Driver gene KRAS aggravates cancer-associated stroke outcomes

The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015

Hierarchy of the Selberg zeta functions

We introduce a Selberg type zeta function of two variables which interpolates several higher Selberg zeta functions. The analytic continuation, the functional equation and the determinant expression of this function via the Laplacian on a Riemann surface are obtained.Comment: 14 page

Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan

BACKGROUND: Data on the risk of cardiovascular-related mortality in patients with cancer are limited. METHODS AND RESULTS: This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. CONCLUSIONS: Cancer survivors have a higher risk of fatal heart disease than the general population.Gon Y., Zha L., Sasaki T., et al. Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan. Journal of the American Heart Association 12, e029967 (2023); https://doi.org/10.1161/JAHA.123.029967

Predictors of Survival in Patients With Ischemic Stroke and Active Cancer: A Prospective, Multicenter, Observational Study

BACKGROUND: Limited data exist on the prognostic factors for patients with ischemic stroke and active cancer. METHODS AND RESULTS: We conducted a prospective, multicenter, observational study in Japan, including patients with acute ischemic stroke and active cancer, to investigate the prognostic factors. We followed up the patients for 1 year after stroke onset. The patients were divided into 2 groups according to cryptogenic stroke and known causes (small-vessel occlusion, large-artery atherosclerosis, cardioembolism, and other determined cause), and survival was compared. The hazard ratios (HRs) and 95% CIs for mortality were calculated using Cox regression models. We identified 135 eligible patients (39% women; median age, 75 years). Of these patients, 51% had distant metastasis. A total of 65 (48%) and 70 (52%) patients had cryptogenic stroke and known causes, respectively. Patients with cryptogenic stroke had significantly shorter survival than those with known causes (HR [95% CI], 3.11 [1.82–5.32]). The multivariable Cox regression analysis revealed that distant metastasis, plasma D-dimer levels, venous thromboembolism (either deep venous thrombosis or pulmonary embolism) complications at stroke onset were independent predictors of mortality after adjusting for potential confounders. Cryptogenic stroke was associated with prognosis in univariable analysis but was not significant in multivariable analysis. The plasma D-dimer levels stratified the prognosis of patients with ischemic stroke and active cancer. CONCLUSIONS: The prognosis of patients with acute ischemic stroke and active cancer varied considerably depending on stroke mechanism, distant metastasis, and coagulation abnormalities. The present study confirmed that coagulation abnormalities were crucial in determining the prognosis of such patients.Gon Y., Sakaguchi M., Yamagami H., et al. Predictors of Survival in Patients With Ischemic Stroke and Active Cancer: A Prospective, Multicenter, Observational Study. Journal of the American Heart Association 12, e029618 (2023); https://doi.org/10.1161/JAHA.123.029618

Validation of an algorithm that determines stroke diagnostic code accuracy in a Japanese hospital-based cancer registry using electronic medical records

Abstract Background This study aimed to validate an algorithm that determines stroke diagnostic code accuracy, in a hospital-based cancer registry, using electronic medical records (EMRs) in Japan. Methods The subjects were 27,932 patients enrolled in the hospital-based cancer registry of Osaka University Hospital, between January 1, 2007 and December 31, 2015. The ICD-10 (international classification of diseases, 10th revision) diagnostic codes for stroke were extracted from the EMR database. Specifically, subarachnoid hemorrhage (I60); intracerebral hemorrhage (I61); cerebral infarction (I63); and other transient cerebral ischemic attacks and related syndromes and transient cerebral ischemic attack (unspecified) (G458 and G459), respectively. Diagnostic codes, both “definite” and “suspected,” and brain imaging information were extracted from the database. We set the algorithm with the combination of the diagnostic code and/or the brain imaging information, and manually reviewed the presence or absence of the acute cerebrovascular disease with medical charts. Results A total of 2654 diagnostic codes, 1991 “definite” and 663 “suspected,” were identified. After excluding duplicates, the numbers of “definite” and “suspected” diagnostic codes were 912 and 228, respectively. The proportion of the presence of the disease in the “definite” diagnostic code was 22%; this raised 51% with the combination of the diagnostic code and the use of brain imaging information. When adding the interval of when brain imaging was performed (within 30 days and within 1 day) to the diagnostic code, the proportion increased to 84% and 90%, respectively. In the algorithm of “definite” diagnostic code, history of stroke was the most common in the diagnostic code, but in the algorithm of “definite” diagnostic code and the use of brain imaging within 1 day, stroke mimics was the most frequent. Conclusions Combining the diagnostic code and clinical examination improved the proportion of the presence of disease in the diagnostic code and achieved appropriate accuracy for research. Clinical research using EMRs require outcome validation prior to conducting a study

Association of the Yips and Musculoskeletal Problems in Highly Skilled Golfers: A Large Scale Epidemiological Study in Japan

The yips are a set of conditions associated with intermittent motor disturbances that affect precision movement, especially in sports. Specifically, skilled golfers suffer from the yips, although its clinical characteristics and pathophysiology have not been well-studied. We surveyed skilled golfers to characterize their yips-related symptoms, to explore potential confounding factors associated with the yips. Golfers’ demographic information, golfing-career-related history, musculoskeletal status and manifestations of the yips are surveyed. Among the 1576 questionnaires distributed, 1457 (92%) responses were received, of which 39% of golfers had experienced the yips. The median age and golfing careers were 48 and 28 years, respectively. Golfers who had experienced the yips were older and had longer golfing careers and more frequent musculoskeletal problems than those without experience of the yips. The multivariate logistic regression analysis revealed that a longer golfing career and musculoskeletal problems were independent factors associated with yips experience. More severe musculoskeletal problems were associated with higher odds of experiencing the yips. A positive association between the yips and musculoskeletal problems was also observed. The yips have similar characteristics to task-specific movement disorders, with a detrimental effect caused by excessive repetition of a routine task. These findings support the notion that the yips are a type of task-specific dystonia

Heart Disease Mortality in Cancer Survivors: A Population‐Based Study in Japan

Background Data on the risk of cardiovascular‐related mortality in patients with cancer are limited. Methods and Results This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74–2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17–3.35), 2.69 (95% CI, 2.60–2.78), and 5.97 (95% CI, 5.38–6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02–1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. Conclusions Cancer survivors have a higher risk of fatal heart disease than the general population

Von Willebrand Factor Antigen Levels Predict Poor Outcomes in Patients With Stroke and Cancer: Findings From the Multicenter, Prospective, Observational SCAN Study

Background Patients with acute ischemic stroke and active cancer have more severe neurological symptoms, elevated risks of stroke recurrence, and death compared with the general population. We examined whether von Willebrand factor (vWF) antigen levels at stroke onset were associated with the poor outcomes of patients with stroke and cancer. Methods and Results Using data from 90 patients with acute ischemic stroke and active cancer who were registered in the SCAN (Ischemic Stroke in Patients With Cancer and Neoplasia) study, a prospective multicenter, observational study in Japan, we divided patients into 2 groups according to their median vWF antigen levels (high, n=46; or low, n=44). The high‐vWF group had a significantly higher initial National Institutes of Health Stroke Scale score (median, 7 [interquartile range, 3–11.25] versus 3 [interquartile range, 1–8.5]; P<0.05) and a significantly higher incidence of cryptogenic stroke (32 [70%] versus 16 [36%]; P<0.01) and venous thromboembolism (7 [15%] versus 0 [0%]; P<0.01), as well as multiple lesions (28 [62%] versus 12 [27%]; P<0.001), than the low‐vWF group. We observed no significant difference in the rate of stroke recurrence within 1 year between the groups. However, increased vWF levels were an independent predictor of death within 1 year of stroke onset, after adjusting for potential confounders (odds ratio, 6.77 [95% CI, 1.49–30.78]; P<0.05). Conclusions Elevated vWF antigen levels were associated with adverse outcomes in patients with cancer‐associated stroke and may represent a useful biomarker to guide future therapeutic interventions