Alter Treatment Decisions Research Articles

Association Between Tibiofemoral Bone Shape Features and Retears After Anterior Cruciate Ligament Reconstruction.

A retear after anterior cruciate ligament (ACL) reconstruction remains a common and devastating complication. Knee bone morphology is associated with the risk of ACL injuries, ACL retears, and osteoarthritis, and a combination of tools that derive bone shape from clinical imaging, such as magnetic resonance imaging (MRI) and statistical shape modeling, could identify patients at risk of developing these joint conditions. To identify bone shape features before primary ACL reconstruction in patients with an eventual retear compared to those with a known intact ACL graft. Case-control study; Level of evidence, 3. Bone was automatically segmented on 2-dimensional proton density-weighted MRI of the knee in patients at the time of the initial ACL injury using deep convolutional neural networks. Patients with a subsequent retear after reconstruction within 3 years (22 femurs, 19 tibias) were compared with those with an intact ACL graft at 3 years (20 femurs, 22 tibias) using statistical shape modeling to identify preoperative bone shape features predictive of a retear after ACL reconstruction. Statistical shape modeling revealed 2 specific bone shape features (modes) in the femur and 1 mode in the tibia that demonstrated significant differences at the time of the initial injury in patients with subsequent retears. In the femur, a narrower intercondylar notch width, a widened medial condylar width, an increased femoral condylar offset ratio, increased surface area along the lateral femoral condyle relative to the medial condyle, and a more prominent trochlear sulcus at the time of the initial injury were associated with retears after ACL reconstruction. In the tibia, a diminished ACL facet prominence, a squared lateral and medial tibial plateaus, and a broader and flattened tibial spine at the time of the initial injury were associated with retears after ACL reconstruction. Using the automatic bone segmentation pipeline on preoperative MRI, the authors identified bone shape features associated with a retear after ACL reconstruction. The use of this pipeline enables large-scale studies of bone shape on MRI and could predict patients at risk of ACL retears to alter treatment decisions.

Identifying thresholds of reaction for different foods.

Current food allergy management universally treats all patients with food allergy as being at risk for anaphylaxis (with the exception perhaps of pollen food allergy syndrome). Thus, patients are told to avoid the allergenic food in all potentially allergic forms and amounts. However, research over the past 2 decades has shown that many patients will tolerate small amounts of the allergen without any allergic reaction. Thus, if one were able to identify the threshold of reactivity, this could change management. At the population level, establishing levels at which the vast majority of patients (e.g., 95%) do not react could have public health ramifications, such as altering labeling laws. At the individual patient level, personal threshold levels could determine avoidance strategies, affect quality of life, and alter treatment decisions, e.g., oral immunotherapy starting doses. In this review, threshold data for various allergens and their potential effect on the management of the patient with food allergy are examined.

A questionnaire-based study on the management of deep carious lesions and exposed pulp among members of the Indian conservative dentistry and endodontic societies

Aim: Lack of unanimity in decision-making regarding the management of deep caries and exposed pulp has been highlighted by several questionnaire-based studies from various geographic regions. There is no research available in the Indian setting. The aim of the present study was to evaluate the perspectives of the Indian Endodontic Society and Indian Association of Conservative Dentistry and Endodontics members using an online questionnaire. Methods: An online structured questionnaire of 17 questions was mailed to 200 members based on the periapical radiographs of two cases (18 and 55 years of age) highlighting deep carious lesions and normal periapex in a mandibular molar. Each case had three hypothetical scenarios based on pulpal symptoms, i.e., asymptomatic pulp, reversible, and irreversible pulpitis, respectively. Results: A response rate of 65.5% (n = 131) was achieved. Nonselective caries removal was chosen by 40% and 36% of the participants in young patients with asymptomatic pulp and reversible pulpitis. On pulpal exposure, direct pulp capping was chosen by a majority of the members (66% and 54%, respectively) in a young patient. For irreversible pulpitis, pulpectomy was favored by 70%. In an older patient, less vital pulp therapy and more pulpectomy were preferred. The symptoms and patient age significantly altered treatment decisions, as determined by Chi-square and Fisher’s exact tests (P < 0.05). Conclusion: There was a lack of agreement in managing deep carious lesions. There was partial awareness of the management of exposed pulp.

A Napaac Survey to Understand Practices in Diagnosis and Treatment of Children with Moderate Aplastic Anemia

Among patients with acquired aplastic anemia, approximately 20% do not meet current classification as severe based on established criteria that reflect blood counts and marrow cellularity. For patients with moderate aplastic anemia (MAA), there is no set of defined diagnostic criteria, or clear standard-of-care for management. Little is known about the natural history of spontaneous recovery versus progression to severe bone marrow failure (BMF), response to conventional immunosuppressive treatment (IST), or evolution to myelodysplasia (MDS). Thus, institutional and individual practice can range from observation to immunosuppression or hematopoietic stem cell transplantation (HSCT). Recent studies of this patient population have begun to identify individuals harboring pathogenic mutations in genes known to cause BMF. To better understand population characteristics and management practices for patients with MAA, a survey was conducted through the North American Pediatric Aplastic Anemia Consortium (NAPAAC), consisting of 52 centers with expertise in BMF across North America. A total of 65 surveys were completed by pediatric hematology-oncology providers (55 attending physicians, 5 nurse practitioners and 5 fellows). Across all groups, there was marked variability of the MAA definition. Cytopenias were the defining criteria for diagnosis, including ANC<1000 cells/ul (79%), platelets <100K cells/ul (43%), and anemia for age (47%). In contrast, bone marrow hypocellularity (<50% cellularity) was considered by less than half (48%) of the respondents to be necessary for diagnosis. The combination of hypocellular bone marrow plus two cytopenias was considered the most common diagnostic definition of MAA (60% of participants). Although genetic testing has begun to transform diagnosis for many hematological diseases and can alter treatment decisions for pediatric BMF disorders, only 51% currently consider next generation sequencing (NGS) and 4% consider whole exome/whole genome sequencing as part of the initial work-up for MAA. Conventional cytogenetics and FISH are used more frequently in the initial work-up (86% and 73%, respectively). The two main triggers for treatment were dependence on red blood cell- (92%) or platelet (87%) transfusions, followed by persistent cytopenias (54%) and cytogenetic abnormalities (53%). Where available, acquired somatic variants triggered treatment in 30% of responses. Interestingly, infections were a less frequent trigger for treatment (35%). The most common management approaches were observation with transfusions (79%), single agent thrombopoietin receptor agonists (71%) or ATG+Cyclosporine based immune suppressive therapy (IST, 61%). Progression to severe aplastic anemia (SAA, 97%), myelodysplastic syndrome (MDS, 97%), or refractoriness to IST (61%) were the most common indications for HSCT.Availability of a matched sibling donor (MSD, 12%) was an infrequent indication for HSCT. A growing body of work, albeit largely in adult patients, suggests that patients with MAA represent a heterogenous group of individuals, some with genetic predisposition to BMF and inherent risk of myelodysplastic evolution. We identified that half of the responding NAPAAC practitioners use NGS panels routinely, suggesting a need for increased awareness to consider this work-up at initial diagnosis. Future studies are important to determine the yield of standard NGS testing, as the diagnosis of inherited BMF syndromes alter the strategy for long term surveillance of patients and genetic counseling for the family, as well as the use of related donor HSCT. We observed variability regarding the diagnostic criteria and management of children with MAA by providers who are members of NAPAAC. The heterogeneous responses to our survey suggest the need to establish management guidelines for uniform work-up and treatment, and to facilitate research of this understudied population. PC, LO: contributed equally as first authors. PK, JD: contributed equally as senior authors

Impact of 18F-FDG PET/CT in the management decisions of breast cancer board on early-stage breast cancer.

Breast cancer is the most common malignancy accounting for 11.7% of all cancer cases, with a rising incidence rate. Various diagnostic methods, including 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT), play a crucial role in breast cancer diagnosis and staging. However, the unnecessary use of advanced imaging techniques such as PET/CT in early-stage breast cancer can have negative effects on both economics and patients. We aimed to investigate the impact of PET/CT on the management decisions of early-stage breast cancer patients by the breast cancer tumor board. A retrospective analysis was performed on a cohort of 81 patients with early-stage breast cancer who were evaluated by breast cancer tumor board from January 2015 to December 2020. Demographic, clinical, and radiographic data, along with surgical procedures and treatment options, were documented and analyzed. The results showed that 18F-FDG PET/CT had a moderate impact on treatment decisions of breast cancer tumor board, as only treatment decisions were changed in 14,86% of the patients. The surgical procedure decision of breast cancer tumor board changed in 12.35% of patients, while 87.65% of patients had consistent decisions before and after PET/CT. Pathological assessments revealed invasive ductal carcinoma as the most prevalent tumor type, and molecular subtypes were predominantly luminal B. PET/CT use had limited impact on surgical procedures and did not significantly alter treatment decisions of breast cancer tumor board in this early-stage breast cancer cohort. In conclusion, this study highlights the importance of adherence to the guidelines and appropriate use of PET/CT in early-stage breast cancer management. PET/CT should be reserved for cases where it is clinically warranted, considering the potential economic burden and minimal impact on treatment decisions of breast cancer tumor board in this patient population.

Reducing the Price of Naïveté in return‐to‐play from sports‐related concussion

Patient‐reported outcomes (PROs) play an increasingly important role in medical decision making. Yet, patients whose objectives differ from their physician's may strategically report symptoms to alter treatment decisions. For example, athletes may underreport symptoms to expedite return‐to‐play (RTP) from sports‐related concussion (SRC). Thus, clinicians must implement treatment policies that mitigate the Price of Naïveté, that is, the reduction in health outcomes due to naïvely believing strategically reported symptoms. In this study, we analyze dynamic treatment cessation decisions with strategic patients. Specifically, we formulate the Behavior‐Aware Partially Observable Markov Decision Process (BA‐POMDP), which optimizes the timing of treatment cessation decisions while accounting for known symptom‐reporting behaviors. We then analytically characterize the BA‐POMDP's optimal policy, leading to several practical insights. Next, we formulate the Behavior‐Learning Partially Observable Markov Decision Process (BL‐POMDP), which extends the BA‐POMDP by learning a patient's symptom‐reporting behavior over time. We show that the BL‐POMDP is decomposable into several BA‐POMDPs, allowing us to leverage the BA‐POMDP's structural properties for solving the BL‐POMDP. Then, we apply the BL‐POMDP to RTP from SRC using data from 29 institutions across the United States. We estimate the Price of Naïveté by comparing the BL‐POMDP to naïve benchmark policies. Accordingly, the BL‐POMDP reduces premature RTP by over 44% and provides up to 3.63 additional health‐adjusted athletic exposures per athlete compared to current practice. Overall, changing the interpretation of reported symptoms can better reduce the Price of Naïveté over adjusting treatment cessation thresholds. Therefore, to improve patients' health outcomes, clinicians must understand how strategic behavior manifests in PROs.

Prostate Biopsy in the Case of PIRADS 5-Is Systematic Biopsy Mandatory?

Combining systematic biopsy (SB) with targeted biopsy (TB) in the case of a positive result from multiparametric magnetic resonance imaging (mpMRI) is a matter of debate. The Prostate Imaging Reporting and Data System (PIRADS) score of 5 indicates the highest probability of clinically significant prostate cancer (csPC) detection in TB. Potentially, omitting SB in the case of PIRADS 5 may have a marginal impact on the csPC detection rate. The aim of this study was to determine whether SB can be avoided in the case of PIRADS 5 and to identify potential factors allowing for performing TB only. This cohort study involved n = 225 patients with PIRADS 5 on mpMRI (PIRADS 2.0/2.1) who underwent transperineal or transrectal combined biopsy (CB). CsPC was diagnosed in 51.6% (n = 116/225) of cases. TB and SB resulted in the detection of csPC in 48% (n = 108/225) and 20.4% (n = 46/225) of cases, respectively (TB vs. SB, p < 0.001). When the TB was positive, SB detected csPC in n = 38 of the cases (38/108 = 35%). SB added to TB significantly improved csPC detection in 6.9% of cases in absolute terms (n = 8/116) (TB vs. CB, p = 0.008). The multivariate regression model proved that the significant predictors of csPC detection via SB were the densities of the prostate-specific antigen-PSAD > 0.17 ng/mL2 (OR = 4.038, 95%CI: 1.568-10.398); primary biopsy setting (OR = 2.818, 95%CI: 1.334-5.952); and abnormal digital rectal examination (DRE) (OR = 2.746, 95%CI: 1.328-5.678). In a primary biopsy setting (n = 103), SB detected 10% (n = 6/60) of the additional cases of csPC (p = 0.031), while in a repeat biopsy setting (n = 122), SB detected 3.5% (n = 2/56) of the additional cases of csPC (p = 0.5). In the case of PSAD > 0.17 ng/mL2 (n = 151), SB detected 7.4% (n = 7/95) of additional cases of csPC (p = 0.016), while in the case of PSAD < 0.17 ng/mL2 (n = 74), SB detected 4.8% (n = 1/21) of the additional cases of csPC (p = 1.0). The omission of SB had an impact on the csPC diagnosis rate in patients with PIRADS 5 score lesions. Patients who have already undergone prostate biopsy and those with low PSAD are at a lower risk of missing csPC when SB is avoided. However, performing TB only may result in missing other csPC foci located outside the index lesion, which can alter treatment decisions.

PD09-12 THE USE OF 68 Ga-FAP-2286 PET IMAGING IN PATIENTS WITH LOCALIZED BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD09-12 THE USE OF 68Ga-FAP-2286 PET IMAGING IN PATIENTS WITH LOCALIZED BLADDER CANCER Domenique Escobar, Vadim Koshkin, Brad Kline, Jonathan Chou, Maxwell Meng, Terence Friedlander, Vipul Kumar, Thomas Hope, and Sima Porten Domenique EscobarDomenique Escobar More articles by this author , Vadim KoshkinVadim Koshkin More articles by this author , Brad KlineBrad Kline More articles by this author , Jonathan ChouJonathan Chou More articles by this author , Maxwell MengMaxwell Meng More articles by this author , Terence FriedlanderTerence Friedlander More articles by this author , Vipul KumarVipul Kumar More articles by this author , Thomas HopeThomas Hope More articles by this author , and Sima PortenSima Porten More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bladder cancer is a common and often aggressive malignancy. Computed tomography (CT), magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET) are used for staging but have limitations in identifying nodal or metastatic disease. Fibroblast activation protein (FAP) is a cell surface protein that is highly expressed on cancer-associated fibroblasts present in many cancers, including bladder cancer. We present the results of a pilot study assessing the diagnostic performance of 68Ga-FAP-2286 (FAP)-PET imaging in a cohort of patients with bladder cancer. METHODS: Patients with solid tumors underwent FAP-PET as part of a clinical trial (NCT04621435), including 16 patients with bladder cancer. We report on ten patients with clinically localized disease treated with curative intent at the time of imaging. Standard imaging with CT, MRI, FDG-PET, or bone scan was performed within 8 weeks of FAP-PET. The maximum standardized uptake value (SUV) and size of FAP-PET-positive lesions (defined as any focus of activity with at least 1.5 times higher SUV compared with mediastinal blood pool) were documented. RESULTS: Patient demographics and clinical stage are summarized in Table 1. Concordance of 12 FAP-PET scans was 33% with standard imaging and 43% with FDG-PET. Of 8 patients with pathologic or radiographic follow up, FAP-PET was concordant with true disease status in 100%. Two patients had FAP-PET before and after neoadjuvant chemotherapy; one had resolution of lymph node uptake and one had decreased but persistent uptake on (pathology from pelvic lymph node dissection positive for urothelial carcinoma). We highlight two cases where FAP-PET altered treatment decisions (Figure 1). CONCLUSIONS: FAP-PET has the potential to change treatment pathways and improve patient care by better identifying metastatic sites or falsely positive lymph nodes in cancers considered clinically localized and by improving response assessment to systemic therapy. Source of Funding: IIT from Clovis © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e245 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Domenique Escobar More articles by this author Vadim Koshkin More articles by this author Brad Kline More articles by this author Jonathan Chou More articles by this author Maxwell Meng More articles by this author Terence Friedlander More articles by this author Vipul Kumar More articles by this author Thomas Hope More articles by this author Sima Porten More articles by this author Expand All Advertisement PDF downloadLoading ...

The role of PET in the management of sarcoidosis.

Purpose of reviewPET has emerged as method to determine the location and extent of disease activity in sarcoidosis. As most clinicians do not routinely utilize PET in the management of sarcoidosis, an understanding of the imaging technique is needed to comprehend the impact that PET abnormalities have on diagnosis, prognosis, and treatment.Recent findingsAlthough PET can detect inflammation because of sarcoidosis throughout the body, it is most often utilized for the diagnosis of cardiac sarcoidosis for which it may provide information about prognosis and adverse events. Whenever PET is combined with cardiac magnetic resonance (CMR), clinicians may be able to increase the diagnostic yield of imaging. Furthermore, PET abnormalities have the potential to be utilized in the reduction or augmentation of therapy based on an individual's response to treatment. Although various biomarkers are used to monitor disease activity in sarcoidosis, an established and reproducible relationship between PET and biomarkers does not exist.SummaryPET has the potential to improve the diagnosis of sarcoidosis and alter treatment decisions but prospective trials are needed to define the role of PET while also standardizing the performance and interpretation of the imaging modality.

Concordance of breast cancer biomarker testing in core needle biopsy and surgical specimens: A single institution experience.

Accurate diagnostic biomarker testing is crucial to treatment decisions in breast cancer. Biomarker testing is performed on core needle biopsies (CNB) and is often repeated in the surgical specimen (SS) after resection. As differences between CNB and SS testing may alter treatment decisions, we evaluated concordance between CNB and SS as well as associated changes in treatment and clinical outcomes. We performed a retrospective analysis of breast cancer patients at our institution between January 2010 and May 2020. Concordance between CNB and SS was assessed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Survival in patients, including recurrence, metastatic recurrence, and death, were assessed using chi-squared likelihood ratio. In total, 961 patients met eligibility criteria. Concordance, minor discordance, total concordance (concordance plus minor discordance), and major discordance between CNB and SS were reported for ER (87.7%, 9.2%, 90.8%, and 2.9%), PR (58.1%, 29.1%, 87.2%, and 12.8%), and HER2 IHC (52.5%, 20.9%, 73.4%, 26.6%), respectively. HER2 FISH concordance and major discordance were 58.5% and 1.2%, respectively. Of major discordance, ER (48.2%, p< 0.001) and HER2 FISH (50.0%) led to more management changes than HER2 IHC (2.4%, p= 0.04) and PR (1.6%, p= 0.10). Patients with ER major discordance had increased risk of death (6.7% concordance vs. 22.2% major discordance, p= 0.004). Overall, retesting ER and HER2 was more clinically beneficial than retesting PR. To aid decision-making and minimize healthcare costs, we propose patient-centered guidelines on retesting biomarker profiles.

A prospective decision impact study to evaluate the utility of the Oncotype DX Breast DCIS score assay in selecting patients with ductal carcinoma in situ (DCIS) following breast conservation surgery (BCS) for radiotherapy.

e12571 Background: There is increasing reliance on data provided by genomic risk assessment assays to guide therapeutic decisions. The objective of this prospective study was to assess the impact of the Oncotype DX Breast DCIS Score assay on radiation treatment recommendations in patients with DCIS undergoing BCS. Methods: This decision impact study is a prospectively enrolled observational study of newly diagnosed patients (n = 135) following BCS for removal of DCIS of all grades 30mm or less with clear margins (i.e. 2 mm or normal re-excised margins). Only patients who were candidates to receive radiation therapy were considered. Fifteen patients withdrew from the study or had insufficient volume of DCIS for assay analysis. Radiation Oncologists were blinded to the Oncotype DX Breast DCIS Score assay prior to recording their recommendation for radiotherapy or not. IRB approval was granted following review of study protocol and informed consent was obtained from all patients. Results: Among 120 patients tested, the Oncotype DX Breast DCIS Score assay determined that 58/120 (48.3%) of patients had a low score (LS) (0-38), 30/120 (25%) had an intermediate score (IS) (39-54) and 32/120 (26.7%) had a high score (HS) (&gt;55). The Oncotype DX Breast DCIS Score assay concurred with the Radiation Oncologists recommendation to proceed with radiation treatment in 96.7% of patients (i.e. 60/62 patients with an IS or HS). The Oncotype DX Breast DCIS Score assay altered treatment decisions in 12.5% (4/32) of patients with a HS and in 7.1% (2/28) patient with an IS. In patients where the Oncotype DX Breast DCIS Score assay altered treatment recommendation all had a low volume (i.e. less than 10mm) of high/intermediate grade DCIS with an IS or HS. Conclusions: This study demonstrates that Oncotype DX Breast DCIS Score assay accurately supports the selection of patients with DCIS for radiation treatment and equally can be helpful in selecting a subgroup of patients with small volumes of intermediate/high grade DCIS who can potentially avoid radiotherapy.

The Extent of Externalities from Medicare Payment Policy

Medicare accounts for roughly 20 percent of medical expenditures in the United States and is the dominant payer for many treatments. Consequently, Medicare payment policy may have diffuse consequences. Using a contemporary bundled payment reform (the “CJR” program) and a difference-in-differences research design, we estimate Medicare’s spillover reach. We find that altered treatment decisions for targeted joint replacement procedures are closely, though not perfectly, mirrored between traditional Medicare, Medicare Advantage, and the nonelderly commercially insured populations. Results for untargeted procedures performed by CJR-affected physicians also show suggestive evidence consistent with a secondary spillover effect; however, this behavior change does not extend to less related procedures. Our findings align with the “norms hypothesis” for physician decision making but do not imply rigid and uniform treatment choices. Instead, key decision nodes appear to gain greater salience under Medicare’s new incentive structure, which leads to revised treatment choices for different payer-procedure combinations. Ignoring the breadth of externalities from Medicare policies risks understating their social welfare impact.

Vertebral fracture: epidemiology, impact and use of DXA vertebral fracture assessment in fracture liaison services

SummaryVertebral fractures are independent risk factors for vertebral and nonvertebral fractures. Since vertebral fractures are often missed, the relatively new introduction of vertebral fracture assessment (VFA) for imaging of the lateral spine during DXA-measurement of the spine and hips may contribute to detect vertebral fractures. We advocate performing a VFA in all patients with a recent fracture visiting a fracture liaison service (FLS). Fracture liaison services (FLS) are important service models for delivering secondary fracture prevention for older adults presenting with a fragility fracture. While commonly age, clinical risk factors (including fracture site and number of prior fracture) and BMD play a crucial role in determining fracture risk and indications for treatment with antiosteoporosis medications, prevalent vertebral fractures usually remain undetected. However, vertebral fractures are important independent risk factors for future vertebral and nonvertebral fractures. A development of the DXA technology, vertebral fracture assessment (VFA), allows for assessment of the lateral spine during the regular DXA bone mineral density measurement of the lumbar spine and hips. Recent approaches to the stratification of antiosteoporosis medication type according to baseline fracture risk, and differences by age in the indication for treatment by prior fracture mean that additional information from VFA may influence initiation and type of treatment. Furthermore, knowledge of baseline vertebral fractures allows reliable definition of incident vertebral fracture events during treatment, which may modify the approach to therapy. In this manuscript, we will discuss the epidemiology and clinical significance of vertebral fractures, the different methods of detecting vertebral fractures, and the rationale for, and implications of, use of VFA routinely in FLS.Summary points• Vertebral fracture assessment is a tool available on modern DXA instruments and has proven ability to detect vertebral fractures, the majority of which occur without a fall and without the signs and symptoms of an acute fracture.• Most osteoporosis guidelines internationally suggest that treatment with antiosteoporosis medications should be considered for older individuals (e.g., 65 years +) with a recent low trauma fracture without the need for DXA.• Younger individuals postfracture may be risk-assessed on the basis of FRAX® probability including DXA and associated treatment thresholds.• Future fracture risk is markedly influenced by both site, number, severity, and recency of prior fracture; awareness of baseline vertebral fractures facilitates definition of true incident vertebral fracture events occurring during antiosteoporosis treatment.• Detection of previously clinically silent vertebral fractures, defining site of prior fracture, might alter treatment decisions in younger or older FLS patients, consistent with recent IOF-ESCEO guidance on baseline-risk-stratified therapy, and provides a reliable baseline from which to define new, potentially therapy-altering, vertebral fracture events.

Genitourinary manifestations of hereditary cancer predisposition syndromes in children.

Several hereditary cancer predisposition syndromes are associated with genitourinary (GU) manifestations in children. The GU manifestation may be the first symptom of a more global syndrome to arise, which places the pediatric urologist in a unique position to impact the health of the child. Some GU manifestations are pathognomonic for a particular hereditary cancer predisposition syndrome, which can prompt genetic testing and enhanced surveillance for other features of the condition. In other cases, knowledge of an underlying hereditary cancer predisposition syndrome alters treatment decisions. This review focuses on hereditary cancer predisposition syndromes that impact the GU tract and are likely to be seen by a pediatric urologist.

Prostate cancer growth patterns beyond the Gleason score: entering a new era of comprehensive tumour grading.

The Gleason grading system is one of the most important factors in clinical decision‐making for prostate cancer patients, and is entirely based on the classification of tumour growth patterns. In recent years it has become clear that some individual growth patterns themselves have independent prognostic value, and could be used for better personalised risk stratification. In this review we summarise recent literature on the clinicopathological value and molecular characteristics of individual prostate cancer growth patterns, and show how these, most particularly cribriform architecture, could alter treatment decisions for prostate cancer patients.

Differential trajectories of neurocognitive functioning in females versus males following treatment for pediatric brain tumors.

Female and male trajectories of cerebellar and lobar brain structures are sexually dimorphic, making sex a potential candidate moderator of neurocognitive late effects from radiation treatment. We sought to evaluate longitudinal neurocognitive functioning in male versus female children treated for posterior fossa brain tumors. Fifty-one female and 63 male survivors of posterior fossa tumors completed neuropsychological testing at 2 timepoints. We included patients treated with surgical resection, chemotherapy, and radiation therapy. Multilevel mixed modeling was used to predict IQ score as a function of patient sex following treatment (~2 or ~4 years post treatment). Effect sizes were used as a measure of clinical significance. Multilevel models resulted in a significant sex by time interaction (F = 6.69, P = 0.011). Females' cognitive scores were considerably higher compared with males at 4 years posttreatment. Females demonstrated an average improvement of 7.61 standard score IQ points compared with a decline of 2.97 points for males at 4 years follow-up. Effect sizes for female IQ compared with male IQ at 4 years posttreatment were between 0.8 and 0.9. Trajectories of neurocognitive functioning following posterior fossa tumor treatment differed between female and male children. Sexual dimorphism in radiation late effects may alter treatment decisions in children. Research into sex-specific neuroprotective mechanisms underlying neurocognitive development following pediatric brain tumor treatments is warranted.

Thinking outside the box: a more efficient diagnostic approach in metastatic colorectal cancer

Thinking outside the box: a more efficient diagnostic approach in metastatic colorectal cancer

The Clinical Utility of Pharmacogenomics Testing in Assessing Tyrosine Kinase Inhibitor Therapy, Intolerance and Responses in Patients with Chronic Myelogenous Leukemia

Background: Chronic myelogenous leukemia (CML) is a BCR-ABL1 driven myeloid neoplasm, with excellent response rates to tyrosine kinase inhibitors (TKI). TKI such as imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) currently US FDA approved, have dramatically changed survival outcomes. That being said, two main challenges exist; suboptimal responses and TKI intolerance. The reason why some patients tolerate/respond to TKI better than others is unknown, but is potentially explainable based on drug metabolism. The field of pharmacogenomics (PGX) is rapidly evolving, with commercial panel's rapidly assessing metabolic pathways such as cytochrome P450 (CYP), UGTA1A, p-glycoprotein/ABCB1. We carried out this study using a 22 gene-PGX panel to assess potential causes of TKI related intolerance and suboptimal responses in compliant patients.Methods: Twenty-nine Mayo Clinic patients with CML were prospectively recruited after informed consent. Buccal swabs were utilized for PGX testing to assess variations/polymorphisms involving CYP3A4/5, 1A2, 2C9, UGT1A1, amongst others (www.Oneome.com). Three groups of patients were recruited, those with i) TKI intolerance, ii) suboptimal responses by ELN criteria, iii) and newly diagnosed cases, to assess if PGX testing could explain TKI intolerance or resistance, or alter choice of therapy in newly diagnosed cases. A pharmacology review was obtained to interpret reports in all cases.Results:29 patients with CML were prospectively enrolled, median age 64 years, 15 (52%) male. At last follow up (median 21 months), 3 (10%) deaths and no disease progressions were documented. 82% received first line IM, whereas 18% received first line DAS. Major metabolic pathways assessed for IM included, CYP3A4 and 5, while minor pathways included 2C19, 2C9 and 2D6. Majority (83%) of IM patients had normal major pathways with 17% being intermediate-normal. With regards to the minor pathways, 25% were rapid metabolizers for 2C19, whereas 29% were intermediate and 4% poor metabolizers for 2C9 and 50% and 16% were intermediate and poor metabolizers for 2D6. In all IM treated patients PGX testing did not completely explain intolerance or resistance and did not change clinical decision making. Front line DAS was used in 18% and the major pathway assessed was CYP 3A4, with 80% being normal and 20% being intermediate metabolizers. Once again PGX testing did not completely explain intolerance/resistance and no therapeutic changes were based on PGX analysis.Seventeen (59%) patients received second line TKI therapy (50% each for intolerance and resistance), with DAS (58%) and NIL (29%), being the two most common. Once again for DAS, 90% had normal 3A4 metabolism while 10% were intermediate and for NIL 80% were normal and 20% intermediate. Only one of 2 NIL treated patients with UGTA1A polymorphisms developed indirect hyperbilirubinemia (grade 1). In the second line setting, PGX testing did not completely explain or alter treatment decisions. BOS was used as a third line agent in 3 (>10%) patients, 2 who remained refractory and one with intolerance, and all three were normal CYP3A4 metabolizers. None of these patients developed diarrhea a common side effect of BOS. PON was used in one patient with intermediate CYP3A4 metabolism as a 5th line agent and the patient continues to have refractory disease with no thrombotic events. In all cases, no changes were made to concomitant medications based on PGX testing.Conclusion: In conclusion, while PGX testing has rapidly evolved and become commercially available, in the context of TKI therapy for CML, while it offers useful insights on minor metabolic derangements and side effects like NIL induced hyperbilirubinemia, in our study, currently limited by a small sample size, it did not completely explain TKI intolerance or resistance. Recruitment of additional patients (n=100) and correlations with plasma drug levels are currently ongoing. DisclosuresAl-Kali:Novartis: Research Funding. Stewart:Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding; Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy.

Autonomic Dysfunction Manifesting as Severe Hypertension Following Cobra Envenomation: An Unusual Occurrence

Introduction: Envenomation due to an elapid snake (krait or cobra) bite is a common life-threatening medical emergency in India and is associated with significant morbidity and mortality. Common cobra (Naja naja) and common krait (Bungarus caeruleus) are the common snake species whose bites are associated with neuroparalysis, which is a key feature of envenomation. Autonomic dysfunction (AD) is another feature of envenomation with varied clinical presentations such as abdominal pain, vomiting, sweating, mydriasis, mild to moderate hypertension (HTN) or hypotension, and cardiac arrhythmia. The occurrence of AD manifesting as severe HTN and tachycardia is unusual following an elapid snake bite. This presentation has been frequently reported with krait envenomation but can also be observed with cobra envenomation.Case Report: We present the case of a 31-year-old male with common cobra (Naja naja) envenomation presenting with neuroparalysis along with severe HTN and tachycardia. The patient had a gradual and sustained recovery with anti-snake venom and other supportive care.Conclusion: Increasing incidences of cobra envenomation warrant that understanding its atypical presentation and its early recognition are of paramount importance as they may alter treatment decisions influencing the overall morbidity and mortality

Abstract 4522: An optimized NGS workflow for detection of FLT3 internal tandem duplication (ITD) in AML samples

Abstract FLT3 ITD, a prognostic marker and drug target, is present in ~19% of AML patients. FLT3 ITD is a tandem repeat of the entire or partial exon 13-15 region. FLT3 ITDs range in size from 3bp to above 300bp and impact RTK signaling. Recent publications have shown that FLT3 ITD can be detected at single nucleotide resolution by NGS panels. However, detection of large FLT3 ITD and accurate reporting of ITD frequency remain challenging for NGS methods. False negative ITD results or inaccurate mutant/wild type allele ratio measurements could negatively alter treatment decisions for AML patients. The Illumina TruSight Myeloid panel (TMP) is a commercial NGS assay that covers 54 genes involved in myeloid malignancies. Although the TMP assay can detect SBS and small indel, medium to large size FLT3 ITD cannot be detected. Here we present an enhanced workflow to overcome these challenges. Positive controls, dynamic range, accuracy, and inter-run reproducibility were validated for the detection of SBS, indel, and FLT3 ITD using reference standards and DNA extracted from cell lines and AML patient EDTA blood and bone marrow aspirate samples. NGS libraries were prepared following Illumina's standard protocol. 275bp X2 sequencing instead of the standard 150bp X2 was run on MiSeq flowcell v3. Data analysis was performed using a MolecularMD custom pipeline. The analysis of FLT3 ITD was conducted using three methods including two off-the-shelf programs, Pindel and ITDseek, as well as Cigar, a MolecularMD developed ITD detection algorithm. FLT3 ITDs at 126 bp and 21 bp in PL-21 and MOLM-13 cell lines, respectively, were detected by TMP assay using the three algorithms. In contrast to ITDseek which only reports ITD sequence without frequency information, Pindel and Cigar report both ITD sequence and frequency. Compared to Pindel, ITD frequency reported by the custom algorithm is closer to that determined by the fragment analysis. Serial dilution of the 126bp ITD into wild type DNA showed the 0.55% ITD (from fragment analysis) can be reproducibly detected at ~0.6% by the Cigar algorithm. FLT3 ITDs ranging in size from 6bp to 300bp were detected in clinical AML samples using the enhanced TMP workflow and confirmed by a fragment analysis method. Limit of detection, reproducibility and accuracy of SBS and indel detection in other key genes by the TMP assay have also been validated. Low-level mutations, i.e. NRAS G12D at 1.7%, NRAS G13D at 2%, and IDH2 R140Q at 1.4%, were detected by TMP panel from AML samples and further confirmed with an independent assay. A long deletion (52bp) in exon 9 of CALR was also detected by the custom pipeline. In summary, the enhanced TMP workflow allows for accurate detection and reporting of SBS, indel and FLT3 ITDs including large duplications. Optimized detection of FLT3 ITDs will improve AML patient selection for targeted therapy. Citation Format: Xiaodong Wang, Zhenyu Yan, Peng Fang, Weihua Liu, Scott Glynn, Jennifer Biroschak, Chad Galderisi, Cindy Spittle, Jin Li. An optimized NGS workflow for detection of FLT3 internal tandem duplication (ITD) in AML samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4522.