Citations

Objectives: To estimate the effects of obesity on all types of upper extremity compression neuropathies (UECN) (carpal tunnel syndrome and other median nerve, radial nerve, and ulnar nerve compression neuropathies) and to assess whether bariatric surgery modifies these effects. Background: UECN are increasingly prevalent and decrease the quality of life of affected individuals. Studies suggest obesity as a risk factor for carpal tunnel syndrome, the most common type of UECN. Methods: A retrospective cohort study was conducted using the PearlDiver Mariner Database, an all-payor claims database containing claims for over 53 million patients from 2010 to 2019 in all 50 US states. Rates and odds of all types of UECN were compared between 1:1:1 exact matched cohorts of obese patients who were medically managed, obese patients who underwent bariatric surgery, and nonobese patients (111,967 patients in each cohort). Results: Compared with nonobese patients, patients with obesity were significantly more likely to develop any UECN (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.09–1.18), carpal tunnel syndrome (OR, 1.15; 95% CI, 1.10–1.30), and 2 or more UECN (OR, 1.34; 95% CI, 1.20–1.48). Compared with obese patients who were managed medically, obese patients who underwent bariatric surgery were significantly less likely to develop any UECN (OR, 0.87; 95% CI, 0.84–0.91) and carpal tunnel syndrome (OR, 0.85; 95% CI, 0.81–0.89). Conclusions: Obese patients have higher odds of both single and concomitant UECN, specifically carpal tunnel syndrome, compared with nonobese patients. Bariatric surgery decreases the odds of developing UECN compared with obese patients not undergoing surgical intervention.

Abstract Multiple myeloma (MM) is a plasma cell malignancy that is characterized by diverse clinical presentations. Although biochemical assessment of disease activity is commonly used to monitor treatment response, findings on magnetic resonance imaging and positron emission tomography (PET)/computed tomography (CT), among other imaging modalities, have proven to harbor prognostic value. We sought to corroborate these findings by examining the prognostic significance of fluorodeoxyglucose PET/CT scanning in the setting of newly diagnosed MM. We retrospectively analyzed 195 patients with a PET/CT available at diagnosis and at 6 months posttreatment to examine their value as an adjuvant metric to conventional hematologic responses in terms of time to next treatment (TTNT) and overall survival (OS). The median TTNT and OS for the entire cohort were 24.6 months (95% confidence interval [CI], 20.4-29.1) and 79 months (95% CI, 63.1-119.1), respectively. When comparing PET/CT negative (−) with PET/CT positive (+) patients, we found significantly prolonged median TTNT (55.2 vs 17.8 months, P < .0001) and OS (unreached vs 60.8 months, P < .0001) in the former group. We then examined the additive value of PET/CT on the hematologic response achieved at 6 months and found that PET/CT (−) is associated with significantly increased median TTNT and OS for the very good partial response (VGPR) group and the less than VGPR group. Importantly, PET/CT retained prognostic significance after adjusting for multiple other predictive variables. We conclude that a PET/CT (−) at 6 months confers a significant prognostic advantage for patients with newly diagnosed MM and adds significant value to the hematologic response assessment.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Abstract Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. Methods We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results Change in H3.3K27M VAF over time (“VAF delta”) correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF “spikes” (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. Conclusion Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

AbstractThe application of machine learning (ML) to the field of orthopaedic surgery is rapidly increasing, but many surgeons remain unfamiliar with the nuances of this novel technique. With this editorial, we address a fundamental topic—the differences between ML techniques and traditional statistics. By doing so, we aim to further familiarize the reader with the new opportunities available thanks to the ML approach.

TPS486 Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death in the U.S. HCC surveillance is associated with improved early detection and receipt of curative treatment. However, current surveillance strategies suffer from low adherence and suboptimal sensitivity. The multi-target HCC blood test (mt-HBT) is a novel early detection assay that provides a qualitative result based on a multiparametric algorithm that incorporates information from methylation markers ( HOXA1, TSPYL5, and B3GALT6), AFP, and patient sex. Here, we describe the protocol for a prospective, multicenter clinical trial designed to investigate the performance of the mt-HBT in patients at risk for HCC. Methods: ALTernative to U/S (ALTUS) is a longitudinal, multicenter, prospective study with a targeted enrollment of 3,000 participants. The main inclusion and exclusion criteria are described in the table. Participants will receive HCC surveillance imaging (either U/S or CT/MRI) and blood collection for the mt-HBT. Those with positive U/S are anticipated to receive standard-of-care imaging follow-up with a multiphase CT or MRI, and those with a negative U/S will receive a study CT/MRI within 30 days of blood collection. Imaging interpretation is based on the CT/MRI LI-RADS (LR) v2018 categories. The primary endpoints are the overall sensitivity and specificity of the mt-HBT to detect HCC, defined as pathology-confirmed HCC or hepatocellular cholangiocarcinoma (cHCC-CCA), LR-4/5, or LR-TIV/M plus definite/probable HCC or cHCC-CCA. The secondary endpoints are mt-HBT early-stage sensitivity, and performance in a) participants with LR-5 or biopsy-confirmed HCC and b) participants confirmed non-HCC. Participants not diagnosed with a liver malignancy at visit one will continue to receive HCC surveillance, returning for a second visit ̃6 months from first blood collection. Blood will be collected after the second visit for the mt-HBT. Data on treatment will be collected for those diagnosed with HCC. Study participants and providers will be blinded to the mt-HBT results. Participants are currently enrolling across the U.S., with 60 targeted sites and an anticipated 12-month enrollment window. Clinical trial information: NCT05064553. [Table: see text]

AbstractCastleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first‐line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti‐IL6 treatment (3), and ASCT (10). The median follow‐up was 4.8 (range: 0.1–15.2) years. The 5‐ and 10‐year overall survival rates were 84% and 71%, respectively. Sixteen patients received high‐dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant‐related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.