A Deep Learning-Based Assessment Pipeline for Intraepithelial and Stromal Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Carcinoma.

Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with epithelial ovarian cancer. However, TIL evaluation has not been used in routine clinical practice because of reproducibility issues. The current study developed two convolutional neural network models to detect TILs and to determine their spatial location in whole slide images, and established a spatial assessment pipeline to objectively quantify intraepithelial and stromal TILs in patients with high-grade serous ovarian carcinoma. The predictions of the established models showed a significant positive correlation with the number of CD8+ T cells and immune gene expressions. Patients with a higher density of intraepithelial TILs had a significantly prolonged overall survival and progression-free survival in multiple cohorts. On the basis of the density of intraepithelial and stromal TILs, patients were classified into three immunophenotypes: immune inflamed, excluded, and desert. The immune-desert subgroup showed the worst prognosis. Gene expression analysis showed that the immune-desert subgroup had lower immune cytolytic activity and T-cell-inflamed gene-expression profile scores, whereas the immune-excluded subgroup had higher expression of interferon-γ and programmed death 1 receptor signaling pathway. The established evaluation method provided detailed and comprehensive quantification of intraepithelial and stromal TILs throughout hematoxylin and eosin-stained slides. It has potential for clinical application for personalized treatment of patients with ovarian cancer.

Comparison of cost and complication rates for profiling hospital performance in lumbar fusion for spondylolisthesis.

BACKGROUND CONTEXT: There is growing interest among payers in profiling hospital value and quality-of-care, including both the cost and safety of common surgeries, such as lumbar fusion. Nonetheless, there is sparse evidence describing the statistical reliability of such measures when applied to lumbar fusion for spondylolisthesis. PURPOSE: To evaluate the reliability of 90-day inpatient hospital costs, overall complications, and rates of serious complications for profiling hospital performance in lumbar fusion surgery for spondylolisthesis. STUDY DESIGN/SETTING: Data for this analysis came from State Inpatient Databases from nine states made available through the Healthcare Cost and Utilization Project. PATIENT SAMPLE: Patients undergoing elective lumbar spine fusion for spondylolisthesis from 2010 to 2017 in participating states. OUTCOME MEASURES: Statistical reliability, defined as the ability to distinguish true performance differences across hospitals relative to statistical noise. Reliability was assessed separately for 90-day inpatient costs (standardized across years to 2019 dollars), overall complications, and serious complication rates. METHODS: Statistical reliability was measured as the amount of variation between hospitals relative to the total amount of variation for each measure. Total variation includes both between-hospital variation ("signal") and within-hospital variation ("statistical noise"). Thus, reliability equals signal over (signal plus noise) and ranges from 0 to 1. To adjust for differences in patient-level risk and procedural characteristics, hierarchical linear and logistic regression models were created for the cost and complication outcomes. Random hospital intercepts were used to assess between-hospital variation. We evaluated the reliability of each measure by study year and examined the number of hospitals meeting different thresholds of reliability by year. RESULTS: We included a total of 66,571 elective lumbar fusion surgeries for spondylolisthesis performed at 244 hospitals during the study period. The mean 90-day hospital cost was $30,827 (2019 dollars). 12.0% of patients experienced a complication within 90 days of surgery, including 7.8% who had a serious complication. The median reliability of 90-day cost ranged from 0.97to 0.99 across study years, and there was a narrow distribution of reliability values. By comparison, the median reliability for the overall complication metric ranged from 0.22 to 0.44, and the reliability of the serious complication measure ranged from 0.30 to 0.49 across the study years. At least 96% of hospitals had high (> 0.7) reliability for cost in any year, whereas only 0-9% and 0-11% of hospitals reached this cutoff for the overall and serious complication rate in any year, respectively. By comparison, 10%-69% of hospitals per year achieved a more moderate threshold of 0.4 reliability for overall complications, compared to 21%-80% of hospitals who achieved this lower reliability threshold for serious complications. CONCLUSIONS: 90-day inpatient costs are highly reliable for assessing variation across hospitals, whereas overall and serious complications are only moderately reliable for profiling performance. These results support the viability of emerging bundled payment programs that assume true differences in costs of care exist across hospitals.

Administrative Data Are Unreliable for Ranking Hospital Performance Based on Serious Complications After Spine Fusion.

STUDY DESIGN: Retrospective analysis of administrative billing data. OBJECTIVE: To evaluate the extent to which a metric of serious complications determined from administrative data can reliably profile hospital performance in spine fusion surgery. SUMMARY OF BACKGROUND DATA: While payers are increasingly focused on implementing pay-for-performance measures, quality metrics must reliably reflect true differences in performance among the hospitals profiled. METHODS: We used State Inpatient Databases from nine states to characterize serious complications after elective cervical and thoracolumbar fusion. Hierarchical logistic regression was used to risk-adjust differences in case mix, along with variability from low case volumes. The reliability of this risk-stratified complication rate (RSCR) was assessed as the variation between hospitals that was not due to chance alone, calculated separately by fusion type and year. Finally, we estimated the proportion of hospitals that had sufficient case volumes to obtain reliable (>0.7) complication estimates. RESULTS: From 2010 to 2017 we identified 154,078 cervical and 213,133 thoracolumbar fusion surgeries. 4.2% of cervical fusion patients had a serious complication, and the median RSCR increased from 4.2% in 2010 to 5.5% in 2017. The reliability of the RSCR for cervical fusion was poor and varied substantially by year (range 0.04-0.28). Overall, 7.7% of thoracolumbar fusion patients experienced a serious complication, and the RSCR varied from 6.8% to 8.0% during the study period. Although still modest, the RSCR reliability was higher for thoracolumbar fusion (range 0.16-0.43). Depending on the study year, 0% to 4.5% of hospitals had sufficient cervical fusion case volume to report reliable (>0.7) estimates, whereas 15% to 36% of hospitals reached this threshold for thoracolumbar fusion. CONCLUSION: A metric of serious complications was unreliable for benchmarking cervical fusion outcomes and only modestly reliable for thoracolumbar fusion. When assessed using administrative datasets, these measures appear inappropriate for high-stakes applications, such as public reporting or pay-for-performance.Level of Evidence: 3.

Unmet Need for Total Joint Arthroplasty in Medicaid Beneficiaries After Affordable Care Act Expansion.

BACKGROUND: The utilization of total hip arthroplasty (THA) and total knee arthroplasty (TKA) increased after Medicaid expansion under the U.S. Affordable Care Act (ACA), suggesting a potential unmet need for THA and TKA. We examined the timing of THA and TKA in patients after obtaining Medicaid expansion insurance coverage. We hypothesized that patients with Medicaid expansion insurance would undergo a surgical procedure sooner than patients in traditional Medicaid populations. METHODS: We used administrative data from a Medicaid managed care company to determine the timing of primary THA and TKA in patients who were 18 to 64 years of age in 4 states with Medicaid expansion (Illinois, Ohio, Oregon, and Washington) and 4 states without Medicaid expansion (Louisiana, Mississippi, Texas, and Wisconsin) from 2008 to 2015. The insurance types were Medicaid expansion, Medicaid plans for Supplemental Security Income (SSI), or Temporary Assistance for Needy Families (TANF). Roughly, these 3 groups correspond to relatively healthy childless adults, relatively unhealthy disabled adults, and parents of children with Medicaid insurance. The main outcome measure was time from enrollment to the surgical procedure. The primary exposure of interest was insurance type. We used a generalized linear regression model to adjust for patient age, sex, social deprivation, surgeon supply and reimbursement, and state-level Medicaid enrollment. RESULTS: In the unadjusted analysis of 4,117 patients, there was a significantly shorter time from enrollment to THA and TKA for the expansion group (median, 7.5 months) relative to the SSI group (median, 16.1 months; p < 0.0001) and the TANF group (median, 12.2 months; p < 0.0001). In the adjusted analysis, the time from enrollment to THA and TKA was significantly shorter in the expansion group (ß, -1.21 [95% confidence interval (CI), -1.35 to -1.07]; p < 0.001) compared with the TANF group (ß, -0.27 [95% CI, -0.38 to -0.17]; p < 0.001) and the SSI group (reference). Compared with the SSI group, these coefficients are equivalent to a 70% shorter time to the surgical procedure in the expansion group and a 24% shorter time to the surgical procedure in the TANF group. CONCLUSIONS: Our findings suggest an unmet need for THA and TKA among newly enrolled Medicaid expansion beneficiaries. This need should be considered by surgeons, hospitals, and policymakers in ensuring access to care. Furthermore, consideration should be given to existing insurance-based disparities in access to orthopaedic care, as these may be exacerbated by an increased demand for THA and TKA from Medicaid expansion beneficiaries.

Assessment of associations between clinical and immune microenvironmental factors and tumor mutation burden in resected nonsmall cell lung cancer by applying machine learning to whole-slide images.

BACKGROUND: It is unclear whether clinical factors and immune microenvironment (IME) factors are associated with tumor mutation burden (TMB) in patients with nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: We assessed TMB in surgical tumor specimens by performing whole exome sequencing. IME profiles, including PD-L1 tumor proportion score (TPS), stromal CD8 tumor-infiltrating lymphocyte (TIL) density, and stromal Foxp3 TIL density, were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, clinical data, and IME factors were assessed by means of a multiple regression model. RESULTS: We analyzed tumors from 200 of the 246 surgically resected NSCLC patients between September 2014 and September 2015. Patient background: median age (range) 70 years (39-87); male 37.5%; smoker 27.5%; pathological stage (p-stage) I/II/III, 63.5/22.5/14.0%; histological type Ad/Sq, 77.0/23.0%; primary tumor location upper/lower, 58.5/41.5%; median PET SUV 7.5 (0.86-29.8); median serum CEA (sCEA) level 3.4 ng/mL (0.5-144.3); median serum CYFRA 21-1 (sCYFRA) level 1.2 ng/mL (1.0-38.0); median TMB 2.19/ Mb (0.12-64.38); median PD-L1 TPS 15.1% (0.09-77.4); median stromal CD8 TIL density 582.1/mm2 (120.0-4967.6);, and median stromal Foxp3 TIL density 183.7/mm2 (6.3-544.0). The multiple regression analysis identified three factors associated with higher TMB: smoking status: smoker, increase PET SUV, and sCEA level: >5 ng/mL (P < .001, P < .001, and P = .006, respectively). CONCLUSIONS: The IME factors assessed were not associated with TMB, but our findings showed that, in addition to smoking, PET SUV and sCEA levels may be independent predictors of TMB. TMB and IME factors are independent factors in resected NSCLC.

Association between socioeconomic status and small-for-gestational-age in Japan: A single center retrospective cohort study.

AIM: Small-for-gestational-age (SGA) status has negative health consequences in neonates and later life. Low socioeconomic status (SES) is a reported risk factor for adverse birth outcomes, such as SGA and preterm birth (PTB). The present study investigated whether maternal SES is associated with adverse outcomes in Japanese pregnant women. METHODS: Retrospective data were collected for 1970 Japanese women with singleton pregnancies who delivered between January 2007 and December 2011 at a single center: low SES group (n = 197); and controls (n = 1773). Low SES was defined according to the criteria of the Japanese pregnant-childbirth hospitalization support policy system. RESULTS: The low SES group included a significantly higher proportion of young women, women with single marital status, greater parity, pre-pregnancy smoking and a lack of regular employment (P < 0.001, respectively). The crude odds ratio (OR) for the association between low maternal SES and SGA was 1.80 (95% confidence interval [CI] 1.15-2.82, P = 0.010). After adjustment for baseline maternal age, parity, body mass index, smoking and gestational weight gain, the adjusted OR for the association between low maternal SES and SGA was 1.92 (95% CI 1.17-3.17, P = 0.010). No significant association was found between maternal SES and PTB. CONCLUSION: The present results suggest that low maternal SES is associated with SGA births in the Japanese population. Mitigation of low maternal SES could be urgent public health to prevent disadvantage birth outcome.

Seeking Consensus on the Terminology of Value-Based Transformation Through use of a Delphi Process.

Collaboration among diverse stakeholders involved in the value transformation of health care requires consistent use of terminology. The objective of this study was to reach consensus definitions for the terms value-based care, value-based payment, and population health. A modified Delphi process was conducted from February 2017 to July 2017. An in-person panel meeting was followed by 3 rounds of surveys. Panelists anonymously rated individual components of definitions and full definitions on a 9-point Likert scale. Definitions were modified in an iterative process based on results of each survey round. Participants were a panel of 18 national leaders representing population health, health care delivery, academic medicine, payers, patient advocacy, and health care foundations. Main measures were survey ratings of definition components and definitions. At the conclusion of round 3, consensus was reached on the following definition for value-based payment, with 13 of 18 panelists (72.2%) assigning a high rating (7- 9) and 1 of 18 (5.6%) assigning a low rating (1-3): "Value-based payment aligns reimbursement with achievement of value-based care (health outcomes/cost) in a defined population with providers held accountable for achieving financial goals and health outcomes. Value-based payment encourages optimal care delivery, including coordination across healthcare disciplines and between the health care system and community resources, to improve health outcomes, for both individuals and populations." The iterative process elucidated specific areas of agreement and disagreement for value-based care and population health but did not reach consensus. Policy makers cannot assume uniform interpretation of other concepts underlying health care reform efforts.

Comprehensive assessment of the expression of the SWI/SNF complex defines two distinct prognostic subtypes of ovarian clear cell carcinoma.

Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (p<0.05). Although BAF250a expression is not related to poor prognosis, the group presenting the loss of at least one SWI/SNF complex subunit exhibited significantly shorter overall and progression-free survivals (p<0.05). A multivariate analysis suggested that the expression status of the SWI/SNF complex serves as an independent prognostic factor (p<0.005). The cases positive for all SWI/SNF subunits demonstrated significantly greater DNA copy number alterations, such as amplification at chromosomes 8q.24.3 and 20q.13.2-20q.13.33 (including ZNF217) and deletion at chromosomes 13q12.11-13q14.3 (including RB1), 17p13.2-17p13.1 (including TP53) and 19p13.2-19p13.12. In conclusion, the CCCs exhibiting the loss of one or multiple SWI/SNF complex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis.

Reliability of patient self-assessment of shoulder range of motion and strength after shoulder arthroplasty.

BACKGROUND: Patient-derived self-assessment potentially minimizes loss of valuable outcomes data, conserves medical resources, and benefits patients by saving valuable time out of work and travel expenses. The purpose of this study was to determine the physician-patient correlation of a patient-derived outcomes questionnaire that assesses range of motion (ROM) and strength after shoulder arthroplasty. METHODS: One hundred twenty consecutive patients completed a home-based questionnaire before their 1-year postoperative visit after shoulder arthroplasty. The questionnaire contained demographic information such as age, gender, type of surgery, education level, and income. Diagram-based questions, in which patients were asked to identify the image representing their own active shoulder ROM in various planes, were included. Patients were asked to perform a strength examination using premeasured zip-lock bags filled with water that correspond to predetermined weights up to 2.72 kg. The κ statistics were used to assess the degree of agreement between the patient's self-assessment and the clinician's measures. RESULTS: The κ statistics indicated moderate clinician-patient agreement (0.5-0.59) on items related to ROM and substantial to almost perfect agreement (0.62-0.92) on items related to strength (forward flexion and abduction). A majority of patients (>88%) correctly estimated their ROM within 1 grade of the clinician's measurement. Patients tended to err toward overestimating their ROM. CONCLUSIONS: This patient-derived questionnaire provides a moderate to high level of agreement with clinician assessment. This assessment questionnaire may be an important tool in facilitating both clinical and research follow-up of patient outcomes after shoulder arthroplasty.

Overview of cancer control programs in Japan.

Japan has a population of about 127 million, with an average life expectancy that is one of the highest in the world. Cancer has been the leading cause of death in Japan since 1981. The incidence of cancer for all sites in 1994 was estimated to be 440 000; crude incidence rates per 100 000 for males and females were 416.3 and 299.4, respectively. In 1997, the number of cancer deaths was 275 413; crude death rates for males and females per 100 000 were 273.0 and 169.9, respectively. Projections for 2015 indicate that 890 000 people will develop cancer and 450 000 will die as a result. It is not too much to say that Japan is now amid a 'Cancer Era'. Meanwhile, the progress in medical sciences is improving survival in cancer patients; in cancer patients diagnosed during 1987-89, relative 5-year survival was reported to be 41.2% for all sites and cancer survivorship research estimated the number of cancer survivors for all sites in 1998 who have lived for between 5 and 24 years after diagnosis to be 1.5 million. The Ministry of Health and Welfare is focusing on five different measures in the implementation of its cancer control programs: public health education, nationwide cancer screening programs, development and support of specialized medical institutions, training of specialists and promotion of basic and clinical cancer research. As a tool for public health education, the Ministry published in 2000 a 10-year health promotion program entitled 'Healthy Japanese in the 21st Century'. In the plan, seven particular goals are enumerated with regard to cancer. In practice, issues of concern include the development of new modalities, telling the truth to cancer patients, clinical trials and bioethical issues.