External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed From a Hospital-Based Administrative Database.

PURPOSE: Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. METHODS: In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. RESULTS: For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). CONCLUSION: We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.

The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis.

We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition.

Breastfeeding leads to lower blood pressure in 7-year-old Japanese children: Tohoku Study of Child Development.

This study investigated the association between breastfeeding and both self-measured home blood pressure (HBP) and conventional blood pressure (CBP) in 7-year-old Japanese children. We obtained data pertaining to breastfeeding and blood pressure for 377 mother-offspring pairs from the Tohoku Study of Child Development, which is a prospective birth cohort study. Information on breastfeeding and other factors were obtained from parental questionnaires during the follow-up period. Based on the duration of breastfeeding as a major source of nutrition, mother-offspring pairs were divided into short-term (mean, 5.1 months) and long-term (mean, 11.3 months) breastfeeding groups. At the age of 7 years (84.4±1.8 months), each child's blood pressure was measured. The HBP in the long-term breastfeeding (LBF) group (92.9 mm Hg systolic/55.1 mm Hg diastolic) was significantly lower (P=0.006/0.04) than in the short-term breastfeeding group (94.7/56.4 mm Hg); however, there were no significant differences in the CBP measurements between the short- and LBF groups. Using multiple regression analysis, the duration of breastfeeding (greater than 8 months) was more strongly associated with HBP (P=0.008/0.05) than with CBP (P=0.4/0.9). Furthermore, the adjusted R-squared values for HBP (0.25/0.12) tended to be higher than those for CBP (0.07/0.03). These findings were independent of the birth weight. In conclusion, breastfeeding has a protective effect against elevated blood pressure even in young children, and subtle, but important, differences were precisely detected by self-measurements performed at home.

Mother-offspring aggregation in home versus conventional blood pressure in the Tohoku Study of Child Development (TSCD).

OBJECTIVE: Few studies described the home blood pressure (HBP) in young children. Using intrafamilial correlations of blood pressure as research focus, we assessed the feasibility of HBP monitoring in this age group. METHODS: We enrolled 382 mothers (mean age 38.8 years) and singletons (7.0 years) in theTohoku Study of Child Development.We measured their conventional blood pressure (CBP; single reading) at an examination centre. Participants monitored HBP in the morning. We used the OMRON HEM-70801C for CBP and HBP measurement. In a separate group of 84 children (mean age 7.7 years), we compared blood pressure readings obtained by the OMRON monitor and the Dinamap Pro 100, a device approved by FDA for use in children. We used correlation coefficients as measure of intrafamilial aggregation, while accounting for the mothers' age, body mass index, heart rate and smoking and drinking habits and the children's age, height, and heart rate. RESULTS: Mother-offspring correlations were closer (P < or = 0.003) for HBP than CBP for systolic pressure [0.28 (P < 0.0001) vs 0.06 (P = 0.26)] and diastolic pressure [0.28 (P < 0.0001) vs 0.02 (P = 0.65)].The between-device differences (OMRON minus Dinamap) averaged 7.8 +/- 6.0 mmHg systolic and 5.8 +/- 5.5 mmHg diastolic. CONCLUSIONS: HBP monitoring is an easily applicable method to assess intrafamilial blood pressure aggregation in young children and outperforms CBP. Validation protocols for HBP devices in young children need revision, because the Korotkoff method is not practicable at this age and there is no agreed alternative reference method.

Novel function of MKP-5/DUSP10, a phosphatase of stress-activated kinases, on ERK-dependent gene expression, and upregulation of its gene expression in colon carcinomas.

Mitogen-activated protein kinase phosphatase 5 (MKP-5)/DUSP10 acts as a phosphatase of stress-activated kinases (JNK and p38), but its activity towards ERK has not been demonstrated. In the present study we observed that MKP-5 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription. These data suggested a novel MKP-5 function as a scaffold protein for the ERK pathway. We analyzed MKP-5 gene expression in several tumors, and found that it is frequently upregulated in colorectal but not in lung and breast cancer, suggesting its association with the malignant phenotype of colon cancer.

Relationship of dysregulation of glucose metabolism with white-coat hypertension: the Ohasama study.

Characteristics of glucose metabolism in subjects with white-coat hypertension (WCHT) have not been fully investigated. The purpose of this study was to determine the relationship between glucose metabolism and WCHT on the basis of blood pressure (BP) at home (HBP) in the general population. Participants were from Ohasama, a rural Japanese community, and included 466 residents (mean age, 61.0 years) who had no history of diabetes mellitus. HBP and oral glucose tolerance test values were measured. Participants were classified into four groups on the basis of their HBP and casual-screening BP (CBP) values: normotension (NT) (HBP<135/85 mm Hg, CBP<140/90 mm Hg); WCHT (HBP<135/85 mm Hg, CBP>/=140/90 mm Hg); masked hypertension (HBP>/=135/85 mm Hg, CBP<140/90 mm Hg); or sustained hypertension (SHT) (HBP>/=135/85 mm Hg, CBP>/=140/90 mm Hg). The relationships between glucose metabolism and BP among the four groups were examined using multivariate analysis adjusted for possible confounding factors. Factors in relation to glucose metabolism, such as fasting glucose level, 2-h postchallenge glucose level and homeostasis model assessment-insulin resistance index, were significantly higher in subjects with WCHT and SHT than in those with NT (all P<0.03). When men and women were analyzed separately, these relationships were more pronounced in women. Our results suggest that dysregulation of glucose metabolism in WCHT might contribute to the increase in the long-term cardiovascular risk among the general population.

The association between masked hypertension and waist circumference as an obesity-related anthropometric index for metabolic syndrome: the Ohasama study.

Masked hypertension has been proven to be associated with an increased risk for cardiovascular diseases. The purpose of this study was to examine the direct associations of obesity-related anthropometric indices, including waist circumference, with masked hypertension. Participants in this population-based survey included 395 residents (> or = 35 years) of Ohasama, a rural Japanese community. They measured blood pressure at home (HBP) and underwent an oral glucose-tolerance test. Participants were classified into four groups on the basis of their HBP and casual-screening blood pressure (CBP) values: sustained normotension, white-coat hypertension, masked hypertension or sustained hypertension. The relationships between the obesity-related anthropometric indices and the four blood pressure groups were examined using multivariate analysis adjusted for confounding factors. The mean waist circumference in men was significantly higher in individuals with masked hypertension (87.3 cm) than in those with sustained normotension (81.0 cm) and white-coat hypertension (79.3 cm), whereas the mean waist circumference in women was significantly higher in individuals with sustained hypertension (79.5 cm) than in those with sustained normotension (75.0 cm). In the multivariate analysis, waist circumference, body mass index (BMI) and waist-to-hip ratio were significantly associated with masked hypertension, particularly in individuals with normal CBP. Our results suggest that HBP measurements might be particularly important in abdominally obese people for the early detection of masked hypertension.