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PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN -inactivating mutations.

Despite the recent attention given to palliative care for patients with heart disease, data about the treatments in their actively dying phase are not sufficiently elaborated. In this study, we used the sampling dataset of a national database to compare the aggressive treatments performed in patients with cancer and those with heart disease. We only included patients deceased in January or July from 2011 to 2015, using the Diagnosis Procedure Combination sampling dataset of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). Patients who were discharged within the first 10 days of each month were excluded. We explored and compared aggressive treatments such as cardiopulmonary resuscitation and intensive care utilization, performed within seven days before death in cancer patients. We used 10,637 (0.4% of the dataset) deceased target population (40.0% female), with 7844 (73.7%) and 2793 (26.3%) being the proportion of cancer and heart disease patients, respectively. Aggressive treatments and procedures such as cardiopulmonary resuscitation (18.4%), intensive care utilization (5.4%), use of inotropes (43.4%), use of respirators (29.1%), and dialysis (4.5%) were frequently observed in heart disease patients. These associations remained after adjusting for age, sex, and disease severity. This study indicates the possible use of an NDB sampling dataset to evaluate the aggressive treatments and procedures in the actively dying phase in both heart disease and cancer patients. Our results showed the differences in aggressive treatment strategies in the actively dying phase between patients with cancer and those with heart disease.

A female patient aged 77 years had refractory watery diarrhea caused by a vasoactive intestinal peptide production tumor. She had impaired consciousness. After presenting to our hospital, we administered opium tincture, after which the diarrhea ceased. Intravenous feeding was able to be stopped along with the potassium load and the infusion of octreotide, and loperamide. The antidiarrheal effects continued after opium tincture was stopped, and the patient was discharged home. These results reveal that opium tincture can be efficacious in treating end-stage refractory diarrhea.

Background: Chronic kidney disease (CKD) is known to be associated with cancer mortality. However, no study has considered the well-known cancer prognostic factors, ECOG Performance Status (PS) and cancer treatment, as confounding factors. We assessed the independent relationship between CKD and cancer death in stage IV cancer patients., Methods: In this retrospective observational study, we included stage IV cancer patients diagnosed from 2009 to 2014 in a single center. We collected baseline clinical and laboratory variables, and cancer-specific variables, and assessed the presence of CKD. Our primary outcome was all-cause mortality. The secondary outcome was cancer-specific mortality and site-specific cancer mortality., Results: Among 961 eligible stage IV cancer patients (median age 69 years, 51.8% male), 150 patients had CKD. During follow-up (median 9.8 months), 638 patients died, of whom 526 patients died from cancer. After adjusting for prognostic variables, including ECOG PS and cancer treatment, all-cause mortality and cancer-specific mortality were significantly higher in CKD patients than in non-CKD patients (HR 1.41, 95% CI 1.13-1.77 and HR 1.43, 95% CI 1.12-1.83, respectively). In patients with breast and kidney and urinary tract cancers, CKD was associated with a significantly increased risk of death (HR 7.01, 95% CI 1.47-33.4 and HR 3.33, 95% CI 1.42-7.78, respectively)., Conclusions: CKD at the time of stage IV cancer diagnosis was associated with all-cause mortality and cancer-specific mortality. Moreover, the association between CKD and cancer-specific death was site specific for breast cancer and kidney and urinary tract cancer.

Background: The fluctuation of hemoglobin A1c (HbA1c) and changes in health habits over time was not considered in previous studies. The aim of this study was to evaluate the time-sequenced association between malignancy incidence and HbA1c with a longitudinal study design using repeated measurements of HbA1c., Methods: A retrospective longitudinal study was conducted at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. All participants who underwent voluntary health check-ups at the hospital were included. Our outcomes were the development of malignancy. We compared these outcomes using HbA1c categories. Longitudinal analyses were conducted with a mixed effects model in which time-dependent HbA1c measurements were applied to consider fluctuations in HbA1c levels, adjusted for covariates., Results: A total of 77,385 nondiabetic participants were included in the study; the mean age was 44.7 and 49.4% of participants were male. During a median follow-up of 1588 (interquartile range 730-2946) days, 4506 (5.8%) participants developed malignancies. The relationship between future malignancies and HbA1c was U-shaped; both the lower HbA1c groups (OR 1.31, 95% CI 1.17-1.46 for < 5.0%) and the higher HbA1c group (OR 1.87, 95% CI 1.03-3.39 for ≥ 7.5%) had significantly higher odds ratios compared to the 5.5-5.9%. The lowest HbA1c was associated with higher odds of breast cancer (OR 1.5, 95% CI 1.21-1.86) and female genital cancer (OR 1.57, 95% CI 1.04-2.37)., Conclusions: Our study found a U-shaped association between HbA1c and future malignancies among nondiabetic people but did not find additional risk at the prediabetic level. Low HbA1c may be associated with the incidence of breast cancer and female genital cancer.

Background: Glycemic variability has been suggested to be related to some unfavorable outcomes, but malignancy development has not been evaluated. The aim of this study was to evaluate the association of glycemic variability with malignancy development among the population without diabetes., Methods: We conducted a retrospective cohort study at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all participants without diabetes who underwent voluntary health check-ups. Our outcome was the development of any malignancy. As a measure of glycemic variability, we calculated the quotient of CV in HbA1c and categorized subjects into quartile groups. A Cox proportional hazard model was applied, adjusting for patient demographics and social and family histories., Results: A total of 42,731 participants were included in this study; the mean age was 53.8 and 48.3% were male. During the median follow up of 2639 (interquartile range (IQR):1787-3662) days, 2435 participants (5.7%) developed malignancies. Participants who had larger glycemic variability (CV in HbA1c; hazard ratio (HR) 1.15, 95%confidence interval (CI):1.02-0.31 for the second quartile group; HR 2.20, 95%CI:1.95-2.48 for the third quartile group, HR 4.66, 95%CI:4.16-5.21 for the fourth quartile group, compared to first quartile group) had a significantly higher risk of malignancies., Conclusion: We found an association between large glycemic variability and a high risk of future malignancies in a dose-dependent manner among people without diabetes. This finding suggests that maintaining a constant level of glucose may have favorable effects on cancer prevention in people without diabetes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background/aim: The aim of this study was to evaluate the association between the frequency of daily tooth brushing and the development of any type of malignancy., Patients and Methods: We conducted a retrospective longitudinal study, including all adult participants who underwent health check-ups. Primary outcome was the development of any type of malignancy, compared to the frequency of daily tooth brushing, adjusting for potential confounders., Results: A total of 71,449 participants were included and 5,025 participants developed a certain type of malignancy. Not brushing everyday (Odds Ratio (OR)=1.52, 95% Confidence Interval (CI)=1.03-2.25) and brushing once a day (OR=1.25, 95%CI=1.16-1.35) had significantly higher ORs for the outcome than brushing after every meal, although those who brushed once to twice a day had significantly lower OR (OR=0.78, 95%CI=0.72-0.83)., Conclusion: As the frequency of daily tooth brushing increased, except for brushing after every meal, the development of all types of malignancies decreased., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Recent studies have shown that patients with diabetes mellitus have a higher risk of tumorigenesis. However, the effect of glycemic variability on tumorigenesis among diabetic patients has not been well investigated. Hence, we performed a retrospective cohort study to analyze the effect of visit-to-visit hemoglobin A1c (HbA1c) variability and later onset of malignancies., Methods: This study included 2640 patients with diabetes mellitus 50 years or older. To analyze visit-to-visit glycemic activity, we calculated intrapersonal SD of all recorded HbA1c and used SD-HbA1c as a measure of glycemic variability. Because the number of individual visits varied, we divided SD-HbA1c by visit times in order to adjust for the potential influence of visit time difference between individuals. Patients were divided into quartiles according to their HbA1c variability, and Cox regression models were used to evaluate the association between glycemic variability and later onset of tumorigenesis., Results: Three hundred thirty patients (12.5%) developed malignancy during follow-up. The median follow-up period was 1511 days (4.1 years; interquartile range, 2487.5 days). Relative to the group with the lowest glycemic variability (first quartile), the groups with higher glycemic variability showed a dose-dependent association with tumorigenesis. The odds ratios for the second, third, and fourth quartiles were 1.20 (95% confidence interval, 0.88-1.65), 1.43 (1.02-2.00), and 2.19 (1.52-3.17), respectively. The mean HbA1c and diabetes mellitus duration periods were not significantly associated with tumorigenesis. This result was consistent when limiting the number of covariates., Conclusions: These results demonstrated that visit-to-visit HbA1c variability is a potential risk factor for later tumorigenesis. The association may be mediated by oxidative stress or hormone variability. Routine cancer screening may be suggested for diabetic patients with unstable glycemic control.

Home care and at-home-based palliative care for cancer patients are being improved bythrough a basic law on cancer control and subsequent institutional reforms in 2007. However, in the revision of the medical treatment fee in 2018, it is a big feature that the facilitystandard for the waiting days and the home return rate was built in the palliative care ward. The number of inpatients in our palliative care department was 3,835 in the 5 years from 2013 to 2018. It consists of 2,414 in general wards and 1,421 in the palliative care ward, regarding the home return rate, the total was 27.5%, but there were 891 from the general ward and 163 from the palliative care ward. In the future, the role of palliative care wards is expected to change, shorting the number of waiting days, and providing a much greater degree of flexibilityin the wayof promoting home care. The important thing is to establish a system to be able to choose the place of recuperation quickly depending on the patient, familysituation, and their hope. Hence, we aim to strengthen the home-visit system by emphasizing the continuityof medical treatment while maintaining the relationship of mutual trust among the local cooperative clinics.

We offer inpatient support for end-stage cancer patients, not only in palliative care units, but also in general medical and long-term care units. We also provide outpatient palliative care and offer emergent backup for the regional home care clinics. From January 2014 to December 2016, 1,832 patients were hospitalized, and among them, 983 patients visited our hospital on an emergency basis. Among the urgent hospitalized patients, 378 patients returned home after adequate palliative care. But 605 patients had to stay admitted in the hospital until their time of death. Ninety-one patients died within 48 hours after urgent hospitalization. Of these 91 patients, 70% came to our hospital because of increasing dyspnea and decreased level of consciousness additionally, 36 of 91 patients had received treatment by home care clinic doctors, and 50% of them had hoped for at-home death. The patients' preference of treatment facility tends to vary depending on their general condition. Hence, we have to offer appropriate facilities for palliative care. Building good relationships between hospitals and regional home care clinics and creating a system for patients to choose the appropriate time and place for treatment with a smooth transition from their home to the hospital during their end-of-life period is important in this process.

Purpose: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients., Methods: Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers)., Results: Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h., Conclusions: Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV., Identifier: NCT01722825.

The idea of a computer-controlled range-compensating system for heavy charged particle radiotherapy, the multibar compensator, is proposed. By stacking multiple energy-absorbing layers along the beam, each of which has structure and behaviour similar to those of a multileaf collimator, variable range compensation will be achieved. The analysis of the conventional range compensators actually used for treatment concluded that the proposed system would not seriously degrade the treatment quality for the most cases, except for tumours in the head and neck region where 1 mm precision may be required. The system will even be able to coexist with the conventional range compensators to provide either method depending on clinical situations.

The authors through individual interviews have analyzed the way cancer patients got to know about their illness and how these information influenced their lives, family and their feelings. Suggestions have been made after evaluating the results reached in this research.