Clinical Risk Grouping Research Articles

Epigenetic Profiling and Machine Learning for Enhanced Risk Stratification in Pediatric Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy with high clinical and biological heterogeneity. Despite advancements in treatment, relapsed patients still face significant mortality rates and long-term complications. Risk-adapted strategies have been implemented to optimize treatment intensity based on prognostic factors. Genomic techniques offer potential for improved risk stratification, but accurate grouping remains challenging. Epigenetic alterations, particularly DNA methylation, have shown promise in tumor classification and prognostication. In this study, we trained machine learning survival models based on DNA methylation signatures to refine risk grouping in pediatric ALL patients. Methods: Clinical annotation and DNA methylation data from pediatric ALL samples were retrieved from the Norlund et al. cohort (n = 763). Age, sex, risk group, and cytogenetic subtype were selected as clinical covariates. The cohort was randomly divided into training (80%) and test (20%) sets. Univariate Cox regression and variable importance analysis were performed to select CpG sites associated with relapse-free survival (RFS) and overall survival (OS). Random survival forest models were constructed using the training set, and their performance was evaluated on the test set using the concordance index (c-index), the time-dependent area under the ROC curve (AUC), and the continuous rank probability scores (CRPS). To assess the generalizability of the risk predictors, we performed external validation using two independent pediatric ALL datasets ( Busche et al., n = 42; and Krali et al., n = 384). Results: The relapse risk predictor (RRP) was constructed using random survival forests based on a signature of 16 CpG sites. The model achieved good predictive accuracy with c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The addition of cytogenetic subtype or age at diagnosis did not significantly change the model's performance. Longitudinal assessment of the RRP revealed its superior performance compared to clinical risk grouping. Combining the RRP with clinical risk grouping improved prognostic accuracy, with a 20-month AUC over 80%. The mortality risk predictor (MRP) was constructed using a signature of 53 CpG sites. The model achieved strong predictive performance with c-indexes of 0.751 and 0.755 in the training and test sets, respectively. Similar to the RRP, the addition of cytogenetic subtype or age at diagnosis did not significantly impact the model's performance. Longitudinal assessment of the MRP demonstrated a higher performance rate than clinical risk grouping at all evaluated time points. Combining the MRP with clinical risk grouping yielded the highest prognostic accuracy. In the external validation of the MRP in the Krali dataset, the MRP score was strongly associated with OS: c-index 0.621, p-value 1.06 x 10 -4. The hazard ratio was 1.073 (95% confidence interval: 1.035-1.112) for each incremental increase in the risk score. On the contrary, a lower reproducibility of the RRP was observed (c-index 0.529), presumptively related to the addition of MRD-driven risk stratification in more recent protocols. Conclusions: Machine learning models built on DNA methylation signatures surpassed the traditional clinical risk grouping both for predicting relapse risk and mortality, while the combination of molecular and clinical factors provided the best prognostic accuracy. Further validation and implementation of these predictors could contribute to personalized risk-adapted treatment strategies for pediatric ALL patients.

Integrated single-cell RNA sequencing analysis reveals a mesenchymal stem cell-associated signature for estimating prognosis and drug sensitivity in gastric cancer.

Mesenchymal stem cells (MSCs) play an important role in regulating all stages of the immune response, angiogenesis, and transformation of matrix components in the tumor microenvironment. The aim of this study was to identify the prognostic value of MSC-related signatures in patients with gastric cancer (GC). MSC marker genes were identified by analyzing single-cell RNA sequencing (scRNA-seq) data for GC from the Gene Expression Omnibus (GEO) database. Using bulk sequencing data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD), as a training cohort, and data from GEO, as a validation cohort, we developed a risk model consisting of MSC prognostic signature genes, and classified GC patients into high- and low-MSC risk subgroups. Multifactorial Cox regression was used to evaluate whether MSC prognostic signature was an independent prognostic factor. An MSC nomogram was constructed combining clinical information and risk grouping. Subsequently, we evaluated the effect of MSC prognostic signature on immune cell infiltration, antitumor drugs and immune checkpoints and verified the expression of MSC prognostic signature by in vitro cellular assays. In this study, 174 MSC marker genes were identified by analyzing scRNA-seq data. We identified seven genes (POSTN, PLOD2, ITGAV, MMP11, SDC2, MARCKS, ANXA5) to construct MSC prognostic signature. MSC prognostic signature was an independent risk factor in the TCGA and GEO cohorts. GC patients in the high-MSC risk group had worse prognoses. In addition, the MSC nomogram has a high clinical application value. Notably, the MSC signature can induce the development of a poor immune microenvironment. GC patients in the high MSC-risk group were more sensitive to anticancer drugs and tended to have higher levels of immune checkpoint markers. In qRT-PCR assays, the MSC signature was more highly expressed in GC cell lines. The MSC marker gene-based risk signature developed in this study can not only be used to predict the prognosis of GC patients, but also has the potential to reflect the efficacy of antitumor therapies.

Geographic variation of decipher genomic classifier in patients with early prostate cancer.

376 Background: External factors such as environmental or lifestyle-related exposure may influence genomic composition of cancer, and therefore its progression and outcome. Thus geographic data is of importance. Decipher is a gene expression classifier used in risk stratification of early non metastatic prostate cancer. Currently, there are no data reporting geographic variation of the test. We aimed to analyze Decipher genomic score results among Israeli patients, in comparison to American patients. Methods: The Decioher database (Decipher Biosciences Inc) contains data from patients who have given consent for broad data-sharing. We identified and analyzed Decipher test results ordered among Israeli patients with localized prostate cancer. Matched analysis to the US population was done. Results: 144 patients (median age 69.5, range 64-74) were included in the present analysis. The clinical NCCN risk grouping was low in 42.4% (n=61), favorable intermediate in 38.9% (n=56), unfavorable intermediate in 17.4% (n=25), and high risk in 1.4% (n=2). Physicians primarily obtained Decipher for low-intermediate NCCN risk. Median Decipher score was 0.57 (Q1 0.385, Q3 0.823). Decipher risk grouping was low in 38.1% (n=61), intermediate in 16.9% (n=27), and high in 45% (n=72). Median Decipher score increased with Grade Group. 46% of NCCN low risk patients had a higher risk as per Decipher. 82% of NCCN favorable intermediate and unfavorable intermediate risk were reclassified to lower or higher risk. 9% of NCCN high risk patients had a lower risk as per Decipher. The present study cohort had a higher proportion of higher Decipher scores than observed in similar grade US population (n=43065) in the Decipher database (Median 0.43, Q1 0.27, Q3 0.66; 52%/18%/30% with low/intermediate/high risk). Conclusions: The preliminary results of the present study suggest a higher proportion of high risk Decipher among Israeli patients with early prostate cancer. These results should be interpreted cautiously. The study and further data collection are ongoing.

Identification of Salivary Gland Tumors (SGT) at Risk for Local or Distant Recurrence After Postoperative Radiation Therapy (PORT) With or Without Systemic Therapy (ST) Using Clinical Risk Grouping

To identify risk groups and patterns of recurrence after curative treatment of primary SGT treated with PORT +/- ST.We retrospectively identified consecutive pts with stage I-IVA SGT, excluding adenoid cystic carcinoma (ca), treated with curative-intent surgery and postoperative IMRT with or without radiosensitizing chemotherapy from 12/2008-02/2020 at a tertiary care center. Pts were classified into clinical risk groups based on histologic diagnoses and pathologic features: (1) low-risk = morphologically low grade (LG) tumors (e.g. acinic cell, secretory, LG mucoepidermoid (MEC), epithelial-myoepithelial, basal cell adenocarcinoma), pN0, without lymphovascular invasion (LVI) or perineural invasion (PNI), including minimally invasive/non-invasive carcinoma ex-pleomorphic adenoma (CXPA); (2) intermediate-risk = intermediate grade morphology (e.g. grade 2 MEC) or LG morphology with PNI or LVI or pN+; (3) high-risk = high grade histology (e.g. salivary duct, high-grade MEC, poorly differentiated ca including invasive CXPA). Kaplan Meier estimates were used for recurrence-free survival (RFS) and univariable predictors.72 pts were included. Median age at surgery was 59.6 years [interquartile range (IQR) 49.7,67.7 yrs]. Sites were: 86% parotid (n = 62), 8% submandibular (n = 6), 4% minor salivary (n = 3), and 1% unknown primary. SGT were classified into clinical risk groups: 26% low (n = 19), 25% intermediate (n = 18), and 49% high-risk (n = 35). Concurrent chemotherapy (CRT) was given to 3% of low-risk (n = 1), 13% of intermediate risk (n = 4), and 71% of high-risk pts (n = 25). Regimens included carboplatin + paclitaxel, cisplatin, and concurrent/adjuvant trastuzumab (in 10 pts with HER2-positive SGT). With a median follow-up of 40.5 months, 2-year OS was 95% (85-98%); there were 11 recurrences (9 distant metastasis (DM), 2 in-field local failure (LF) both in pts with gross residual after surgery), with 82% (9 of 11) having received CRT. All recurrences were in the high-risk group with 2-year RFS of 73% (54%-85%) and 2-year cumulative incidence of DM 21% and LF 6%. Factors associated with RFS included positive margins (P = 0.004) and low-neck positive lymph nodes (level III/IV/V vs. level I/II, P = 0.04). Thirteen pts (18%) had targeted genomic sequencing (4 with recurrence); common mutations included TP53 (n = 4), HRAS (n = 3), NFKBIZ (n = 3), and PIK3CA (n = 3). Mutations in NF1 (n = 3) and HNFA1 (n = 2) were observed only in pts that recurred.DM are the primary mode of recurrence in pts with resected SGT treated with PORT +/- ST and occurred only in high-risk pts. After randomized trials like RTOG 1008 determine the added benefit of chemo to PORT, DM is likely to remain an unmet need. Further studies incorporating molecular characterization of high-grade SGT may identify potentially actionable targets to prevent distant recurrence.

Treatment barriers and clinical outcome of children with medulloblastoma in China: a report from the Chinese Children's Cancer Group (CCCG).

BackgroundMedulloblastoma (MB) is the most common malignant central nervous system tumor of childhood. Management requires interdisciplinary care and is associated with unique challenges in developing regions. Here, we report the characteristics, clinical outcome and treatment barriers for Chinese children with MB based on a multi-institutional cohort from the Chinese Children’s Cancer Group (CCCG).MethodsRetrospective cohort study among 12 Chinese pediatric oncology units from the CCCG Brain Tumor Workgroup on patients aged <18 years diagnosed with MB from 2016 to 2019.Results221 patients (male:female = 138:83) were included, 175 (79%) were ≥3 years of age, and 46 (21%) <3 years. 177 patients (80%) were completely staged, among which 50 (28%) had metastasis and 70 (40%) were considered to have high-risk (HR) disease. Gross/near-total resection was achieved in 203 patients (92%). In patients where molecular grouping could be assigned, 19 (16%), 35 (29%), and 65 (54%), respectively had WNT-activated, SHH-activated, and Group 3/4 MB. The median duration between resection and initiation of adjuvant therapy was 36 days. Respective 2-year PFS and OS rates were 76.0 ± 3.0% and 88.0 ± 2.3%. PFS was significantly associated with age, metastatic status and clinical risk grouping. Chemotherapy use during CSI or alkylator choice were not significant predictors for patient outcome.ConclusionsWe reported the clinical profiles and outcome from the largest cohort of Chinese children with MB after multi-modal therapy. Strengths and limitations on the local provision of neuro-oncology service are identified.

Radiotherapy Significantly Improves Long-Term Survival And Local Control Of Head And Neck Rhabdomyosarcoma (HNRMS) In Adults: Retrospective Analysis Of 64 Patients

Rhabdomyosarcomas in adults were rarely reported in the literature. The aim of this study was to analyze the primary site, stage, treatment and prognosis of HNRMS in Adults. The clinical data of adult patients with pathologic diagnosis of HNRMS admitted from October 1999 to July 2018 in Chinese Academy of Medical Sciences Cancer Hospital were retrospectively analyzed. The clinical staging and risk grouping were performed according to International RMS Study Group (IRSG) criterion. A total of 64 patients were included (30 males, 34 females). The median age was 28 years (16-69ys). The pathological type consisted of 28 (43.8%) embryonic RMS, 25 (39.1%) alveolar RMS and 5 (7.9%) pleomorphic RMS. 21 patients (32.8%) got tumors invasion of parameningeal, 38 patients (59.4%) had orbital invasion, included 19 patients (29.7%) had both orbital and parameningeal invasion. IRSG I-IV stage accounted for 57.8%, 10.9%, 18.8%, 12.5% of all the patients. 35.6% patients were classified as low risk, 50.8% patients as medium risk and 13.6% patients as high risk. 28 patients (43.8%) received radical resection, 13 patients achieved R0 resection. 54 patients (84.4%) received radical /adjuvant radiotherapy. Median dose was 69.96Gy (37.5-71.04Gy) of GTV / GTVtb. 46 patients (85.2%) received cervical lymphatic drainage area radiation. A total of 44 patients (68.8%) median completed 4 cycles (1-12 cycles) of chemotherapy. The main chemotherapy regimen was IFO + EPI (52.3%) and CTX + VCR + EPI (25%). Median follow-up for surviving patients was 48 months. 47 patients (73.4%) failed after the treatment, 14 (21.9%) had local recurrence, 34 (53.1%) had distant metastasis. 43 patients (67.2%) were died. The overall 1-, 3- and 5-year over survival (OS) rates were 81.7%, 35.7% and 23.7%, respectively. The median survival time was 20 months. The addition of radiotherapy in treatment significantly improved the OS, progression free survival (PFS) and local-regional recurrence free survival (LRRFS) (3ys OS 36.5% vs 21.8% P = 0.03, 3ys-PFS 27.2% vs 0% P < 0.01, 3ys-LRRFS 77.1% vs 0% P < 0.01). There was no significant difference in LRRFS between patients who received radical radiotherapy and patients received radical surgery (3ys-LRRFS 76.2% vs 70.9% P = 0.79). Multivariate analysis indicated that addition of radiotherapy was the only independent prognostic factor associated with improved OS (RR:0.40, 95%CI 0.20-0.90, P = 0.03). The Adult HNRMS is a kind of tumor with high malignancy and poor prognosis. Radiotherapy added to treatment significantly improved long-term OS and PFS. However, multimodality treatment (surgery, radiotherapy, and chemotherapy) planning and risk stratification is required for all patients to improve the prognosis of Adult HNRMS.

Caregiver Health: An Epidemiological Study of Active Duty Parents with Special Needs Children

Caregivers of children with Special Healthcare Needs (SHN) are at an elevated risk for adverse health outcomes among the general population; research among military populations is lacking. Records of active duty personnel and children born between 2007 and 2009 were extracted from two military databases. Children with SHN were identified using 3M Clinical Risk Grouping (CRG) software. Active duty personnel were categorized into three parental groups and were followed through 2014 for diagnoses of hypertension, migraines, and sleep disorders. Data analyses included descriptive statistics and logistic regression analyses. The total study population consisted of 1,423,216 active duty personnel, and 10% of parents had a child with SHN. For migraines and sleep disorders, parents of children with SHN showed the highest odds of diagnoses. The odds of hypertension diagnoses were lowest in parents of children without SHN. Effects of parental status also varied by sex. The present study is the first to examine differences in military personnel health outcomes as a function of both parenting status and sex. Findings support continued use and possible expansion of current military programs designed to support families of children with SHN.

Prediction of Minor Salivary Gland Carcinoma: A Novel Nomogram and Risk Classification System for Overall Survival and Cancer-Specific Survival.

Minor salivary gland carcinoma (MiSGC) is rare, and the understanding of this disease is insufficient. This study aimed to identify independent risk factors and develop a nomogram for evaluating the overall survival (OS) and cancer-specific survival (CSS) of patients with MiSGC. Retrospective cohort study. SEER database (Surveillance, Epidemiology, and End Results). We collected data from patients diagnosed with MiSGC between 2004 and 2015 from the SEER database. According to patient registration, all patients were randomly allocated to training sets and validation sets (2:1). Then, Kaplan-Meier product limit curves and Cox proportional hazard regressions were performed to estimate the prognostic effect of variables. Nomograms based on Cox proportional hazard regressions were established to estimate 3- and 5-year OS and CSS. Finally, the nomogram was developed by the training set, and validation was performed with the concordance index, calibration curves, and decision curve analyses. In total, 1787 MiSGC cases were registered in SEER. The concordance index for internal validation of OS and CSS prediction was 0.842 and 0.816; that of external validation was 0.871 and 0.831. The calibration plots showed good consistency between nomogram prediction and actual survival. The decision curve analysis showed substantial net benefits of the new predictive model. We constructed nomograms and a corresponding risk classification system predicting the OS and CSS of patients with MiSGC. These tools can generate simple-to-use clinical risk grouping and determine the relationship between adjuvant therapy and active surveillance.

Survival of head and neck rhabdomyosarcoma in children: a clinical analysis of 98 cases

Objective To analysis the prognosis of head and neck rhabdomyosarcoma (RMS) in pediatrics. Methods The clinical data of 98 pediatric patients with head and neck RMS admitted from February 2005 to September 2017 were retrospectively analyzed. The clinical staging and risk grouping were performed according to international rhabdomyosarcoma study group criterion. The treatment included chemotherapy, radiotherapy and surgery accordingly. The association of prognosis with the disease characters, treatment strategy of 98 patients RMS was analyzed by Chi-square test and Kaplan-Merier analysis with SPSS 20.0 software. Results There were 53 boys (54.1%) and 45 girls (45.9%) with a median age of 70 months (2-161 months). There were 43 cases of orbit RMS (43.9%) , 46 cases of paramenigneal RMS (46.9%) and 9 cases of non-paramenigneal and non-orbit RMS (9.2%) . Twenty seven patients were classified as low risk (27.6%), 42 patients as medium risk (42.9%), and 29 patients as high risk (29.5%). The patients were followed up for a medium of 42 months (9-149 months), 37 cases were dead, 60 cases were survival, and 1 lost the follow-up. Kaplan-Merier survival analysis showed that the overall survival (OS) was 61.9% (60/97), and the average survival time was (92.3±6.9) months. Univariate analysis showed that the OS of patients with paramenigneal RMS was poorer than that of patients with orbit RMS, non-paramenigneal and non-orbit RMS. The OS of high risk RMS patients was poorer than that of intermediate and low risk patients (χ2=6.132, P=0.047) . Conclusions The prognosis of head and neck RMS in children is generally good, but the prognosis of paramenigneal RMS and high-risk RMS is significantly declined. The primary site of paramenigneal and high risk are independent risk factors for the prognosis of head and neck RMS in children. Key words: Rhabdomyosarcoma; Child; Head and neck neoplasms; Prognosis

Impact of Magnetic Resonance Imaging on Prostate Cancer Staging and European Association of Urology Risk Classification

To investigate the impact of magnetic resonance imaging (MRI) information on clinical staging, risk stratification, and treatment recommendations for prostate cancer (PCa) according to the European Association of Urology (EAU) guidelines. We performed a single-center analysis of 180 men with PCa, undergoing clinical staging by digital rectal examination (DRE) as well as MRI before their robot-assisted radical prostatectomy. Patients were stratified according to the EAU guidelines into 4 well-defined risk categories, based on their clinical T-stage assessed by either DRE or MRI. Descriptive statistics of categorical variables are shown as frequencies and proportions. Differences between both scenarios (DRE- vs MRI-staged) were analyzed using a paired-samples sign test. Use of MRI information instead of DRE information leads to significant upstaging of clinical T-stage (33%) and EAU risk grouping (31%). When comparing these results with the pathologic T-stage, MRI showed a higher sensitivity than DRE to detect nonorgan-confined PCa (59% vs 41%; P <.01). In contrast, the specificity of MRI was lower than DRE (69% vs 95%; P <.01). Incorporation of MRI-based instead of DRE-based staging in the treatment decision process would alter the surgical treatment strategy in 49/180 patients (27%). The incorporation of MRI information substantially affects the treatment choice in PCa patients as compared to using the current available EAU guidelines based on DRE information. More specifically, treatment intensification would be recommended in 1 out of 4 patients.

Tumor regression grade as a clinically useful outcome predictor in patients with rectal cancer after preoperative chemoradiotherapy

The prognostic role of tumor regression grade is not clear. This study evaluated the prognostic significance of tumor regression grade in patients with rectal cancer after preoperative chemoradiotherapy. A total of 639 patients with confirmed rectal cancer who had undergone preoperative chemoradiotherapy and radical resection during the period October 2002 through December 2011 were included in this study. The tumor regression grade was graded: TRG0 (complete response), TRG1 (moderate), TRG2 (minimal), and TRG3 (poor). The prognostic significance of tumor regression grade was evaluated. With a median follow-up of 56.7 months, the rates of 5-year overall survival, disease-free survival, and local recurrence-free survival among the TRG groups differed significantly (all P < .001). For patients with TRG0, TRG1, and TRG2-3, disease-free survivals were different between the ypStage (P < .001, P < .001, and P = .043). Multivariate analysis revealed findings to substantiate that the tumor regression grade represents a valuable and independent prognostic factor for long-term, disease-free survival (P = .041). Independent predictors of TRG2-3 consisted of lymphovascular invasion, tumor budding, and the pretreatment serum level of carcinoembryonic antigen in multivariate regression analysis. Clinical risk grouping, using 3 predictors for TRG2-3 was different (P < .001). The tumor regression grade may represent a useful prognostic variable to better individualize the prognosis and potentially further therapy for each rectal cancer patient who underwent chemoradiotherapy.

Feasibility of recruiting publicly insured children with special health care needs for a population-based clinical study.

Assess the feasibility of recruiting children with special health care needs (CSHCN) into a clinical study using Medicaid data. We used the 3M Clinical Risk Grouping software to identify and classify Medicaid-enrolled CSHCN ages 7-17 years in Washington into one of three chronic condition severity groups: episodic, life-long, or malignancy/catastrophic. We compared contact, recruitment, enrollment, and data completion proportions across severity groups using the Pearson chi-square or Fisher's exact test. Of the 2,666 CSHSN in the Medicaid files, we contacted 922 and recruited 211 CSHCN (22.8 percent). One-hundred-thirteen made their study visit (53.6 percent) and 98 had complete data (86.7 percent). We contacted and recruited significantly larger proportions of CSHCN with malignancies/catastrophic conditions (P < 0.01). Across severity groups, there were no differences in enrollment (P = 0.27), but a smaller proportion of CSHCN with life-long conditions had complete data (P = 0.03). It is feasible to recruit CSHCN from Medicaid files for clinical studies.

MP47-04 REFINING SELECTION CRITERIA FOR NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER: COMBINING CLINICAL RISK FEATURES AND INTRINSIC MOLECULAR SUBTYPES

You have accessJournal of UrologyBladder Cancer: Invasive IV1 Apr 2018MP47-04 REFINING SELECTION CRITERIA FOR NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER: COMBINING CLINICAL RISK FEATURES AND INTRINSIC MOLECULAR SUBTYPES Jonathan Duplisea, Michael Metcalfe, Debasish Sundi, Jed Ferguson, Roger Li, Shanna Pretzsch, Ashish Kamat, Neema Navai, Jay Shah, Jolanta Bondaruk, Bogdan Czerniak, Woonyoung Choi, David McConkey, Peter Black, and Colin Dinney Jonathan DupliseaJonathan Duplisea More articles by this author , Michael MetcalfeMichael Metcalfe More articles by this author , Debasish SundiDebasish Sundi More articles by this author , Jed FergusonJed Ferguson More articles by this author , Roger LiRoger Li More articles by this author , Shanna PretzschShanna Pretzsch More articles by this author , Ashish KamatAshish Kamat More articles by this author , Neema NavaiNeema Navai More articles by this author , Jay ShahJay Shah More articles by this author , Jolanta BondarukJolanta Bondaruk More articles by this author , Bogdan CzerniakBogdan Czerniak More articles by this author , Woonyoung ChoiWoonyoung Choi More articles by this author , David McConkeyDavid McConkey More articles by this author , Peter BlackPeter Black More articles by this author , and Colin DinneyColin Dinney More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1483AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clinical and pathologic high-risk (HR) features have been identified to select patients with muscle-invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). Recently, genomic studies have identified intrinsic basal, p53-like, and luminal molecular subtypes of MIBC. The basal subtype is associated with a worse prognosis when treated by RC alone, but has a favorable response to NAC. We sought to study the value of NAC in patients with basal tumors, and to confirm that subtype predicts response to chemotherapy irrespective of clinical risk grouping. METHODS We identified patients with MIBC who underwent RC with or without NAC at two institutions. Patients were considered HR based on the presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection (TURBT). Low-risk (LR) tumors did not possess these features. Whole-genome analysis was performed on TURBT specimens classifying them into basal, luminal or p53-like subtypes. Overall survival (OS) outcomes were compared for each subtype and clinical risk criteria. RESULTS 165 patients were included in our analysis. 52 (32%) were LR and 113 (68%) HR; 99 (60%) patients received NAC and of these, 82 (83%) and 17 (17%) were HR and LR respectively. 49 (30%) of patients had basal tumors. A significant survival benefit with NAC was seen in patients with basal tumors in both HR and LR cohorts (p<0.0001) Fig 1. There was no statistically significant difference in benefit for NAC in patients with either luminal (p=0.2374), or p53-like subtype tumors (0.4134). CONCLUSIONS NAC chemotherapy appears to benefit patients with basal tumors regardless of their clinical risk stratification. Once validated, the risk criteria used to identify HR tumors may include basal tumors, especially since their OS is prolonged after NAC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e616 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Jonathan Duplisea More articles by this author Michael Metcalfe More articles by this author Debasish Sundi More articles by this author Jed Ferguson More articles by this author Roger Li More articles by this author Shanna Pretzsch More articles by this author Ashish Kamat More articles by this author Neema Navai More articles by this author Jay Shah More articles by this author Jolanta Bondaruk More articles by this author Bogdan Czerniak More articles by this author Woonyoung Choi More articles by this author David McConkey More articles by this author Peter Black More articles by this author Colin Dinney More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The role of the clinical risk group classification system in the management of oncologic patients in need of high complexity of care. A pilot study in the local health unit “USL Umbria 2”

Background: Complex oncologic patients require high standards of care, multidisciplinary approach and great resources. The aim of our study is to evaluate the capability of the 3M Clinical Risk Group (3M CRG) system in identifying and managing this specific type of population. Patients and methods: The study was conducted on a cohort of oncologic patients in need of highly complex care provided by six districts in the Umbria 2 Local Health Unit (USL) during 2013. This cohort of patients was identified through the 3M Clinical Risk Grouping Software by using individual demographic, morbidity and pharmaceutical information retrieved from administrative data (e.g. inpatient, outpatient, drug). The same system (CRG) stratified the population from nine mutually exclusive health status up to 1080 risk groups. Both the analysis of the healthcare provided and the analysis of costs entailed were computed in all the six districts. Results: In 2013, USL Umbria 2 provided health care to 2682 patients (0.7% of the total population; 11% of the total health care expenditure) assigned by 3M CRG to the health status 8 (dominant and metastatic malignancies) and 5 severity of illness. The patients were predominantly males (51.52%) and belonging to 55-74 years age group (47.76%). 97.95% of the cohort was hospitalized. In all the six districts, the largest amount of resources was provided for inpatient care. Terni district had the largest number of patients with health status 8 (33.89%). Orvieto district recorded the highest healthcare cost (€17978.7). Conclusions: Our study confirmed CRG as a useful system to identify different high-need population and manage complex oncologic patients by assessing their needs and adjusting interventions and resources. The CRG system combines inpatient data with information from territorial services. For this reason it can be a useful tool for epidemiological analysis, governance of therapeutic-diagnostic pathways and continuity of healthcare in sync with “Italian plan of the chronicity”.

Outcomes in stage I non-small cell lung cancer following the introduction of stereotactic body radiotherapy in Alberta – A population-based study

PurposeTo review outcomes of patients with stage I non-small cell lung cancer (NSCLC) following the introduction of stereotactic body radiation therapy (SBRT). MethodsSBRT cases were linked to the cancer registry database along with clinical, treatment and health service parameters for n=2146 cases of stage I NSCLC diagnosed between 2005 and 2011. The pre-diagnosis Aggregated Clinical Risk Grouping score (ACRG3) was used as a proxy for pre-treatment patient comorbidity. A Cox regression model and the concordance statistic (C-statistic) were used to examine variables predicted for overall survival (OS). ResultsThe SBRT utilization rate increased annually with superior OS to conventional RT (median survival [MS] of 39.4 VS. 23.5months, P<0.001) despite higher ACRG3 scores. Surgical patients were younger, had lower ACRG3, achieving MS of 69.6months. Regression analysis indicated both Surgery (hazard ratio [HR]=0.23, 95% CI: 0.18–0.28) and SBRT (HR=0.33, 95% CI: 0.21–0.51) remained most strongly associated with OS. ACRG3 (HR=0.79, P<0.001) and age (HR=0.83, P=0.03) were independently associated with OS. The OS model was associated with the C-statistic at 0.86, 95% CI: 0.81–0.90. ConclusionIn stage I NSCLC patients treated with surgery have the best survival. SBRT demonstrates improved OS compared to conventional RT. C-statistic result demonstrates discrimination of treatment selection factors on OS.

Outcomes in stage I non-small cell lung cancer following the introduction of stereotactic body radiotherapy in Alberta, Canada.

306 Background: Stereotactic body radiotherapy (SBRT) is a treatment option for patients with Stage I (T1-T2N0M0) NSCLC (non-small cell lung cancer) who decline surgery or are medically inoperable. Case series suggest superior outcomes with lung SBRT compared to conventional radiotherapy and high local control rates. The primary study objective was to describe population outcomes in the initial management of stage 1 NSCLC patients including treatment utilization rates and survival. Methods: Clinical records of patients diagnosed with Stage 1 NSCLC who attended any SBRT clinic in Alberta between 2005 and 2011 were examined with REB approval. These cases were linked to the Alberta Cancer Registry and Provincial Health Administration databases. Clinical, treatment, pre-diagnosis 3M Aggregate Clinical Risk Grouping (ACRG3) scores as a proxy for prevailing patient comorbidity and health services characteristics pertaining to all cases of stage 1 NSCLC between 2005 and 2011 were determined. A cox regression model was constructed to examine the influence of these factors and their interactions on cancer outcomes. Results: 2,146 patients were diagnosed with stage 1 NSCLC. Median patient age was 72 and overall 43.0% of cases had a 1 year pre-treatment ACRG3 score of 10-49. Observed treatment utilization rates; surgery 63.4% (95%CI: 61.4-65.4), conventional RT 9.0% (7.9-10.3%), SBRT 3.6% (2.8-4.4%), chemotherapy 0.8% (0.5-1.4%) and no treatment 23.2% (21.4-25.0%). Median survival ranged from 69.6 months for surgery to 17.0 months if no active treatment was delivered. SBRT had survival outcomes superior to conventional radiotherapy: median survival of 39.4 vs. 23.5 months (p&lt;0.001), despite more patients 69.9% vs 63.0% having an ACRG3-1y of 50 or higher. On multivariate analysis, while accounting for all modeled variables including ACRG3 pre-treatment and compared to patients receiving no active treatment, primary surgical intervention HR= 0.23 (95%C.I.:0.18-0.28) and SBRT HR=0.33 (0.21-0.51) remained most strongly associated with survival.No significant variable interactions (p&lt;0.05) between treatment modality, patient age, pathology diagnosis and ACRG3 scores were demonstrated to impact on survival outcomes. Conclusions: Surgery for Stage I NSCLC patients is associated with the best overall survival. SBRT patients have improved survival over conventional radiotherapy. Improvements in population level outcomes may result from an increased utilization of SBRT in the non-surgical management of stage I lung cancer.

Impact of chronic condition status and severity on dental utilization for Iowa Medicaid-enrolled children.

Although Medicaid-enrolled children with a chronic condition (CC) may be less likely to use dental care because of factors related to their CC, dental utilization for this population is poorly understood. To assess the relationship between CC status and CC severity, respectively, on dental utilization for Iowa Medicaid-enrolled children. Retrospective cohort study of Iowa Medicaid data (January 1, 2003 to December 31, 2006). Medicaid-enrolled children aged 3 to 14 (N = 71,115) years. The 3M Corporation Clinical Risk Grouping methods were used to assess CC status (no/yes) and CC severity (episodic/life-long/malignancy/complex). The outcome variable was any dental utilization in 2006. Secondary outcomes included use of diagnostic, preventive, routine restorative, or complex restorative dental care. After adjusting for model covariates, Iowa Medicaid-enrolled children with a CC were significantly more likely to use each type of dental care except routine restorative care (P = 0.86) than those without a CC, although the differences in the odds were small (4%-6%). Compared with Medicaid-enrolled children with an episodic CC, children with a life-long CC were less likely to use routine restorative care (P < 0.0001), children with a malignancy were more likely to use complex restorative care (P < 0.03), and children with a complex CC were less likely to use each type of dental care except complex restorative care (P = 0.97). There were differences in dental utilization for Iowa Medicaid-enrolled children by CC status and CC severity. Children with complex CCs were the least likely to use dental care. Future research efforts should seek to understand why subgroups of Medicaid-enrolled children with a CC exhibit lower dental utilization.

Impact of chronic condition status and severity on the time to first dental visit for newly Medicaid-enrolled children in Iowa.

To assess the extent to which chronic condition (CC) status and severity affected how soon children had a dental visit after enrolling in Medicaid. Data Source. Enrollment and claims data (2003-2008) for newly Medicaid-enrolled children ages 3-14 in Iowa. 3M Clinical Risk Grouping methods were used to identify CC status (no/yes) and CC severity (less severe/more severe). Survival analysis was used to identify the factors associated with earlier first dental visits after initially enrolling in Medicaid. Children with a CC were 17 percent more likely to have earlier first dental visits after enrolling in Medicaid (p < .0001). There was no significant difference by CC severity. Children who lived in a dental health professional shortage area and those who did not utilize primary medical care had significantly later first Medicaid dental visits, whereas these factors failed to reach statistical significance for children with a CC. While newly Medicaid-enrolled children with a CC were significantly more likely to have earlier first dental visits, we failed to detect a relationship between CC severity and the time to first Medicaid dental visit. The determinants of first Medicaid dental visits were heterogeneous across subgroups of newly Medicaid-enrolled children. Future studies should identify the sociobehavioral factors associated with CCs that are potential barriers to earlier first Medicaid dental visits for newly Medicaid-enrolled children.

Impact of chronic condition status and severity on dental treatment under general anesthesia for Medicaid‐enrolled children in Iowa state

To assess the impact of chronic condition (CC) status and CC severity, respectively, on the odds of receiving dental treatment under general anesthesia (GA) for Medicaid-enrolled children by age group. This was a retrospective analysis of Iowa Medicaid-enrolled children <15 years (n = 62 721) from 2005 to 2008. 3M Clinical Risk Grouping Software identified each child's CC status (yes/no) and assigned children with a CC into a hierarchal CC severity group (episodic/life-long/complex). Multiple variable logistic regression models were used to identify the determinants of dental treatment under GA. Less than 1% of children received dental treatment under GA. While there was no significant difference in dental treatment under GA by CC status for children <6, those with a life-long CC were twice as likely to receive dental treatment under GA as demographically similar children with an episodic CC (P < 0.05). Children ages 6-14 with a CC were three times as likely as those without a CC to receive treatment under GA (P = 0.001). There was also a direct relationship between CC severity and dental treatment under GA use for older children. Those living in nonmetropolitan areas were more likely to receive treatment under GA as were children who previously received dental treatment under GA. Chronic condition status and severity were more important determinants of dental treatment under GA for Medicaid-enrolled children ages 6-14 than for those <6. Understanding these relationships is a critical step in developing clinical strategies and interventions aimed at preventing dental disease for Medicaid-enrolled children whose reasons for needing dental treatment under GA are modifiable.

Gleason Scoring Varies Among Pathologists and this Affects Clinical Risk in Patients with Prostate Cancer

To investigate whether our practice of specialist review of all diagnostic biopsies was necessary to prevent misgrading of referred prostate cancer patients, and whether this misclassification, if any, would have resulted in misclassification of clinical risk grouping (Seattle Risk Grouping [SRG]) and subsequent treatment strategy and prognosis. Important prognostic indicators for prostate cancer include the presenting prostate-specific antigen (PSA), clinical stage and Gleason sum of the tumour. These three variables are incorporated into the SRG cohorts to establish treatment strategy. Patients with prostate cancer referred for brachytherapy had their prostate biopsies reviewed by a reference pathologist (PD) with a special interest in prostate cancer. We compared the agreement between the scoring of the referring pathologists with that of PD, and evaluated if any differences changed the SRG and therefore the clinical risk and treatment strategy for the patients. In only 52% (43/83) of cases, was there total agreement between the two sets of pathologists. The inter-rater agreement was statistically 'fair' (unweighted kappa statistic 0.27). In 90% (36/40) of cases with disagreement, PD assigned higher Gleason sums. In 40% (16/40) of cases with disagreement, the change in Gleason sum altered the SRG; in one out of 16 cases, the SRG was downgraded from 'intermediate' to 'low' risk disease; in six out of 16 cases, it was upgraded from 'low' to 'intermediate' risk, and, in nine out of 16, from 'intermediate' to 'high' risk. Our findings confirm previous reports of only limited correlation between pathologists in reporting Gleason sums. In this study, 19% (16/83) of cases had their grading changed to a level that altered clinical risk, almost always (94%; 15/16) to one that worsened prognosis. This would have significantly affected treatment strategy for these patients, and thus we recommend that all centres ensure accurate Gleason grading by the use of pathologists with special interests in prostate cancer.