Multivariate Survival Models Research Articles

\u201cCursed is the ground because of you\u201d:

This paper analyses culture as a determinant of technology adoption in a developing country. While the literature discusses the influence of culture upon economic growth, little attention has been paid to the mechanisms at the micro level. Therefore, we postulate that culture plays a crucial role in hindering or fostering the diffusion of innovation, a key trigger of the engine of growth. This empirical study uses the Ethiopia Rural Household Survey to disentangle between individual cultural traits, namely, ethnicity and religion, and the cultural homogeneity of the environment as co-determinants of fertiliser adoption. To examine our hypotheses, we apply a multivariate survival model for clustered and correlated observations to account for time and location effects. The results reveal significant differences in the probability of adopting fertiliser among cultural groups. Moreover, habits and social norms, proxied by ethnicity, provide a better explanation for the role of culture, than religious beliefs, as usually posited in the literature. Also, the cultural environment turns out tobe a decisive trigger. The probability of adoption is higher in rural societies with a homogeneous ethnic environment but distinct religious variety.

Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.

Growth Differentiation Factor-15 (GDF15) is a member of the TGF-β superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD. We measured serum and urinary GDF15 in a prospective cohort of 84 patients who underwent kidney biopsy and assessed their association with outcomes (survival, kidney replacement therapy) during a follow-up of 29 ± 17months. There was a statistically significant correlation between serum and urine GDF15 values. However, while serum GDF15 values increased with decreasing glomerular filtration rate, urinary GDF15 did not. Immunohistochemistry located kidney GDF15 expression mainly in tubular cells, and kidney GDF15 staining correlated with urinary GDF15 values. Urine GDF15 was significantly higher in patients with a histologic diagnosis of diabetic nephropathy than in diabetic patients without diabetic nephropathy. This was not the case for serum GDF15. Both serum and urine GDF15 were negatively associated with patient survival in multivariate models. However, when both urine and serum GDF15 were present in the model, lower urine GDF15 predicted patient survival [B coefficient (SEM) - 0.395 (0.182) p 0.03], and higher urine GDF15 predicted a composite of mortality or kidney replacement therapy [0.191 (0.06) p 0.002], while serum GDF15 was not predictive. Decision tree analysis yielded similar results. The area under the curve (AUC) of the receiver operating curve (ROC) for urine GDF15 as a predictor of mortality was 0.95 (95% CI 0.89-1.00, p < 0.001). In conclusion, urinary GDF15 is associated with kidney histology patterns, mortality and the need for renal replacement therapy (RRT) in CKD patients who underwent akidney biopsy.

Artificial neural networks for multi-omics classifications of hepato-pancreato-biliary cancers: towards the clinical application of genetic data

PurposeSeveral multi-omics classifications have been proposed for hepato-pancreato-biliary (HPB) cancers, but these classifications have not proven their role in the clinical practice and been validated in external cohorts. Patients and methodsData from whole-exome sequencing (WES) of The Cancer Genome Atlas (TCGA) patients were used as an input for the artificial neural network (ANN) to predict the anatomical site, iClusters (cell-of-origin patterns) and molecular subtype classifications. The Ohio State University (OSU) and the International Cancer Genome Consortium (ICGC) patients with HPB cancer were included in external validation cohorts. TCGA, OSU and ICGC data were merged, and survival analyses were performed using both the ‘classic’ survival analysis and a machine learning algorithm (random survival forest). ResultsAlthough the ANN predicting the anatomical site of the tumour (i.e. cholangiocarcinoma, hepatocellular carcinoma of the liver, pancreatic ductal adenocarcinoma) demonstrated a low accuracy in TCGA test cohort, the ANNs predicting the iClusters (cell-of-origin patterns) and molecular subtype classifications demonstrated a good accuracy of 75% and 82% in TCGA test cohort, respectively. The random survival forest analysis and Cox’ multivariable survival models demonstrated that models for HPB cancers that integrated clinical data with molecular classifications (iClusters, molecular subtypes) had an increased prognostic accuracy compared with standard staging systems. ConclusionThe analyses of genetic status (i.e. WES, gene panels) of patients with HPB cancers might predict the classifications proposed by TCGA project and help to select patients suitable to targeted therapies. The molecular classifications of HPB cancers when integrated with clinical information could improve the ability to predict the prognosis of patients with HPB cancer.

Under-5 Child Mortality Determinants in Rural-Urban Areas of Bangladesh: Proportional Hazard Models

The People’s Republic of Bangladesh is a South Asian country with a vast population. The early childhood mortality is a noticeable public health problem. The study work aims to determine the factors related to under-5 aged child mortality in both rural and urban areas of Bangladesh; data pulled out from BDHS (Bangladesh Demographic and Health Survey)-2014. In rural and urban areas, 5306 and 2454 less than five years aged children born before in 5 years preceding the survey respectively. The Kaplan-Meier log-rank test is applied to determine the risk factors in bivariate analysis to multivariate survival models. In multivariate analysis to find out the risk factors of under-five aged child mortality, the Cox proportional hazard model and the Cox frailty model were employed. Religion, father’s educational level, number of antenatal care visits, multiplicity of birth, child size at birth, place of delivery, total children ever born, number of living children are the significant factors of child mortality in rural, urban areas. The variability among children for mortality is 0.000529 and 0.001225 in rural and urban areas individually. Proper notable attention needed for significant determinants, which may increase child survival.

Association of Weight Change, Inflammation Markers and Disease Staging with Survival of Patients Undergoing Chemotherapy for Pancreatic Adenocarcinoma

Introduction Cancer-associated-cachexia represents a systemic syndrome of unintended weight-loss (WL) and systemic inflammation, affecting >80% patients with pancreatic adenocarcinoma (PA). We aimed to evaluate the association of weight change (WC) with survival of patients treated with chemotherapy (ChT) for PA and the influence of disease staging. We also studied the prognostic and predictive value of inflammation-based scores. Methods Observational, retrospective cohort study. Individuals were divided into two cohorts, according to WC (WL ≥5% vs. non-WL <5%) after ChT. Main endpoints were weight change and survival time. Statistical analysis was performed using Stata software. Results Sixty-five patients were included (median age 69; 48% female), 60% with advanced disease. At 3 months after ChT start, 54% experienced WL. Advanced disease independently predicted WL (OR 2.10; 95% CI, 1.11–19.6; p = 0.041). With median follow-up of 14.8 mo, median survival time of patients with WL was 18.5 mo, vs. 33.2 vs. for non-WL (HR 2.28; 95% CI, 1.15–4.52; p = 0.019). In patients with early-stage disease, WL was associated with decreased survival time (21.9 vs. 67.6 mo; HR 23.68; 95% CI 2.39–234.75; p = 0.007), while the association of WL on survival time in advanced disease was not significant (HR 0.74; 95% CI, 0.34-1.60; p = 0.449). The multivariate survival model showed that WL (HR 1.11, 95% CI 1.03–1.20, p = 0.005) and cachexia (HR 3.76, 95% CI 1.07-13-18), p = 0.041) were associated with survival time, as well as location in body or tail (HR 3.05; 95% CI, 1.75–5.31; p < 0.001) and high Neutrophil-to-lymphocyte ratio (NLR) at 3 months (HR 6.20; 95% CI, 2.59–14.87; p < 0.001). Conclusion WL was an independent prognostic factor for survival. Particularly in early stage disease, interventions targeting this modifiable factor may translate into better outcomes for PA patients. NLR may be a surrogate marker of systemic inflammatory status in this setting.

Aspirin Use and the Development of Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) has limited treatment options and results in significant mortality. Data in adult heart transplant (HTx) recipients suggests that aspirin (ASA) use may reduce the risk of CAV. However, there are limited pediatric data on this topic. This study aimed to assess the use of ASA in pediatric HTx recipients and its association with CAV. <h3>Methods</h3> All patients in the Pediatric Heart Transplant Society database < 17 years of age who underwent primary HTx and had > 3 years of follow up were included. ASA use during the first 3 years post-transplant was defined as continuous, intermittent, or no ASA use. Time to CAV and graft loss was compared across groups using the Kaplan Meier method. A multivariable survival model was constructed for each outcome to assess the impact of early post-HTx ASA use. <h3>Results</h3> A total of 3,011 patients were identified for inclusion with 387 (13%) continuous, 676 (22%) intermittent, and 1948 (65%) with no ASA use. ASA use was more common in older patients (p<0.001). Patients receiving continuous ASA were less likely to receive induction therapy at HTx compared to other groups (p<0.001). ASA use was highly variable across centers, ranging from 0% to 100% (Figure 1a). Patients receiving continuous ASA therapy demonstrated worse freedom from CAV (p= 0.002) and inferior graft survival (p<0.001) (Figures 1b-c). In multivariable analyses, early ASA use was not associated with improvements in freedom from CAV or graft survival. <h3>Conclusion</h3> ASA use varies widely across pediatric HTx centers. Early ASA use did not reduce the risk of CAV or graft loss.

Unfractionated and Low-Molecular-Weight Heparin for Bridging Patients with Left Ventricular Assist Device: An Event-Based Analysis.

The relative efficacy of bridging with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in left ventricular assist device (LVAD) patients has not been established. We performed a retrospective, longitudinal cohort study to evaluate safety and efficacy of bridging strategies including all adult LVAD patients implanted at the Medical University of South Carolina from August 2014 to July 2017. In addition to LMWH and UFH exposure, we recorded any time period a patient did not receive a bridging agent for a subtherapeutic international normalized ratio (INR) value as a control group; these events were defined as nonbridging (NB) events. Multivariable Cox regression survival models were utilized for analysis. There were 563 episodes evaluated in 50 patients. Compared with NB events, UFH (adjusted hazard ratio [aHR], 3.75; 95% CI, 1.45-9.73; p = 0.007) and LMWH (aHR, 2.25; 95% CI, 1.03-4.94; p = 0.043) were both associated with an increased risk of bleeding. Compared with NB events, LMWH was not associated with a decreased risk of clotting events (aHR, 1.56; 95% CI, 0.28-8.73; p = 0.616). In the 381 NB events, a nonsignificant signal was noted toward increased risk of thrombotic events in those with an INR ≤ 1.5 (aHR, 2.99; 95% CI, 0.57-15.8; p = 0.2). Among all 563 episodes, those with a baseline INR ≥ 2.0 demonstrated an increased risk of bleeding events (aHR, 2.35; 95% CI, 1.18-5.69; p = 0.016). Our data suggest that the efficacy of LMWH bridging in LVAD patients warrants further investigation.

Disease Distribution at Presentation Impacts Benefit of IP Chemotherapy Among Patients with Advanced-Stage Ovarian Cancer.

Ovarian cancer with miliary disease spread is an aggressive phenotype lacking targeted management strategies. We sought to determine whether adjuvant intravenous/intraperitoneal (IV/IP) chemotherapy is beneficial in this disease setting. Patient/tumor characteristics and survival data of patients with stage IIIC epithelial ovarian cancer who underwent optimal primary debulking surgery from 01/2010 to 11/2014 were abstracted from records. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables. The Kaplan-Meier method was used to estimate survival curves, and outcomes were compared using log-rank tests. Factors significant on univariate analysis were combined into multivariate logistic regression survival models. Among 90 patients with miliary disease spread, 41 (46%) received IV/IP chemotherapy and 49 (54%) received IV chemotherapy. IV/IP chemotherapy, compared with IV chemotherapy, resulted in improved progression-free survival (PFS; 23.0 versus 12.0 months; p = 0.0002) and overall survival (OS; 52 versus 36 months; p = 0.002) in patients with miliary disease. Among 78 patients with nonmiliary disease spread, 23 (29%) underwent IV/IP chemotherapy and 55 (71%) underwent IV chemotherapy. There was no PFS or OS benefit associated with IV/IP chemotherapy over IV chemotherapy in these patients. On multivariate analysis, IV/IP chemotherapy was associated with improved PFS (HR, 0.28; 95% CI 0.15-0.53) and OS (HR, 0.33; 95% CI 0.18-0.61) in patients with miliary disease compared with those with nonmiliary disease (PFS [HR, 1.53; 95% CI 0.74-3.19]; OS [HR, 1.47; 95% CI 0.70-3.09]). Adjuvant IV/IP chemotherapy was associated with oncologic benefit in miliary disease spread. This survival benefit was not observed in nonmiliary disease.

P09.04 Changing Survival and Treatment Patterns in Patients with Stage IV Non-Small Cell Lung Cancer (NSCLC) in Alberta, Canada

We have previously reported that rapid physical decline and poor performance status means that only a minority of patient with metastatic NSCLC receive systemic treatment. Over the last decade, treatment advances in the form of maintenance chemotherapy, targeted therapies and immunotherapy for advanced disease have shown benefit in randomized phase III trials and been adopted as standard of care. Nevertheless, there are conflicting reports of trends in overall survival. We therefore looked at real-world patterns of treatment and survival in a cohort of patients with metastatic NSCLC. We performed a retrospective analysis of a cohort of 4400 patients diagnosed with de novo stage IV NSCLC in Alberta, Canada between 2011-2016 using the Glans-Look database. Data was derived from the provincial cancer registry and supplemented with additional chart review for a subset of cases. Univariate survival analysis used the Log-Rank method, and multivariate analysis Cox Regression. All other tests were Chi-Squared. Median survival in months is shown with 95% confidence intervals. The number of patients included for specific tests is indicated in cases where there was missing data. There was a trend towards improving overall survival over the study period (4.67 (4.24 – 5.10) months in 2011, and 5.90 (5.22 – 6.58) months in 2016; univariate P = 0.092). We observed an increasing proportion of patients with no smoking history (N = 1257; 11.2% in 2011 vs 31.6% in 2016; P < 0.001), an increasing proportion of patients receiving systemic therapy (29.1% in 2011 vs 38.0% in 2016; P < 0.001), and an increasing proportion of patients treated with systemic therapy that received 1st line targeted therapy (N = 541; 20.3% in 2011 vs 39.1% in 2016; P < 0.001). These factors were also associated with improved overall survival in univariate analysis: never smoker vs ever smoker (N = 541; 17.47 (14.61 – 20.33) months vs 6.33 (5.47 – 7.19) months; P < 0.001); receipt of systemic therapy (12.00 (11.30 – 12.70) months vs 3.10 (2.94 – 3.26) months; P < 0.001) targeted therapy vs chemotherapy (N = 541 ; 19.30 (16.06 – 22.54) months vs 15.98 (14.37 – 17.56) months; P = 0.015). Younger age at diagnosis, female gender, receiving systemic therapy, and use of 1st line targeted therapy vs chemotherapy were all significantly associated with improved survival in multivariate models (smoking status excluded from analysis due to number of cases with missing data). We observed a trend towards improving survival from 2011 to 2016 in patient with stage IV NSCLC in Alberta, Canada. While we cannot account for all potentially relevant changes to the management of NSCLC over that time, we observed increasing rates of systemic therapy administration and use of 1st line targeted therapy, which may be in part responsible for improving survival.

Abstract PS1-35: Combined primary site resection and metastasectomy in patients with metastatic breast cancer

Abstract Background: We previously reported a significant survival benefit of surgery in patients with de novo stage IV breast cancer. However, prospective trials, focusing predominantly on the impact of lumpectomy or mastectomy in metastatic breast cancer (mBC) (versus metastatic resection, i.e. ‘metastasectomy’), have yielded inconclusive results. We sought to assess whether a combination of surgical approaches may be associated with optimal survival. Methods: This is a retrospective analysis of patients diagnosed with mBC between 2004 and 2016 using the National Cancer Database. We identified a cohort of patients undergoing both primary site resection and metastasectomy, describing them using frequency and distribution statistics. Subsequently, we conducted a multivariate Cox regression survival model to understand whether this surgical approach was associated with better overall survival (OS) compared to patients undergoing lumpectomy/mastectomy alone, metastasectomy alone, or no surgery. This model controlled for relevant sociodemographic and clinicopathologic factors. Finally, we used the Kaplan-Meier method to demonstrate the utility of surgery in: 1) patients with mBC involving only 1 site, stratifying by tissue type as bone, brain liver, or lung and 2) patients with mBC involving &amp;gt;1 site. Results: A total of n=55,125 patients with mBC were included in this analysis. N=13,478 patients underwent lumpectomy/mastectomy alone, n=2116 underwent metastasectomy alone, n=912 underwent combined lumpectomy/mastectomy + metastasectomy, and n=38,619 did not undergo surgery. Of those that underwent combined resection, n=713 (78.2%) were White; n=132 (14.5%) were Black, and n=47 (5.2%) were Asian. Multivariate Cox regression survival modeling showed mBC patients undergoing combined resection exhibited the best OS (median OS: 50 months, HR 0.882, p=0.012) compared to patients undergoing lumpectomy/mastectomy alone (median OS: 43 months – reference category); while patients undergoing metastasectomy alone had worse OS (median OS: 30 months, HR 1.327, p&amp;lt;0.0001), and those who did not undergo surgery had the worst OS (median OS: 21 months, HR 1.824, p&amp;lt;0.0001). Kaplan-Meier modeling corroborated this survival benefit when mBC involved 1 site and when it involved multiple sites (log-rank p&amp;lt;0.001). In further subgroup univariate analysis of patients with metastasis to 1 site, patients undergoing combined lumpectomy/mastectomy + metastasectomy exhibited superior survival compared to lumpectomy/mastectomy alone, when metastatic disease involved the liver or lung (log-rank p&amp;lt;0.001), but not when it involved bone or the brain. Additionally, in patients with mBC involving only the lung, metastasectomy alone was also associated with a superior survival benefit to lumpectomy/mastectomy alone (log-rank p&amp;lt;0.001), highlighting the potential impact of pulmonary metastasectomy. Conclusions: Patients with newly-diagnosed mBC undergoing primary site resection in combination with metastasectomy exhibited longer survival compared to those undergoing only lumpectomy/mastectomy and those not undergoing surgery, particularly when metastasis involved only the liver or lung. Table 1: Multivariate Cox regression model for overall survival in de novo stage IV patientsDe Novo Stage IV Patients (n=55,125)aVariableNo. (%)Median OS (95% CI)#HR (95%CI)p-valueSurgical approach&amp;lt;0.0001Lumpectomy/mastectomy alone (ref)13,478 (24.4%)43 (42-44)1Metastasectomy alone2116 (3.8%)30 (28-32)1.327 (1.249-1.410)&amp;lt;0.0001Lumpectomy/mastectomy + metastasectomy912 (1.7%)50 (45-54)0.882 (0.799-0.973)0.012No surgery38,619 (70.1%)21 (21-22)1.824 (1.774-1.875)&amp;lt;0.0001Age&amp;lt;0.0001&amp;lt;50 (ref)10,057 (18.2%)39 (38-41)150-7029,437 (53.4%)29 (28-29)1.203 (1.166-1.242)&amp;lt;0.0001&amp;gt;7015,631 (28.4%)16 (15-17)1.623 (1.566-1.681)&amp;lt;0.0001Race&amp;lt;0.0001White (ref)40,128 (72.8%)27 (27-28)1Black9476 (17.2%)21 (21-22)1.097 (1.067-1.128)&amp;lt;0.0001Hispanic3038 (5.5%)38 (36-40)0.733 (0.696-0.772)&amp;lt;0.0001Asian1492 (2.7%)35 (33-38)0.812 (0.755-0.874)&amp;lt;0.0001Other991 (1.8%)32 (28-36)0.805 (0.738-0.878)&amp;lt;0.0001Charlson/Deyo comorbidity index&amp;lt;0.00010 (ref)44,069 (79.9%)29 (29-30)117982 (14.5%)19 (18-20)1.274 (1.238-1.312)&amp;lt;0.00012+661 (1.2%)11 (10-12)1.644 (1.576-1.715)&amp;lt;0.0001Molecular subtype&amp;lt;0.0001TNBC (ref)6721 (12.2%)12 (12-12)1HR+, HER2-27,905 (50.6%)32 (31-32)0.610 (0.588-0.632)&amp;lt;0.0001HR-. HER2+4171 (7.6%)30 (28-31)0.556 (0.529-0.585)&amp;lt;0.0001HR+, HER2+7394 (13.4%)40 (38-41)0.592 (0.566-0.619)&amp;lt;0.0001Radiation therapy&amp;lt;0.0001No (ref)36,848 (66.8%)24 (24-25)1Yes17,715 (32.1%)31 (31-32)1.036 (1.012-1.060)0.004Hormonal therapy&amp;lt;0.0001No (ref)24,662 (44.7%)14 (14-15)1Yes28,635 (51.9%)37 (36-37)0.449 (0.438-0.462)&amp;lt;0.0001Chemotherapy&amp;lt;0.0001No (ref)25,360 (46.0%)21 (20-21)1Yes28,342 (51.4%)32 (31-32)0.632 (0.616-0.649)&amp;lt;0.0001Immunotherapy&amp;lt;0.0001No (ref)48,276 (87.6%)25 (25-25)1Yes6616 (12.0%)41 (40-43)0.668 (0.639-0.698)&amp;lt;0.0001aNumber of cases with documented surgical status and survival data included in this model. #Median OS in months. Citation Format: Nadeem Bilani, Leah Elson, Hong Liang, Elizabeth Elimimian, Zeina Nahleh. Combined primary site resection and metastasectomy in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-35.

Lung microbiota predict chronic rejection in healthy lung transplant recipients: a prospective cohort study

Alterations in the respiratory microbiome are common in chronic lung diseases, correlate with decreased lung function, and have been associated with disease progression. The clinical significance of changes in the respiratory microbiome after lung transplant, specifically those related to development of chronic lung allograft dysfunction (CLAD), are unknown. The aim of this study was to evaluate the effect of lung microbiome characteristics in healthy lung transplant recipients on subsequent CLAD-free survival. We prospectively studied a cohort of lung transplant recipients at the University of Michigan (Ann Arbor, MI, USA). We analysed characteristics of the respiratory microbiome in acellular bronchoalveolar lavage fluid (BALF) collected from asymptomatic patients during per-protocol surveillance bronchoscopy 1 year after lung transplantation. For our primary endpoint, we evaluated a composite of development of CLAD or death at 500 days after the 1-year surveillance bronchoscopy. Our primary microbiome predictor variables were bacterial DNA burden (total 16S rRNA gene copies per mL of BALF, quantified via droplet digital PCR) and bacterial community composition (determined by bacterial 16S rRNA gene sequencing). Patients' lung function was followed serially at least every 3 months by spirometry, and CLAD was diagnosed according to International Society of Heart and Lung Transplant 2019 guidelines. We analysed BALF from 134 patients, collected during 1-year post-transplant surveillance bronchoscopy between Oct 21, 2005, and Aug 25, 2017. Within 500 days of follow-up from the time of BALF sampling, 24 (18%) patients developed CLAD, five (4%) died before confirmed development of CLAD, and 105 (78%) patients remained CLAD-free with complete follow-up. Lung bacterial burden was predictive of CLAD development or death within 500 days of the surveillance bronchoscopy, after controlling for demographic and clinical factors, including immunosuppression and bacterial culture results, in a multivariable survival model. This relationship was evident when burden was analysed as a continuous variable (per log10 increase in burden, HR 2·49 [95% CI 1·38-4·48], p=0·0024) or by tertiles (middle vs lowest bacterial burden tertile, HR 4·94 [1·25-19·42], p=0·022; and highest vs lowest, HR 10·56 [2·53-44·08], p=0·0012). In patients who developed CLAD or died, composition of the lung bacterial community significantly differed to that in patients who survived and remained CLAD-free (on permutational multivariate analysis of variance, p=0·047 at the taxonomic level of family), although differences in community composition were associated with bacterial burden. No individual bacterial taxa were definitively associated with CLAD development or death. Among asymptomatic lung transplant recipients at 1-year post-transplant, increased lung bacterial burden is predictive of chronic rejection and death. The lung microbiome represents an understudied and potentially modifiable risk factor for lung allograft dysfunction. US National Institutes of Health, Cystic Fibrosis Foundation, Brian and Mary Campbell and Elizabeth Campbell Carr research gift fund.

Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

The clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.

Pre-radiotherapy lymphocyte count and platelet-to-lymphocyte ratio may improve survival prediction beyond clinical factors in limited stage small cell lung cancer: model development and validation.

BackgroundFew small sample size studies have reported lymphocyte count was prognostic for survival in small-cell lung cancer (SCLC). This study aimed to validate this finding, to build prediction model for overall survival (OS) and to study whether novel models that combine lymphocyte-related variables can predict OS more accurately than a conventional model using clinical factors alone in a large cohort of limited-stage SCLC patients.MethodsThis study enrolled 544 limited-stage SCLC patients receiving definitive chemo-radiation with pre-radiotherapy lymphocyte-related variables including absolute lymphocyte count (ALC), platelet-to-lymphocyte ratio (P/L ratio), neutrophil-to-lymphocyte ratio (N/L ratio), and lymphocyte-to-monocyte ratio (L/M ratio). The primary endpoint was OS. These patients were randomly divided into a training dataset (n=274) and a validation dataset (n=270). Multivariate survival models were built in the training dataset, and the performance of these models were further tested in the validation dataset using the concordance index (C-index).ResultsThe median follow-up time was 36 months for all patients. In the training dataset, univariate analysis showed that ALC (P=0.020) and P/L ratio (P=0.023) were significantly correlated with OS, while L/M ratio (P=0.091) and N/L ratio (P=0.436) were not. Multivariate modeling demonstrated the significance of ALC (P=0.063) and P/L ratio (P=0.003), and the improvement for OS prediction in combined models with the addition of ALC (C-index =0.693) or P/L ratio (C-index =0.688) over the conventional model (C-index =0.679). The validation dataset analysis confirmed a modest improvement of C-index with the addition of ALC or P/L ratio. All these models showed reasonable discriminations and calibrations.ConclusionsThis study validated the significant value of pre-radiotherapy ALC and P/L ratio on OS in limited-stage SCLC. The combined model with ALC or P/L ratio showed additional OS prediction values than the conventional model with clinical factors alone.

Pediatric hepatic cancer incidence and survival: 30-year trends in Ontario, Canada; the United States; and Australia.

Pediatric hepatic cancer is a rare malignancy, comprising only approximately 2% of all cancers diagnosed in children aged <15 years. The authors sought to describe trends in pediatric hepatic cancer incidence and survival in Ontario, Canada; the United States; and Australia. Children aged <15 years who were diagnosed with hepatic cancer from 1985 through 2013 were ascertained through population-based registries and followed from the time of diagnosis until December 31, 2015. Age-standardized incidence and 5-year relative survival were calculated for each jurisdiction. Multivariable flexible parametric survival models were used to explore predictors of hepatic cancer mortality. A total of 794 children were identified in Ontario (148 children), the United States (400 children), and Australia (246 children). The average annual incidence increased by 2.2% (95% CI, 0.5%-4.0%) in Australia, 2.1% (95% CI, 0.9%-3.3%) in the United States, and 1.3% (95% CI, -0.4% to 3.0%) in Ontario. The 5-year relative survival rate improved from 60% to 82% (P = .08) in Ontario and 62% to 78% (P = .02) in the United States between the diagnostic periods 1985 through 1994 and 2005 through 2013, whereas in Australia the rate remained constant (between 74% and 77%) during the study period. On multivariable analysis, there was no significant difference noted with regard to the hazard of death between jurisdictions (P = .06). Older age, the presence of metastatic disease, and being diagnosed with hepatocellular carcinoma were found to be associated with mortality. The incidence of hepatic cancer in children appears to have increased over the last 30 years in Australia and North America. Survival differences between Australia; Ontario, Canada; and the United States observed in the 1980s and 1990s were no longer apparent and only marginal geographical differences in the hazard of mortality were observed.

Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research &amp; Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: &amp;lt;60 years (n=66) versus &amp;gt;60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p&amp;lt;0.001). Baseline characteristics were otherwise similar. Neutrophil engraftment (&amp;gt;500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p&amp;lt;0.001). Platelet engraftment (&amp;gt;20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients &amp;gt;60 years approximate outcomes in patients &amp;lt;60 years. While NRM was inferior in the older patient group, this difference did not result in significant differences in long term OS or DFS. Instead, other variables such as the hematopoietic comorbidity index and the disease risk index were better indicators of survival outcomes. Additionally, these survival outcomes with haplo PBSCT with PTCy appear to be similar to prior published data with haplo BMT with PTCy in older patients (Kasamon, et al. JCO. 2015). Based on this study, haplo PBSCT with PTCy is an appropriate transplant platform for elderly patients. Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Outcomes of Adjuvant Therapy after Cholecystectomy in Patients With Gallbladder Cancer From The National Cancer Database, 2004-2015

There are limited prospective data evaluating the optimal adjuvant therapy in patients with resected gallbladder cancer. This National Cancer Data Base (NCDB) analysis was conducted to compare the overall survival (OS) of adjuvant therapy regimens after cholecystectomy in patients with gallbladder cancer. The NCDB was queried for patients with T0-4, N0-2 gallbladder cancer who underwent cholecystectomy and were classified according to their adjuvant treatment as chemotherapy (CT), radiotherapy (RT), chemoradiotherapy (CRT), or none (surgery only). Univariable and multivariable frailty survival models were used to quantify the effect of each therapy modality on overall survival. From 2004-2015, 7,258 patients met eligibility criteria. Of these, 4098 (56.5%) underwent surgery alone, 1368 (18.9%) received CT, 283 (3.9%) received RT, and 1509 (20.8%) received CRT. The median age of patients was 67.7, with median follow-up of 59 months. On multivariable analysis, after controlling for age, gender, race, Charlson-Deyo Comorbidity Score, geographic region, TNM stage and surgical margin status, CRT was associated with higher OS (Hazard ratio [HR] = 0.80, 95% Confidence interval [CI] = 0.73-0.87, p = <.001) than surgery alone, whereas CT (HR = 1.33, CI = 1.22-1.44, p = <.001) was associated with lower OS than surgery alone. In this NCDB analysis, CRT was associated with a higher OS, suggesting a role for CRT as optimal adjuvant therapy patients with resected gallbladder cancer. Given the inherent biases of population-based analyses, these results warrant further investigation in randomized clinical trials.

Longitudinal Analysis of Continuous Pulse Oximetry as Prognostic Factor in Neonatal Respiratory Distress.

Analysis of longitudinal data can provide neonatologists with tools that can help predict clinical deterioration and improve outcomes. The aim of this study is to analyze continuous monitoring data in newborns, using vital signs to develop predictive models for intensive care admission and time to discharge. We conducted a retrospective cohort study, including term and preterm newborns with respiratory distress patients admitted to the neonatal ward. Clinical and epidemiological data, as well as mean heart rate and saturation, at every minute for the first 12 hours of admission were collected. Multivariate mixed, survival and joint models were developed. A total of 56,377 heart rate and 56,412 oxygen saturation data were analyzed from 80 admitted patients. Of them, 73 were discharged home and 7 required transfer to the intensive care unit (ICU). Longitudinal evolution of heart rate (p < 0.01) and oxygen saturation (p = 0.01) were associated with time to discharge, as well as birth weight (p < 0.01) and type of delivery (p < 0.01). Longitudinal heart rate evolution (p < 0.01) and fraction of inspired oxygen at admission at the ward (p < 0.01) predicted neonatal ICU (NICU) admission. Longitudinal evolution of heart rate can help predict time to transfer to intensive care, and both heart rate and oxygen saturation can help predict time to discharge. Analysis of continuous monitoring data in patients admitted to neonatal wards provides useful tools to stratify risks and helps in taking medical decisions. · Continuous monitoring of vital signs can help predict and prevent clinical deterioration in neonatal patients.. · In our study, longitudinal analysis of heart rate and oxygen saturation predicted time to discharge and intensive care admission.. · More studies are needed to prospectively prove that these models can helpmake clinical decisions and stratify patients' risks..

A prognostic gene expression signature for oropharyngeal squamous cell carcinoma.

BackgroundRobust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles.MethodsTumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature.FindingsA 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28·32, P = 4·3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30·55, P = 7·0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3·94, P = 0·0018) and the Vanderbilt cohort (HR 8·50, P = 5·7E-09) for overall survival.InterpretationThe prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients.FundingNational Institutes of Health.

Long-term survival in patients with primary intracranial germ cell tumors treated with surgery, platinum-based chemotherapy, and radiotherapy: a single-institution study.

The current study aimed to evaluate the treatment outcomes and toxicities of patients with intracranial germ cell tumors (GCTs). This study retrospectively included 110 consecutive patients (70 patients in the germinomatous group and 40 patients in the nongerminomatous GCT [NGGCT] groups) receiving surgery, platinum-based chemotherapy, and radiotherapy for newly diagnosed primary intracranial GCTs. In the authors' protocol, patients with GCTs were further divided into the following four groups: the germinomatous group and the NGGCT groups (mature teratoma, intermediate prognosis, or poor prognosis). The median overall survival (OS) and progression-free survival (PFS) rates of the patients in the germinomatous group were significantly higher than those in the NGGCT group (p < 0.001). The 5-, 10-, and 20-year OS rates in the germinomatous group were 97.1%, 95.7%, and 93.2%, respectively, with a median follow-up of 11.0 years. On the contrary, the 5-, 10-, and 20-year OS rates in the NGGCT group were 67.3%, 63.4%, and 55.4%, respectively. The 5-, 10-, and 20-year PFS rates were 91.4%, 86.6%, and 86.6%, respectively, in the germinomatous group, whereas those of the NGGCT group were approximately 67.4%, 60.2%, and 53.5%, respectively. Based on the four types of classification in our study, the 5-, 10-, and 20-year OS rates in the NGGCT intermediate prognosis group were 78.9%, 71.8%, and 53.8%, respectively. On the contrary, the 3- and 5-year OS rates in the NGGCT poor prognosis group were 42.9% and 34.3%, respectively. Moreover, toxicities with the treatment of intracranial GCTs were found to be tolerable in the present study population. The multivariate survival models for OS in the NGGCT intermediate prognosis and poor prognosis groups demonstrated that only the alpha-fetoprotein status was significantly associated with worsened OS (HR 3.88, 95% CI 1.29-11.66; p = 0.02). The authors found that platinum-based chemotherapy and radiotherapy result in favorable survival outcomes in patients with germinomatous GCTs. Clinical outcomes were still unfavorable in the NGGCT intermediate prognosis and poor prognosis groups; therefore, a new protocol that increases the survival rate of patients belonging in both groups should be considered.

Clinicopathological analysis of appendiceal goblet cell adenocarcinoma with peritoneal metastasis: World Health Organization grade predicts survival following cytoreductive surgery with intraperitoneal chemotherapy.

Peritoneal spread is the most common route of metastasis in appendiceal goblet cell adenocarcinoma. The aim of this study was to assess the prognostic significance of the World Health Organization (WHO) 5th edition grading criteria in peritoneal metastases of goblet cell adenocarcinoma. We evaluated the clinicopathological features and survival of 63 patients with peritoneal metastasis of goblet cell adenocarcinoma who underwent cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), stratified according to the WHO 5th edition and the Tang etal. grading schemes. The patients were also compared with 120 patients with peritoneal metastasis of appendiceal mucinous neoplasia. Most (73%) peritoneal metastases of goblet cell adenocarcinoma were WHO Grade 3 (G3), there being fewer cases of Grade 2 (G2) (16%) and Grade 1 (G1) (11%) disease. No significant differences in overall survival were observed between WHO G1 and G2 tumours or between the three Tang grades. In the multivariable model of survival, WHO G3 [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.02-7.70] and the presence of >50% extracellular mucin (HR 2.30, 95% CI 1.09-4.88) were associated with reduced overall survival for patients with goblet cell adenocarcinoma. As compared with patients with peritoneal metastasis of mucinous neoplasia, patients with goblet cell adenocarcinoma had significantly reduced survival (median overall survival of 37months versus 102months, P<0.001), which was attributed to the reduced survival of patients with G1/G2 goblet cell adenocarcinoma as compared with patients with G1 mucinous neoplasia (median survival of 98months versus 204months, P<0.001). Grade of peritoneal goblet cell adenocarcinoma determined according to the WHO 5th edition criteria is a clinically relevant measure that independently predicts survival in patients treated with CRS-HIPEC.