Using Failure Mode and Effects Analysis to Evaluate Risk in the Clinical Adoption of Automated Contouring and Treatment Planning Tools.

PURPOSE: In this study, we applied the failure mode and effects analysis (FMEA) approach to an automated radiation therapy contouring and treatment planning tool to assess, and subsequently limit, the risk of deploying automated tools. METHODS AND MATERIALS: Using an FMEA, we quantified the risks associated with the Radiation Planning Assistant (RPA), an automated contouring and treatment planning tool currently under development. A multidisciplinary team identified and scored each failure mode, using a combination of RPA plan data and experience for guidance. A 1-to-10 scale for severity, occurrence, and detectability of potential errors was used, following American Association of Physicists in Medicine Task Group 100 recommendations. High-risk failure modes were further explored to determine how the workflow could be improved to reduce the associated risk. RESULTS: Of 290 possible failure modes, we identified 126 errors that were unique to the RPA workflow, with a mean risk priority number (RPN) of 56.3 and a maximum RPN of 486. The top 10 failure modes were caused by automation bias, operator error, and software error. Twenty-one failure modes were above the action threshold of RPN = 125, leading to corrective actions. The workflow was modified to simplify the user interface and better training resources were developed, which highlight the importance of thorough review of the output of automated systems. After the changes, we rescored the high-risk errors, resulting in a final mean and maximum RPN of 33.7 and 288, respectively. CONCLUSIONS: We identified 126 errors specific to the automated workflow, most of which were caused by automation bias or operator error, which emphasized the need to simplify the user interface and ensure adequate user training. As a result of changes made to the software and the enhancement of training resources, the RPNs subsequently decreased, showing that FMEA is an effective way to assess and reduce risk associated with the deployment of automated planning tools.

Multiple Cavitary Lung Lesions in an Adolescent: Case Report of a Rare Presentation of Nodular Lymphocyte Predominant Hodgkin Lymphoma.

A 14-year-old male patient presented with a nonproductive cough, weight loss, fatigue, and malaise. A chest radiograph showed large bilateral cavitary lung lesions in both upper and lower lobes that failed to improve with antibiotics and anti-inflammatory medications. Infectious and rheumatologic work-ups were negative. Thoracoscopic lung biopsies were diagnostic for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). The patient received combination chemotherapy and immunotherapy based on current treatment standards with an excellent clinical response. NLPHL is a rare B-cell lymphoma that typically presents as peripheral lymph nodal disease, clinically distinct from classical Hodgkin lymphoma. The prognosis of NLPHL in children is favorable, although relapse rates are high. This case details several unique features of NLPHL and describes the presentation, diagnosis, and treatment of an adolescent male with a rare pulmonary and cervical NLPHL, the first such case described in a pediatric patient.

Programmed Death-ligand 1 Expression in Upper Tract Urothelial Carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is the most common malignancy of the urinary tract. Upper tract (renal pelvis and ureter) urothelial carcinomas (UTUC) account for approximately 5% of UCs but a significant subset are invasive and associated with poor clinical outcomes. OBJECTIVE: To evaluate programmed death-ligand 1 (PD-L1) expression in UTUC. DESIGN, SETTING, AND PARTICIPANTS: UTUC cases from 1997-2016 were retrospectively identified from the surgical pathology database at a single large academic institution. The cohort included 149 cases: 27 low-grade and 24 high-grade pathologic T (pT)a, 29 pT1, 23 pT2, 38 pT3, and eight pT4. PD-L1 immunohistochemistry (IHC) was performed on representative whole tumor sections using anti-PD-L1 primary antibody clone 5H1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PD-L1 expression was evaluated using a previously established cut-off for positivity (≥ 5% membranous staining). Association between PD-L1 IHC expression and clinicopathologic parameters was examined with Fisher's exact test; the effect of PD-L1 expression on cancer-specific mortality was assessed using the Cox proportional hazard model. RESULTS AND LIMITATIONS: Approximately one-third (32.7%) of invasive primary UTUC and 23.5% of all primary UTUC (invasive and noninvasive tumors) demonstrated positive PD-L1 expression. Positive PD-L1 expression was associated with high histologic grade, high pathologic stage, and angiolymphatic invasion. Cancer-specific survival was not significantly associated with positive PD-L1 expression using a 5% cut-off. Study limitations include the retrospective nature and the fact that PD-L1 expression by IHC is an imperfect surrogate for response to therapy. CONCLUSIONS: Positive PD-L1 expression in approximately one-third of primary invasive UTUC and association with high-risk clinicopathologic features provide a rational basis for further investigation of PD-L1-based immunotherapeutics in these patients. PATIENT SUMMARY: Upper tract urothelial carcinoma is often associated with poor clinical outcome. While current treatment options for advanced upper tract urothelial carcinoma are limited, programmed death-ligand 1 positivity in approximately one-third of invasive tumors provides a rational basis for further investigation of programmed death-ligand 1-based immunotherapeutics in these patients.

Anatomical patterns of recurrence following biochemical relapse after post-prostatectomy salvage radiation therapy: a multi-institutional study.

OBJECTIVES: To characterise the frequency and detailed anatomical sites of failure for patients receiving post-radical prostatectomy (RP) salvage radiation therapy (SRT). PATIENTS AND METHODS: A multi-institutional retrospective study was performed on 574 men who underwent SRT between 1986 and 2013. Anatomical recurrence patterns were classified as lymphotrophic (lymph nodes only), osteotrophic (bone only), or multifocal if both were present. Isolated first failure sites were defined as sites of initial clinically detected recurrence that remained isolated for at least 3 months. RESULTS: The median follow-up after SRT was 6.8 years. The 8-year rates of local, regional, and distant failure for patients undergoing SRT were 2%, 6%, and 21%, respectively. Of the 22% men (128 of 574) who developed a clinically detectable recurrence, 17%, 50%, and 31% were lymphotrophic, osteotrophic, and multifocal, respectively. The trophic nature of metastases was prognostic for distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS); the 10-year rates of DMFS were 18%, 5%, and 7% (P < 0.01), and PCSS were 78%, 68%, and 56% (P < 0.01), for lymphotrophic, osteotrophic, and multifocal failure patterns, respectively. CONCLUSIONS: We demonstrate that trophism for metastatic site has significant prognostic impact on PCSS in men treated with SRT. Radiographic local failure is an uncommon event after SRT when compared to historical data of patients treated with surgery monotherapy. However, distant failure remains a challenge in this patient population and warrants further therapeutic investigation.

Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery.

Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS.

Very Early Salvage Radiotherapy Improves Distant Metastasis-Free Survival.

PURPOSE: Early salvage radiotherapy following radical prostatectomy for prostate cancer is commonly advocated in place of adjuvant radiotherapy. We aimed to determine the optimal definition of early salvage radiotherapy. MATERIALS AND METHODS: We performed a multi-institutional retrospective study of 657 men who underwent salvage radiotherapy between 1986 and 2013. Two comparisons were made to determine the optimal definition of early salvage radiotherapy, including 1) the time from radical prostatectomy to salvage radiotherapy (less than 9, 9 to 21, 22 to 47 or greater than 48 months) and 2) the level of detectable pre-salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 or greater than 0.5 ng/ml). Outcomes included freedom from salvage androgen deprivation therapy, and biochemical relapse-free, distant metastases-free and prostate cancer specific survival. RESULTS: Median followup was 9.8 years. Time from radical prostatectomy to salvage radiotherapy did not correlate with 10-year biochemical relapse-free survival rates (R2 = 0.18). Increasing pre-salvage radiotherapy prostate specific antigen strongly correlated with biochemical relapse-free survival (R2 = 0.91). Increasing detectable pre-salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 and greater than 0.5 ng/ml) predicted worse 10-year biochemical relapse-free survival (62%, 44% and 27%), freedom from salvage androgen deprivation therapy (77%, 66% and 49%), distant metastases-free survival (86%, 79% and 66%, each p <0.001) and prostate cancer specific survival (93%, 89% and 80%, respectively, p = 0.001). On multivariable analysis early salvage radiotherapy (prostate specific antigen greater than 0.2 to 0.5 ng/ml) was associated with a twofold increase in biochemical failure, use of salvage androgen deprivation therapy and distant metastases compared to very early salvage radiotherapy (prostate specific antigen 0.01 to 0.2 ng/ml). CONCLUSIONS: The duration from radical prostatectomy to salvage radiotherapy is not independently prognostic for outcomes after salvage radiotherapy and it should not be used to define early salvage radiotherapy. Grouping all patients with pre-salvage radiotherapy prostate specific antigen 0.5 ng/ml or less may be inadequate to define early salvage radiotherapy and it has a relevant impact on ongoing and future clinical trials.

Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies.

Non-Hodgkin lymphoma of the orbit and ocular adnexa is the most common primary orbital malignancy. Treatments for low- (extra-nodal marginal zone and follicular lymphomas) and high-grade (diffuse large B-cell lymphoma) are associated with local and vision-threatening toxicities. High-grade lymphomas relapse frequently and exhibit poor survival rates. Despite advances in genomic profiling and precision medicine, orbital and ocular adnexal lymphomas remain poorly characterized molecularly. We performed targeted next-generation sequencing (NGS) profiling of 38 formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas obtained from a single-center using a panel targeting near-term, clinically relevant genes. Potentially actionable mutations and copy number alterations were prioritized based on gain- and loss-of-function analyses, and catalogued, approved, and investigational therapies. Of 36 informative samples, including marginal zone lymphomas (n=20), follicular lymphomas (n=9), and diffuse large B-cell lymphomas (n=7), 53% harbored a prioritized alteration (median=1, range 0-5/sample). MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hotspot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas. Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes). Single prioritized alterations were also identified in the histone methyltransferases KMT2B (follicular lymphoma) and KMT3B (diffuse large B-cell lymphoma). Loss-of-function mutations and copy number alterations in the tumor suppressors TP53 (diffuse large B-cell and follicular lymphoma), CDKN2A (diffuse large B-cell and marginal zone lymphoma), PTEN (diffuse large B-cell lymphoma), ATM (diffuse large B-cell lymphoma), and NF1 (diffuse large B-cell lymphoma), and gain-of-function mutations in the oncogenes HRAS (follicular lymphoma) and NRAS (diffuse large B-cell lymphoma) were also observed. Together, our study demonstrates that NGS can be used to profile routine formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas for identification of somatic-driving alterations and nomination of potential therapeutic strategies.