Citations

AbstractThe multicenter, phase Ib CC‐122‐DLBCL‐001 dose‐expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide‐naïve, 10 lenalidomide‐treated]). Median age was 62 years (range, 33–84 years), and patients had received a median of 3 (range, 1–8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab‐refractory at study entry and 10.0% were lenalidomide‐refractory. The most common any‐grade avadomide‐related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide‐related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide‐naïve and ‐treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.

The lamina propria within the vocal fold (VF) is a complex multi-layered tissue that increases in stiffness from the superficial to deep layer, where this characteristic is crucial for VF sound production. Tissue engineered scaffolds designed for VF repair must mimic the biophysical nature of the native vocal fold and promote cell viability, cell spreading, and vibration with air flow. In this study, we present a unique tri-layered, partially-degradable hydrogel scaffold that mimics the multi-layered structure of the VF lamina propria. Using thiol-norbornene photochemistry, tri-layered hydrogel scaffolds were fabricated via layer-by-layer stacking with increasing polymer concentration from the top to middle to deep layer. Mechanical analysis confirmed hydrogel modulus increased with increasing polymer concentration. Partially-degradable hydrogels promoted high cell viability and cell spreading in 3D as assessed via live/dead and cytoskeleton staining, respectively. Importantly, partially-degradable hydrogels maintained some degree of the 3D polymer network following protease exposure, while still enabling encapsulated cells to remodel their local environment via protease secretion. Finally, the tri-layered hydrogel scaffold successfully vibrated and produced sound in proof-of-concept air flow studies. This work represents a critical first step towards the design of a multi-layered, hydrogel scaffold for vocal fold tissue engineering.

BackgroundTreatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI‐HFF) and magnetic resonance elastography (MRE‐SS), respectively, are biomarkers for hepatic steatosis and fibrosis.PurposeThis study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]‐FGF21v) on MRI‐HFF and MRE‐SS in a NASH mouse model.Study TypePreclinical.Animal ModelThis study included a choline‐deficient, amino acid‐defined, high‐fat diet (CDAHFD) model and 6‐week‐old, male C57BL/6J mice (N = 78).Field Strength/SequenceThis study was performed using: 3T: gradient‐echo two‐point Dixon and spin‐echo (SE) echo‐planar imaging elastography (200 Hz) and 7T: SE two‐point Dixon and SE elastography (200 Hz).AssessmentMRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG‐FGF21v dosing (baseline), and after PEG‐FGF21v treatment (WK4/8). Regions of interest for MRI‐HFF and MRE‐SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured.Statistical TestsTwo‐tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE‐SS at WK8, posterior means, and 95% credible intervals were presented.ResultsCDAHFD significantly increased baseline MRI‐HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE‐SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG‐FGF21v significantly decreased MRI‐HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE‐SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RDI) were −68% (−90%, −44%; 3T) and −64% (−78%, −52%; 7T). MRI‐HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92).Data ConclusionsMRI‐HFF and MRE‐SS showed PEG‐FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data.Level of Evidence1Technical Efficacy Stage2

Objectives/HypothesisDevelop a patient‐specific tissue engineered construct for laryngeal reconstruction following a partial laryngectomy.Study DesignBench and animal research.MethodsA construct made from a porous polyethylene scaffold shaped in a canine‐specific configuration and seeded with autologous canine adipose‐derived stem cells in fibrin glue was implanted in a canine following a partial laryngectomy. After 1 year, the construct was first evaluated in vivo with high‐speed imaging and acoustic–aerodynamic measures. It was then explanted and evaluated histologically.ResultsThe canine study at 1 year revealed the construct provided voicing (barking) with acoustic and aerodynamic measures within normal ranges. The canine was able to eat and breathe normally without long‐term support. The construct was integrated with epithelialization of all areas except the medial portion of the vocal fold structure. No anti‐infective agents were needed after the standard perioperative medications were completed.ConclusionThis study provided a successful first step toward developing a patient‐specific composite construct for patients undergoing partial laryngectomies.Level of EvidenceNA Laryngoscope, 132:S1–S11, 2022

Abstract Background Ozanimod was approved by the FDA to treat patients (pts) with moderately to severely active Ulcerative Colitis (UC) based on the results from the 52-week (wk) phase 3 True North (TN) study. We sought to evaluate long-term efficacy and safety of ozanimod. Methods We examined data from an interim analysis of pts in the TN parent study who entered the ongoing TN open-label extension (OLE). Pts entered the TN OLE from the phase 3 TN study if they were non-responders at the end of induction, lost response during maintenance, or completed maintenance treatment, or from the phase 2 Touchstone OLE if they remained at study closure and received once-daily oral ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg). Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Wks 46, 94, and 142 in the TN OLE for all pts who entered the OLE from the TN parent study, and in the subset of pts in clinical response at the OLE entry. The data were analysed in the intent-to-treat population using observed cases (OC), which used the number of pts remaining in the study at the corresponding time point, and non-responder imputation (NRI), which used the number of pts remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed. Treatment-emergent adverse events were evaluated from the pooled phase 2 and phase 3 UC studies. Results A total of 823 pts from TN entered the TN OLE; as of the cut-off date (Sept 30, 2020), 64% completed Wk 46, 34% completed Wk 94, and 14% completed Wk 142 of the OLE. The most common reason for discontinuation was lack of efficacy (21%). Baseline demographics were similar as in the TN study. A total of 261 pts were in clinical response at the time of OLE entry. OC analyses showed that the percentage of pts achieving clinical remission, clinical response, endoscopic improvement, and CS-free remission was maintained over time (Table). Efficacy in the responders was higher compared to the total population and was comparable within the endpoints at Wks 46 and 94. Using the more conservative NRI analysis, the proportion of pts achieving each endpoint was lower than in the OC; however, after 94 wks of OLE treatment, 34% of all pts and 55% of the responders still maintained clinical response. No new safety signals were seen with longer-term ozanimod use in the 1158 pts in the pooled population. Conclusion UC pts from the phase 3 TN study demonstrated maintenance of response with long-term ozanimod treatment. These data reflect approximately 2 years of additional ozanimod treatment, with no new safety signals identified.

519 Background: KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS mutations occur in approximately 90% of pancreatic cancer, and approximately 2% of these are KRASG12C mutations. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state; adagrasib has been optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), extensive tissue distribution, dose-dependent PK, as well as CNS penetration. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combinations in pts with advanced solid tumors harboring a KRASG12C mutation. Here we report preliminary data from pts enrolled in a Phase 2 cohort evaluating single-agent adagrasib administered orally at 600 mg BID in previously treated pts with unresectable or metastatic solid tumors (excluding NSCLC and CRC), including pancreatic and other GI cancers. Study endpoints include clinical activity, safety, and PK. Results: The data cutoff was 10 September 2021. A total of 42 pts were enrolled in this cohort (median age 63.5 years, range 21–89; 52% female; 71% white; 29%/71% ECOG PS 0/1; median 2 prior lines of therapy, range 1–7; median follow-up 6.3 months), of whom 30 pts had KRASG12C-mutant GI tumors (12 PDAC, 8 biliary tract, 5 appendiceal, 2 gastro-esophageal junction, 2 small bowel, and 1 esophageal). In a preliminary analysis, 27 pts with GI tumors were evaluable for clinical activity; partial responses (PRs) were seen in 41% (11/27, including 3 unconfirmed PRs); the disease control rate (DCR) was 100% (27/27). Of the 12 pts with PDAC (median 3 prior lines of therapy; median follow-up 8.1 months), 10 were evaluable for clinical activity; PRs were seen in 50% (5/10, including 1 unconfirmed PR); the DCR was 100% (10/10). Median progression-free survival (PFS) was 6.6 months (95% CI 1.0–9.7), and treatment was ongoing in 50% of pts with PDAC. Among the 17 evaluable pts with other GI tumors, 6 achieved PR (35%; 2 unconfirmed) with a DCR of 100% (17/17); 11 pts were still receiving treatment. In the overall cohort, treatment-related adverse events of any grade occurred in 91% (38/42), the most frequent being nausea (48%), diarrhea (43%), vomiting (43%), and fatigue (29%); grade 3/4 events occurred in 21% of pts, with no grade 5 events. Conclusions: Adagrasib monotherapy is well tolerated and demonstrates encouraging clinical activity in pretreated pts with PDAC and other GI tumors harboring a KRASG12C mutation. Further exploration of adagrasib is ongoing in this pt population (NCT03785249). Clinical trial information: NCT03785249.

8 Background: Standard 1L therapies for mCRC include a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. NIVO may enhance antitumor activity in combination with 1L standard therapies within a subset of patients (pts) with mCRC. CheckMate 9X8 evaluated NIVO + mFOLFOX6/BEV vs mFOLFOX6/BEV in 1L mCRC (NCT03414983). Methods: Adults with previously untreated, unresectable, mCRC were randomized 2:1 to NIVO 240 mg + mFOLFOX6/BEV Q2W (NIVO + standard-of-care [SOC]) or mFOLFOX6/BEV Q2W (SOC). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival (OS), and safety. Results: 195 pts were randomized to NIVO + SOC (n = 127) or SOC (n = 68). Median (range) follow-up was 23.7 (0–33.2) months (mo; NIVO + SOC) vs 23.2 (0–32.3) mo (SOC). Median (range) duration of therapy was 9.9 (0.1–31.8+) mo (NIVO + SOC) and 7.7 (0.1–26.7+) mo (SOC). The HR (95% CI) for PFS was 0.81 (0.53–1.23; P = 0.30), which did not meet the prespecified threshold for statistical significance (median PFS, 11.9 mo in both arms; Table). PFS rates after 12 mo were higher with NIVO + SOC vs SOC (Table). ORR was 60% (NIVO + SOC) and 46% (SOC; odds ratio 1.72 [95% CI 0.96–3.10]) and median (95% CI) DOR was 12.9 (9.0–13.1) mo (NIVO + SOC) and 9.3 (7.5–11.3) mo (SOC; Table). Rates of grade 3−4 treatment-related adverse events (TRAEs) were higher with NIVO + SOC; however, no new safety signals were identified (Table). Biomarker analyses, including tumor mutational burden and baseline CD8 levels, will be presented. Conclusions: The primary endpoint of PFS was not met; however, NIVO + SOC showed higher PFS rates after 12 mo, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in 1L mCRC. Clinical trial information: NCT03414983. [Table: see text]

Abstract Background Inflammatory myofibroblastic tumors, previously known as inflammatory pseudotumors, are rare soft tissue carcinomas with variable presentation and location. Due to non-specific symptoms and location, the diagnosis of this condition is often clinically challenging. Only a handful of case reports have been published in the literature describing this tumor, and there is still a lack of consensus on pathogenesis, risk factors, and treatment strategy. Most tumors have shown mutation in the anaplastic lymphoma receptor tyrosine kinase (ALK) gene. In this article, we describe a case of ALK-negative malignant inflammatory myofibroblastic tumor. Case A 46 years old male with no risk factors presented with a mass in the inguinal region. The ultrasound was suggestive of a mixed echoic mass suggestive of inguinal hernia, which led to surgical repair with resection of the tumor segment. Subsequently, histopathology and immunohistochemistry confirmed that the mass was an inflammatory myofibroblastic tumor which then recurred in a few years and failed to respond to multiple chemotherapy regimens, and over time, it progressively metastasized to the anterior abdominal wall and lungs. The patient is currently receiving palliative chemotherapy and symptomatic treatment. Conclusion This rare soft tissue tumor has not received much attention, and clinicians often miss the diagnosis. We stress that further study should be carried out on these soft tissue tumors, and adequate diagnostic and therapy recommendations should be developed.

The records in 40 cases of congenital atresia of the extrahepatic biliary tract, proved at surgical exploration or necropsy or both, were studied at the Mayo Clinic with reference to clinical and pathologic aspects. Histologic examination of the liver was carried out in 21 of these cases; the muscular injections of vitamin K; each of these patients died during hospitalization.