Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study.

BACKGROUND: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. METHODS: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. RESULTS: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. CONCLUSIONS: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

Psychosocial Experiences Related to Dietary Behavior of Japanese Lactating Women: A Qualitative Study.

Adequate dietary intake during the lactation period is important for breast milk components, postpartum recovery, and physical and mental health. This study aimed to clarify the psychosocial experiences related to dietary behavior around one month postpartum among Japanese lactating women. Semi-structured interviews were conducted with 18 women between February and June 2022 in Osaka, Japan. The data were analyzed using qualitative descriptive approaches. Four core categories were identified. All participants had a [desire to have healthy meals for themselves or their families] to improve their postpartum health, regain their pre-pregnancy body shape, produce sufficient and good-quality breast milk, and keep their families healthy. Some participants, who had [subjective difficulties in getting information on diet and preparing meals] due to insufficient or complicated information and viewing meal preparation as a burden, used [services and support regarding their postpartum diet] to alleviate these difficulties. They had [postpartum-specific appetite and dietary views], including an increased appetite triggered by breastfeeding and postpartum stress and the effects of the dietary changes during pregnancy. Some of these psychosocial experiences were influenced by Japanese traditional customs in the postpartum period and familiar food preferences in the Japanese. Healthcare professionals should consider these experiences when providing tailored dietary guidance.

Efficacy and safety of talazoparib in Japanese patients with germline BRCA-mutated locally advanced or metastatic breast cancer: results of the phase 1 dose-expansion study.

BACKGROUND: Talazoparib, a poly(ADP-ribose) polymerase enzyme inhibitor, is approved for the treatment of patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative advanced breast cancer. This two-part study, a recently published dose-escalation part followed by the dose-expansion part reported here, evaluated the efficacy and safety of talazoparib in Japanese patients with gBRCA1/2-mutated advanced breast cancer. METHODS: In this open-label, multicenter phase 1 study (NCT03343054), the primary endpoint of the dose-expansion part was confirmed objective response rate (ORR), determined by investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Patients received the recommended phase 2 dose (1 mg/day; 0.75 mg/day moderate renal impairment). RESULTS: Nineteen Japanese patients with gBRCA1/2-mutated locally advanced or metastatic breast cancer were enrolled. Confirmed ORR was 57.9% (11/19; 90% confidence interval [CI] 36.8-77.0). Stable disease was observed in 36.8% (7/19) of patients. Per investigator assessment, median PFS was 7.2 months (95% CI 4.1-not estimable) and 12-month OS rate was 84.7% (90% CI 57.5-95.1). Median OS was not reached; 17/19 patients were alive and censored at 12 months. All patients experienced treatment-related adverse events (AEs); the majority were hematologic. The most common treatment-related AE was anemia (68.4%; [13/19]). Grade 3/4 treatment-related AEs were observed in 52.6% (10/19) of patients. During the safety period, there were no grade 5 treatment-emergent AEs, treatment-related serious AEs, or deaths. CONCLUSIONS: In Japanese patients with gBRCA mutations and locally advanced or metastatic breast cancer, talazoparib monotherapy was generally well tolerated and resulted in clinically meaningful ORRs. GOV IDENTIFIER: NCT03343054.

Association of Lifestyle Changes Due to the COVID-19 Pandemic with Nutrient Intake and Physical Activity Levels during Pregnancy in Japan.

The coronavirus disease 2019 (COVID-19) pandemic has introduced changes in our lifestyles, such as refraining from unnecessary outings. This study aimed to clarify the association of lifestyle changes due to the COVID-19 pandemic with nutrient intake and physical activity levels during pregnancy in Japan. A cross-sectional study involving 168 healthy pregnant Japanese women was conducted in 2020. Nutrient intake and physical activity levels were assessed using validated self-administered questionnaires. Participants who reported experiencing changes in both dietary habits and physical activity due to the COVID-19 pandemic were classified as the lifestyle-affected group. Analysis of covariance was used. Among primiparas, intake of the following nutrients was significantly higher in the lifestyle-affected group (n = 14) than in the unaffected group (n = 77): protein, potassium, calcium, magnesium, and vitamin B6. Among multiparas, the intake of dietary fiber and ß-carotene were significantly lower in the lifestyle-affected group (n = 13) than in the unaffected group (n = 64). No significant differences in physical activity levels were observed in accordance with the lifestyle changes. These findings suggest that lifestyle changes due to the COVID-19 pandemic have positive effects on nutrient intake during pregnancy in primiparas, whereas in multiparas, these changes have negative effects.

[Urological oncology emergencies].

Urologic emergencies in malignancies are difficult to treat for non-urological medical staff because of their anatomical specificity and sensational susceptibility. Urological cancer pain involves somatic and neuropathic problems. In pelvic malignancies, almost always NSAIDs, micro-2-agonisitic opioids and adjuvant analgesics are necessary for pain palliation. The inducements of hemorrhagic cystitis are radiation, chemotherapy and tumor invasion. Although there are some conservative treatments such as hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis, in emergency circumstances selective embolization of the internal iliac artery may be beneficial with fewer side effects. In uncontrollable tumor bleeding, palliative radiotherapy(maximum dose of 30-36 Gy)is effective. The most important problem in voiding disturbance is bladder outlet obstruction. Sometimes patients are treated with alfa-adrenergic blockers effectively, but eventually they may need an indwelling catheter. Obstructive nephropathy due to malignant ureteral obstruction is an ominous sign of progressive disease, especially in pelvic malignancies. The mean survival rate of 12 months was less than 30%.

[Pain management for cancer patients with critical pathway on computer].

For relief from cancer pain, we developed critical pathway (CP) as an effective strategy for the medical staff treating cancer patients. This CP was made out of Microsoft Excel, and was used on personal computers. "Good sleeping" was set as the first goal and the second was "No pain in rest position." To achieve this, physicians and nurses evaluate medical efficacy and complications including nausea/vomiting, constipation, somnolence and hallucination everyday using controlled release oxycodone in addition to NSAIDs and prochlorperazine, stool softener and peristaltic stimulant for adverse effects. These outcomes lead to the medication change the next day by calculation using visual basic function due to opioid titration theory. In twelve patients this CP was acceptable, and all of them achieved the second goal within a week without severe adverse effects except constipation.

Assessment of reasons for referral and activities of hospital palliative care teams using a standard format: a multicenter 1000 case description.

CONTEXT: The many benefits of hospital palliative care teams (PCTs) are well known. However, their specific activities have not been fully clarified, and no standardized methods for reporting PCT activities are available. OBJECTIVES: The aim of this study was to investigate, through the use of a standard format, the activities performed by hospital PCTs in Japan. METHODS: This was a prospective observational study. A total of 21 hospital PCTs were included in this study, and each recruited approximately 50 consecutively referred patients. Participating PCTs filled in a standard form for reporting activities. RESULTS: We obtained data from 1055 patients who were referred to PCTs. Of the 1055 patients, 1005 patients (95%) had cancer. The median number of reasons for referral and problems identified by PCTs was two (0-22) and four (0-18), respectively. The two major reasons for referral were pain (63%) and anxiety/depression/grief/emotional burden (22%). The major recommendations were pharmacological treatment (74%), care for the patient's physical symptoms (49%), and support for patient's decision making (38%). The major activities performed by the PCTs were comprehensive assessment (90%), care for the patient's physical symptoms (77%), and pharmacological treatment (74%). CONCLUSION: The components of hospital PCT activities were successfully measured using the Standard Format for Reporting Hospital PCT Activity. The results of this study and the format for reporting hospital PCT activity could be effective in improving hospital PCT practice and for the education of new hospital PCT members.

Calpain-mediated cleavage negatively regulates the expression level of ABCG1.

OBJECTIVE: The ATP-binding cassette transporter ABCG1 mediates cholesterol efflux from macrophages, and prevents the progression of macrophage foam-cell formation. Much less is known about the regulatory mechanism of ABCG1, although its physiological importance is becoming clearer. Here, we show the role of calpain in ABCG1 degradation. METHODS AND RESULTS: Purified µ-calpain cleaved ABCG1 in crude membrane fractions prepared from human ABCG1-expressing HEK293 (ABCG1-HEK) cells. In ABCG1-HEK cells, calpeptin treatment, a calpain inhibitor, inhibited ABCG1 degradation, and thereby increased the expression and cholesterol efflux function of ABCG1. Biotinylation study demonstrated greater ABCG1 induction with calpeptin treatment in cell surface than that in whole cell lysates. Together with the result that increased ABCG1 expression with calpeptin treatment was observed under clathrin heavy-chain (CHC) knockdown conditions, where ABCG1 internalization was prevented, calpain is considered to catalyze ABCG1 cleavage on the plasma membrane. In mouse peritoneal macrophages as well as in ABCG1-HEK cells, calpeptin treatment inhibited ABCG1 degradation and enhanced ABCG1 expression, even under CHC-depleted conditions. CONCLUSION: These observations indicate that calpain promotes ABCG1 degradation by cleaving cell surface-resident ABCG1, and consequently reduces the expression and cholesterol efflux function of ABCG1. Inhibition of ABCG1 cleavage by calpain could be a novel approach to suppress the progression of atherosclerosis.