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Na cidade de São Paulo (SP), a construção civil de edifícios residenciais de múltiplos pavimentos intensificou-se na década de 1930, com estruturas de concreto armado e alvenaria de vedação. Esse processo construtivo se mantém majoritário nos edifícios paulistanos, ocorrendo, contudo, modificações nos aspectos construtivos e projetuais. Neste artigo, um edifício construído em 1973 foi selecionado como objeto de estudo. Essa escolha foi motivada pela sua construção ter ocorrido em um período anterior às novas normas e códigos de obras elaborados após as tragédias de incêndios nos Edifícios Andraus e Joelma, em 1972 e 1974, respectivamente. A partir da análise evolutiva, conclui-se que novas técnicas surgiram para promover a industrialização de processos artesanais, garantir a manutenibilidade dos subsistemas, inserir o fator sustentabilidade, aumentar a segurança e aplicar ou criar novos equipamentos, ferramentas e materiais desenvolvidos entre as décadas de 1980 e 2010, na construção de edifícios residenciais.

Background Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the ‘Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)’. Methods Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. Results The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. Conclusion The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients.We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups.A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib.Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

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.

Naomi Hayashi,1 Yasuyoshi Sato,1 Yu Fujiwara,1,2 Naoki Fukuda,1 Xiaofei Wang,1 Kenji Nakano,1 Testuya Urasaki,1 Akihiro Ohmoto,1 Makiko Ono,1 Junichi Tomomatsu,1 Yukiko Sato,3 Hiroki Mitani,4 Takashi Toshiyasu,5 Shunji Takahashi1 1Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York City, NY, USA; 3Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 4Head and Neck Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanCorrespondence: Yasuyoshi SatoThe Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, JapanTel +8135200111Fax +81335200141Email yasuyoshi.sato@jfcr.or.jpPurpose: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer.Patients and Methods: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients.Results: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of < 4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting.Conclusion: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.Keywords: head and neck cancer, squamous cell carcinoma of head and neck, sarcopenia, cachexia, muscle, skeletal, chemoradiotherapy, prognosis

BACKGROUND/AIM Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. While mitotane is the only agent approved for ACC, clinical data are scarce, especially in the Asian population. We reviewed 10 patients with ACC who received mitotane as a single agent or in combination with other agents in our institution. Patient characteristics, clinical outcomes, and toxicities were analyzed. Mitotane was administered to 2 patients as an adjuvant therapy and to 8 patients for systemic control. In the latter 8 patients, 1 patient had locally advanced disease and 1 had metastatic disease at the time of initial diagnosis, whereas the other 6 patients experienced metastatic relapse at mitotane initiation. The administered regimen was mitotane alone in 7 patients, and mitotane plus cytotoxic chemotherapy in 3 patients. The initial daily mitotane dose was 3.0 g in 2 patients, 1.5 g in 7 patients, and 1.0 g in 1 patient. The median duration of treatment was 3.7 (range, 0.7-22.1) months. In 8 systemic cases, the median overall survival from chemotherapy initiation was 7.2 months, and only 1 patient survived over 1 year. The median interval from mitotane termination to death in systemic cases was 2.8 months, and the cause was progressive disease in 4 patients and toxicity (hallucination, mycobacteriosis, or liver injury) in 3 patients. As a second-line regimen, 2 systemic cases and 1 adjuvant case were enrolled in clinical trials. Our analysis exhibited extremely poor prognosis under mitotane-based regimens, and further treatment strategies are warranted to improve outcomes.

Background: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC.Methods: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors including tumor growth rate (TGR) was conducted.Results: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5% and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) TGR was associated with worse PFS (hazard ratio [HR] 7.00, 95%CI 1.34–36.53, p = 0.02) and OS (HR 29.33, 95%CI 3.38–254.80, p Conclusions: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Simple Summary Second-line systematic therapy options for soft-tissue sarcoma (STS) have remained unchanged for decades due to the rarity and various histological types associated with STS. Challenges with molecular-targeted treatments for STS led to the approval of pazopanib and its wide use for STS. However, predictive markers of pazopanib treatment for STS have not been identified. Baseline neutrophil-to-lymphocyte ratio (NLR) is known as a candidate biomarker for several cancers. In this retrospective study, we investigated the use of the NLR as a predictor for the efficacy and prognosis of pazopanib in patients with STS. Our findings could be useful for the development of biomarker-targeted therapies for STS. Abstract Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS.

Background: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. Methods and Patients: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts’ characteristics, chemotherapy details, and prognoses. Results: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1–6) in cohort R and three lines (range: 1–9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9–42.8) and 27.1 months (cohort E; 95% CI: 21.6–32.5) (p = 0.549). Conclusion: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

Comprehensive cancer genomic profile (CGP) tests are being implemented under Japanese universal health insurance system. However, the clinical usefulness of CGP test for breast cancer patients has not been evaluated. Of the 310 patients who underwent CGP testing at our institution between November 2019 and April 2021, 35 patients with metastatic breast cancer whose treatment strategy was discussed by our molecular tumor board within the study period were investigated after exclusion of 2 cases that could not be analyzed. The turn-around time, drug accessibility, and germline identification detection were evaluated. The subtype was luminal in 20 patients (57.1%), triple-negative in 12 patients (34.3%), and luminal-HER2 in 3 patients (8.6%). Actionable gene mutations were detected in 30 patients (85.7%), and 7 patients (20.0%) were recommended for clinical trial participation, with the drug administered to 2 patients (5.7%). Three patients (8.6%) died due to disease progression before the test results were disclosed. We report the results of an initial assessment of the utility of CGP testing for patients with metastatic breast cancer under Japanese universal health insurance system. Conducting CGP tests at a more appropriate time could provide patients with greater benefit from treatments based on their specific gene mutations.

Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.

Background/Aim: Trabectedin and eribulin are widely used for the treatment of soft-tissue sarcoma (STS). Previously it was shown that the baseline neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of eribulin for STS. However, prognostic factors for trabectedin on STS have not been identified to date. Patients and Methods: We conducted a retrospective study of data collected prospectively from 39 patients treated with trabectedin for recurrent or metastatic STS between October 2012 and December 2019. To determine the predictive factors of overall survival (OS) and progression-free survival (PFS), univariate and multivariate analyses were performed. Results: Age ≥40 (HR=0.33, 95% CI=0.15-0.71; p=0.0050) and changes in NLR (ΔNLR)

Background: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy. Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24). Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, >20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development. Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.

Background: Beneficial effects of napping on cognition have been suggested in cross-sectional studies. This study aimed to clarify longitudinal associations between cognitive decline and sleep characteristics, particularly daytime napping, over a 5-year period in older adults. Methods: Study participants were 389 community-dwelling individuals aged ≥65 years living in Ojiya City, Niigata, Japan. Baseline and follow-up examinations were conducted in 2011-2013 and 2016-2018, respectively. Trained nurses visited and interviewed participants to collect the following information: demographic characteristics, disease history, lifestyle habits including sleep and daytime napping, and cognitive function at baseline; and cognitive function at follow-up. The assessment of cognitive function was performed using the revised Hasegawa’s dementia scale (HDS-R), with cognitive decline defined as a 5-year change in HDS-R of ≤–3. Odds ratios (ORs) for cognitive decline were calculated using multiple logistic regression analysis.Results: Mean age of participants was 74.6 years (SD 6.4), and the cumulative incidence of cognitive decline was 106/389 (27.3%). The multivariable-adjusted OR for 1-29 min daytime napping was significantly lower compared to that for no napping (OR=0.47, 95%CI: 0.23-0.96). Bedtime was inversely associated with cognitive decline (multivariable-adjusted P for trend=0.0480).Conclusion: Short daytime napping (

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

Background/Aim: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. Patients and Methods: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. Results: The disease control rate was better in patients with lower NLR (

Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer.Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS).Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66).CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN.UMIN000012535.

The application of 3D printing technology for generating tablets is attracting the attention of the pharmaceutical industry following approval of a 3D printed tablet (Spritam) by the US Food and Drug Administration. Here we focused on hollow-type suppository formulations typically prepared as suppository shells by pharmacists in hospitals. We used a fused deposition modeling-type 3D printer and polyvinyl alcohol filament as a water soluble material to print suppository shells with various thicknesses and different inner structures by changing the printing conditions for the 3D designed objects. The hardness of the suppository shell was dependent on the thickness and designed inner structure. An active pharmaceutical ingredient ionic liquid, a novel type of liquid drug formulation, was loaded in the suppository shells. The drug dissolution profile of the suppository formulations differed depending on the type of suppository shell. Composite suppository formulations (two drugs in separate compartments in the suppository shell) were prepared as a model tailored medicine for pediatric patients. Our findings suggest that 3D printing technology is applicable to the preparation of hollow-type suppository formulations and may be compatible with on-site hospital production.

A fixed-dose formula that combines Ombitasvir (OBV), Paritaprevir (PTV) and Ritonavir (RTV) has been launched into the field of anti-HCV therapy in Japan for patients infected with HCV genotypes 1 and 2 in 2015. However, little is yet known as to the efficacy and safety of this novel therapy in patients on maintenance haemodialysis (HD). The present report describes a preliminary experience in 10 patients (five males and five females) who underwent maintenance HD. All of them had HCV genotype 1b, without having the resistance-associated variants at Y93 or L31 in the nonstructural proteins 5A (NS5A) region. After the treatment, eight patients successfully achieved virus eradication and sustained a virological response at 12 weeks (SVR12). In addition, mac-2 binding protein glycosylation isomer (M2BPGi), a biomarker for liver fibrosis, was reduced after the therapy. Two patients withdrew from the therapy due to the development of erythema multiforme and a strong drowsiness, respectively. These results suggest that triple therapy combining OBV, PTV and RTV is effective in achieving SVR12 in most of the HCV-infected patients on HD. In addition, this combination therapy contributed to retard the progression of liver fibrosis. However, we suggest that further trial will be required to establish its clinical efficacy and safety.

Introduction:The captopril challenge test (CCT) is the major confirmatory test for primary aldosteronism (PA), and frequently carried out because of its convenience. However, it presents false-negative results with a certain probability, and as there are many criteria for CCT, it is not concluded yet which criteria to use.Materials and methods:A total of 71 PA patients were evaluated. We compared CCT-positive and CCT-negative patients in the following three criteria: plasma aldosterone/renin ratio (ARR) >200 after the CCT (criterion 1); plasma aldosterone concentration (PAC) >120 pg/ml after the CCT (criterion 2); and PAC suppression Results:The positive rate was 70.4%, 64.8% and 54.9% for criterion 1, criterion 2 and criterion 3, respectively. With criterion 1, the baseline plasma renin activity was lower, thus baseline ARR was higher in CCT-positive patients. With criterion 2, PAC was higher and estimated sodium intake and K were lower in CCT-positive patients. With criterion 3, K and PAC were lower in CCT-positive patients. Although it was not significant, in the patients with high sodium intake, the positive rate of criterion 1 was higher than that of the other criteria.Conclusions:ARR>200 is the valuable criterion for the diagnosis of PA.

e18007 Background: Concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. Three cycles of 100 mg/m2 CDDP for every three weeks (Q3W) are now recommended but compliance with CCRT is relatively low due to its severe toxicity. Therefore, the potential de-escalation strategies for LAHNC have been discussed to decrease the therapeutic toxicity. Methods: Patients with LAHNC who underwent definitive CCRT with CDDP between 2012 and 2018 at The Cancer Institute Hospital of Japanese Foundation for Cancer Research were analyzed. Patients were classified into two groups based on the planned CDDP dose: (A) 100 mg/m2 and (B) 80 mg/m2 Q3W for three times. One-to-one propensity score matching was performed to minimize bias between two groups. After patients in two groups were matched by using propensity score, the overall survival (OS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), and metastatic recurrence-free survival (MRFS) were analyzed by the Kaplan-Meier method with the Cox proportional hazards model. The follow-up term was set as two years to evaluate the early survival benefit. The dose and density of CDDP and the objective adverse events were also assessed. Results: A total of 304 patients were included with the median age of 62 (Interquartile range [IQR]: 54-67) years. Among them, 249 patients (82%) were male. Patients were treated with 100 mg/m2 CDDP (n = 145) and 80 mg/m2 CDDP (n = 159) regimens. After the propensity score matching, 119 patients were included in each group, respectively. There were no significant differences in baseline characteristics between two propensity-matched cohorts. The median follow-up time was 24 months in each group. Two-year OS was 93.0% (95% confidence interval [CI]: 88.4-97.8) in group A and 94.9% (91.0-99.0) in group B. Two-year RFS was 86.5% (80.6-92.9) in group A and 83.1% (76.6-90.1) in group B, respectively. No significant difference was observed in OS (Hazard ratio [HR] = 1.42, 95% CI: 0.49-4.08, p = 0.52), RFS (HR = 0.81, 95% CI: 0.42-1.57, p = 0.54), LRFS (HR = 0.57, 95% CI: 0.24-1.36, p = 0.20), and MFS (HR = 1.32, 95% CI: 0.52-3.35, p = 0.56). The median cumulative dose of CDDP was significantly higher in group A (300 mg, interquartile range [IQR]: 240-300) than in group B (240 mg, IQR:160-240) but the frequency of hematological, hepatic, renal, electrolytic, and grade 3-5 any adverse events was not significantly different between two groups. Conclusions: Our study showed no survival difference at 2-year follow-up between 100 mg/m2 and 80 mg/m2 CDDP regimens of definitive CCRT for LAHNC. This result could support the tide of the de-escalation strategy in head and neck cancer treatment. Longer follow-up is necessary and further prospective trials comparing CDDP dosage are warranted.

Three-dimensional (3D) printers have been applied in many fields, including engineering and the medical sciences. In the pharmaceutical field, approval of the first 3D-printed tablet by the U.S. Food and Drug Administration in 2015 has attracted interest in the manufacture of tablets and drugs by 3D printing techniques as a means of delivering tailor-made drugs in the future. In current study, polyvinylalcohol (PVA)-based tablets were prepared using a fused-deposition-modeling-type 3D printer and the effect of 3D printing conditions on tablet production was investigated. Curcumin, a model drug/fluorescent marker, was loaded into PVA-filament. We found that several printing parameters, such as the rate of extruding PVA (flow rate), can affect the formability of the resulting PVA-tablets. The 3D-printing temperature is controlled by heating the print nozzle and was shown to affect the color of the tablets and their curcumin content. PVA-based infilled tablets with different densities were prepared by changing the fill density as a printing parameter. Tablets with lower fill density floated in an aqueous solution and their curcumin content tended to dissolve faster. These findings will be useful in developing drug-loaded PVA-based 3D objects and other polymer-based articles prepared using fused-deposition-modeling-type 3D printers.

Some targeted therapies alter muscle mass due to interference with pathways of muscle metabolism. The effects of mammalian target of ra pamycin (mTOR) inhibitors on muscle mass have yet to be fully elucidated. In the present study, the computerized tomography (CT) scans of patients receiving mTOR inhibitors for at least 6 months taken at baseline and post-therapy were retrospectively retrieved, and body composition analyses were performed using the software, sliceOmatic version 5.0 (TomoVision, Inc., Magog, QC, Canada). The difference in body composition parameters was evaluated for significance. The time to treatment (TTF) failure was also compared between the sarcopenic and non-sarcopenic patients at the baseline. Of the 75 patients studied, 20 matched the inclusion criteria (including 16 males). The mean duration between the CT scans was 14.4±2.0 months. A total of 12 (60%) patients were sarcopenic at the baseline, whereas three more (75% in total) became sarcopenic following treatment. The use of mTOR inhibitors significantly decreased the skeletal muscle area (P=0.011) and lean body mass (P=0.007), although it had no effect on adipose tissue (P=0.163) or body weight (P=0.262). The rate of skeletal muscle wasting was 2.6 cm2/m2, or 2.3 kg in 6 months. The TTF did not differ between sarcopenic and non-sarcopenic patients, and was not significantly associated with any other parameter. To the best of our knowledge, this is the first study to demonstrate that the long-term use of mTOR inhibitors induces a marked loss of muscle mass. Due to the predictive and prognostic role of sarcopenia in cancer patients, these findings may have important clinical implications.

Myeloma cast nephropathy is a major complication of multiple myeloma. Recent evidence has demonstrated that the earlier induction of bortezomib-based chemotherapy with plasma exchange (PE) provides better results for kidney function and patient survival. Due to its non-selectivity, PE with albumin replacement carries the risk of fibrinogen loss, leading to bleeding. We herein report a case of successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy and selective PE. A 61-year-old woman who had a 20-year history of type II diabetes mellitus was admitted to our hospital for the evaluation of hypercalcemia, severe kidney dysfunction, and anemia. Subsequent bone marrow evaluation and renal biopsy revealed that she had multiple myeloma (IgG-κ) and myeloma cast nephropathy. Ten days after admission, bortezomib-based chemotherapy with selective PE achieved rapid and thorough free light-chain (FLC) reduction; within a month, her kidney function had been recovered (creatinine level, 1.2 mg/dl). Her serum fibrinogen level was not reduced, and no bleeding complication occurred. Five months later, autologous hematopoietic stem-cell transplantation was performed successfully, and the patient’s kidney function was stable (creatinine level, 1.1 mg/dl) thereafter. This case report demonstrates the importance of early induction therapy with bortezomib-based chemotherapy and PE in a patient with myeloma cast nephropathy, which is especially applicable in patients aged

Introduction: Adrenal venous sampling is useful for discriminating unilateral and bilateral hypersecretion in patients with primary aldosteronism, but it is relatively invasive. To determine the site of hypersecretion more non-invasively, we evaluated predictors of unilateral hypersecretion. Materials and methods: We evaluated the baseline characteristics and the results of confirmatory tests of 123 patients with primary aldosteronism who underwent adrenal venous sampling. Results: Unilateral hypersecretion was identified in 22.0%. The plasma aldosterone concentration and aldosterone–renin ratio were significantly higher and serum potassium concentration and plasma renin activity were significantly lower in patients with unilateral hypersecretion. Plasma aldosterone concentrations after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were significantly higher among patients with unilateral hypersecretion. The plasma aldosterone concentration reduction ratio in saline infusion test and plasma aldosterone concentration elevation ratio during rapid adrenocorticotropic hormone stimulation test were significantly higher in patients with unilateral hypersecretion. However, areas under the curve for these parameters were not superior to the values after confirmatory tests. Conclusions: The plasma aldosterone concentration values after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were useful for identifying patients with unilateral hypersecretion. However, value changes or ratios during confirmatory tests are less useful for this aim.

The sympathoinhibitory mechanism of azilsartan was investigated in an adenine-induced chronic renal failure model. Azilsartan exerted an antihypertensive effect, though BP elevation induced by adenine was marginal. The creatinine value was significantly lower in the azilsartan group (AZ) than in the vehicle group (VEH); furthermore, proteinuria was suppressed, and sodium excretion was augmented in the AZ group. The low frequency (LF) of systolic BP was suppressed (VEH: 4.07 ± 2.67 mmHg2 vs. AZ: 3.32 ± 1.93 mmHg2 P

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.

Aneurysm formation is a potential complication of granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis. It is a very rare complication, but immediate diagnosis and therapy should be performed because an aneurysm can be life-threatening if it ruptures. An accessory left gastric artery (ALGA) is also a rare variant gastric artery that may obtain its blood supply from the left hepatic artery and left gastric artery. We herein describe a 57-year-old Japanese man who was diagnosed with GPA complicated by aneurysm rupture in an ALGA. Emergency surgery was performed after failure of arterial coil embolization to interrupt blood flow in the ALGA. The patient underwent partial resection of the lesser omentum, which contained all aneurysms. During partial resection of the lesser omentum, both the left gastric artery and ALGA were ligated because they were thought to be feeders of the aneurysms. Postoperative recovery was uneventful; no bleeding or recurrence of the aneurysms occurred. Immediate diagnosis and therapy should be performed for patients with GPA with symptoms of vascular ischemia or aortitis. Endovascular intervention is the first-choice therapy especially for hemodynamically stable patients with ruptured aneurysms or aneurysms located on variant arteries, which may have multiple blood supplies. In the present case, although endovascular treatment failed, the approach described herein was helpful during open surgery.

818 Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment 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 of 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 most frequently used oral opioids 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 = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record 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 that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.

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.