Citations

TPS3634 Background: Among patients with MSI-H/dMMR CRC, BRAF mutations occur in approximately 30%. MSI-H/dMMR and BRAF mutations are both associated with poor prognosis; in patients who have both biomarkers, poor prognosis is thought to be driven by the BRAF mutation. Pembrolizumab is indicated for the treatment of patients with MSI-H/dMMR unresectable or metastatic CRC (mCRC). The BRAF inhibitor encorafenib, in combination with cetuximab, is indicated for previously treated patients with BRAF V600E-mutant mCRC. Currently, there are no first-line treatment options indicated specifically for patients with both MSI-H/dMMR and BRAF V600E-mutant mCRC. To assess the safety and efficacy of combining pembrolizumab with encorafenib + cetuximab, the SEAMARK study (NCT05217446) will evaluate this combination vs pembrolizumab alone in patients with previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC. Methods: SEAMARK is an open-label, multicenter, randomized, phase 2 study. Approximately 104 patients (randomized 1:1; stratified by Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 vs 1) will receive either pembrolizumab + encorafenib + cetuximab or pembrolizumab. Enrolled patients must be aged ≥16 or ≥18 years (per country-specific regulations) and have previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC; measurable disease (Response Evaluation Criteria in Solid Tumors v1.1); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients who received prior treatment with BRAF/EGFR inhibitors or immune checkpoint inhibitors, or who have brain metastases (unless radiologically stable) or RAS mutation (or unknown RAS status), will be excluded. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment will begin in April 2022. Clinical trial information: NCT05217446.

3525 Background: Tumor-infiltrating lymphocytes (TILs) are significantly associated with clinical outcomes in patients with colon cancer. However, the potential for a differential effect of TILs on prognosis based on primary tumor sidedness has not been studied. We determined the interaction between TILs and tumor sidedness in relationship to disease-free survival (DFS). Methods: We analyzed data on TIL densities by primary tumor sidedness in 1532 stage III colon carcinomas from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy (NCCTG N0147). TIL densities were dichotomized as low or high (≤3 /HPF) based on an optimized cutoff previously identified for DFS in this cohort. Right-sided tumors were defined as proximal to the splenic flexure. Analysis of TILs and sidedness with DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Overall, tumors with high vs low TILs had the best DFS [HRadj: 0.58 (95%CI: 0.45-0.74); Padj <0.0001]. The association of TIL densities with 5-yr DFS differed significantly by primary tumor sidedness ( Pinteraction (adj) = 0.045). Among right-sided tumors, high vs low TILs were significantly associated with improved DFS ( Padj <0.0001)[Table]. Among left-sided tumors, however, DFS did not differ significantly for high vs low TILs ( Padj =0.173)[Table]. Similar results for TILs and DFS by sidedness were found for pMMR cancers. We then analyzed our data in low risk (T1-3, N1) and high risk (T4 and/or N2) tumors. Among low risk tumors, high vs low TILs was significantly associated with improved 5-yr DFS only in right-sided tumors ( Padj =0.006) [Table]. Among high risk tumors, high vs low TILs were significantly associated with better DFS in both right-sided ( Padj<0.001) and left-sided ( Padj =0.024) tumors. Conclusions: Overall, tumors with high TIL densities had significantly better DFS in right-sided but not left-sided cancers. Among low risk patients, the association of high TILs with better DFS was limited to right-sided tumors. These findings suggest that TILs should be interpreted by sidedness for prognostication. ClinicalTrials.gov Identifier: NCT00079274 . [Table: see text]

Abstract H3K27-altered diffuse midline glioma (DMG) is a uniformly lethal CNS cancer that predominately occurs in children. In the last decade, while studies revealing the molecular underpinnings of the disease have paved the way for novel therapeutic strategies, this tumor remains a death sentence. Our lab and others have identified numerous drugs of high interest for treating this devasting disease, however, every trial has failed to show benefit. Is our failure to translate these laboratory findings due to the fact we have not found the right drugs or treatment regimens yet? Or is this a failure to get the drugs to the tumor? Or is this simply a very bad disease to treat? The answer is likely multifactorial. Our lab, in collaboration with others, have strong data to show that simply getting drugs to the tumor will not result in a positive benefit. Most drugs are rapidly cleared from their target space. Utilizing techniques that increase the drug-tumor resonance time is necessary to translate our basic science findings to our patients. Picking the right drug and the delivery mechanism is not enough for a positive effect. Here, we assessed the efficacy of a previously identified inhibitor, alisertib, delivered by short-term convection-enhanced delivery or a continuous osmotic pump and found that continuous, direct delivery results in a significant increase in survival (p = 0.0002). Furthermore, long-term survivors showed a decreased tumor burden and on-target drug effects. These data support that translation into patients must consider three factors: 1) selection of a potent therapy, 2) selection of the proper delivery method for that therapy, 3) modulation to ensure that the therapy remains in the targeted tissue long enough for desired effect. Keeping these basic tenets at the forefront of development may finally lead to a more effective treatment strategy for this devastating disease

Abstract Background and Aims Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. Approach and Results By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta‐Catenin with high Male predominance) is characterized by prominent β‐catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient‐derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. Conclusions Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Introduction: Primary prevention implantable cardioverter defibrillators (ICDs) reduce mortality in select patients with left ventricular systolic dysfunction (LVSD). The occurrence of device therapies after ICD implantation in contemporary clinical practice is not well described, especially in patient subgroups designated in the Centers for Medicare and Medicaid Services (CMS) 2005 Coverage with Evidence Development (CED). Methods: The Longitudinal Study of ICDs assessed rates and correlates of device therapies (overall and those requiring shock) up to 3 years post-implant among 2540 patients with LVSD receiving first-time primary prevention ICDs in 7 US health care systems from 2006-2009. Implant data from the National Cardiovascular Data Registry ICD Registry were linked to electronic longitudinal health care system data and a novel centrally adjudicated repository of device therapies abstracted from medical records. Proportional hazard models evaluated associations with device therapies by appropriateness, adjusted for demographic and clinical factors. Results: Subjects were 26% women, 35% <65 years old, and 59% non-Hispanic white. Over a mean 26 months, 738 (29.1%) received at least 1 therapy (median 2). Estimated 3-year risk of any device therapy was 36% (24% appropriate, 12% inappropriate); for therapy requiring shock, corresponding values were 24%, 14%, 9%. The rate of appropriate therapy was higher in men than women (adjusted hazard ratio 1.84, 95% confidence interval 1.43-2.35). The rate of inappropriate therapy was higher for subjects <65 than for those >=65 years (1.40, 1.04-1.88), and lower among 2009 implants compared to 2006 (0.66, 0.46-0.95). Regarding the 3 CMS CED patient subgroups, neither ejection fraction nor heart failure symptom severity was associated with device therapy; for LVSD etiology, the rate of inappropriate therapy was nominally but not significantly higher among subjects with non-ischemic cardiomyopathy of < 9 months duration (1.38, 0.88-2.18). Conclusions: In a representative cohort of primary prevention ICD patients in usual care, rates of device therapies were somewhat lower than in landmark trials, differed by some patient characteristics, but did not differ meaningfully for CMS CED subgroups.

Abstract Background Anorectal manometry (ARM) comprehensively assesses anorectal sensorimotor functions. Purpose This review examines the indications, techniques, interpretation, strengths, and weaknesses of high‐resolution ARM (HR‐ARM), 3‐dimensional high‐resolution anorectal manometry (3D‐HR‐ARM), and portable ARM, and other assessments (i.e., rectal sensation and rectal balloon expulsion test) that are performed alongside manometry. It is based on a literature search of articles related to ARM in adults. HR‐ARM and 3D‐HR‐ARM are useful for diagnosing defecatory disorders (DD), to identify anorectal sensorimotor dysfunction and guide management in patients with fecal incontinence (FI), constipation, megacolon, and megarectum; and to screen for anorectal structural (e.g., rectal intussusception) abnormalities. The rectal balloon expulsion test is a useful, low‐cost, radiation‐free, outpatient assessment tool for impaired evacuation that is performed and interpreted in conjunction with ARM. The anorectal function tests should be interpreted with reference to age‐ and sex‐matched normal values, clinical features, and results of other tests. A larger database of technique‐specific normal values and newer paradigms of analyzing anorectal pressure profiles will increase the precision and diagnostic utility of HR‐ARM for identifying abnormal mechanisms of defecation and continence.

Background: Although prophylactic antibiotics are considered the standard of care, data with regard to the comparative efficacy of specific antibiotics in the prevention of periprosthetic joint infection (PJI) have remained limited. This study evaluated whether perioperative antibiotic choice affects rates of PJI development in shoulder arthroplasty. Methods: From 2000 to 2019, all primary shoulder arthroplasty types (hemiarthroplasty, anatomic total shoulder arthroplasty, reverse shoulder arthroplasty) performed for elective and trauma indications with perioperative antibiotic data and a minimum follow-up of 2 years were identified from a single institution. Demographic characteristics, PJI risk factors, and PJI-free survivorship data were retrieved. Multivariable analyses were conducted to determine the association between the antibiotic administered and the development of PJI. Results: Of 7,713 shoulder arthroplasties, cefazolin was administered in 6,879 procedures (89.2%) and non-cefazolin antibiotics consisting of vancomycin (465 procedures [6.0%]), clindamycin (345 procedures [4.5%]), and alternative regimens (24 procedures [0.31%]) were administered in 834 procedures (10.8%). PJIs occurred in 101 shoulder arthroplasties (1.3%), with Cutibacterium acnes as the most common pathogen (44 procedures [43.6%]). PJI-free survivorship was greater in shoulder arthroplasties in which cefazolin was administered compared with those in which non-cefazolin antibiotics were administered, with 0.91% greater survival free of PJI at 1 month, 1.4% at 1 year, and 2.7% at 15 years (p < 0.001). Cefazolin administration, compared with non-cefazolin administration, was associated with a 69% reduction in all-cause PJI risk and a 78% reduction in C. acnes PJI risk (p < 0.001). A higher risk of PJI for both groups was observed with vancomycin; the hazard ratio [HR] was 2.32 (95% confidence interval [CI], 1.22 to 4.40; p = 0.010) for all-cause PJI and 2.94 (95% CI, 1.12 to 7.49; p = 0.028) for C. acnes PJI. A higher risk of PJI was also observed for both groups for clindamycin; the HR was 5.07 (95% CI, 2.83 to 9.05; p < 0.001) for all-cause PJI and 8.01 (95% CI, 3.63 to 17.42; p < 0.001) for C. acnes PJI. Conclusions: In primary shoulder arthroplasty, cefazolin administration was associated with a significantly lower rate of PJI compared with non-cefazolin alternatives, including both vancomycin and clindamycin. These risk discrepancies were observed across all infectious pathogens and may be considered even greater when C. acnes was the infecting bacterium. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

BackgroundUncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion‐weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within‐subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.PurposeEvaluation of the repeatability (same‐day) and reproducibility (multi‐day) of whole‐prostate and focal‐lesion ADC assessment in a multi‐site setting.Study TypeProspective multi‐institutional.SubjectsTwenty‐nine males, ages 53 to 80 (median 63) years, following diagnosis of prostate cancer, 10 with focal lesions.Field Strength/Sequence3T, single‐shot spin‐echo diffusion‐weighted echo‐planar sequence with four b‐values.AssessmentSites qualified for the study using an ice‐water phantom with known ADC. Readers performed DWI analyses at visit 1 (“V1”) and visit 2 (“V2,” 2–14 days after V1), where V2 comprised scans before (“V2pre”) and after (“V2post”) a “coffee‐break” interval with subject removal and repositioning. A single reader segmented the whole prostate. Two readers separately placed region‐of‐interests for focal lesions.Statistical TestsReproducibility and repeatability coefficients for whole prostate and focal lesions derived from median pixel ADC. We estimated the wCV and 95% confidence interval using a variance stabilizing transformation and assessed interreader reliability of focal lesion ADC using the intraclass correlation coefficient (ICC).ResultsThe ADC biases from b0–b600 and b0–b800 phantom scans averaged 1.32% and 1.44%, respectively; mean b‐value dependence was 0.188%. Repeatability and reproducibility of whole prostate median pixel ADC both yielded wCVs of 0.033 (N = 29). In 10 subjects with an evaluable focal lesion, the individual reader wCVs were 0.148 and 0.074 (repeatability) and 0.137 and 0.078 (reproducibility). All time points demonstrated good to excellent interreader reliability for focal lesion ADC (ICCV1 = 0.89; ICCV2pre = 0.76; ICCV2post = 0.94).Data ConclusionThis study met the QIBA claim for prostate ADC. Test–retest repeatability and multi‐day reproducibility were largely equivalent. Interreader reliability for focal lesion ADC was high across time points.Level of Evidence1Technical EfficacyStage 2TOC CategoryPelvis