Non-cancer-related Deaths in Cancer Survivors: A Nationwide Population-Based Study in Japan.

BACKGROUND: Advancements in cancer care have improved survivorship, potentially leading to changes in mortality causes. This study aimed to investigate the causes of death among cancer survivors, specially focusing on non-cancer-related mortality. METHODS: This nationwide population-based cohort study analyzed the causes of death based on the time since cancer diagnosis using data from the National Cancer Registry in Japan between January 2016 and December 2019. Non-cancer-related deaths were identified, and mortality risks associated with non-cancer diseases were compared to those of the Japanese general population using standardized mortality ratios (SMRs) with 95% confidence intervals (CIs). Follow-up period was up to 4 years after cancer diagnosis. RESULTS: A total of 3,990,661 patients (45.8%, women) were included in the analysis, yielding 6,237,269 person-years of follow-up. Of these, 1,001,857 (25.1%) patients died during the study period. Cancer-related and non-cancer-related causes accounted for 86.6% and 13.4% of deaths, respectively. The proportion of non-cancer-related deaths increased from 10.2% at 6 months to 31.6% at 4 years after cancer diagnosis. Heart disease (21.8%), cerebrovascular disease (9.8%), and pneumonia (9.1%) were the leading cause of non-cancer-related deaths: The SMRs for these diseases were 2.69 (95% CI, 2.66-2.72), 2.07 (95% CI, 2.03-2.10), and 2.41 (95% CI, 2.36-2.45), respectively. The SMR for suicide was 1.81 (95% CI, 1.74-1.89); however, it lost significance in males and females 2 and 2.5 years after cancer diagnosis, respectively. CONCLUSIONS: The proportion of non-cancer-related deaths among cancer patients has increased over time, emphasizing the need to manage cancer and its comorbidities carefully.

Prevalence of survivors of childhood cancer based on a population-based cancer registry in Osaka, Japan.

Although the survival rate of patients with childhood cancer has greatly improved, long-term survivors face specific problems such as the late effects of cancer treatment. In this study, we estimated the number of people who had experienced childhood cancer to predict their needs for medical care and social resources. Using data from the population-based Osaka Cancer Registry, we identified children aged 0-14 years who were diagnosed with cancer between 1975 and 2019. We estimated the prevalence on December 31, 2019, and the 5- and 10-year prevalence (i.e., the number of survivors living up to 5 or 10 years after the diagnosis of cancer) over time. The prevalence proportion was age-standardized using a direct standardization method. The prevalence estimates for Osaka were applied to the national population to determine the national prevalence in Japan. Among 8186 patients diagnosed with childhood cancer in Osaka, 5252 (987 per million) survived until December 31, 2019. The 5-year prevalence per million increased from 194 in 1979 to 417 in 2019 (+116%), while the 10-year prevalence increased from 391 in 1984 to 715 in 2019 (+83%). Based on the long-term registry data, an estimated 73,182 childhood cancer survivors were living in Japan by the end of 2019. The increasing 5-year and 10-year prevalence proportions indicate the continued need for cancer survivorship support for children, adolescents, and young adults. These estimates of the prevalence of childhood cancer survivors, including long-term survivors, may be useful for policymakers and clinicians to plan and evaluate survivorship care.

Prognostic impact of coexisting cardiovascular disease in patients with cancer: A multicenter retrospective cohort study.

Background: The incidence of malignancy and cardiovascular disease (CVD) is increasing worldwide. However, it is not entirely clear how the coexistence of CVD at the time of cancer diagnosis affects the overall survival of patients with cancer. Methods and results: We used the cancer registries and administrative claims data of patients diagnosed with cancer at 36 designated cancer care hospitals in Osaka, Japan, from 2010 to 2015. The Cox proportional hazard model was used to examine how coexisting CVD (heart failure [HF], ischemic heart disease, peripheral arterial disease, cerebrovascular accidents, and atrial fibrillation) affected overall survival and the impact of HF severity, as documented by the New York Heart Association (NYHA) classification. Of the 131,701 patients with cancer, 9704 had coexisting CVD. The 3-year survival rates for patients with and without coexisting CVD were 62.9 % and 77.6 %, respectively. The adjusted hazard ratio (aHR) for all-cause mortality for coexisting CVD was 1.47 (95 % confidence interval, 1.41-1.52). Among the CVD subtype, patients with coexisting HF had the poorest prognosis. The aHRs in patients with HF by NYHA classification, using the patients without HF as a reference, were as follows: Class I: 1.33 (p = 0.217); II: 1.68 (p < 0.001); III: 1.54 (p = 0.011); IV: 2.47 (p < 0.001). Conclusion: Coexisting CVD and HF severity at cancer diagnosis is associated with survival in patients with cancer.

Prognostic impact of the presence or absence of prior cancer in patients with cancer using cure models: A population-based study.

Developing a subsequent cancer is one of the major concerns for cancer survivors; however, whether prior cancer could affect their prognosis is unknown. We therefore aimed to analyze how prognosis varies depending on prior cancer in patients with newly developed cancer, focusing on cancer that had been "cured." We used the record-linked database of the Osaka Cancer Registry and Vital Statistics to select 186,798 patients with stomach, colorectal, or lung cancer aged ≥40 years from 1995 to 2009 in Osaka, Japan. These cancers were defined as index cancers. We classified the patients into two groups according to whether they had a prior cancer diagnosis within 10 years before the index cancer diagnosis. The cured proportion was defined as the proportion of cancer patients with the same mortality as the general population and was estimated using the parametric mixture cure model. The cured proportion of patients with prior cancer by sex and age group was not significantly lower than those without prior cancer, except for patients with stomach cancer aged ≥65 years. According to the index cancer stage in the localized stomach or colorectal cancer, the cured proportion in patients with prior cancer was lower than in those without prior cancer. However, at any stage of lung cancer, the proportion of patients with prior cancer who had been cured was similar to patients without prior cancer, therefore prior cancer had a prognostic impact only in some patient groups based on the characteristics of their index cancer.

Age-Dependent Causes of Death among Patients with Breast Cancer Based on Osaka Cancer Registry and Vital Statistics in Japan.

We aimed to clarify the differences in causes of death among patients with breast cancer according to age at diagnosis and years elapsed since diagnosis. Using data from the Osaka Cancer Registry and Vital Statistics databases, 40,690 female patients diagnosed with primary breast cancer between 1985 and 2006 were included in this study. The statistics on all deaths between 1985 to 2016 were collected, and the observation period was 10 years (2006-2016). Mortality hazards according to age at diagnosis and years elapsed since diagnosis were estimated using a flexible parametric estimation. Of the 40,690 patients, 13,676 (34%) died from all-cause death, and the 10-year survival rate was 65.74% (95% confidence interval: 65.28-66.21). The proportions of deaths were 10,531 (77%) from breast cancer, 1048 (8%) from other cancers, and 2097 (15%) from non-cancer causes. The mortality hazard for deaths from breast cancer was initially high and then declined, whereas that for deaths from other cancers and non-cancer causes was initially low and then increased. The more likely causes of death 5 years after breast cancer diagnosis were other cancers or non-cancer causes among patients aged ≥70 years.

Cause of Death among Long-Term Cancer Survivors: The NANDE Study.

Survival information for Japanese patients with cancer is based only on survival status and the cause of death among these patients remains unclear. In this study, Osaka Cancer Registry data (1985-2014) and vital statistics data (1985-2016) were linked to create a database, permitting the extraction of data on the causes of death. In total, 522,566 subjects diagnosed with cancer between 1995 and 2011 were analyzed. Follow-up for vital status was conducted 5 and 10 years after cancer diagnosis. To evaluate the three causes of death (index cancer, non-index cancer, and non-cancer death), cause-specific hazard and cumulative incidence functions were estimated using a life table and Gray's methods. The number of deaths owing to any of the causes in the observation period (median: 3.51 years, mean: 4.90 years) was 394,146. The 5- and 10-year cancer-specific survival rate was 48.56% and 39.92%, respectively. Immediately after cancer onset, the hazard of index cancer death was high. The proportion of non-index cancer deaths was high in patients with mouth and pharynx cancers. The hazard of index cancer death remained constant for breast and liver cancers. In prostate, breast, and laryngeal cancers with good prognosis, the hazard of non-index cancer and non-cancer death constantly increased.

Short-term association of air pollution with lung cancer mortality in Osaka, Japan.

Long-term air pollution exposure has been linked to increased lung cancer mortality. However, little is known about whether day-to-day fluctuations in air pollution levels are in relation to lung cancer mortality, particularly in low-exposure settings. This study aimed to evaluate the short-term associations between air pollution and lung cancer mortality. Daily data on lung cancer mortality, fine particulate matter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and weather conditions were collected from Osaka Prefecture, Japan, from 2010 to 2014. Generalized linear models were combined with quasi-Poisson regression were applied to evaluate the associations between each air pollutant and lung cancer mortality after adjusting for potential confounders. Mean (standard deviation) concentrations of PM2.5, NO2, SO2, and CO were 16.7 (8.6) µg/m3, 36.8 (14.2) µg/m3, 11.1 (4.0) µg/m3, and 0.51 (0.16) mg/m3, respectively. Interquartile range increases in concentrations of PM2.5, NO2, SO2, and CO (2-d moving average) were associated with 2.65% (95% confidence intervals [CIs]: 0.96%-4.37%), 4.28% (95% CIs: 2.24%-6.36%), 3.35% (95% CIs: 1.03%-5.73%), and 4.60% (95% CIs: 2.19%-7.05%) increased risk of lung cancer mortality, respectively. Stratified analyses showed that the associations were strongest in the older population and men. Exposure‒response curves showed a continuously increasing mortality risk from lung cancer with elevation of air pollution levels, without discernible thresholds. In summary, we found evidence of increased lung cancer mortality in relation to short-term elevations in ambient air pollution. These findings may merit further research to better understand this issue.

The Effect of High Molecular Weight Hyaluronic Acid and Latanoprost Eyedrops on Tear Functions and Ocular Surface Status in C57/BL6 Mice.

Anti-glaucoma eye drop treatment often induces ocular surface problems, including dry eyes, and may be associated with poor medication compliance. This study aimed to investigate the effects of a novel high molecular weight hyaluronic acid and Latanoprost eye drop on intraocular pressure, as well as the tear function and ocular surface alterations in wild type mice, comparing the results with the mice receiving commercially available Latanoprost eye drops and mice receiving no treatment. The mice were divided into three groups: Group I, control group (no treatment group); Group II, commercial Latanoprost eye drop (LP); and Group III, Comfort Shield (CS) + Latanoprost (LP) eye drop (CS + LP). The CS + LP eye drop group had an IOP lowering effect comparable to the commercial LP eye drop group. The mice receiving LP eye drops had significantly worse corneal staining scores, lesser goblet cell density(GCD), higher numbers of CD45+ staining cells, significantly higher tear film concentrations of IL-6 and IL1-b, and a significantly lower expression of corneal ZO-1 mRNA compared with the mice receiving CS + LP 7 days after eye drop instillations (p < 0.05). In conclusion, the new CS + LP formulation appeared to induce less inflammation, less corneal vital staining, and a better barrier status with an IOP lowering effect comparable to the commercial LP eye drops.

Patterns of staging, treatment, and mortality in gastric, colorectal, and lung cancer among older adults with and without preexisting dementia: a Japanese multicentre cohort study.

BACKGROUND: Little is known about dementia's impact on patterns of diagnosis, treatment, and outcomes in cancer patients. This study aimed to elucidate the differences in cancer staging, treatment, and mortality in older cancer patients with and without preexisting dementia. METHODS: Using cancer registry data and administrative data from 30 hospitals in Japan, this multicentre retrospective cohort study examined patients aged 65-99 years who were newly diagnosed with gastric, colorectal, or lung cancer in 2014-2015. Dementia status (none, mild, and moderate-to-severe) at the time of cancer diagnosis was extracted from clinical summaries in administrative data, and set as the exposure of interest. We constructed multivariable logistic regression models to analyse cancer staging and treatment, and multivariable Cox regression models to analyse three-year survival. RESULTS: Among gastric (n = 6016), colorectal (n = 7257), and lung (n = 4502) cancer patients, 5.1%, 5.8%, and 6.4% had dementia, respectively. Patients with dementia were more likely to receive unstaged and advanced-stage cancer diagnoses; less likely to undergo tumour resection for stage I, II, and III gastric cancer and for stage I and II lung cancer; less likely to receive pharmacotherapy for stage III and IV lung cancer; more likely to undergo tumour resection for all-stage colorectal cancer; and more likely to die within three years of cancer diagnosis. The effects of moderate-to-severe dementia were greater than those of mild dementia, with the exception of tumour resection for colorectal cancer. CONCLUSION: Older cancer patients with preexisting dementia are less likely to receive standard cancer treatment and more likely to experience poorer outcomes. Clinicians should be aware of these risks, and would benefit from standardised guidelines to aid their decision-making in diagnosing and treating these patients.

Impact of coexisting diabetes on survival and risk of developing second primary cancer in diabetes patients receiving drug therapy: A multicenter retrospective cohort study of patients with cancer in Japan.

AIMS/INTRODUCTION: We investigated the association between coexisting diabetes at the time of cancer diagnosis, and the overall survival and incidence of second primary cancer in patients with cancer and receiving drug therapy for diabetes. MATERIALS AND METHODS: We used cancer registry and administrative data of patients diagnosed with cancer at designated cancer care hospitals in Osaka Prefecture between 2010 and 2015. The presence of diabetes was identified from the prescription records of antidiabetic drugs in Diagnosis Procedure Combination System data. After adjusting for patient characteristics, we compared overall survival between patients with cancer with coexisting diabetes and those without coexisting diabetes using the Cox proportional hazards model. In addition, the impact of coexisting diabetes on the risk of developing second primary cancer was evaluated using a competing risk analysis. RESULTS: Of the 131,701 patients with cancer included in the analysis, 6,135 (4.7%) had coexisting diabetes. The 5-year survival rates for patients with and without coexisting diabetes were 56.2% (95% confidence interval 54.8-57.6) and 72.7% (95% confidence interval 72.4-73.0), respectively. Coexisting diabetes was associated with a higher risk of developing second primary cancer (subdistribution hazard ratio 1.23; 95% confidence interval 1.08-1.41). In site-specific analysis, coexisting diabetes was associated with an increased risk for the development of second primary cancer of multiple myeloma, and cancer of the uterus, pancreas and liver. CONCLUSIONS: Coexisting diabetes was associated with a higher mortality and risk of developing second primary cancer in Japanese patients with cancer and on drug therapy for diabetes.

Do prognoses of patients with second primary cancers differ from those of patients with no prior cancer? A population-based study.

BACKGROUND: Some cancer survivors develop second primary cancers. However, differences in prognosis between patients who have and have not had prior cancer have not been established. We examined and compared the prognoses of such patients. METHODS: Using the record-linked database of the population-based Cancer Registry of Osaka Prefecture and Vital Statistics in Japan, we identified patients aged ≥ 40 years who were diagnosed with stomach (n = 70,946), colorectal (n = 60,582), or lung (n = 58,016) cancers during 1995-2009. We defined these cancers as index cancers. Patients were classified into three groups according to history of prior cancer and interval between diagnosis of index and prior cancer: single (no prior cancer or interval of ≥10 years), synchronous (interval ≤3 months), and metachronous (interval 3 months to 10 years). The 5-year prognosis from index cancer diagnosis was investigated using the Kaplan-Meier method and log-rank test. RESULTS: 5-year prognoses of patients with synchronous stomach and colorectal cancers were significantly worse than that of patients with single primary, about 60 % of these patients' deaths being attributable to the prior cancer. In contrast, 5-year prognoses of patients with metachronous primaries were not significantly worse, except for men with colorectal cancer. The percentages of index cancer deaths were 1.7-4.3 times those for non-index cancer deaths. CONCLUSION: A prior cancer contributed to an inferior prognosis in patients with synchronous stomach and colorectal cancers. The prognoses of patients with metachronous primaries were more affected by the index than by the prior cancer, whereas most of them had similar or better prognoses than did patients with a single primary. This finding would help to relieve cancer survivors' anxiety about their development and prognosis of metachronous second primary cancer.

Noninvasive Visualization of the Tear Film Microaerosol During Noncontact Tonometry Measurements.

PURPOSE: To investigate the aerosol generation by a noninvasive real-time observation device and assess the conditions relating to aerosolization during intraocular pressure (IOP) measurements using a commercial noncontact tonometer (NCT). STUDY DESIGN: Prospective experimental and healthy eye studies. METHODS: In an initial experimental study, we devised a model mannequin eye to investigate how air puff pressure and IOP of the eye affected aerosol generation. In the human study including 20 healthy volunteer control subjects, the number of tear aerosol particles generated at 20 and 40 mm Hg air puff pressures with and without eye drop was investigated. The recorded aerosol visualization video was analyzed and the number of aerosol particles generated in 5 seconds after IOP measurement was measured. RESULTS: The experimental and human studies confirmed the aerosol generation during NCT measurements. In the experimental study, when the air puff pressures were set at 20 and 40 mm Hg, a lower IOP (5 mm Hg) generated significantly more aerosols than a higher IOP (25 mm Hg) (20 mm Hg, P = .0159; 40 mm Hg, P = .0079). There was also a significant positive correlation between the air puff pressure and the number of aerosol particles in both high- and low-IOP eyes (P < .001). At an air puff pressure of 40 mm Hg, the amount of aerosol generated was significantly higher with eye drop than without eye drop (P = .047). CONCLUSIONS: NCT generates significant aerosolization from the tear film, the amount of which is determined by the IOP and the air puff pressure and the presence of eye drop use before the measurements.

Incidence and relative risk of metachronous second primary cancers for 16 cancer sites, Osaka, Japan, 2000-2015: Population-based analysis.

BACKGROUND: An increasing number of cancer survivors have developed multiple primaries. This study aims to describe the incidence and risk patterns of metachronous second primary cancers (SPCs) in Osaka, Japan. METHODS: Data were obtained from the Osaka Cancer Registry, a population-based database of all cancers diagnosed in Osaka. The study subjects were individuals who were first diagnosed with invasive cancers in 16 major cancer sites during 2000-2014, aged 15-79 years, survived at least 3 months, and were followed up for 10 years. We measured incidence rates, cumulative risks, and standardized incidence ratios (SIRs: with the Osaka general population as the referent) of developing SPCs during 3 months to 10 years after the first diagnosis. RESULTS: During 2000-2015, among 418,791 cancer survivors, 24,368 (5.8%) developed SPCs within 10 years of first diagnosis. Males had higher incidence rates than females except among young-onset survivors (aged 15-39 years). 10-year cumulative risks among survivors aged 70-79 years (the most dominant age group) were 24.0% (male) and 11.8% (female). 10-year SIRs were 1.38 (95% CI, 1.36-1.40; male) and 1.44 (95% CI, 1.41-1.48; female) with higher estimates among younger survivors in both sexes. Strong bidirectional associations were observed between oral/pharyngeal, esophageal, and laryngeal cancers. Survivors of any smoking-related cancers had elevated SIRs of developing smoking-related SPCs. Similar results were observed for alcohol-related cancers. CONCLUSIONS: Cancer survivors are at excess risk of developing SPCs compared to the general population. Continued surveillance is warranted to inform survivorship care through risk-based long-term care planning and lifestyle-changing efforts to prevent new cancers.

The Effects of High Molecular Weight Hyaluronic Acid Eye Drop Application in Environmental Dry Eye Stress Model Mice.

Hyaluronic acid (HA) ophthalmic solution is widely used in dry eye treatment worldwide. However, there are no reports comparing the dry eye treatment effects of high molecular weight HA with low molecular weight HA. Sixty eight-week-old C57BL/6 mice were assigned to the following 6 groups and exposed to environmental dry eye stress (EDES) that mimics office work environment: 1) 0.1% low molecular weight HA (LMWHA) eye drops, 2) 0.3% LMWHA eye drops, 3) 3% diquafosol sodium (DQ) eye drops, 4) 0.15% high molecular weight HA (HMWHA) eye drops, 5) no treatment with exposure to EDES (EDES+/Treatment-), and 6) no treatment without exposure to EDES (EDES-/Treatment-). After EDES, the HMWHA group had significantly longer break-up time (BUT) than the 0.1%, 0.3% LMWHA groups and the DQ group. After EDES, the HMWHA group had significantly lower lissamine green staining scores than the LMWHA and DQ groups. Subepithelial presumed dendritic cell density in the HMWHA group was significantly lower than the EDES+/Treatment- group. After EDES exposure, Conjunctival Muc5AC mRNA expression in the HMWHA group was significantly higher than the 0.1 and 0.3% LMWHA groups. Ophthalmic HMWHA solution may have a better dry eye treatment effect than LMWHA or DQ solution, owing to its anti-inflammatory effect.

Feasibility of Strip Meniscometry for Tear Volume Evaluation in Lacrimal Passage Obstruction.

Strip meniscometry tube (SMTube) is useful for assessing tear volume in dry eye disease. We performed an in vitro and a clinical study to examine whether the SMTube can also be used to evaluate tear quantity in lacrimal passage obstruction (LPO). In vitro experiments showed that the SMTube value and the amount of water absorption were significantly correlated (R2 = 0.816, p = 0.0008), but the measured value peaked when 4 µL was absorbed. In the clinical study, 12 eyes of 9 LPO patients and 17 eyes of 17 healthy control subjects were included. The patients' SMTube values were significantly higher than those of the control subjects (p < 0.05). The SMTube value significantly decreased after silicon tube intubation (p < 0.05). Tear meniscus height (TMH) and area (TMA), measured by anterior segment optical coherence tomography, exhibited a significant positive correlation with the SMTube value (TMH, p < 0.001, R2 = 0.396; TMA, p < 0.001, R2 = 0.366). Moreover, the SMTube value significantly correlated positively with the subjective symptom of epiphora (p = 0.012, R2 = 0.255). Thus, SMTube was useful for evaluating the tear volume and therapeutic effects in patients with LPO.

IL-1ß/ATF3-mediated induction of Ski2 expression enhances hepatitis B virus x mRNA degradation.

Hepatitis B virus (HBV) -x protein is a transcriptional regulator required for the HBV life cycle. HBx also induces complications in the host such as hepatocellular carcinoma. We previously showed that HBx mRNA is degraded by the Ski2/RNA exosome complex. In the present study, we report the regulation of this system through the control of Ski2 expression. We identified interleukin (IL) -1ß as an inducer of expression from the Ski2 promoter. IL-1ß induced the expression of ATF3 transcription factor, which in turn binds to cyclic AMP-responsive element sequence in the Ski2 promoter and is responsible for Ski2 promoter induction by IL-1ß. We previously reported that Ski2 expression increases HBx mRNA degradation; consistent with those data, we showed here that HBx mRNA is degraded in response to IL-1ß treatment. Interestingly, HBx also significantly induced Ski2 expression. To our knowledge, this is the first report to show activation of the Ski2/RNA exosome complex by both the host and HBV. Understanding the regulation of the Ski2/RNA exosome system is expected to facilitate prevention of HBx-mediated complications through targeting the posttranscriptional degradation of HBx mRNA; and will also help shedding a light on the role of RNA decay systems in inflammation.

Effects of liquid konjac on parameters related to obesity in diet-induced obese mice.

Konjac-mannan has been suggested to exert a protective effect against visceral obesity. However, there is little knowledge about the effects of liquid konjac (LK) that is partially alkali gelled. The purpose of the present work was to evaluate the potential beneficial effects of a LK powder on obesity in mice. Male C57BL/6J mice were fed a high-fat diet supplemented with either 2.5 or 5% LK powder for 80 days. Growth parameters, abdominal fat content, serum biochemical markers, and hepatic lipid accumulations were measured. Dietary supplementation with LK resulted in decreased body weight gain and abdominal fat accumulation. Dose-dependent decreases were observed in accumulation of hepatic lipids and serum total cholesterol, leptin, insulin concentrations. The study findings indicated that LK had preventing effect against obesity, including the reduction of abdominal and hepatic lipid accumulation and serum parameters related to obesity.