Flexible Parametric Models Research Articles

Sleep Duration, Sleep Quality, and the Development of Nonalcoholic Fatty Liver Disease: A Cohort Study.

INTRODUCTION:The longitudinal relationship between sleep duration, sleep quality, and the risk of nonalcoholic fatty liver disease (NAFLD) is unknown. We aimed to examine the association between sleep duration, sleep quality, and NAFLD development.METHODS:Using the Pittsburgh Sleep Quality Index, sleep duration and quality were evaluated for 143,306 NAFLD-free Korean adults with a mean age of 36.6 years, who were followed for an average of 4.0 years. Hepatic steatosis (HS) was assessed using ultrasonography and liver fibrosis by the fibrosis-4 index (FIB-4) or the NAFLD fibrosis score. Flexible parametric proportional hazard models were used to determine the hazard ratios (HRs) and 95% confidence intervals.RESULTS:There were 27,817 subjects with incident HS, of whom 1,471 had incident HS plus intermediate/high FIB-4. Multivariable-adjusted HRs (95% confidence intervals) for incident HS comparing sleep durations of ≤5, 6, 8, and ≥ 9 hours with 7 hours were 1.19 (1.14–1.23), 1.07 (1.04–1.10), 0.98 (0.94–1.02), and 0.95 (0.87–1.03), respectively. The corresponding HRs for incident HS plus intermediate/high FIB-4 were 1.30 (1.11–1.54), 1.14 (1.01–1.29), 1.11 (0.93–1.33), and 1.08 (0.71–1.63). The association between sleep duration and HS plus intermediate/high FIB-4 was inverse in individuals with good sleep quality but tended to be U-shaped in those with poor sleep quality. The results were similar if FIB-4 was replaced by the NAFLD fibrosis score.DISCUSSION:In young adults, short sleep duration was independently associated with an increased risk of incident NAFLD with or without intermediate/high fibrosis score, suggesting a role for inadequate sleep quantity in NAFLD risk and severity.

Sex and survival following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a Scandinavian observational cohort study.

Studies have suggested sex-related survival differences in chronic thromboembolic pulmonary hypertension (CTEPH). Whether long-term prognosis differs between men and women following pulmonary endarterectomy for CTEPH remains unclear. We investigated sex-specific survival after pulmonary endarterectomy for CTEPH. We included all patients who underwent pulmonary endarterectomy for CTEPH at two Scandinavian centers and obtained baseline characteristics and vital statuses from patient charts and national health-data registers. Propensity scores and weighting were used to account for baseline differences. Flexible parametric survival models were employed to estimate the association between sex and all-cause mortality and the absolute survival differences. The expected survival in an age-, sex-, and year of surgery matched general population was obtained from the Human Mortality Database, and the relative survival was used to estimate cause-specific mortality. A total of 444 patients were included, comprising 260 (59%) men and 184 (41%) women. Unadjusted 30-day mortality was 4.2% in men versus 9.8% in women (p = 0.020). In weighted analyses, long-term survival did not differ significantly in women compared with men (hazard ratio: 1.36; 95% confidence interval: 0.89–2.06). Relative survival at 15 years conditional on 30-day survival was 94% (79%–107%) in men versus 75% (59%–88%) in women. In patients who underwent pulmonary endarterectomy for CTEPH, early mortality was higher in women compared with men. After adjustment for differences in baseline characteristics, female sex was not associated with long-term survival. However, relative survival analyses suggested that the observed survival in men was close to the expected survival in the matched general population, whereas survival in women deviated notably from the matched general population.

The role of multimorbidity in short-term mortality of lung cancer patients in Spain: a population-based cohort study

AimChronic diseases often occur simultaneously and tend to be associated with adverse health outcomes, but limited research has been undertaken to understand their role in lung cancer mortality. Therefore, this study aims to describe the prevalence and patterns of having one (comorbidity) or ≥ 2 chronic diseases (multimorbidity) among lung cancer patients in Spain, and to examine the association between comorbidity or multimorbidity and short-term mortality risk at six months after cancer diagnosis.MethodsIn this population-based cohort study, data were drawn from two Spanish population-based cancer registries, Girona and Granada, and electronic health records. We identified 1259 adult lung cancer patients, diagnosed from 1st January 2011 to 31st December 2012. We identified the most common patterns of individual comorbidities and their pairwise correlations. We used a flexible parametric modelling approach to assess the overall short-term mortality risk 6 months after cancer diagnosis by levels of comorbidity after adjusting for age, sex, smoking status, province of residence, surgery, cancer stage, histology, and body mass index.ResultsWe found high prevalence of comorbidity in lung cancer patients, especially among the elderly, men, those diagnosed with advanced-stage tumours, smokers, and obese patients. The most frequent comorbidities were chronic obstructive pulmonary disease (36.6%), diabetes (20.7%) and heart failure (16.8%). The strongest pairwise correlation was the combination of heart failure with renal disease (r = 0.20, p < 0.01), and heart failure with diabetes (r = 0.16, p < 0.01). Patients with either one or two or more comorbidities had 40% higher overall mortality risk than those without comorbidities (aHR for comorbidity: 1.4, 95%CI: 1.1–1.7; aHR for multimorbidity: 1.4, 95%CI: 1.1–1.8), when relevant confounding factors were considered.ConclusionsThe presence of comorbid diseases, rather than the number of comorbidities, was associated with increasing the risk of short-term lung cancer mortality in Spain. Comorbidity was a consistent and independent predictor of mortality among lung cancer patients, six months after diagnosis. The most common comorbid conditions were age-, obesity- and tobacco-related diseases. Our findings highlight the need to develop targeted preventive interventions and more personalised clinical guidelines to address the needs of lung cancer patients with one or more comorbidities in Spain.

658 BETTER SURVIVAL IN FEMALES THAN MALES AFTER RESECTION OF OESOPHAGEAL OR GASTROESOPHAGEAL JUNCTION CANCER: A COHORT STUDY IN SWEDEN

Abstract Accumulating evidence points to a better survival in female patients after a curative oesophageal cancer surgery. However, there is a need for more well-designed and sufficiently powered studies for limitations in previous studies. Better understanding of sex differences in the postoperative survival may be helpful for a sex-specific treatment. Methods This is a population-based cohort study including all patients in Sweden with oesophageal cancer that underwent a curative surgical treatment between 2006 and 2017. Sex difference in postoperative survival was explored with excess mortality rate ratio (EMRR) and absolute difference of excess mortality rate along the whole follow-up time, using flexible parametric model. Age at the time of surgery, Charlson comorbidity index, ASA score, tumor stage, post-operative complications, marital status, education level and hospital volume were considered as covariates in the analysis model. Stratification analysis by clinical stages, perioperative neoadjuvant treatment and post-operative complications was also performed. Results In all, there were 1301 patients resected for oesophageal adenocarcinoma and 305 patients for oesophageal squamous cell carcinoma. For both oesophageal adenocarcinoma and oesophageal squamous cell carcinoma, female patients had a lower excess mortality rate than males (adjusted EMRR: 0.77, 95% CI: 0.58–1.01, P = 0.059; 0.53, 95% CI: 0.33–0.85, P = 0.009, respectively). This sex difference was particularly strong shortly after surgery then gradually decreased over the ensuing years (Figure) and was more profound in the early clinical stages, and in patients receiving neoadjuvant treatment and without post-operative complications. Conclusion Female patients seem to have a better survival shortly after esophagectomy for patients with oesophageal adenocarcinoma and oesophageal squamous cell carcinoma, and the sex difference thereafter weakened. Our results may imply a different response to oesophageal cancer surgery between the sexes, and associated pre- and post-operative treatment, thus a sex-specific strategy may be considered in further work.

523 STAGING PET-CT LENGTH AND SURVIVAL IN PATIENTS UNDERGOING RESECTIONS FOR ESOPHAGEAL ADENOCARCINOMA

Abstract Esophagectomy is associated with considerable morbidity and mortality and a significant reduction in quality of life. Early identification of patients at high-risk of early recurrence and death would allow a more informed discussion about the benefits of surgery. Previous studies have shown that histological tumour length may be an independent predictor of survival. In this study we have determined whether tumour length at diagnosis can predict survival after esophagectomy. Methods From a single-centre prospective clinical database (2012 to 2018), we obtained data on tumour characteristics and 18F-FDG PET-CT (PET-CT) measurement of tumour length. The primary endpoint was overall survival (OS).We performed multivariate modelling using semi-parametric Cox models, and additionally explored flexible parametric modelling using fractional polynomials to explore non-linear relationships. Relationships between tumour length and known prognosticators were assessed using standard statistical techniques. Results We included 300 patients with esophageal adenocarcinoma and pre-operative PET-CT imaging. Tumour length was measurable on PET-CT in 91% of patients (274) (median 4.7 cm, range 1.3–12). 77% of patients received neo-adjuvant therapy. One and five-year overall survival rates were 79% and 44%, respectively. There was no relationship between survival and tumour length. One year survival for patients with tumours greater than 8 cm was 67% compared with 82% for tumours less than 8 cm although this was not statistically significant (p = 0.86). Tumour length was associated with tumour stage but not resection margin positivity or number of positive lymph nodes. Conclusion Tumour length as measured by PET-CT at diagnosis does not predict survival in patients undergoing esophagectomy for esophageal adenocarcinoma. This data supports the notion that tumour length by itself should not be used as a means of stratifying treatment.

Fatty liver disease and changes in dense breasts in pre- and postmenopausal women: the Kangbuk Samsung Health Study.

While increased breast density is a risk factor for breast cancer, the effect of fatty liver disease on breast density is unknown. We investigated whether fatty liver is a risk factor for changes in breast density over ~ 4years of follow-up in pre- and postmenopausal women. This study included 74,781 middle-aged Korean women with mammographically determined dense breasts at baseline. Changes in dense breasts were identified by more screening mammograms during follow-up. Hepatic steatosis (HS) was measured using ultrasonography. Flexible parametric proportional hazards models were used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), and a Weibull accelerated failure time model (AFT) was used to determine the time ratios (TRs) and 95% CIs. During a median follow-up of 4.1years, 4022 women experienced resolution of the dense breasts. The association between HS and dense breast resolution differed by the menopause status (P for interaction < 0.001). After adjusting for body mass index and other covariates, the aHRs (95% CI) for dense breast resolution comparing HS to non-HS were 0.81 (0.70-0.93) in postmenopausal women, while the association was converse in premenopausal women with the corresponding HRs of 1.30 (1.18-1.43). As an alternative approach, the multivariable-adjusted TR (95% CI) for dense breast survival comparing HS to non-HS were 0.81 (0.75-0.87) and 1.19 (1.06-1.33) in premenopausal and postmenopausal women, respectively. The association between HS and changes in dense breasts differed with the menopause status. HS increased persistent dense breast survival in postmenopausal women but decreased it in premenopausal women.

250Different perspectives of survival outcomes for Australian cancer patients

Abstract Background While relative survival is commonly used to describe cancer prognosis, its interpretation remains confusing. Alternative measures provide additional insights into the survival experience of Australian cancer patients. Methods Population-based cohort of over 2 million Australians diagnosed with 19 types of primary invasive cancer from 1982 to 2014 with mortality follow-up to 31 December 2015. Flexible parametric survival models were used to estimate loss of life expectancy, avoidable cancer deaths, crude survival, probability of cure and survival of uncured population for cancers diagnosed in Australia. Results There has been an overall decrease in the loss of life expectancy caused by a cancer diagnosis. Australians diagnosed in 2014 will gain an extra 432,588 life years due to the improvement in relative survival since 1982. Similarly, 29% (females) and 40% (males) of expected cancer deaths among the 2005-2014 cohort will be avoided compared to the 1985-1994 cohort. While the 10- year crude probability of cancer deaths decreased over time, patterns varied by cancer type. The crude probability of competing deaths increased with age. Between 1982 and 2009, the cure proportion increased significantly for all cancers. Conclusion Alternative measures of survival may help communicate the reducing impact that a cancer diagnosis has on average life expectancy. Key messages The growing number of Australian cancer survivors can pose emerging challenges to these patients, their caregivers, medical professionals and health-care systems in accessing or providing evidence-based survivorship and psychosocial care after a cancer diagnosis.

1506Flexible parametric survival models investigating factors associated with diabetes-related foot ulcer time-to-healing

Abstract Background Diabetes-related foot ulcers (DFU) take months to heal, reduce patient’s quality-of-life, and induce large healthcare expenditure. Various factors have been identified to influence DFU healing at fixed periods, however, data on factors associated with time-to-healing is scarce. Methods Patients presenting with DFU to Diabetic Foot Services across Queensland, Australia between July 2011 and December 2017 were included and had their demographics, disease history and treatments examined at baseline. Outcome of interest was healing of all ulcers within two-year follow-up time. Time-to-healing and associated factors were examined using flexible parametric survival models, which easily enabled including time-varying coefficients and predicting proportions healed. Results Of 4,709 included patients (median age 63 years, 69.5% male, 10.5% Indigenous), median time-to-healing was 112 days, and 68% healed within two years. Younger age (&amp;lt;60 years), geographical remoteness, smoking, neuropathy, deep ulcers, infection, not receiving offloading, and no recent podiatry treatment were independently associated with longer time-to-healing. Time-varying effects of peripheral artery disease and ulcer size were identified for the first time: both had a negative influence on healing with effects diminishing after six months. The predicted proportions healed, for example, within six months is 65.0% (63.3-66.7) for people residing in a major city, 54.6% (52.6-56.8) in regional area, and 40.3% (34.6-47.1) in remote area. Conclusions This study identified novel and confirmatory factors influencing time-to-healing over 24 months in a large real-world cohort of people with diabetes-related foot ulcers. Visualizing the adjusted predicted proportion healed revealed the influence each factor had on healing rates over time. Key messages Flexible parametric survival model provided flexibility in investigating time-varying effects and outcome prediction in those with diabetes-related foot ulcer healing.

Opportunities for prevention: a data-linkage study to inform a public health response to youth offending in the Northern Territory, Australia

BackgroundNumerous studies have demonstrated a strong link between child maltreatment and subsequent youth offending, leading to calls for early intervention initiatives. However, there have been few whole-population studies into the dimensions of statutory child maltreatment responses that can inform these programs. The aim of this study was to investigate the sex-specific association between level and timing of child protection system (CPS) contact and youth offending.MethodsThis retrospective cohort study used linked individual-level records from multiple agencies, for 10,438Aboriginal children born in the Northern Territory between 1999 and 2006. The outcome measure was the first alleged offence. Key explanatory variables were level (no contact through to out-of-home care) and timing (0–4 years, 5–9 years, or both) of CPS contact. The Kaplan–Meier method was used to estimate cumulative incidence and a flexible parametric survival model to estimate hazard ratios (HR).ResultsChildren with no record of CPS contact before age 10 had the lowest cumulative incidence of first alleged offence by age 18 (boys: 23.4% [95%CI:21.0–26.1]; girls: 6.6% [95%CI:5.3–8.2]) and those with a record of out-of-home care the highest CI (boys: 45.5% [95%CI:37.0–54.9]; girls: 18.6% [95%CI:13.0–26.2]). The association of CPS contact with the relative risk of a first alleged offence was greatest for children aged 10–13 years and decreased with age. Timing of CPS contact was also associated with increasing cumulative incidence. The relative risk for first alleged offence was generally higher for children with CPS contact, of any type, during both developmental phases including notifications during both phases (boys, HR at age 11: 8.9 [95%CI:4.2–17.2]; girls, HR at age 11: 13.7 [95%CI:3.8–48.9]) and substantiations during both phases (boys, HR at age 11: 17.0 [95%CI:9.6–30.0]; girls, HR at age 11: 54.1 [95%CI:18.1–162]).ConclusionThe increased risk of offending associated with level and timing of early CPS contact highlights opportunities for a differentiated public health response to improve life trajectories for children and to reduce youth crime. Although children with unsubstantiated notifications of maltreatment do not meet the criteria for a statutory CPS response, the higher risk of offending among these children supports their inclusion in targeted preventive interventions.

Performance Evaluation of Parametric and Nonparametric Methods When Assessing Effect Measure Modification.

Effect measure modification is often evaluated using parametric models. These models, although efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often require larger samples to achieve a given accuracy. We conducted a simulation study to evaluate performance tradeoffs between correctly specified parametric and nonparametric models to detect effect modification of a binary exposure by both binary and continuous modifiers. We evaluated generalized linear models and doubly robust (DR) estimators, with and without sample splitting. Continuous modifiers were modeled with cubic splines, fractional polynomials, and nonparametric DR-learner. For binary modifiers, generalized linear models showed the greatest power to detect effect modification, ranging from 0.42 to 1.00 in the worst and best scenario, respectively. Augmented inverse probability weighting had the lowest power, with an increase of 23% when using sample splitting. For continuous modifiers, the DR-learner was comparable to flexible parametric models in capturing quadratic and nonlinear monotonic functions. However, for nonlinear, nonmonotonic functions, the DR-learner had lower integrated bias than splines and fractional polynomials, with values of 141.3, 251.7, and 209.0, respectively. Our findings suggest comparable performance between nonparametric and correctly specified parametric models in evaluating effect modification.

Flexible parametric copula modeling approaches for clustered survival data.

Copula-based survival regression models, which consist of a copula function and marginal distribution (i.e., marginal survival function), have been widely used for analyzing clustered multivariate survival data. Archimedean copula functions are useful for modeling such dependence. For the likelihood inference, one-stage and two-stage estimation methods have been usually used. The two-stage procedure can give inefficient estimation results because of separate estimation of the marginal and copula's dependence parameters. The more efficient one-stage procedure has been mainly developed under a restrictive parametric assumption of marginal distribution due to complexity of the full likelihood with unknown marginal baseline hazard functions. In this paper, we propose a flexible parametric Archimedean copula modeling approach using a one-stage likelihood procedure. In order to reduce the complexity of the full likelihood, the unknown marginal baseline hazards are modeled based on a cubic M-spline basis function that does not require a specific parametric form. Simulation results demonstrate that the proposed one-stage estimation method gives a consistent estimator and also provides more efficient results over existing one- and two-stage methods. The new method is illustrated with three clinical data sets. The Appendix provides an R function so that the proposed method becomes directly accessible to interested readers.

From Normal Cognition to Cognitive Impairment and Dementia: Impact of Orthostatic Hypotension.

[Figure: see text].

Survival disparities among recently diagnosed Aboriginal and Torres Strait Islander cancer patients in Australia remain.

Australian Aboriginal and Torres Strait Islander diagnosed with cancer are known to experience poorer survival, with these survival disparities mainly restricted to the first 2years after diagnosis. With improved accuracy and completeness of identifying Aboriginal and Torres Strait Islander peoples over the whole study period, our goal was to examine whether the survival disparity among Aboriginal and Torres Strait Islander peoples diagnosed with cancer in Queensland has changed over time. Population-based data from the Queensland Cancer Register between 1998 and 2017 for Queenslanders aged 15years and over at diagnosis (n = 377,963; 1.6% Aboriginal and/or Torres Strait Islander) were used to determine whether this disparity has reduced over time. Flexible parametric survival models incorporating time-varying coefficients were used to examine the association between Aboriginal and Torres Strait Islander status and cancer-specific survival within 5years of diagnosis. The adjusted 5-year cancer-specific survival rate for Aboriginal and Torres Strait Islander people diagnosed with cancer increased from 60.5% (95% CI 59.2-61.9%) in 1998-2007 to 65.5% (95% CI 64.3-66.6%) in 2008-2017, with the corresponding estimates for other Queenslanders being 66.6% (95% CI 66.4-66.8%) and 70.1% (95% CI 69.9-70.3%). The survival disparity was significant only for the first 3years since diagnosis for 1998-2007; however, it was significantly (p ≤ 0.02) elevated for all five time intervals for 2008-2017, with similar average hazard ratios (95% CIs) over the 5-year interval after diagnosis of 1.45 (1.36-1.55) for 1998-2007 and 1.42 (1.34-1.50) for 2008-2017. Although survival has increased over time, the lack of improvement in the disparity in cancer survival experienced by Aboriginal and Torres Strait Islander cancer patients highlights the urgent need to better understand the multifaceted and completed factors that underlie this gap to guide targeted, evidence-based interventions and support their implementation across the health sector.

Age-specific rates of onset of cannabis use in Mexico

BackgroundOver the previous two decades, the lifetime prevalence of cannabis use has risen among Mexico’s population. AimsEstimate the sex- and age-specific rates of onset of cannabis use over time. DesignFive nationally representative cross-sectional surveys, the Mexican National Surveys of Addictions (1998, 2002, 2008, 2012) and the Mexican National Survey on Drugs, Alcohol, and Tobacco Consumption (2016). SettingMexico. ParticipantsPooled sample of 141,342 respondents aged between 12 and 65 years of which 43.6%(n = 61,658) are male and 56.4% (n = 79,684) are female. MeasurementsWe estimated the age-specific rates of onset of cannabis as the conditional rate of consuming cannabis for the first time at a specific age. MethodsTime-to-event flexible-parametric models with spline specifications of the hazard function. Stratified analysis by sex and control for temporal trends by year of data collection or decennial birth cohort. FindingsAge-specific rates of onset of cannabis use per 1,000 individuals increased over time for females and males. Peak rates of onset of cannabis use per 1,000 ranged from 0.935 (95%CI = [0.772, 1.148]) in 1998, to 5.391 (95%CI = [4.924, 5.971]) in 2016 for females; and from 7.513 (95%CI = [6.732, 10.063]) in 1998, to 26.107 (95%CI = [25.918,30.654]) in 2016 for males. Across decennial birth-cohorts, peak rates of onset of cannabis use per 1,000 individuals for females ranged from 0.234 (95%CI = [0.078, 0.768]) for those born in the 1930s, to 14.611 (95%CI = [13.243, 16.102]) for those born in the 1990s; and for males, from 4.086 (95%CI = [4.022, 7.857]) for those born in the 1930s, to 38.693 (95%CI = [24.847, 48.670]) for those born in the 1990s. ConclusionRates of onset of cannabis increased over the previous two decades for both females and males but remained higher for males. Across recent cohorts, the rates of onset have increased at a faster rate among females than males.

Abstract 880: Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China

Abstract Background This study aims to develop a set of electronic health record (EHR)-based absolute risk prediction models for esophageal cancer (EC), which are nationally applicable and easily integrated into the EHR system in China. Methods The study used data from China Kadoorie Biobank (CKB), a large nationwide prospective cohort recruited during 2004-2008 in ten regions. In a random two-thirds of the 510,145 participants with no prior cancer diagnoses, we developed four nested models, according to the availability of predictors in EHRs. A flexible parametric survival model was fitted to calculate a 10-year absolute risk of EC accounting for the competing risk of mortality from other diseases. Besides discrimination and calibration, we estimated a range of performance indices (e.g. sensitivity and specificity) and compared the model performance with current screening criteria in the remaining one-third. Results During a median of 11.1 years of follow-up, we observed 2,550 EC incident cases. The most sophisticated model included EHR variable (age, sex, region risk level [of ten regions: Hui county in Henan province and Pengzhou in Sichuan province], education level, family history of cancer, smoking, alcohol drinking, body mass index), and physical activity, hot tea consumption, and fresh fruit consumption. In the validation dataset, as more predictors included, the area under the receiver-operating characteristic curve statistically increased from 0.748 (0.732-0.763) to 0.883 (0.867-0.895). We observed a great agreement between predicted and observed risk, except for a slight underestimation in the top deciles. Taking 0.40% as the 10-year risk cut-off, models had sensitivities and specificities of around 80% and largely outperformed the current screening criteria. Conclusions Based only on non-invasive predictors, even the model including only five predictors in the EHRs exhibited excellent calibration and discrimination. Utilizing limited predictors in EHRs, our models are useful to develop nationwide risk-stratified screening strategies for esophageal cancer. Citation Format: Yuting Han, Canqing Yu, Yu Guo, Pei Pei, Ling Yang, Yiping Chen, Huaidong Du, Junshi Chen, Zhengming Chen, Dezheng Huo, Jun Lv, Liming Li. Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 880.

P-13 Efficacy of FOLFOX4 regimen with advanced hepatocellular carcinoma and prognostic factors for survival

The objective of this study was to determine the efficacy of the FOLFOX4 regimen (oxaliplatin + 5-fluorouracil/leucovorin) in terms of overall survival (OS), progression-free survival (PFS), response rate (RR) and explore prognostic factors for survival in Thai patients with advanced hepatocellular carcinoma (HCC) who cannot access targeted therapy. A retrospective cohort study was conducted in Surin hospital between July 2014 and April 2020. All medical records of 38 patients were reviewed for demographic data, risk factors, staging, treatment and outcomes. Kaplan-Meier model was used for survival time analysis. Prognostic factors were performed by flexible parametric regression model both univariate and multivariate analysis. The mean age was 58.1 (±10.0) years and patients were predominantly male (81.6%). Hepatitis B infection and alcoholic consumption were common risk factors. Most of patients were BCLC stage C (94.8%). Median PFS and OS at prespecified time point were 2.9 months (95%CI, 2.2-4.1) and 4.2 months (95%CI, 2.6-5.0), respectively. The response rate (RR) and disease control rate (DCR) were 29.2% and 41.7%. Female gender, BCLC stage C and D, hepatitis B infection, hepatitis C infection and alpha-fetoprotein (AFP) >400 ng/ml were poor prognostic factors by univariate analysis. According to multivariate analysis, BCLC stage D (HR 231.83; 95%CI, 6.42-8370.24; p=0.003), hepatitis B infection (HR 4.39; 95%CI, 1.01-19.00; p=0.048) and hepatitis C infection (HR 30.93; 95%CI, 4.56-209.69; p < 0.001) were independent prognostic factors for poor survival. These results of PFS, OS and RR, suggest that FOLFOX4 regimen may confer some benefit and can be an option for treatment of advanced HCC in those who cannot access targeted therapy. Poor prognostic factors for survival could be useful for clinicians considering treatment decisions.

Gender-Based Differences in Efficacy of Immuno-Chemotherapy for Diffuse Large B-Cell Lymphoma Revisited: A Danish Population-Based Study

Background: The addition of CD20 antibodies (rituximab) to CHOP(-like) chemotherapy has been the single most important progress in the treatment of diffuse large B-cell lymphoma (DLBCL) for decades. Clinical studies suggested more pronounced outcome improvements following immuno-chemotherapy in female DLBCL as compared to male patients, which was supported by pharmacokinetic studies showing faster clearance of rituximab in elderly male patients.Aims: To explore gender-specific differences in DLBCL outcome in a population-based setting and to estimate the gender-specific improvements in relative survival seen with the introduction of immuno-chemotherapy for DLBCL.Patients and Methods: The study was based on the nationwide Danish lymphoma registry (LYFO), which contains detailed information on lymphoma patients treated at Danish hematology departments. Patients diagnosed in the period 2000-2014 and treated upfront with CHOP or CHOP-like therapy were analyzed according to the use of rituximab or not. During the surveyed time period, rituximab was given intravenously at a dose of 375mg/m2 synchronously with CHOP(-like) chemotherapy. A relative survival approach was applied using flexible parametric survival models (1) in which the expected mortality was given by age-, sex-, and year-matched lifetables from Statistics Denmark. The overall effect of rituximab was estimated by a model with two levels (rituximab, R+ vs. no rituximab, R-) and five degrees of freedom for the baseline excess hazard; based on this model 0-5 years relative survival and excess hazard ratio (EHR) were estimated. Gender-specific outcome improvements were estimated by expanding the model with gender as an effect modification of rituximab. The life-year gain attributable to rituximab in the first five years after diagnosis was estimated by the differences in loss in expectation of life (2) for male and female DLBCL patients treated with or without rituximab. All analyses were performed using Stata (StataCorp. 2015. Stata Statistical Software: Release 14 . College Station, TX: StataCorp LP).Results: In total, 4,368 DLBCL patients were included (3,321 in the R+ group and 1,047 in the R- group). Patient characteristics, treatment information, complete remission rates, and 5-year overall survival (OS) estimates are shown in Table 1. Men treated with rituximab were older than men without rituximab treatment suggesting a shift over time toward more intensive treatment for elderly. For both women and men the following was seen: higher Ann Arbor stage, higher R-IPI risk group, higher proportion of patients in CR, and longer 5-year OS when comparing patients with vs. without rituximab treatment. Figure 1A shows relative survival curves. Five-year relative survival of DLBCL patients was 67% (95% CI: 63% - 70%) for patients treated without rituximab and 77% (95% CI: 75% - 79%) for patients with rituximab, and the excess hazard ratio (EHR) was 1.47 (1.27 - 1.70) for patients treated without rituximab. Rituximab was also associated with substantial improvements in relative survival for male and female DLCBL patients analyzed separately (figure 1B-C). The gains of lifetime attributed to rituximab in the first 5 years after diagnosis were 0.26 years (95% CI: 0.10 - 0.43) and 0.40 years (95% CI: 0.21 - 0.61) for men and women, respectively. The effect modification of gender on rituximab was not statistically significant (p = 0.236).Conclusions: In the present study, there was no statistically significant effect modification of gender on rituximab with respect to relative survival. There was a trend toward marginally larger gain in lifetime for women after inclusion of rituximab when compared to men, although this difference was also not statistical significant and may be explained by other factors.

The effect of surgical approach in total knee replacement on outcomes. An analysis of 875,166 elective operations from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

BackgroundTotal knee replacement (TKR) is clinically and cost-effective. The surgical approach employed influences the outcome, however there is little generalisable and robust evidence to guide practice. We compared outcomes between the common primary TKR surgical approaches. Methods875,166 primary TKRs captured in the National Joint Registry, linked to hospital inpatient, mortality and patient reported outcome measures (PROMs) data, with up to 15.75 years follow-up were analysed. There were 10 surgical approach groups: medial parapatellar, midvastus, subvastus, lateral parapatellar, ‘other’ and their minimally invasive versions. Survival methods were used to compare revision rates and 45-day mortality. Groups were compared using Cox proportional hazards regression and Flexible Parametric Survival Modelling (FPM). Confounders included age at surgery, sex, risk group (indications additional to osteoarthritis), American Society of Anesthesiologists grade, TKR fixation, year of primary, body mass index, and for mortality, deprivation and Charlson comorbidity subgroups. PROMs were analysed with regression modelling or non-parametric methods. ResultsThe conventional midvastus approach was associated with lower revision rates (Hazard Rate Ratio (HRR) 0.80 (95% CI 0.71–0.91) P = 0.001) and the lateral parapatellar with higher revision rates (HRR 1.35 (95% CI 1.12–1.63) P = 0.002) compared to the conventional medial parapatellar approach. Mortality rates were similar between approaches. PROMs showed statistically significant, but not clinically important, differences. ConclusionsThere is little difference in PROMs between the various surgical approaches in TKR with all resulting in good outcomes. However, the conventional midvastus approach (used in 3% of cases) was associated with a 20% reduced risk of revision surgery compared to the most commonly used knee approach (the conventional medial parapatellar: used in 91.9% of cases). This data supports the use of the midvastus approach and thus surgeons should consider utilising this approach more frequently. Minimally invasive approaches did not appear to convey any clinical advantage in this study over conventional approaches for primary TKR.

Joint effect of changes in physical activity and weight on incident non-alcoholic fatty liver disease

BackgroundIncreases in physical activity (PA) and weight have opposite effects on the risk of non-alcoholic fatty liver disease (NAFLD), but their joint effect remains unknown. We examined the dose-effect of...

Weight stability masks changes in body composition in colorectal cancer: a retrospective cohort study

There is an emerging viewpoint that change in body weight is not sufficiently sensitive to promptly identify clinically meaningful change in body composition, such as skeletal muscle depletion. We aimed to determine whether body weight stability is associated with skeletal muscle depletion and whether skeletal muscle depletion is prognostic of death independently of change in body weight. This retrospective cohort included 1921 patients with stage I-III colorectal cancer. Computed tomography (CT)-based skeletal muscle characteristics and body weight were measured at diagnosis and after a mean 15.0-mo follow-up. Body weight stability was defined as weight change less than ±5% during follow-up. Sarcopenia and myosteatosis were defined using established thresholds for patients with cancer. Multivariable-adjusted logistic and flexible parametric proportional hazards survival models were used to quantify statistical associations. At follow-up, 1026 (53.3%) patients were weight stable. Among patients with weight stability, incident sarcopenia and myosteatosis occurred in 8.5% (95% CI: 6.3%, 10.6%) and 13.5% (95% CI: 11.1%, 15.9%), respectively. Men were more likely to be weight stable than were women (56.7% compared with 49.9%; P=0.04). Weight-stable men were less likely to develop incident sarcopenia (5.4% compared with 15.4%; P=0.003) and myosteatosis (9.3% compared with 20.8%; P=0.001) than weight-stable women. Among all patients, the development of incident sarcopenia (HR: 1.40; 95% CI: 1.02, 1.91) and of myosteatosis (HR: 1.41; 95% CI: 1.05, 1.90) were associated with a higher risk of death, independently of change in body weight. Patient sex did not modify the relation between skeletal muscle depletion and death. Body weight stability masks clinically meaningful skeletal muscle depletion. Body composition quantified using clinically acquired CT images may provide a vital sign to identify patients at increased risk of death. These data may inform the design of future cachexia trials.