferences of individual dogs. We evaluated the relationship between reward and learning efficiency. Fifteen dogs were allocated to 3 different reward groups (food, stroking, and praise) and trained by an identical process. The food reward was the only one that shortened the time taken for the response to the command to be completed. However, this difference occurred only in the early training stages and not later in the training process.

Plant metabolomics developed as a powerful tool to examine gene functions and to gain deeper insight into the physiology of the plant cell. In this study, we screened Arabidopsis lines overexpressing rice full-length (FL) cDNAs (rice FOX Arabidopsis lines) using a gas chromatography-time-of-flight mass spectrometry (GC-TOF/MS)-based technique to identify rice genes that caused metabolic changes. This screening system allows fast and reliable identification of candidate lines showing altered metabolite profiles. We performed metabolomic and transcriptomic analysis of a rice FOX Arabidopsis line that harbored the FL cDNA of the rice ortholog of the Lateral Organ Boundaries (LOB) Domain (LBD)/Asymmetric Leaves2-like (ASL) gene of Arabidopsis, At-LBD37/ASL39. The investigated rice FOX Arabidopsis line showed prominent changes in the levels of metabolites related to nitrogen metabolism. The transcriptomic data as well as the results from the metabolite analysis of the Arabidopsis At-LBD37/ASL39-overexpressor plants were consistent with these findings. Furthermore, the metabolomic and transcriptomic analysis of the Os-LBD37/ASL39-overexpressing rice plants indicated that Os-LBD37/ASL39 is associated with processes related to nitrogen metabolism in rice. Thus, the combination of a metabolomics-based screening method and a gain-of-function approach is useful for rapid characterization of novel genes in both Arabidopsis and rice.

The tobacco N protein recognizes the helicase domain (p50) of the Tobacco mosaic virus (TMV) replicase as an elicitor and mediates hypersensitive response (HR). We obtained two cDNA clones encoding novel N-like (NL) proteins NL-C26 and NL-B69 from Nicotiana tabacum cv. Samsun NN. NL-C26 and NL-B69 had a Toll-interleukin-1 receptor/nucleotide-binding site/leucine-rich repeat (TIR–NBS–LRR) structure and showed 78% and 73% identities to N, respectively. The NL-C26 and NL-B69 genes were also expressed in N. tabacum cv. Samsun nn, which lacks the N gene. Unlike N, NL-C26 and NL-B69, when coexpressed with p50, failed to induce HR on the sites of agroinfiltration in Samsun nn leaves. However, the elicitor-dependent HR in Samsun nn was induced efficiently by chimeric N proteins with the continuous TIR–NBS domains of NL-C26 and NL-B69. On the other hand, the efficiency of HR induction varied significantly among chimeric N proteins with either of the TIR and NBS domains of the NL proteins. In contrast, chimeras carrying the LRR domains of the NL proteins did not induce HR. Thus, the TIR–NBS domains of NL-C26 and NL-B69 could functionally adapt to the LRR domain of N, which may determine the specificity for the elicitor. We speculate that the NL genes are potential HR-inducing resistance genes for undetermined pathogens other than TMV.

Although hepatitis is a common feature of primary Epstein-Barr virus (EBV) infection, severe liver injury is rare and its pathogenesis is unclear. A previously healthy girl developed severe hepatitis with prolonged jaundice. Serologic examination showed that she had primary infection with EBV. An extremely high Epstein-Barr viral load was observed in her peripheral blood. The viral load decreased in parallel with symptomatic improvement. Histologic examinations showed spotty necrosis of the liver parenchyma and infiltration by CD8(+) T cells. The CD8(+) T cells, not hepatocytes, were positive for EBV. Possible mechanisms of viral hepatitis without infection of hepatocytes are discussed.

Subacute sclerosing panencephalitis (SSPE) is a degenerative disease of the central nervous system that leads to death within a few years. Recently, it has been reported that combination therapy with intraparenchymal interferon-alpha (INF-alpha) and intraventricular ribavirin is effective. An 11-year-old SSPE patient whose clinical symptoms progressed rapidly, was treated first with intraventricular INF-alpha and then with combined intraventricular INF-alpha and ribavirin therapy. To monitor viral load over the course of the therapy, measles virus RNA was quantified using a real-time polymerase chain reaction assay. Measles virus RNA decreased rapidly after the INF-alpha therapy was started, paralleling the decrease in the measles antibody titer in the cerebrospinal fluid and the improvement in the neurological disability. After intraventricular ribavirin was combined with INF-alpha therapy, no further improvement was observed. The neurological disability gradually progressed, although the amount of virus RNA remained low.

A radioanalytical method for low level samarium-151 ( 151 Sm) and promethium-147 ( 147 Pm) in environmental samples has been studied for the environmental assessment around nuclear facilities. In this study, we use the separation method with high performance liquid chromatography (HPLC) to determine 151 Sm and 147 Pm in environmental samples such as sea sediments and marine organisms. Samarium-151 and 147 Pm in environmental samples are coprecipitated with other lanthanoids alter adding neodymium (Nd). These nuclides are purified by anion exchange methods in methanol-mineral acid media. After the purification, 151 Sm and 147 Pm are separated with HPLC in lactic acid-sodium hydroxide media, and determined with liquid scintillation counting, respectively. The Nd is determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) to correct chemical recoveries of these nuclides. The detection limits for 151 Sm and 147 Pm in this method are about 0.01 Bq/sample

Purpose The aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression in Japanese patients with metastatic colorectal cancer (mCRC). Methods Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression free survival (PFS), response rate (RR), disease control rate (DCR) and safety. Results In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to 17.5 months). Thirty one patients went on to receive second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5 months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, the primary endpoint, was 18.0 months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7 to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after median follow up period of 35.9 months. No critical events associated with bevacizumab were observed during the second-line therapy. Concluson The planned continuation of bevacizumab during second-line treatment is feasible for Japanese mCRC patients. A prospective randomized control study to confirm efficacy is warranted. Disclosure All authors have declared no conflicts of interest.