Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Frequentist analysis of basket trials with one-sample Mantel-Haenszel procedures.

Recent substantial advances of molecular targeted oncology drug development is requiring new paradigms for early-phase clinical trial methodologies to enable us to evaluate efficacy of several subtypes simultaneously and efficiently. The concept of the basket trial is getting of much attention to realize this requirement borrowing information across subtypes, which are called baskets. Bayesian approach is a natural approach to this end and indeed the majority of the existing proposals relies on it. On the other hand, it required complicated modeling and may not necessarily control the type 1 error probabilities at the nominal level. In this article, we develop a purely frequentist approach for basket trials based on one-sample Mantel-Haenszel procedure relying on a very simple idea for borrowing information under the common treatment effect assumption over baskets. We show that the proposed Mantel-Haenszel estimator for the treatment effect is consistent under two limiting models of the large strata and sparse data limiting models (dually consistent) and propose dually consistent variance estimators. The proposed estimators are interpretable even if the common treatment effect assumptions are violated. Then, we can design basket trials in a confirmatory matter. We also propose an information criterion approach to identify effective subclasses of baskets.

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.

Contralateral lower limb radiculopathy by extraforaminal disc herniation following oblique lumbar interbody fusion in degenerative lumbar disorder: illustrative cases.

BACKGROUND: Contralateral lower limb radiculopathy is a potential early complication of oblique lumbar interbody fusion (OLIF) in degenerative lumbar disorders. Among several pathologies related to contralateral radiculopathy following OLIF, extraforaminal disc herniation during the OLIF procedure is very rare. OBSERVATIONS: Case 1 is a 68-year-old male underwent L4-5 and L5-6 OLIF for recurrent lumbar canal stenosis-expressed right leg pain and muscle weakness after surgery. Case 2 is a 76-year-old female on whom L4-5 OLIF was performed for L4 degenerative spondylolisthesis and who presented right leg pain and numbness postoperatively. In both patients, OLIF cages were inserted into the posterior part of the disc space or obliquely and the extraforaminal extruded disc compressed opposite exiting nerve roots (L5 root in case 1 and L4 root in case 2) as shown on magnetic resonance imaging (MRI). Surgical decompression with discectomy was required for pain relief and neurological improvement in both cases. LESSONS: When emerging from new-onset opposite limb radiculopathy attributed to the OLIF procedure, extraforaminal disc herniation should be considered a potential pathology and MRI is useful for early diagnosis and selecting a subsequent management, including surgery.

Major Causes of Death among Older Adults after the Great East Japan Earthquake: A Retrospective Study.

This retrospective study investigated the 3-year impact of the Great East Japan Earthquake (GEJE) of 2011 on deaths due to neoplasm, heart disease, stroke, pneumonia, and senility among older adults in the primarily affected prefectures compared with other prefectures, previous investigations having been more limited as regards mortality causes and geographic areas. Using death certificates issued between 2006 and 2015 (n = 7,383,253), mortality rates (MRs) and risk ratios (RRs) were calculated using a linear mixed model with the log-transformed MR as the response variable. The model included interactions between the area category and each year of death from 2010 to 2013. The RRs in the interaction significantly increased to 1.13, 1.17, and 1.28 for deaths due to stroke, pneumonia, and senility, respectively, in Miyagi Prefecture in 2011, but did not significantly increase for any of the other areas affected by the GEJE. Moreover, increased RRs were not reported for any of the other years. The risk of death increased in 2011; however, this was only significant for single-year impact. In 2013, decreased RRs of pneumonia in the Miyagi and Iwate prefectures and of senility in Fukushima Prefecture were observed. Overall, we did not find evidence of strong associations between the GEJE and mortality.

Impact of S-1 adjuvant chemotherapy longer than 6 months on survival in patients with resected pancreatic cancer: a nationwide survey by the Japan Pancreas Society based on real-world data.

BACKGROUND: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC. METHODS: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days. RESULTS: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis. CONCLUSIONS: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment.

The usefulness of the total metabolic tumor volume for predicting the postoperative recurrence of thoracic esophageal squamous cell carcinoma.

BACKGROUND: Induction or adjuvant therapies are not always beneficial for thoracic esophageal squamous cell carcinoma (ESCC) patients, and it is thus important to identify patients at high risk for postoperative ESCC recurrence. We investigated the usefulness of the total metabolic tumor volume (TMTV) for predicting the postoperative recurrence of thoracic ESCC. METHODS: We retrospectively analyzed the cases of 163 thoracic ESCC patients (135 men, 28 women; median age of 66 [range 34-82] years) treated at our hospital in 2007-2012. The TMTV was calculated from the fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the primary lesion and lymph node metastases. The optimal cut-off values for relapse and non-relapse were obtained by the time-dependent receiver operating curve analyses. Relapse-free survival (RFS) was evaluated by the Kaplan-Meier method, and between-subgroup differences in survival were analyzed by log-rank test. The prognostic significance of metabolic parameters and clinicopathological variables was assessed by a Cox proportional hazard regression analysis. The difference in the failure patterns after surgical resection was evaluated using the χ2-test. RESULTS: The optimal cut-off value of TMTV for discriminating relapse from non-relapse was 3.82. The patients with a TMTV ≥3.82 showed significantly worse prognoses than those with low values (p < 0.001). The TMTV was significantly related to RFS (model 1 for preoperative risk factors: TMTV: hazard ratio [HR] =2.574, p = 0.004; model 2 for preoperative and postoperative risk factors: HR = 1.989, p = 0.044). The combination of the TMTV and cN0-1 or pN0-1 stage significantly stratified the patients into low-and high-risk recurrence groups (TMTV cN0-1, p < 0.001; TMTV pN0-1, p = 0.004). The rates of hematogenous and regional lymph node metastasis were significantly higher in the patients with TMTV ≥3.82 than those with low values (hematogenous metastasis, p < 0.001, regional lymph node metastasis, p = 0.011). CONCLUSIONS: The TMTV was a more significantly independent prognostic factor for RFS than any other PET parameter in patients with resectable thoracic ESCC. The TMTV may be useful for the identifying thoracic ESCC patients at high risk for postoperative recurrence and for deciding the patient management.

Association between respiratory and heart rate fluctuations and death occurrence in dying cancer patients: continuous measurement with a non-wearable monitor.

BACKGROUND: The present study aimed to explore the association between impending death and continual changes in respiratory and heart rates measured using a non-wearable monitor every minute for the final 2 weeks of life in dying cancer patients. METHODS: In this longitudinal study, we enrolled patients in a palliative care unit and continuously measured their respiratory and heart rates via a monitor and additionally captured their other vital signs and clinical status from medical records. RESULT: A dataset was created comprising every 24-h data collected from every-minute raw data, including information from 240 days prior to death from 24 patients (345,600 data); each patient's data were measured for 3-14 days until death. After confirming the associations between the respiratory and heat rate values on the day of death (n = 24) or other days (2-14 days before death, n = 216) and the mean, maximum, minimum, and variance of respiratory and heart rates every 24 h by univariate analyses, we conducted a repeated-measures logistic regression analysis using a generalized estimating equation. Finally, the maximum respiratory rate and mean heart rate were significantly associated with death occurring within the following 3 days (0-24 h, 0-48 h, and 0-72 h), except for the maximum respiratory rate that occurs within 0-24 h. CONCLUSION: The maximum respiratory rate and mean heart rate measured every minute using a monitor can warn family caregivers and care staff, with the support of palliative care professionals, of imminent death among dying patients at home or other facilities.

Summary concordance index for meta-analysis of prognosis studies with a survival outcome.

In prognosis studies to evaluate association between a continuous biomarker and a survival outcome, investigators often classify subjects into two subclasses of the high- and low-expression groups and apply simple survival analysis techniques of the Kaplan-Meier method and the logrank test. The high- and low-expressions are defined according to whether or not the observation of the biomarker is higher than the cut-off value, which is heterogeneous across studies. The heterogeneous definitions of the cut-off value make it difficult to apply the standard meta-analysis techniques. We propose a method to estimate the concordance index for a survival outcome synthesizing published prognosis studies, in which the Kaplan-Meier estimates for the high- and low-expression groups are reported. We illustrate our proposed method with a real dataset for meta-analysis of prognosis studies evaluating Ki-67 in early breast cancer and evaluate its performance with a simulation study.

Predicting tumor response and prognosis to neoadjuvant chemotherapy in esophageal squamous cell carcinoma patients using PERCIST: a multicenter study in Japan.

PURPOSE: To investigate the usefulness of the positron emission tomography response criteria in solid tumors 1.0 (PERCIST1.0) for predicting tumor response to neoadjuvant chemotherapy and prognosis and determine whether PERCIST improvements are necessary for esophageal squamous cell carcinoma (ESCC) patients. PATIENTS AND METHODS: We analyzed the cases of 177 ESCC patients and examined the association between PERCIST and their pathological responses. Associations of whole-PERCIST with progression-free survival (PFS) and overall survival (OS) were evaluated by a Kaplan-Meier analysis and Cox proportional hazards model. To investigate potential PERCIST improvements, we used the survival tree technique to understand patients' prognoses. RESULTS: There were significant correlations between the pathologic response and PERCIST of primary tumor (p < 0.001). The optimal cutoff value of the primary tumors' SULpeak response to classify pathologic responses was -50.0%. The diagnostic accuracy of SULpeak response was 87.3% sensitivity, 54.1% specificity, 68.9% accuracy, positive predictive value 60.5%, and negative predictive value 84.1%. Whole-PERCIST was significantly associated with PFS and OS. The survival tree results indicated that a high reduction of the whole SULpeak response was significantly correlated with the patients' prognoses. The cutoff values for the separation of prognoses were - 52.5 for PFS and - 47.1% for OS. CONCLUSION: PERCIST1.0 can help predict tumor responses and prognoses. However, 18F-FDG-PET/CT tends to underestimate residual tumors in histopathological response evaluations. Modified PERCIST, in which the partial metabolic response is further classified by the SULpeak response (-50%), might be more appropriate than PERCIST1.0 for evaluating tumor responses and stratifying high-risk patients for recurrence and poor prognosis.

High neutrophil/lymphocyte ratio at cancer diagnosis predicts incidence of stroke in cancer patients.

Although cancer increases the incidence and severity of ischaemic stroke, there is no reliable method for predicting ischaemic stroke in cancer patients. To evaluate the prognostic capacity of the neutrophil-to-lymphocyte ratio at cancer diagnosis for predicting the incidence of ischaemic stroke, we used a hospital-based cancer registry that contained clinical data from all patients treated for cancer at Osaka University Hospital between 2007 and 2015. The neutrophil-to-lymphocyte ratio was calculated after dividing absolute neutrophil counts by absolute lymphocyte counts. These counts were obtained within 1 month after cancer diagnosis. The primary endpoint was new-onset ischaemic stroke within 2 years after cancer diagnosis. Of the 18 217 included cancer patients (median age: 65.2 years), 69 (0.38%) had ischaemic stroke. Unadjusted Cox regression analysis stratified by cancer site demonstrated that each 1-unit increase in the neutrophil-to-lymphocyte ratio was associated with a significant 7.2% increase in the risk of an ischaemic stroke event (95% confidence interval 1.041-1.103, P < 0.001). Survival tree analysis and the Kaplan-Meier method suggested that patients with and without atrial fibrillation who had increased neutrophil-to-lymphocyte ratios had a higher risk of ischaemic stroke. Multivariate Cox proportional hazard models, adjusted for cancer site and stage, revealed that patients with high neutrophil-to-lymphocyte ratios (>15) had higher ischaemic stroke risk than patients with low neutrophil-to-lymphocyte ratios (<5). This was true among cancer patients both with (hazard ratio 11.598; 95% confidence interval 0.953-141.181) and without (hazard ratio 7.877; 95% confidence interval 2.351-26.389) atrial fibrillation. The neutrophil-to-lymphocyte ratio at cancer diagnosis is associated with the incidence of ischaemic stroke among cancer patients and might thus be useful for identifying patients at high risk of ischaemic stroke, allowing us to guide future preventive interventions.

The Effect of a Cancer History on Patients with Acute Myocardial Infarction After Percutaneous Coronary Intervention.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P < 0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.

An immature inhibin-α-expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis.

Inhibin-α, a member of transforming growth factor-ß, is elevated in multiple tumors, but its specific roles are poorly understood. Here, we examined the feature of inhibin-α-expressing cells in ovarian tumors. Immunohistochemically, inhibin-α-expressing tumor cells were detected only in ovarian clear cell carcinoma (OCCC) among various types of ovarian tumors. By comparing the expression of inhibin-α and Ki-67, inhibin-α-expressing tumor cells were revealed to be less proliferative. When spheroids and chemoresistant cells were derived from OCCC cell lines, the expression level of inhibin-α was elevated, and that of an immature marker, aldehyde dehydrogenase, was also elevated. In consistent with this, inhibin-α expression was correlated with other immature markers, such as OCT3/4 and SOX2, and inversely correlated with proliferative marker MKI67 in public database on OCCC. Knockdown of inhibin-α in OCCC cell decreased chemoresistance. Moreover, prognostic analysis with 69 surgically resected OCCC cases revealed that the increased inhibin-α expression was an independent unfavorable prognostic factor. These findings suggested that inhibin-α-expressing subpopulation of OCCC tumor cells appeared to be less proliferative, immature, and angiogenic and to be related to acceleration of malignant progression.

The Effect of Chemotherapy on Stroke Risk in Cancer Patients.

BACKGROUND: Chemotherapy may be a cause of cancer-associated stroke, but whether it increases stroke risk remains uncertain. We investigated how chemotherapy affects stroke risk in cancer patients. METHODS: Of 27,932 patients in a hospital-based cancer registry (which contains clinical data on all patients treated for cancer at Osaka University Hospital) screened between 2007 and 2015, medical records of 19,006 patients with complete data were investigated. A validated algorithm was used to identify stroke events within 2 years of cancer diagnosis. Patients were divided based on whether their initial treatment plan included chemotherapy. The association between chemotherapy and stroke was analyzed using the Kaplan-Meier method and stratified Cox regression. RESULTS: Of 19,006 patients, 5,887 (31%) were in the chemotherapy group. Stroke occurred in 44 (0.75%) and 51 (0.39%) patients in the chemotherapy and nonchemotherapy group, respectively. Kaplan-Meier curve analysis showed that patients in the chemotherapy group had a higher stroke risk than those in the nonchemotherapy group (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.23-2.75). However, this difference was insignificant after adjustment for cancer status using inverse probability of treatment weighting with propensity scores (HR 1.20; 95% CI 0.76-1.91). Similarly, in the stratified Cox regression model, chemotherapy was not associated with stroke after adjustment for cancer status (HR 1.26; 95% CI 0.78-2.03). CONCLUSION: In our study, the elevated stroke risk in cancer patients who received chemotherapy was presumably due to advanced cancer stage; chemotherapy was not associated with the increased risk of stroke.

Doubly robust inference procedure for relative survival ratio in population-based cancer registry data.

Cancer registry system has been playing important roles in research and policy making in cancer control. In general, information on cause of death is not available in cancer registry data. To make inference on survival of cancer patients in the absence of cause of death information, the relative survival ratio is widely used in the population-based cancer research utilizing external life tables for the general population. Another difficulty arising in analyzing cancer registry data is informative censoring. In this article, we propose a doubly robust inference procedure for the relative survival ratio under a certain type of informative censoring, called the covariate-dependent censoring. The proposed estimator is doubly robust in the sense that it is consistent if at least one of the regression models for the time-to-death and for the censoring time is correctly specified. Furthermore, we introduced a doubly robust test assessing underlying conditional independence assumption between the time-to-death and the censoring time. This test is model based, but is doubly robust in the sense that at least one of the models for the time to event and for the censoring time is correctly specified, it maintains its nominal significance level. This notable feature entails us to make inference on cancer registry data relying on assumptions, which are much weaker than the existing methods and are verifiable empirically. We examine the theoretical and empirical properties of our proposed methods by asymptotic theory and simulation studies. We illustrate the proposed method with cancer registry data in Osaka, Japan.

The effect of dehydroepiandrosterone administration on intestinal calcium absorption in ovariectomized female rats.

PURPOSE: Dehydroepiandrosterone (DHEA) administration reportedly recovers osteoporosis, a bone disorder associated with bone deficiency in postmenopausal women. However, the physiological mechanism of DHEA in osteoporosis remains elusive, especially in terms of intestinal calcium absorption. Therefore, we investigated the effect of DHEA administration on calcium absorption in ovariectomized (OVX) female rats using an estrogen receptor antagonist. METHODS: Female Sprague-Dawley rats (n=23, 6 weeks old) were randomized into three groups: OVX control group (OC, n=7), OVX with DHEA treatment group (OD, n=8), and OVX with DHEA inhibitor group (ODI, n=8) for 8 weeks. RESULTS: Intestinal calcium accumulation, as well as the rate of absorption, demonstrated no significant differences during the experimental period among investigated groups. The bone mineral density (BMD) of the tibia at the proximal metaphysis was higher in the OD group than that in the OC group (p<0.05); however, BMD of the ODI group showed no significant difference from investigated groups. Furthermore, the BMD of the tibia at the diaphysis did not significantly differ among these groups. CONCLUSION: We revealed that DHEA administration does not involve intestinal Ca absorption, although this treatment improves BMD levels in OVX rats. These observations indicate that the effect of DHEA on the bone in postmenopausal women is solely due to its influence on bone metabolism and not intestinal calcium absorption.