Citations

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Abstract Background: PDAC is a highly morbid disease with no validated biomarkers for first-line (1L) treatment selection. The PurIST single-sample molecular subtyping gene signature, initially described by Rashid et al. (Clin. Cancer Res., 2020), classifies PDAC tumors as basal or classical. Prior work showed that these subtypes are associated with prognosis and that basal subtype patients have significantly lower objective response rate to FOLFIRINOX (FFX) compared to classical subtype patients. This suggests potential implications for treatment with FFX versus gemcitabine and nab-paclitaxel (GnP). Here, we retrospectively demonstrate the clinical validity of PurIST implemented as a laboratory developed test (LDT) on the Tempus Labs sequencing platform using a real-world dataset of advanced PDAC patients. Methods: De-identified PDAC patients were selected from the Tempus Oncology Data Ecosystem under an IRB-approved protocol according to the following inclusion criteria: no systemic treatment, surgically unresectable/metastatic, available RNA-sequencing data from primary or metastatic tissue, and FFX or GnP as 1L systemic therapy with available outcomes. Sequencing was performed by the CAP/CLIA validated Tempus xT assay. The PurIST model was applied to normalized RNA-sequence abundance files to compute a basal or classical subtype label. Predefined statistical analysis parameters included 12-month survival rate and median overall survival (OS) in FFX treated patients. OS was compared using Kaplan-Meier estimates, hazard ratios, and log-rank statistical tests. Results: 258 PDAC patients (64.9 +/- 9.9 yrs, 42% female), were identified for analysis with median OS of 11.7 months (95% CI: 10.6-13.7) and 12-month censorship rate of 12.8%. 151 patients were treated with FFX and 107 with GnP. 42 patients (28%) receiving FFX and 31 patients (29%) receiving GnP were classified as basal. Among FFX treated patients, median OS was 14.4 months (95% CI: 12.5-16.9) in classical patients vs. 9.4 months (95% CI: 8.3-14.5) in basal patients (HR = 1.72, 95% CI = 1.2-2.6, p=0.006). The 12-month survival rate was significantly lower in basal patients receiving FFX vs. classical patients (33.3% vs. 59.4%, p=0.011). In basal patients, no difference in OS was observed between FFX and GnP groups (p=0.6). Classical patients receiving FFX had a 14.4 months median OS vs. 10.8 months for patients receiving GnP (p=0.046). Conclusions: In this real-world cohort, we validate the association between PurIST subtypes and PDAC patient survival when administered FFX or GnP. Among FFX-treated patients, classical patients had significantly better outcomes compared to basal patients. Moreover, classical patients appeared to have improved outcomes with FFX vs. GnP. These findings represent underlying biological PDAC differences and demonstrate the clinical validity of PurIST as a prognostic marker in PDAC patients when performed as an LDT on the Tempus xT platform. Ongoing evaluation of PurIST performance will be continuously monitored through the Tempus Oncology Data ecosystem. Citation Format: Stephane Wenric, James M. Davison, Yun E. Wang, Gregory M. Mayhew, Kirk Beebe, Hyunseok P. Kang, Michael V. Milburn, Vincent Chung, Tanios Bekaii-Saab, Charles M. Perou. Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A002.

Abstract1q gain (+1q) is the most common high‐risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097–1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk‐scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re‐stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression‐free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high‐risk patients, therefore underlining the necessity for their re‐stratification. The proposed simple risk‐scoring model can estimate the outcomes of patients with +1q, which may help guide risk‐adapted treatment for such patients.

INTRODUCTION: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1–15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL.

Background: To assess the safety and effectiveness of transoral robotic thyroidectomy (TORT) in thyroid tumor. Methods: PubMed, Embase, Web of Science, SCOPUS, Cochrane database, and Google Scholar up to June 2022. Studies comparing outcomes and complications between TORT and control groups (robotic bilateral axillo-breast, trans-axillary, postauricular approach, conventional open thyroidectomy (OT), and transoral endoscopic approach) were analyzed. Results: Ten studies of 1420 individuals. The operative time (SMD 1.15, 95%CI [0.48; 1.89]) was significantly longer and the number of retrieved lymph nodes (LNs) (SMD −0.27, 95%CI [−0.39; −0.16]) was fewer in TORT than in the control group. The postoperative cosmetic satisfaction score (SMD 0.60, 95%CI [0.28; 0.92]) was statistically higher in TORT than in the control group. In subgroup analysis, there was no significant difference between robotic surgeries. However, TORT had significantly longer operative times (SMD 2.08, 95%CI [0.95; 3.20]) and fewer retrieved LNs (SMD −0.32, 95%CI [−0.46; −0.17]) than OT. TORT satisfied significantly more patients in cosmetic view. However, it increased hospitalization days and postoperative pain on the operation day and first day compared to OT. Conclusions: TORT is not inferior to other robotic-assisted approaches. Its operation time and hospitalization days are longer and postoperative pain is greater than OT, although its cosmetic satisfaction is high.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P &amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P &amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P &amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.