Citations

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tyrosine kinase inhibitors (TKIs) are approved as a first-line treatment for unresectable HCC. Lenvatinib and cabozantinib are two of the most used TKIs, but the therapeutic duration is limited due to the development of drug resistance. Therefore, understanding the mechanisms of resistance and combining TKIs with other drugs antagonizing resistance should lead to antitumor synergy, eliminating drug resistance. It turns out that the simultaneous use of TKIs together with an inhibitor of stearoyl-CoA desaturase 1 (SCD1) prevents the development of drug resistance, leading to a durable response. SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis, converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). MUFAs are an alternative energy source to glucose, integral to cellular membranes, and prevent endoplasmic reticulum (ER) stress and other signaling pathways. In our laboratory, we developed a novel, highly specific SCD1 inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We tested the concomitant use of SSI-4 with lenvatinib and cabozantinib, tyrosine kinase inhibitors (TKIs) FDA-approved for HCC, in HCC cell lines in vitro and using HCC PDX in vivo mouse models. Our studies showed that the combination of the SCD1 inhibitor with both lenvatinib and cabozantinib showed a highly synergistic effect and no development of drug resistance i.e. durable response versus single TKI therapy. Ongoing mechanistic studies are examining whether known molecular targets of tested TKI’s such as VEGFR1, 2, and 3, PDGFRα, FGFR, KIT, and RET dominate in HCC drug resistance to lenvatinib and cabozantinib, and how the use of SSI-4 overcomes the phenomenon of resistance. Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland. Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5489.

12114 Background: A retrospective study suggested a potential benefit from rose geranium in sesame oil nasal spray for alleviating nasal vestibulitis symptoms in patients (pts) undergoing chemotherapy. Methods: Pts undergoing active chemotherapy who reported moderate or worse nasal symptoms were randomized 1:1 to receive a rose geranium in sesame oil nasal spray (RG) or an isotonic saline nasal spray (IS), administered twice daily for two weeks. Consenting pts completed nasal symptom questionnaires at baseline and then weekly while on treatment. The number and percentage of pts experiencing improvements in their nasal symptoms 2 weeks after initiating the nasal spray, defined as symptoms moderately (2) or very much (3) better on a 7-point global impression of change score (ranging from scores of -3: very much worse, to 3: very much better), was estimated within and then between each randomized arm, using Fisher’s exact test (5% significance level). The estimated odds ratio was determined (95% confidence interval). After 2 weeks, pts initially randomized to IS were allowed to cross-over to RG and completed weekly surveys. Results: 106 pts consented to this study; 43 pts in the RG arm and 41 in the IS arm were evaluable for the primary endpoint. Pts had a mean age of 57.8 (SD 13.9). Demographic characteristics and baseline nasal symptoms were similar between arms. The most prominent baseline nasal symptoms were dryness (36%) and bleeding (35%). Of the 43 evaluable pts who received RG, 67.4% reported improved nasal symptoms, compared with 36.6% of the 41 pts who received IS (p=0.009; Table). On the global impression of change score, pts who received RG had a mean score of 1.93 (SD 1.16), compared to a mean score of 0.98 (SD 1.41) among pts who received IS. Adjusting for potential confounding factors, pts who received RG had a 4.56 odds of responding to the nasal spray, compared with those who received IS (p=0.005). There were no significant differences between pt responses based upon type of nasal symptoms, age, allergies, or gender. Adverse events were sparse and did not differ between arms. 34 pts crossed over to RG after week 2. Among the 29 pts who completed final surveys, 37% reported a response on IS, 79% reported a response on RG. Conclusions: Rose geranium in sesame oil nasal spray significantly improves nasal vestibulitis symptoms among patients undergoing chemotherapy. Clinical trial information: NCT04620369 . [Table: see text]

7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . [Table: see text]

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance, and pancreatic islet cell dysfunction. T2DM is associated with non-alcoholic fatty liver disease (NAFLD) because of impaired glucose metabolism in both conditions. However, it is widely assumed that people with T2DM in sub-Saharan Africa (SSA) have a lower prevalence of NAFLD than in other parts of the world. With our recent access to transient elastography, we aimed to investigate the prevalence of, severity of, and contributing factors to NAFLD in persons with T2DM in Ghana. We performed a cross-sectional study recruiting 218 individuals with T2DM at the Kwadaso Seventh-Day Adventist and Mount Sinai Hospitals in the Ashanti region of Ghana using a simple randomized sampling technique. A structured questionnaire was used to obtain socio-demographic information, clinical history, exercise and other lifestyle factors, and anthropometric measurements. Transient elastography was performed using a FibroScan® machine to obtain the Controlled Attenuation Parameter (CAP) score and liver fibrosis score. The prevalence of NAFLD among Ghanaian T2DM participants was 51.4% (112/218), of whom 11.6% had significant liver fibrosis. An evaluation of the NAFLD group (n = 112) versus the non-NAFLD group (n = 106) revealed a higher BMI (28.7 vs. 25.2 kg/m2, p = 0.001), waist circumference (106.0 vs. 98.0 cm, p = 0.001), hip circumference (107.0 vs. 100.5 cm, p = 0.003), and waist-to-height ratio (0.66 vs. 0.62, p = 0.001) in T2DM patients with NAFLD compared to those without NAFLD. Being obese was an independent predictor of NAFLD in persons with T2DM than known history of hypertension and dyslipidaemia.

Renal diseases pose a significant socio‐economic burden on healthcare systems. The development of better diagnostics and prognostics is well‐recognized as a key strategy to resolve these challenges. Central to these developments are MRI biomarkers, due to their potential for monitoring of early pathophysiological changes, renal disease progression or treatment effects. The surge in renal MRI involves major cross‐domain initiatives, large clinical studies, and educational programs. In parallel with these translational efforts, the need for greater (patho)physiological specificity remains, to enable engagement with clinical nephrologists and increase the associated health impact. The ISMRM 2022 Member Initiated Symposium (MIS) on renal MRI spotlighted this issue with the goal of inspiring more solutions from the ISMRM community. This work is a summary of the MIS presentations devoted to: 1) educating imaging scientists and clinicians on renal (patho)physiology and demands from clinical nephrologists, 2) elucidating the connection of MRI parameters with renal physiology, 3) presenting the current state of leading MR surrogates in assessing renal structure and functions as well as their next generation of innovation, and 4) describing the potential of these imaging markers for providing clinically meaningful renal characterization to guide or supplement clinical decision making. We hope to continue momentum of recent years and introduce new entrants to the development process, connecting (patho)physiology with (bio)physics, and conceiving new clinical applications. We envision this process to benefit from cross‐disciplinary collaboration and analogous efforts in other body organs, but also to maximally leverage the unique opportunities of renal physiology.Level of Evidence1Technical Efficacy Stage2

Abstract Aims In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrials.gov Identifier NCT03737110

Background: The effectiveness of ultrasound-based surveillance for HCC in patients with cirrhosis is limited by suboptimal sensitivity for early tumor detection and poor adherence. Emerging blood-based biomarkers have been proposed as an alternative surveillance strategy. We aimed to evaluate the comparative effectiveness of a multitarget HCC blood test (mt-HBT)—with and without improved adherence—against ultrasound-based HCC surveillance. Methods: We developed a Markov-based mathematical model that simulated a virtual trial in patients with compensated cirrhosis comparing potential surveillance strategies: biannual surveillance using ultrasound, ultrasound plus AFP, and mt-HBT with or without improved adherence (+10% increase). We used published data to inform underlying liver disease progression rates, HCC tumor growth patterns, performance characteristics of surveillance modalities, and efficacy of treatments. Primary outcomes of interest were the number of early-stage HCCs detected and life years gained. Results: Per 100,000 patients with cirrhosis, mt-HBT detected 1680 more early-stage HCCs than ultrasound alone and 350 more early-stage HCCs than ultrasound + AFP, yielding an additional 5720 and 1000 life years, respectively. mt-HBT with improved adherence detected 2200 more early-stage HCCs than ultrasound and 880 more early-stage HCCs than ultrasound + AFP, yielding an additional 8140 and 3420 life years, respectively. The number of screening tests needed to detect one HCC case was 139 with ultrasound, 122 with ultrasound + AFP, 119 with mt-HBT, and 124 with mt-HBT with improved adherence. Conclusions: mt-HBT is a promising alternative to ultrasound-based HCC surveillance, particularly given anticipated improved adherence with blood-based biomarkers could increase HCC surveillance effectiveness.

PURPOSE Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529 ). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.

ABSTRACT Mpox is a rare infection caused by the zoonotic orthopoxvirus. We present the case of a 44-year-old man with HIV and a history of kidney transplant who presented with mpox and developed proctitis-associated bowel obstruction, urinary retention, and eosinophilia. Our case highlights potential gastrointestinal manifestations of severe mpox infection.