Citations

The NCCN Guidelines for Thyroid Carcinoma address the management of different types of thyroid carcinoma, including papillary, follicular, oncocytic, medullary, and anaplastic carcinoma. The NCCN Thyroid Carcinoma Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on the panel’s most recent recommendations regarding systemic therapies for thyroid carcinoma as well as the supporting clinical data.

Background: The direct anterior approach (DAA) is a popular approach for primary total hip arthroplasty (THA). However, the contemporary outcomes for DAA THA need further elucidation. Therefore, we aimed to describe implant survivorship, complications, and clinical outcomes after DAA THA. Methods: From our multi-institutional total joint registry, 3,184 patients who had undergone 3,698 primary DAA THA between 2010 and 2019 were identified. The identified patients had a mean age of 65 years and a mean body mass index (BMI) of 29 kg/m 2 , and 53% of patients were female. The indications for revision and reoperation and the incidence of complications were collected and analyzed. Potential risk factors, including age, sex, BMI, and high-volume compared with low-volume operating surgeons, were examined. Descriptive statistics and Kaplan-Meier survivorship with Cox regression analyses were performed. Results: At 10 years following primary DAA THA, the cohort had 96% (95% confidence interval [CI], 95% to 98%) survivorship free of any revision and 94% (95% CI, 92% to 96%) survivorship free of any reoperation. The leading indications for revision were periprosthetic joint infection (PJI) (n = 24; 5-year cumulative incidence, 0.93% [95% CI, 0.6% to 1.5%]), periprosthetic fracture (n = 20; 5-year cumulative incidence, 0.62% [95% CI, 0.4% to 1.0%]), and aseptic loosening (n = 14; 11 femoral, 3 acetabular; 5-year cumulative incidence, 0.84% [95% CI, 0.5% to 1.5%]). A BMI of ≥40 kg/m 2 was found to be significantly associated with PJI (hazard ratio [HR], 6.4; p < 0.001), reoperation (HR, 3.5; p < 0.001), and nonoperative complications (HR, 2.3; p = 0.018). Survivorship free of recurrent instability was 99.6% (95% CI, 99.4% to 99.8%) at 5 and 10 years, and the cumulative incidence of revision for instability was 0.14% at 5 years. Conclusions: In one of the largest published series to date, survivorship following DAA THA was satisfactory at early to intermediate follow-up. The leading indications for revision were PJI, periprosthetic fracture, and aseptic loosening. Instability after DAA THA was uncommon and infrequently led to revision. As a note of caution, a BMI of ≥40 kg/m 2 was identified as a risk factor for adverse outcome after DAA THA. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Introduction Multiple Myeloma (MM) precursors Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) have variable risk of progression to active MM, and identifying which patients may progress remains a clinical challenge. Deep proteome profiling of peripheral blood (PB) plasma may advance non-invasive precursor disease staging, monitoring and characterization. Here, we performed plasma proteomic profiling on patients across the MM disease continuum as well as progressive and stable disease to provide insights into MM disease biology and identify protein-based high-risk disease features that may improve prognostication. Methods We performed high-throughput profiling of &gt;5400 proteins using the Olink® Explore HT library and Proximity Extension Assay (PEA) technology. We profiled 529 PB plasma samples from 485 individuals, including MGUS (n=100), SMM (n=203), MM (n=100), and healthy donors (HDs) (n=82). Sequential samples from SMM-MM progressors (n=32) and stable SMM-SMM non-progressors (n=32) were also profiled, where precursor samples ranged 1.04-6.91 years (median 2.33 years) prior to MM progression. T-tests, ANOVAs, and linear mixed effect (LME) models were used to identify significant proteins across disease stages, progression status, and time. Results were adjusted for multiple testing using Benjamini-Hochberg procedure. A subset of 86 individuals (13 HDs, 14 MGUS, 41 SMM, 18 MM) also had single-cell RNA sequencing (scRNA-seq) performed on tumor and immune cells from paired PB/BM collected at the same timepoint to enable cellular mapping of signals detected in plasma. Results We successfully captured significantly dysregulated proteins including proteins highly expressed on the surface of plasma cells, such as BCMA, SLAMF7 and CD38, highlighting the utility of PEA technology to monitor soluble levels of clinically relevant targets. Given SMM patients are clinically heterogeneous and can resemble MGUS or MM, we aimed to improve discrimination of disease states using biological features obtained from the plasma proteome. We developed a classifier using an Elastic Net model for each stage, where plasma proteins such as SLAMF7, BCMA, TACI, FCRL5 and others had the highest importance scores for the model. We demonstrated 97% SMM/MM samples could be identified from healthy samples (AUC=0.82), indicating our classifier could reliably screen disease-related cases. Moreover, 84% of SMM cases were correctly classified as clinically defined SMM, while misclassified samples were labelled as MM cases. Interestingly, the misclassified patients had consistently rising M-spike levels during clinical follow-up but without a shift in clinical stage or risk status, suggesting the plasma proteome may provide earlier indication of evolving disease. Since proteomic information may also hold value for improved risk stratification, we evaluated protein levels in precursor stage timepoint samples from SMM-MM progressors and stable SMM non-progressors. We identified a prognostic five-protein signature that was significantly elevated in SMM-MM progressors, of which BCMA and TACI were top proteins, as well as proteins vital for calcium homeostasis and integrin-mediated cell adhesion. BCMA and TACI levels also had a strong positive correlation with BM plasma cell infiltration, which suggests these proteins may be useful surrogates of BM tumor burden during routine blood-based assessment of precursor patients. Lastly, integrative analysis of scRNA-seq of tumor and immune cells was used to elucidate cell origin level information of the prognostic signature proteins. Four proteins were highly expressed in malignant versus non-malignant plasma cells, suggesting our prognostic signature partially provides a readout of plasma cell biology. Meanwhile, one protein was constitutively expressed on most leukocytes, suggesting that the interplay of other cell types in the immune microenvironment involved in progression may also be reflected in the plasma. Conclusion We performed the first comprehensive analysis of the plasma proteome of MM and its precursor conditions. Overall, we developed a classifier that utilizes plasma proteins alone to accurately classify disease stages and identified a prognostic protein signature associated with progressive disease.

Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in &gt;1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.

Abstract Task Group (TG) 314 of the American Association of Physicists in Medicine (AAPM) was charged to develop guidance for recovering from fault states in radiation therapy, specifically regarding the delivery of photon or electron beams using a linear accelerator (linac) including ancillary systems. The fault conditions addressed may involve software, hardware, or a combination of causes. The report provides detailed recommendations for the proactive steps to be taken before a fault, the actions to be taken at the time of a fault, and the safety steps before returning a linac to clinical service, as well as the activities that device manufacturers and standard organizations can do to prevent and resolve the faults. A user‐maintained log of prior faults; establishment of remote access by the vendor; and user training in emergency gantry, couch, and door motions are all useful proactive steps. At the moment of downtime and after ensuring the safety of the patient, the report stresses the importance of capturing fault information, prompt contact with the service engineer after the initial assessment, and considerations for communicating the estimated duration before the linac is returned to service. The medical physicist has a critical responsibility to assess the impact of the fault on patient care. Before resuming clinical use, the medical physicist must both determine the level of testing required to ensure safe operation of the linac and ensure any partially or totally delivered treatments have been correctly saved for accurate completion of the treatment fraction. The report stresses the roles of the radiation therapist, medical physicist, and service engineer to efficiently and safely address linac downtime. The appendices contain a description of the efforts of several organizations regarding linac safety: Integrating the Healthcare Enterprise—Radiation Oncology, International Standards Organization/International Electrotechnical Commission, Radiation Oncology Safety Stakeholder Initiative, and the AAPM Vendor Relations and Product Usability Subcommittee. Disclaimer: The recommendations of this TG should not be used to establish regulations. These recommendations are guidelines for Qualified Medical Physicists and others to use and appropriately interpret for their institution and clinical setting. Each institution may have site‐specific or state‐mandated needs and requirements which may modify their usage of these recommendations.

Background: Regional analgesia is a critical component of enhanced recovery after surgery pathways for cystectomy, but there is little research comparing different modalities. Transversus abdominis plane block is a well-established procedure used for postoperative regional analgesia, whereas erector spinae plane block is a recently described technique that some contend improves pain control. Objective: We sought to compare these modalities in patients undergoing cystectomy, with primary end points of pain scores and total narcotic utilization measured in morphine milliequivalents. Methods: We retrospectively reviewed 77 consecutive patients who underwent open radical cystectomy. Patients who did not undergo erector spinae plane block or transversus abdominis plane block or who used chronic narcotics were excluded. Pain intensity scores were measured immediately postoperatively and in 24-hour intervals until 72 hours postoperatively. Cumulative narcotic utilization at 72 hours, return to bowel function, and length of stay were measured. Results: Fifty-one patients met inclusion criteria. Seventeen patients underwent erector spinae plane block and 34 transversus abdominis plane block. Erector spinae plane block patients reported lower pain scores immediately postoperatively (P = .046), at 48 hours (P = .019), and 72 hours (P = .019). Erector spinae plane block patients used less narcotics after 72 hours than transversus abdominis plane block patients (median: 62.50 morphine milliequivalents vs 146.25 morphine milliequivalents, P = .008). Conclusions: Compared with transversus abdominis plane block, erector spinae plane block reduced total narcotic utilization by 234% while also reducing subjective patient pain scores. Increased adoption of erector spinae plane block could have major impacts on both clinical outcomes and patient satisfaction in patients undergoing radical cystectomy.

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising a collection of molecularly and clinically distinct entities. Group 3 and Group 4-MB subgroups originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3 and Group 4-MB. However, the molecular consequences of these alterations remain largely undefined. METHODS We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. RESULTS Analysis of differential chromatin states across MB subgroups using a Hidden Markov Model revealed a significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 4-MB which localized to promoters of neurodevelopmental genes and transcription factors. To functionally dissect the pathogenetic significance of the enriched EnhBiv state in Group 4-MB, we sought to identify key regulators that confer this state. Integrative bioinformatics coupled with CUT&RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo. Mechanistically, inhibition of KDM2B disrupted chromatin bivalency by blocking PRC2 complex recruitment and reducing H3K27me3 deposition, profoundly derepressing PRC2 targets involved in neuronal differentiation. CONCLUSIONS Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and nominating KDM2B as a selective dependency in Group 3/4-MB that should be prioritized as an attractive therapeutic target.

PURPOSE: This study aimed to analyze organ system-based causes and non-organ system-based mechanisms of death (COD, MOD) in people with myelomeningocele (MMC), comparing urological to other COD. METHODS: A retrospective review was performed of 16 institutions in Canada/United States of non-random convenience sample of people with MMC (born > = 1972) using non-parametric statistics. RESULTS: Of 293 deaths (89% shunted hydrocephalus), 12% occurred in infancy, 35% in childhood, and 53% in adulthood (documented COD: 74%). For 261 shunted individuals, leading COD were neurological (21%) and pulmonary (17%), and leading MOD were infections (34%, including shunt infections: 4%) and non-infectious shunt malfunctions (14%). For 32 unshunted individuals, leading COD were pulmonary (34%) and cardiovascular (13%), and leading MOD were infections (38%) and non-infectious pulmonary (16%). COD and MOD varied by shunt status and age (p < = 0.04), not ambulation or birthyear (p > = 0.16). Urology-related deaths (urosepsis, renal failure, hematuria, bladder perforation/cancer: 10%) were more likely in females (p = 0.01), independent of age, shunt, or ambulatory status (p > = 0.40). COD/MOD were independent of bladder augmentation (p = >0.11). Unexplained deaths while asleep (4%) were independent of age, shunt status, and epilepsy (p >= 0.47). CONCLUSION: COD varied by shunt status. Leading MOD were infectious. Urology-related deaths (10%) were independent of shunt status; 26% of COD were unknown. Life-long multidisciplinary care and accurate mortality documentation are needed.