Citations

3084 Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs) in cancer cells. CYT-0851 inhibits HR leading to an accumulation of unrepaired DSBs and tumor cell death. We are reporting the completed Phase 1 dose-escalation results and RP2D selection to support ongoing development of CYT-0851. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 following a 3+3 design. The primary objective was determining the maximum tolerated dose. Secondary objectives included safety, pharmacokinetics, and anti-tumor activity. Results: As of a 15 Nov 2021 data cutoff (DCO), 73 pts with advanced cancers (NHL n = 18; Sarcoma n = 16; Pancreas n = 11; Breast n = 8; HNSCC n = 6; Ovarian n = 4; SCLC n = 4; Other n = 4; Myeloma n = 2) were treated in 12 cohorts (total daily doses: 30 mg to 1200 mg). One pt experienced a dose-limiting toxicity (DLT) of reversible metabolic acidosis at 1200 mg. Two of 3 pts at 800 mg experienced reversible DLT-like events in Cycle 2 of Gr3 dry skin and Gr3 myalgia and polyarthritis, respectively. Three of 10 pts treated at 600 mg experienced DLT-like events in Cycle 1: 1 pt experienced an SAE of Gr3 anorexia with Gr3 stomatitis, vomiting, and dehydration and 2 pts had Gr3 fatigue. No DLTs occurred at 400 mg daily which was selected as the RP2D. 42 pts (57.5%) experienced a CYT-0851-related adverse event (AE), including 12 (16.4%) with a Gr3/4 AE. There were no treatment-related deaths. AE leading to CYT-0851 withdrawal were reported in 2 pts (2.7%) treated with 600 and 800 mg. The most common CYT-0851-related AEs were primarily Gr1/2 and included fatigue (20.5%), hyperuricemia (11%), nausea (11%), alopecia (9.6%), constipation (8.2%) and headache (8.2%). CYT-0851 exposure was approximately dose-proportional across the evaluated doses with an effective half-life of ̃3 days. Exposure at 400 mg daily was consistent with efficacy in preclinical models. 46 pts were evaluable for response at the DCO. 12 pts with NHL were evaluable by Lugano and included 1 CR in FL and 1 PR in DLBCL treated for 393+ and 244 days respectively. 34 pts with solid tumors were evaluable by RECIST v1.1 with 1 PR in a pt with myxofibrosarcoma treated for 313 days and 16 pts with stable disease. Fifteen pts were treated for 100+ days and 5 for 180+ days. Conclusions: CYT-0851 has demonstrated promising and broad clinical activity in a Ph 1 population of pts with advanced cancers. The safety profile is favorable as characterized by events that were infrequent, primarily Gr1/2, and reversible. Six expansion cohorts (DLBCL, Follicular Lymphoma, Myeloma, Pancreatic, Ovarian and Sarcoma) are enrolling to characterize activity at the RP2D. Ph 1 evaluation of CYT-0851 in combination with 3 chemotherapy backbones is also ongoing. Clinical trial information: NCT03997968.

Many individuals travel to high altitude each year. Acclimatization to altitude occurs over the course of several days as the body adequately adapts to function in an environment with reduced partial pressure of oxygen. However, with a faster accent to attitude, comes an increased potential for maladaptations to occur, leading to the development of acute mountain sickness (AMS). Each year scientists and support workers are transported by plane from McMurdo Station in Antarctica (sea level) to the Amundsen‐Scott South Pole Station (2835m). This uniform and rapid deployment to altitude provides a unique opportunity to study the effects of hypobaric hypoxia on gene expression, which may help to illustrate the body’s ability to acclimatize to these environmental conditions. Purpose To detect pathway specific gene expression changes associated with the development of AMS and help identify potential targets that may aid in the prediction of risk in the development of AMS symptoms due to rapid exposure to high altitude. Methods Venous blood samples were collected from 53 (height 176.65±8.91cm, weight: 80.49±14.36kg) healthy subjects (38 (27 males; 11 females) that did not develop AMS and 15 (10 males; 5 females) that did develop AMS, as defined by the Lake Louis symptom questionnaire, collected at 2 different time points, with the first being at sea level and the second being after 48hr of altitude exposure). Microarray analysis was performed on the peripheral blood mononuclear cells (PBMCs) from the collected samples, and a logistic regression was performed to determine probe set association with AMS. Results There was a total of 178 significant (p<0.05) probe sets, with 156 of the probe sets being associated with AMS and 22 of the probe sets being associated with no AMS. The probe sets were entered into the Reactome Pathway Database (reactome.org). Pathways identified in association with AMS involved immune system pathways (interleukin signaling) and cellular responses to stimuli pathways (oxidative stress induced senescence signaling), and gene transcription pathways (mitochondrial biogenesis signaling, differentiation of hematopoietic stem cells). Interestingly, pathways identified in association with no development of AMS involved cell cycling pathways (mitotic signaling), chromatin organization pathways (chromatin modifying enzymes), metabolism pathways (utilization of ketone bodies) and the circadian clock pathway (circadian gene expression signaling). Conclusion These findings indicate potential maladaptive responses within the immune system and mitochondrial function, may play a key role in why some individuals develop AMS symptoms. An individual’s ability to sufficiently utilize different metabolic fuel sources and adapt their circadian rhythm may also prevent the development of AMS symptoms.

Introduction: Heart failure (HF) is associated with limited blood flow reserve due to reduced cardiac output (Q). HF is also associated with generalized respiratory muscle weakness, despite patients being exposed to an increased work and cost of breathing due primarily to increased flow resistive work from an altered breathing pattern. We hypothesized that the use of a respiratory training device during aerobic exercise training would positively impact patients with HF by training the inspiratory muscles and modifying their respiratory response to exercise. Methods: 15 subjects completed all study visits (age 67.5±10.0 yr, Ht 179.3±6.1cm, BMI 28.8±5.7 m/cm 2 ). Patients diagnosed with HF and currently enrolled in cardiac rehabilitation (CR) completed the Minnesota living with heart failure questionnaire (MLHFQ), pulmonary function testing, and measures during exercise that included Q (soluble gas method), ventilation (V E ) and respiratory gas exchange. Measures were made at baseline and after completion of CR. Participants were randomized to no respiratory resistance (NR) or mild-moderate inspiratory resistance (MR, 15 to 20 cmH 2 O) provided by a respiratory resistance mask (Training Mask Co., Cadillac, MI) worn during aerobic portions of CR. Results: Participants completed on average 23.9 ± 2.5 CR sessions with 10 subjects in the MR group and 5 in the NR group. The MR group had a decrease on the MLHFQ score of 19.9±26.9 and the NR group had a decrease of 6.0±23.4 (p=0.330). At a matched workload of 30 Watts (W), V E declined by 4.0±7.0 L/min and increased by 2.2±13.1 L/min for subjects in the MR and NR groups, respectively (p=0.06). Respiratory rate (RR) decreased in MR by 1.2± 4.9 and decreased in NR by 0.67± 5.9 (p>0.05). Heart rate at 30W decreased with time in both the MR and NR groups 10.4±12.4 and 3.9±8.9 respectively (p=0.036, no difference between groups). Stroke volume at 30W tended to increase for both MR and NR (p>0.05, no difference between groups). Conclusion: The addition of moderate inspiratory resistance to the aerobic training during CR was well tolerated by HF patients and preliminarily suggests trends toward improved ventilatory responses when assessed during submaximal exercise.

Background: An increased posterior tibial slope (PTS) results in greater force on the anterior cruciate ligament (ACL) and is a risk factor for ACL injuries. Biomechanical studies have suggested that a reduction in the PTS angle may lower the risk of ACL injuries. However, the majority of these investigations have been in the adult population. Purpose: To assess the mean medial and lateral PTS on pediatric cadaveric specimens without known knee injuries. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 39 pediatric knee specimens with computed tomography scans were analyzed. Specimens analyzed were between the ages of 2 and 12 years. The PTS of each specimen was measured on sagittal computed tomography slices at 2 locations for the medial and lateral angles. The measurements were plotted graphically by age to account for the variability in development within age groups. The anterior medial and lateral tibial plateau widths were measured. The distance between the top of the tibial plateau and the physis was measured. The independent-samples t test and analysis of variance were used to analyze the measurements. Results: The mean PTS angle for the medial and lateral tibial plateaus was 5.53° ± 4.17° and 5.95° ± 3.96°, respectively. The difference between the PTS angles of the medial and lateral tibial plateaus was not statistically significant ( P > .05). When plotted graphically by age, no trend between age and PTS was identified. Conclusion: This data set offers values for the PTS in skeletally immature specimens without a history of ACL injury and suggests that age may not be an accurate predictive factor for PTS.

AbstractBackgroundEvidence suggests that select hippocampal subfields are implicated in the initial stages of Alzheimer’s disease (AD) and are selectively involved in objective memory. Less is known whether subfields are associated with informant-reported memory difficulties of individuals with a diagnosis of mild cognitive impairment (MCI).MethodData from 56 participants with a diagnosis of amnestic MCI were included in the present study. To test whether FreeSurfer derived hippocampal subfields (CA1–4, subiculum, presubiculum, and dentate gyrus) were associated with objective (learning and delayed recall) and informant-reports of memory difficulties, we used multiple linear regression analysis. Subfields were adjusted for total intracranial volume, and age, sex, and years of education were included as covariates in all models.ResultsLarger presubiculum, subiculum, and CA4/dentate gyrus volumes were associated with higher delayed recall scores, and larger subiculum and CA4/dentate gyrus volumes were associated with fewer informant-reports of memory difficulties. There were no statistically significant associations between subfields and learning scores.DiscussionFindings from the present study support the idea that difficulties with memory-dependent everyday tasks in older adults with MCI may signal a neurodegenerative process while increasing understanding of subfields correlates of these memory-specific functional difficulties. Continued investigations into identifying patterns of subfield atrophy in AD may aid early identification of those at higher risk of dementia conversion while advancing precision medicine.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Objective: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. Summary Background Data: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. Methods: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. Results: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. Conclusions: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

AbstractSaccular aneurysms (SAs) are focal outpouchings from the lateral wall of an artery. Depending on their morphology and location, minimally invasive treatment options include coil embolization, flow diverter stents, stent‐assisted coiling, and liquid embolics. Many drawbacks are associated with these treatment options including recanalization, delayed healing, rebleeding, malpositioning of the embolic or stent, stent stenosis, and even rupture of the SA. To overcome these drawbacks, a nanoclay‐based shear‐thinning hydrogel (STH) is developed for the endovascular treatment of SAs. Extensive in vitro testing is performed to optimize STH performance, visualization, injectability, and endothelialization in cell culture. Femoral artery saccular aneurysm models in rats and in pigs are created to test stability, efficacy, immune response, endothelialization, and biocompatibility of STH in both ruptured and unruptured SA. Fluoroscopy and computed tomography imaging consistently confirmed SA occlusion without recanalization, migration, or nontarget embolization; STH is also shown to outperform coil embolization of porcine aneurysms. In pigs with catastrophic bleeding due to SA rupture, STH is able to achieve instant hemostasis rescuing the pigs in long‐term survival experiments. STH is a promising semisolid iodinated embolic agent that can change the standard of medical practice and potentially save lives.