Competing Risks Methods Research Articles

Cardiac Events and Survival in Patients With EGFR-Mutant Non–Small Cell Lung Cancer Treated With Osimertinib

Although it has been reported that osimertinib mesylate provides better survival benefits compared with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), it remains unclear whether osimertinib is associated with more cancer therapy-related cardiac events (CTRCEs) compared with other EGFR TKIs, as does the extent of the association these adverse effects may have with overall survival. This issue is particularly critical due to the high prevalence of EGFR variants within Asian populations, including that of Taiwan. To compare CTRCEs and their association with survival in patients treated with osimertinib vs other EGFR TKIs. This cohort study was conducted at the National Cheng Kung University Hospital, a college hospital and tertiary academic referral center in Taiwan. The median follow-up duration was 23.2 (IQR, 15.2-31.5) months. A total of 401 patients with EGFR-mutant non-small cell lung cancer (NSCLC) beginning treatment with EGFR TKIs from September 1, 2019, to July 31, 2022, were retrospectively analyzed. CTRCEs included newly emerging arrhythmias, valvular heart diseases (moderate and more), myocardial infarction, and heart failure and were analyzed after adjusting for age, sex, smoking, alcohol consumption, body mass index, cardiovascular comorbidities, thoracic radiotherapy, and cardiovascular medications. Follow-up was completed January 31, 2024. Osimertinib. The Cox proportional hazards model was used to estimate CTRCEs in patients treated with osimertinib or other EGFR TKIs. Considering that death can lower the incidence of CTRCEs, the competing risk method was used to calculate CTRCEs after adjusting for potential confounders. Multivariable Cox proportional hazard regression analysis for overall survival was used to explore whether CTRCEs were independently associated with overall survival. Among the 401 patients (253 [63.1%] female; mean [SD] age, 69.2 [11.3] years), 195 (48.6%) treated with osimertinib were matched with 206 (51.4%) treated with other EGFR TKIs. Occurrence of CTRCEs in patients receiving osimertinib was significantly higher compared with patients treated with other EGFR TKIs (29 [14.9%] vs 9 [4.4%]; hazard ratio [HR], 3.37; 95% CI, 1.56-7.26; P = .002). After adjustment for relevant cardiovascular risk factors, the HR of CTRCEs was significantly higher in the group treated with osimertinib (adjusted subdistribution HR, 4.00; 95% CI, 1.81-8.85; P < .001). In addition, CTRCEs were independently associated with overall survival (HR, 4.02; 95% CI, 2.44-6.63; P < .001). In this cohort study of patients with EGFR-mutant NSCLC, osimertinib was associated with a higher incidence of CTRCEs compared with other EGFR TKIs; CTRCEs were independently associated with overall survival. These findings highlight the need for ongoing cardiac monitoring in these patients, regardless of preexisting cardiac risk factors.

Clinical Outcomes, Patterns of Failure, and Salvage Therapies of a Large Modern Cohort of Patients With Anal Squamous Cell Carcinoma Treated With Definitive-Intent Intensity-Modulated Radiation Therapy

PurposePatterns of failure and salvage therapy options for patients with anal squamous cell carcinoma (ASCC) who recur after definitive-intent intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy are not well described. Patients and MethodsWe identified consecutive patients with ASCC treated with definitive-intent IMRT between July 2005 and December 2019. Relevant patient and tumor parameters, disease outcomes (locoregional failure (LRF), distant failure (DF), progression-free survival (PFS), colostomy-free survival (CFS), and overall survival (OS)), patterns of failure, and salvage therapies were collected. Failures were analyzed by competing risks methods, whereas survival endpoints were estimated by Kaplan-Meier method. Univariate and multivariate analyses were performed. Landmark analyses were conducted by considering whether patients had LRF within 12 months from completing IMRT. Results375 patients were identified with a median follow-up of 6 years. Stage breakdown was 15%, 23%, and 62% for AJCC stage 0-I, II, and III, respectively. Six-year rates of LRF, DF, PFS, CFS, and OS were 12%, 13%, 73%, 76%, and 80%, respectively. Disease recurred in 74 patients. Among the 45 patients with LRF, 39 (87%) failed within the anorectum, with 25 anal canal, 6 anal margin, and 8 rectal recurrences. Only 4 (9%) patients had isolated nodal failure. Patients experiencing LRF had worse six-year OS than patients without LRF (44% versus 86%, P<0.0001). Approximately 30% of patients who underwent salvage therapy were alive ten years after recurrence, compared with none of the patients who were managed with chemotherapy alone or best supportive care. ConclusionsThis large ASCC cohort managed with definitive-intent IMRT demonstrated excellent rates of locoregional control and survival. Isolated regional nodal failures were uncommon, whereas the majority of LRFs occurred within the anorectum, despite dose escalation by tumor stage. We observed poor outcomes for patients experiencing locoregional disease recurrence, even after aggressive salvage treatment.

Comparison of proximal and distal gastric neuroendocrine carcinoma based on SEER database

The occurrence of gastric neuroendocrine carcinoma (GNEC) is on the rise, and its prognosis is extremely poor. We compared survival outcomes between distal and proximal GNEC and developed a nomogram incorporating tumor site to enhance personalized management for patients with GNEC. 1807 patients were divided into DGNEC and PGNEC groups. We performed analyses by using propensity score matching (PSM) and Fine-Gray competing risk methods. A predictive nomogram for the prognosis of GNEC was constructed and validated. The cumulative incidence of cancer-specific death (CSD) in the DGNEC group was lower than that in the PGNEC group. Subgroup analysis showed lower CSD of DGNEC in males, females, tumor sizes (≤ 2 cm, 2 < tumor size ≤ 5 cm, > 5 cm, and unknown), grade stage I-II, and AJCC stage I-III, chemotherapy or no chemotherapy, surgery or no surgery groups (P < 0.05). Multivariate analysis revealed a significant association between PGNEC and CSD (HR, 1.4; 95% CI 1.13–1.73; P = 0.02). The independent predictors of CSD in patients with GNEC were primary site, gender, age, tumor size, AJCC stage, T stage, N stage, grade stage, and surgery. A predictive model based on multivariate analysis was constructed to estimate the probability of CSD at 1-, 3-, and 5-year. The calibration curves demonstrated excellent consistency between the predicted and observed probabilities of CSD. Patients with DGNEC have a better prognosis than those with PGNEC. The model exhibits strong predictive capability for these patients.

The impact of large aneurysm diameter on the outcomes of thoracoabdominal aneurysm repair by fenestrated and branched endografts.

Aim of the study was to analyse the impact of preoperative thoracoabdominal aneurysm diameter on the outcomes of fenestrated/branched endografting. Patients who underwent endovascular thoracoabdominal repair at 2 European centres (2011-2021) were analysed. Median diameter was calculated; the third quartile was considered a cut-off. Outcomes were compared in 2 groups based on the diameter value. Primary endpoints were technical success, spinal cord ischaemia and 30-day/in-hospital mortality. Survival, freedom from reintervention and target visceral vessels instability were follow-up outcomes. Out of 247 thoracoabdominal aortic aneurysms, the median diameter was 65 mm, first quartile was 57 mm; third quartile was 80 mm, set as cut-off value. Fifty-nine (24%) patients had diameter ≥80 mm. Custom-made and off-the-shelf branched endograft were used in 160 (65%) and 87 (35%), respectively. Technical success was 93% (<80 mm: 91% vs ≥80 mm: 94%; P = 0.47). Twenty-three (9%) patients had spinal injury (<80 mm: 7% vs ≥80mm: 17%; P = 0.03). Twenty-two (9%) patients died within 30-day/in-hospital (<80 mm: 7% vs ≥80 mm: 15%; P = 0.06). Multivariate analysis did not report preoperative diameter ≥80 mm as significant risk factor for primary endpoints. The median follow-up was 13 (interquartile range: 2-37) months and at 3-year survival and freedom from reintervention rates were 65% and 62%, respectively. After univariate and multivariate analyses, preoperative diameter ≥80 mm was considered an independent risk factor for reinterventions [hazard ratio (HR): 1.9; 95% confidence interval (CI) 1.1-3.6; P = 0.04], and for target visceral vessels instability (HR: 3.1; 95% CI: 1.3-5.1; P = 0.04), occurred in 45 (18%) cases. However, after competing risk methods, preoperative diameter did not show significance for follow-up results. A preoperative thoracoabdominal aortic aneurysm diameter >80 mm has not had a direct impact on early technical and clinical outcomes. A diameter≥80 mm is considered risk factor for reinterventions and target vessels instability is considered separately during follow-up.

Heart failure and major haemorrhage in people with atrial fibrillation

BackgroundHeart failure (HF) is not included in atrial fibrillation (AF) bleeding risk prediction scores, reflecting uncertainty regarding its importance as a risk factor for major haemorrhage. We aimed to report...

Selection Bias in Reporting of Median Waiting Times in Organ Transplantation

Median organ waiting times published by transplant organizations may be biased when not appropriately accounting for censoring, death, and competing events. This can lead to overly optimistic waiting times for all transplant programs and, consequently, may deceive patients on the waiting list, transplant physicians, and health care policymakers. To apply competing-risk multistate models to calculate probabilities for transplantation and adverse outcomes on the Swiss national transplant waiting list. The WAIT (Waitlist Analysis in Transplantation) study was a retrospective cohort study of all transplant candidates in Switzerland listed from January 1, 2018, or later and observed until December 31, 2023. Transplant candidates were listed in 1 of the 6 transplant centers (Basel, Bern, Geneva, Lausanne, St Gallen, and Zurich) for heart, liver, lungs, kidney, or pancreas and/or islet transplant. A total of 4352 candidates were listed during the study period, of whom 709 (16.3%) were excluded due to living-donor transplant (691 in the kidney program and 18 in the liver program). Waiting for organ transplant. Time to transplantation, death, or delisting. Competing-risk multistate models were used to analyze time-to-event data from the national organ waiting list with the Aalen-Johansen estimator to compute probabilities for both transplant and adverse outcomes. Results were compared with the sample median among only those undergoing transplant and the Kaplan-Meier method with censoring of competing events. Data from 3643 transplant candidates (2428 [66.6%] male; median age, 56 [range, 0-79] years) were included in the analysis. The median time to transplantation (MTT) was 0.91 (95% CI, 0.83-1.07) years for heart, 3.10 (95% CI, 2.57-3.77) years for kidney, 1.32 (95% CI, 0.76-1.55) years for liver, 0.80 (95% CI, 0.37-1.12) years for lung, and 1.62 (95% CI, 0.91-2.17) years for pancreas and/or islet programs. Alternative estimation methods introduced bias to varying degrees: the sample median among only persons undergoing transplantation underestimated the waiting time by 38% to 61% and the Kaplan-Meier method by 2% to 12% compared with the MTT. In this cohort study of transplant candidates in Switzerland, the MTT, the duration at which the transplant probability is 0.50, was used as a measure of average waiting time. Suboptimal methods led to biased and overly optimistic waiting time estimations; thus, applying appropriate competing-risk methods to address censoring and competing events is crucial.

Fracture risk assessment in the presence of competing risk of death.

To identify the optimal statistical approach for predicting the risk of fragility fractures in the presence of competing event of death. We used real-world data from the Dubbo Osteoporosis Epidemiology Study that has monitored 3035 elderly participants for bone health and mortality. Fragility fractures were ascertained radiologically. Mortality was confirmed by the State Registry. We considered four statistical models for predicting fracture risk: (i) conventional Cox's proportional hazard model, (ii) cause-specific model, (iii) Fine-Gray sub-distribution model, and (iv) multistate model. These models were fitted and validated in the development (60% of the original sample) and validation (40%) subsets, respectively. The model performance was assessed by discrimination and calibration analyses. During a median follow-up of 11.3 years (IQR: 7.2, 16.2), 628 individuals (34.5%) in the development cohort fractured, and 630 (34.6%) died without a fracture. Neither the discrimination nor the 5-year prediction performance was significantly different among the models, though the conventional model tended to overestimate fracture risk (calibration-in-the-large index = - 0.24; 95% CI: - 0.43, - 0.06). For 10-year risk prediction, the multistate model (calibration-in-the-large index = - 0.05; 95% CI: - 0.20, 0.10) outperformed the cause-specific (- 0.23; - 0.30, - 0.08), Fine-Gray (- 0.31; - 0.46, - 0.16), and conventional model (- 0.54; - 0.70, - 0.39) which significantly overestimated fracture risk. Adjustment for competing risk of death has minimum impact on the short-term prediction of fracture. However, the multistate model yields the most accurate prediction of long-term fracture risk and should be considered for predictive research in the elderly, who are also at high mortality risk. Fracture risk assessment might be compromised by the competing event of death. This study, using real-world data found a multistate model was superior to the current competing risk methods in fracture risk assessment. A multistate model is considered an optimal statistical method for predictive research in the elderly.

Cause-specific and all-cause mortalities in vegetarian compared with those in nonvegetarian participants from the Adventist Health Study-2 cohort

BackgroundThere have been mixed results reported internationally when associating vegetarian dietary patterns with all-cause and cause-specific mortalities. ObjectivesThis study aimed to extend our previous results by evaluating, with a larger number of deaths (N = 12,515), cause-specific mortalities comparing different vegetarian types with nonvegetarians. MethodsThis prospective study used data from the Adventist Health Study-2 cohort. Mortality was ascertained between study baseline, 2002–2007, and follow-up through 2015. Dietary data were collected at baseline using a validated quantitative food frequency questionnaire and then categorized into 5 dietary patterns: nonvegetarian, semivegetarian, pescovegetarian, lacto-ovovegetarian, and vegan. Main outcomes and measures include all-cause and cause-specific mortalities using Cox proportional hazards regression models and competing risk methods. ResultsThe analytic sample included 88,400 participants who provided 971,424 person-years of follow-up. We report results pairwise as estimated at ages 65 and 85 y owing to age dependence of many hazard ratios (HRs). Compared with nonvegetarians, vegetarians had lower risks of mortality, overall (HR: 0.89; 95% confidence interval [CI]: 0.83, 0.95; HR: 0.98; 95% CI: 0.91, 1.04), from renal failure (HR: 0.52; 95% CI: 0.38, 0.70; HR: 0.65; 95% CI: 0.55, 0.76), infectious disease (HR: 0.57; 95% CI: 0.40, 0.82; HR: 0.90; 95% CI: 0.70, 1.17), diabetes (HR: 0.51; 95% CI: 0.33, 0.78; HR: 0.69; 95% CI: 0.53, 0.88), select cardiac (HR: 0.75; 95% CI: 0.65, 0.87; HR: 0.89; 95% CI: 0.83, 0.95), and ischemic heart disease causes (HR: 0.73; 95% CI: 0.59, 0.90; HR: 0.84; 95% CI: 0.75,0.94). Vegans, lacto-ovovegetarians, and pescovegetarians were also observed to have lower risks of total mortality and several similar cause-specific mortalities. However, higher cause-specified neurologic mortalities were observed among older vegetarians (estimated at age 85 y), specifically stroke (HR: 1.17; 95% CI: 1.02, 1.33), dementia (HR: 1.13; 95% CI: 1.00, 1.27), and Parkinson's disease (HR: 1.37; 95% CI: 0.98, 1.91). Results in Black subjects for vegetarian/nonvegetarian comparisons largely followed the same trends, but HRs were less precise owing to smaller numbers. ConclusionsVegetarian diets are associated with lower risk for all-cause and many cause-specific mortalities, especially among males and in younger subjects. However, higher risks are observed among older vegetarians for stroke and dementia. These results need further support and investigation.

Modeling home property listings’ time-on-market duration and listing outcome using copula-based competing risk method

Modeling home property listings’ time-on-market duration and listing outcome using copula-based competing risk method

The conditional recurrence-free survival after R0 hepatectomy for locally advanced intrahepatic cholangiocarcinoma: A competing risk analysis based on inflammation-nutritional status

BackgroundConditional survival analysis can serve as a dynamic prognostic metric, which helps to estimate the real-time survival probability over time. The present study conducted a conditional recurrence-free survival (CRFS) analysis for locally advanced intrahepatic cholangiocarcinoma (ICC) after R0 hepatectomy from an inflammatory-nutritional perspective using the competing risk method. MethodsWe extracted the medical data of 164 locally advanced ICC patients after R0 resection from Sun Yat-sen University Cancer Center. The calculation formula of the CRFS rate is CRFS(y/x) = RFS(y + x)/RFS(x). Univariable and multivariable COX regression analysis and competing risk analysis were conducted to identify RFS indicators. ResultsConsidering death before recurrence as a competing risk factor, the conditional RFS rates every 6 months gradually increased over time. The 24-month RFS rate increased from 29.2 % to 49.9 %, 68.5 %, and 85.1 % given 6, 12, and 18-month already recurrence-free survival, respectively. Both in multivariate COX regression analysis and competing risk analysis, tumor diameter and number, lymph node metastasis, aggregate systemic inflammation index score (AISI), and albumin-bilirubin score (ALBI) all remained significant. For both AISI and ALBI variables, the CRFS rates in the low-value set were higher than those of the high-value set. ConclusionsConditional RFS rates of locally advanced ICC after R0 hepatectomy dynamically increased over time, which contributed to reducing survivors' psychological distress and facilitating personalized follow-up schedules. In addition, a person's inflammatory and nutritional status significantly impact the recurrence risk. Oncologists should consider the role of inflammation-nutritional status when making decisions for patients with locally advanced ICC.

Abstract PO1-02-14: Breast cancer in older women - long-term prognosis by age and subtype in a large population-based cohort

Abstract Background Compared to middle-aged women, older women have a higher risk of breast cancer death. Whether the increased risk of breast cancer death is present in all subgroups of older adults with breast cancer, or negligible in the subgroups receiving adequate surgical and oncological treatment, has been debated. We studied long-term prognosis by age and subtype, adjusting for stage, treatment, socioeconomic status and comorbidity, clarifying which subgroups of older patients that are at increased risk of breast cancer death. Methods In a nation-wide cohort of 45,949 women aged ≥60 years at diagnosis of breast cancer 1997-2014, we estimated crude probabilities of breast cancer death and from other causes using competing risk methods. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CI. Results In this large population-based cohort study of older women with breast cancer, we found an increasing risk of breast cancer death with increasing age at diagnosis, both at 5- and 10-year follow up. The strong association between age and breast cancer death was found for all breast cancer subtypes, being most prominent in Her2-positive breast cancer. The age effect was also significant in Luminal A breast cancer where treatment opportunities are not necessarily affected by age. High-risk tumors were equally common in all age groups above 60 years. In multivariable analysis, stage, subtype, grade and treatment were important explanatory variables to the age-related differences in survival, while comorbidity and socioeconomic status contributed minorly. After adjustments, older age remained an independent risk factor for both overall and breast cancer survival. Older women with triple-negative (60-79 years) or Her2-positive (60-84 years) tumors had a 5-year risk of breast cancer death exceeding the risk of death by other causes. Conclusions Older women had a significantly higher risk of breast cancer death irrespective of breast cancer subtype, also in Luminal A disease where treatment opportunities are not necessarily affected by age. Table 3. Crude probabilities of breast cancer specific death and death by other cause (competing cause of death) at 5, 10 and 15 years. Table 4. Multivariable analysis of prognostic factors affecting 15-year overall (OS) and breast cancer- specific survival (BCSS) Table 5. Multivariable analysis of prognostic factors affecting 15-year overall (OS) and breast cancer- specific survival (BCSS) by age at diagnosis and subtype. Citation Format: Amelia Chiorescu, Anna L V Johansson, Antonis Valachis, Alexios Matikas, Jan Frisell, Lars Holmberg, Irma Fredriksson. Breast cancer in older women - long-term prognosis by age and subtype in a large population-based cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-14.

Impact of Radiation Therapy Modalities on Loco-regional Control in Inflammatory Breast Cancer

In inflammatory breast cancer, radiation therapy intensification is considered a standard of care by some teams, although the level of evidence remains low. We sought to analyze the impact of radiation therapy modalities on the risk of loco-regional and distant relapse. This retrospective multicenter study included patients with localized inflammatory breast cancer treated between 2010 and 2017. Standard postmastectomy radiation therapy consisted of daily fractions to a total dose of 50 Gy equivalent without a boost or bolus, while intensified radiation therapy referred to the use of a boost or bolus. The cumulative incidence curves of locoregional and distant recurrence were displayed using the competing risk method. Of the 241 included patients, 165 were treated with standard and 76 with intensified radiation therapy. There was significantly more nodal involvement in the intensified group. With a median follow-up of 40 months postradiation therapy, there was no difference between standard versus intensified radiation therapy regarding the cumulative incidence of locoregional (P = .68) or distant recurrence (P = .29). At 5 years, the risks of locoregional and distant recurrence were 12.1% (95% CI, 7.5; 17.7) and 29.4% (95% CI, 21.8; 37.3) for patients treated with standard radiation therapy and 10.4% (95% CI, 4.4; 19.3) and 21.4% (95% CI, 12.6; 31.9) for those treated with intensified radiation therapy. In multivariate analyses, triple-negative subtype and absence of complete pathologic response were associated with a higher risk of loco-regional recurrence. Radiation therapy intensification had no significant impact on locoregional and distant recurrence. For patients with a non-complete pathologic response (n = 172, 71.7%), no significant differences were observed between the 2 groups for loco-regional (P = .80) and distant (P = .39) recurrence. Severe toxicity rates were similar in both groups. Contrary to other important series, this large retrospective multicentric study did not show a locoregional or distant control benefit of intensified radiation therapy. Pooled prospective studies and meta-analyses of intensified radiation therapy are warranted to endorse this approach.

Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors.

This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

Less than whole uterus irradiation for patients with locally advanced cervical cancer

IntroductionCurrent consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. MethodsWe identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. ResultsThe median follow-up time was 65 months (range 3–352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3–9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. ConclusionsIncluding less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

Clinical outcomes of simultaneous pancreas-kidney transplantation in elderly type II diabetic recipients

The effect of age on outcomes after simultaneous pancreas-kidney transplantation (SPK) among type II diabetes (T2DM) recipients remains inconclusive. This study aimed to analyze the relationship between the age at time of transplantation and mortality, graft loss and metabolic profiles of T2DM SPK recipients. A retrospective cohort consisting of T2MD SPK recipients in a single transplant center was established. The baseline clinical characteristics and outcomes were collected and analyzed based on the age groups divided by 55-year-old. Time-to-event data analysis was performed using Kaplan-Meier method, and competing risk method was adopted to calculate the cumulative incidence of graft loss. A mixed regression model was applied to compare metabolic outcomes including glycated hemoglobin (HbA1c), fasting blood glucose, triglyceride, cholesterol, low-density lipoprotein, and higher estimated glomerular filtration rate (eGFR). 103 T2DM SPK recipients were included, of which 35 were > = 55 years old and 68 were < 55 years old. Baseline characteristics were comparable between age groups. The results indicated that comparable 5-year survival outcomes between groups with functioning grafts perioperatively. Additionally, no relationship of age with graft loss, complications and metabolic outcomes was detected.

A review on statistical and machine learning competing risks methods.

When modeling competing risks (CR) survival data, several techniques have been proposed in both the statistical and machine learning literature. State-of-the-art methods have extended classical approaches with more flexible assumptions that can improve predictive performance, allow high-dimensional data and missing values, among others. Despite this, modern approaches have not been widely employed in applied settings. This article aims to aid the uptake of such methods by providing a condensed compendium of CR survival methods with a unified notation and interpretation across approaches. We highlight available software and, when possible, demonstrate their usage via reproducible R vignettes. Moreover, we discuss two major concerns that can affect benchmark studies in this context: the choice of performance metrics andreproducibility.

Natural history of cancer-associated splanchnic vein thrombosis

BackgroundThere is uncertainty in the management of cancer-associated isolated splanchnic vein thrombosis (SpVT). ObjectivesTo describe the natural history of SpVT by cancer type and thrombus composition and to review anticoagulation (AC) practices and associated rates of usual-site venous thromboembolism (VTE), major and clinically relevant nonmajor bleeding (MB/CRNMB), recanalization/progression, and mortality. MethodsWe performed a retrospective cohort study in patients with SpVT at 2 cancer care centers in Houston, Texas. We estimated the incidence of usual-site VTE and MB/CRNMB at 6 months using competing risk methods and examined venous patency in a subset of patients with repeat imaging. We assessed associations with mortality using Cox regression. ResultsAmong 15 342 patients with an incident cancer diagnosis from 2011 to 2020, we identified 298 with isolated SpVT. Patients with hepatocellular carcinoma (HCC) and SpVT (n = 146) had the highest disease prevalence (20%), lowest rate of AC treatment (2%), and similar rate of usual-site VTE (4.2%) vs those without SpVT (5.2%) at 6 months, though tumor thrombus vs bland was associated with worse overall survival. In patients with non-HCC bland SpVT (n = 114), AC (n = 37) was more common in those with non-upper gastrointestinal cancers and fewer comorbidities. AC was associated with more recanalization (44% vs 15%, P = .041) but no differences in usual-site VTE, MB/CRNMB, or mortality at 6 months. ConclusionCancer-associated isolated SpVT is a common but heterogeneous thrombotic disease that is treated differently from usual-site VTE. Tumor thrombus is a negative prognostic factor. Initiation of AC in bland thrombi requires judicious consideration of thrombotic and bleeding risk.

The cumulative live birth rates of 18 593 women with progestin-primed ovarian stimulation-related protocols and frozen-thawed transfer cycles.

What are the odds of achieving pregnancy when adopting progestin-primed ovarian stimulation (PPOS)-related protocols combined with repetitive frozen-thawed transfer (FET) cycles in patients with different clinical characteristics? The cumulative live birth rates (CLBRs) of women undergoing different PPOS-related protocols can be significantly and consistently enhanced within six FET cycles when the female age is <40 years (or even <45 years) and when >5 oocytes are retrieved, regardless of antral follicle count (AFC). There have been numerous studies on the live birth rate of the first FET cycle in patients with PPOS-related protocols. These studies have focused mainly on comparing pregnancy outcomes with those of other stimulation protocols. However, owing to the unique features of the PPOS-related strategy, such as its flexible timing of oocyte retrieval and repeated transfer of frozen embryos, studies using the CLBR as an overall indicator of success and investigating which types of patients would benefit from this protocol are lacking. This retrospective cohort study included 18 593 women who underwent PPOS-related protocols (dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, and luteal-phase ovarian stimulation protocol) from 1 March 2011 to 31 September 2022 in our centre. The population was categorized by female age, number of oocytes retrieved, and AFC in the analysis of CLBR within six FET cycles. The age groups (Groups 1-5, respectively) were <30, 30-34, 35-39, 40-44, and ≥45 years. The number of oocytes retrieved was grouped as 1-5, 6-10, 11-15, 16-20, and >20. AFC was grouped as <5, 5-10, 11-15, and >15. The Kaplan-Meier analysis (optimistic method), which hypothesized that patients who did not continue treatment had the same chance of achieving a live birth as those who continued, and the competing risk method (conservative method) which hypothesized they had no chance of achieving a live birth, were applied. In further analyses, the Cox model and Fine-Gray model were adopted: the former corresponds to the optimistic scenario, and the latter corresponds to the pessimistic scenario. CLBR had a declining trend with female age over six FET cycles (Groups 1-5, respectively: optimistic: 96.9%, 96.6%, 91.4%, 67.3%, and 11.7%; conservative: 87.3%, 85.0%, 74.0%, 41.3%, and 7.5%), requiring more FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 4, and >6 cycles; conservative: 2, 2, 2, >,6 and >6 cycles). CLBR showed an increasing trend with the number of oocytes retrieved (Groups 1-5, respectively: optimistic: 93.8%, 94.3%, 95.8%, 96.0%, and 95.6%; conservative: 66.2%, 78.3%, 85.6%, 88.9%, and 91.0%). All groups needed the same number of FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 2, and 2 cycles; conservative: 2, 2, 2, 2, and 2 cycles). Furthermore, the CLBR within six FET cycles had an increasing trend with AFC number (Groups 1-4, respectively: optimistic: 89.2%, 94.8%, 95.9%, and 96.3%; conservative: 67.4%, 78.2%, 83.9%, and 88.1%), with all four groups achieving a success rate of at least 50% by the second FET cycle. The current research is limited by its retrospective design and single-centre nature, which may restrict the generalizability of our findings. This work describes two models (the Kaplan-Meier analysis and the competing risk method) to evaluate the clinical outcome of patients using PPOS-related protocols, which are especially useful for patients of advanced age or those with diminished ovarian reserve. Our findings encourage patients below 45 years old, especially younger than 40 years, and patients with lower AFCs and fewer retrieved oocytes to try this new protocol. Moreover, this study demonstrates the degree of improvement in the CLBR within six FET cycles for patients with different clinical characteristics, providing a valuable point of reference to determine whether to continue ART after a transfer failure. The study was supported by grants from the National Natural Science Foundation of China (82071603 to L.W., 82001502 to Y.L.). There are no conflicts of interest to declare. N/A.

Prospective Clinical and Biomarker Validation of the ASTCT Consensus Definition for Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Introduction: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-hematopoietic cell transplantation (HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed new consensus diagnostic criteria for standard risk (ASTCT-SR) and high risk (ASTCT-HR) but their correlation with older criteria based on microangiopathic hemolytic anemia (MAHA) or diagnostic complement biomarkers used in previous TA-TMA studies, such as levels of the terminal complement activation product sC5b-9 and the alternative complement pathway activation product Factor Ba, is unknown. Using data and samples from an ongoing prospective pediatric cohort study, we compared the two definitions and their associations with biomarkers. Methods: Patients aged 0 to 18 years who underwent first allogeneic HCT 2021-2023 at Texas Children's Hospital were included in the clinical and biomarker study. Those who did not have at least 100-day post-HCT event-free follow-up were excluded. Two different definitions for TA-TMA were applied. Clinical TMA (cTMA) was diagnosed if a patient 1) met 4/4 concurrent criteria of MAHA (schistocytosis, thrombocytopenia, anemia, and elevated lactate dehydrogenase (LDH)) at least twice in 14 days and 2) clinically adjudicated to exclude known mimics or alternative causes of TMA. In contrast, ASTCT-HR TMA was diagnosed if a patient 1) met 4/7 non-concurrent criteria (schistocytosis, thrombocytopenia, anemia, elevated LDH, elevated blood pressure, elevated urinary protein excretion, and elevated sC5b9) at least twice in 14 days and 2) had evidence of LDH &amp;gt;2x normal, proteinuria ≥1 mg/mg, elevated sC5b9, acute graft-versus-host disease, active bacterial/viral infection, or end-organ damage. Cumulative incidence of TA-TMA was assessed by the competing risk method. Overall survival was compared by the Kaplan Meier estimator and log-rank test. Biomarker levels for samples collected at day 15 (+/- 14 days) were compared using the t-test. Results: A total of 32 patients met the inclusion criteria. The median age was 5.7 years (range 1.1-18.8) and most were White (68.8%) and Hispanic (56.2%). Malignant disease was the indication for HCT in 50% of patients. While the classic MAHA-based cTMA definition had an incidence of 12.7%, the newly proposed ASTCT-HR definition doubled it to 28.5% by day-100 (Figure 1). In contrast to patients with concordant TA-TMA diagnosis (+/+) who had significantly worse post-transplant survival (p=0.0047) compared with those with concordant non-TMA (-/-), those reclassified as TA-TMA by the new definition only (-/+) had an unexpectedly good prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Longitudinal biomarker analysis was conducted on 29 patients. The highest average plasma levels of sC5b-9 and Ba during the first 100 days were observed in patients meeting both cTMA and ASTCT-HR criteria (+/+). When focused on early biomarkers measured around day 15, sC5b-9 (P=0.041) and Ba (P=0.004) were significantly elevated in the doubly positive TMA group (+/+) vs. non-TMA group (-/-) (Figure 2). We did not observe significant differences for ASTCT-HR singly positive (-/+) vs. non-TMA group (-/-). Conclusions: In the current prospective clinical and biomarker study, the recently proposed ASTCT-HR definition was more sensitive but less prognostic than the traditional cTMA definition for TA-TMA. Patients who solely met the ASTCT-HR diagnostic criteria but not the cTMA criteria had benign complement biomarker profiles and excellent survival prognosis without TMA-directed therapy. While clinicians need to be vigilant for this infrequent yet potentially severe complications, it is crucial that diagnostic criteria accurately identify affected patients given the expense and potential complications of treatment. We recommend ongoing validations of the new consensus diagnostic criteria from other prospective cohort studies with larger sample sizes and extended follow-up.

Investigation of Age-Specific Differences in Survival and Cause of Death Among Diffuse Large B-Cell Lymphoma Patients with and without HIV in the Modern Era of Antiretroviral Therapy: A Population-Based Analysis from 2010 to 2017

Introduction Despite improved prognosis with combined antiretroviral therapy (cART) among patients with human immunodeficiency virus (PWHIV) diagnosed with diffuse large B-cell lymphoma (DLBCL), population-based studies suggest inferior survival rates compared to patients without HIV. Uncertainty remains about the persistence of this survival difference across age groups. Examining outcomes across ages may help identify higher-risk groups in the current era of cART, providing insights for designing and conducting age-specific interventions. Methods A retrospective population-based cohort was conducted using US population-based cancer registry data among patients aged 15-79 years with newly diagnosed DLBCL from 2010 to 2017, with follow-up through 2019. The 2010-2017 period reflects the availability of integrase inhibitors and the introduction of distinct lymphoma subtypes to the World Health Organization classification system in cancer registries. HIV status was reported at lymphoma diagnosis. Patients were classified into three age groups: adolescents and young adults (AYAs, 15-39 years), adults (40-59 years), and older adults (60-79 years). Overall survival (OS) was defined from diagnosis to death of any cause. Probabilities were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox regression models were fitted to assess all-cause mortality, adjusting for cancer stage, race/ethnicity, sex, year of diagnosis, and age. We estimated the cumulative incidence of infections and HIV-related deaths using the competing risk method. Results Patient characteristics: A total of 26,905 DLBCL patients were identified (1,030 PWHIV and 25,758 patients without HIV). Compared to patients without HIV, PWHIV were younger (median age at diagnosis 48 years vs. 62 years), predominantly male (85% vs. 56%), more likely to be non-Hispanic Black (38% vs. 8%) and Hispanic (24% vs. 18%), and more likely to have advanced-stage disease at diagnosis (71% vs. 56%) (Table 1). OS in DLBCL PWHIV vs. patients without HIV:Within each age group, OS was significantly lower among PWHIV with DLBCL compared to patients without HIV(Table 1 and Figure 1). With a median follow-up of 67 months, 5-year OS was particularly low among AYAs (53% vs. 87%, p&amp;lt;0.0001) and adults (48% vs. 74%, p&amp;lt;0.0001). Similarly, older adults experienced lower 5-year OS rates (45% vs. 57%, p&amp;lt;0.0001). Multivariable Cox models suggest that PWHIV has an increased risk of all-cause mortality within each age group (Figure 1). OS in different age groups by HIV status: For PWHIV, age was not a significant factor for increased all-cause mortality, with 5-year OS rates ranging from 45% in adults to 53% in AYAs (p=0.170). Conversely, in DLBCL patients without HIV, AYAs had superior 5-year OS rates (87%, p&amp;lt;0.001) compared to adults (74%) and older adults (57%). Cause of death by HIV status: Among both PWHIV and without HIV, lymphoma/leukemia-related mortality was the most common cause of death reported in death certificates (47% and 73% respectively). However, the 5-year cumulative incidence of infection mortality was higher among PWHIV (range 3-4% across age groups) compared to patients without HIV (1% across age groups). For PWHIV, other HIV-related mortality had a 5-year cumulative incidence ranging from 9% to 14% across age groups. Results stratified by cancer stage (early- or advanced-stage disease) were consistent with those presented above. Conclusion This study highlights worse outcomes among PWHIV diagnosed with DLBCL compared to patients without HIV within each age group at the population level in the modern era of cART, notably among AYAs. Unlike the findings in DLBCL patients without HIV, age was not significantly associated with mortality among PWHIV with DLBCL. Future studies should explore age-specific demographic, biological, or healthcare system factors mediating these outcome disparities. The considerable HIV-related mortality suggests refining HIV surveillance approaches among PWHIV with DLBCL in prospective studies or clinical trials. Identifying the optimal integration of chemotherapy and cART may improve outcomes in this vulnerable population.