Propensity Score Matching Analysis Comparing Ruxolitinib Vs Historical Controls in 2 nd Line or Beyond Treatment for Chronic Gvhd after Therapy Failure

Background The REACH3 study has reported greater overall response and failure-free survival (FFS) with Ruxolitinib (RUX) as 2 nd line therapy for steroid-refractory chronic graft versus host disease (cGVHD) in comparison to best available therapy (BAT; NEJM 2021). In addition, our Canadian retrospective study as a real-world experience has reported a promising activity of 64.6% FFS and 83.3% overall survival (OS) at 12 months in 115 patients (pts) treated with RUX from 2016 to 2021 for heavily pretreated cGVHD (ASH 2021). Also, 47.6% pts could reduce corticosteroid dose below 0.1mg/kg/day within 6 months. The present study compared treatment outcomes using a propensity-score matching (PSM) analysis between RUX pts ("RUX group", n=115) and a historical cohort of cGVHD pts treated with BAT as 2 nd line therapy or beyond from 2005 to 2013 ("BAT group", n=311). Statistical endpoints such as FFS, OS and steroid dose reduction were evaluated instead of overall response due to limited response assessment available from retrospective chart reviews. Patients and methods BAT included mycophenolate (43%), prednisone (29%), prednisone/cyclosporine (12%), extracorporeal photopheresis (6%), rituximab (3%), and others (7%). The pts and disease characteristics between the RUX vs BAT groups were not well balanced, as expected: RUX group showed a higher number of pts with severe grade GVHD (59.1% in RUX vs. 20.3% in BAT; p<0.0001), and more heavily pretreated with 4 th line or beyond (84.3% in RUX vs. 17.0% in BAT; p<0.0001). FFS and OS were calculated from the day of starting RUX or BAT therapy, while daily prednisone doses at months 0, 3 and 6 were calculated divided by body weight (kg). PSM analysis was applied to adjust risk factors that were unbalanced between the 2 groups, including GVHD severity at therapy start (mild/moderate vs severe grade), HCT-CI score (0-2 vs 3 or beyond), and treatment line (2nd vs 3rd vs 4th line or beyond). A total of 100 patients (i.e. 50 case-control pairs) were finally extracted through PSM process within 0.2 of calliper difference. PSM analysis balanced out the risk factors between the 2 groups: GVHD severity (p=1.0), HCT-CI score (p=1.0) and treatment line (p=1.0). The FFS and OS rate at 12 months were compared using Cox's proportional hazard model. Results In the overall population (n=426), with a median 19 months follow-up duration, 244 failures (57.3%) were noted. While both groups showed similar failure rates due to non-relapse mortality (NRM), the RUX group showed significantly lower failure rate from cGvHD resistance requiring therapy switch. Failure was noted in 40 pts (33.4%) in RUX due to resistance requiring a switch of therapy (n=23; 20.0%), NRM (n=14, 12.2%) and relapse (n=3; 2.6%), while failure occurred in 204 pts (65.6%) in BAT due to resistance requiring a switch of therapy (n=142; 45.7%), NRM (n=36; 11.6%) and relapse (n=26; 12.7%). The 12 months' FFS rate were 64.7% and 40.1% in RUX vs. BAT group (p<0.0001; Fig 1A), while the 12 months' OS rate were 83.4% and 83.7% in RUX vs. BAT group (p=0.913; Fig 1B). In the propensity score matched (PSM) cohort (n=100), the RUX group showed a survival benefit over the BAT group: the 12 months' FFS rate was 74.0% and 29.7% in RUX vs. BAT group (p<0.0001; Fig 2A), while the 12 months' OS rate were 90.5% and 80.2% in RUX vs. BAT group (p=0.109; Fig 2B). Multivariate analysis in the PSM cohort confirmed that RUX is superior to BAT for FFS (p<0.001, HR 0.267 [0.139-0.516]) together with HCT-CI score 0-2 vs ≥3 (p=0.037, HR 0.490 [0.251-0.959]) with a trend to better survival in RUX over BAT (p=0.110, HR 0.402 [0.131-1.228]). The prednisone dose was gradually reduced over time: the median doses of prednisone at months 0, 3, and 6 were 0.34, 0.16 and 0.02 mg/kg/day in the RUX group, and 0.95, 0.24 and 0.15 mg/kg/day at months 0, 3 and 6 in the BAT group. RUX facilitates the discontinuation of prednisone. The proportions of patients who discontinued prednisone at months 0, 3 and 6 were 8.7%, 15.9% and 24.1% in RUX, and 0.7%, 0% and 2.0% in BAT group. The differences in proportions of pts that discontinued prednisone between the RUX vs BAT groups at months 0, 3, and 6 were 8.0%, 15.9% and 22.1% (Fig 3). Conclusion: The current PSM analysis study suggests that RUX showed a superior FFS to BAT as 2nd line therapy or beyond in cGVHD patients after therapy failure. RUX showed better steroid tapering compared to BAT. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Elemary: Pfizer, Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz, BMS, Abbvie, Novartis, Pfiz: Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Paladin: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding.

Assessment of Quality of Life in Chinese Patients with Chronic Lymphocytic Leukemia

Background: Despite the changing landscape of treatment of chronic lymphoma leukemia (CLL) and in contrast to the large number of quality of life (QoL) and psychosocial studies in patients with solid tumors, relatively few studies have reported QoL in patients with CLL. This study aims to assess depression, anxiety, stress and QoL in a Chinese CLL cohort. Patients and Methods: Taking advantage of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 accompanying CLL-specific module QLQ-CLL17 questionnaire and DASS-21 questionnaire, a total of 50 Chinese patients with CLL completed self-reported questionnaires from December 2019 to July 2021, assessing the level of depression, anxiety, stress and QoL. Results: Among the 50 CLL patients, 34 patients were male. The median age was 57 (22-77) years old. 66% of the patients were uncertain about the staging of the disease. 36% of the patients were uncertain about therapeutic implications of CLL. According to EORTC QLQ-C30, patients had low level of physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning were 80%, 32%, 68%, 66%, 64%, respectively. Patients in active-treatment group had significantly lower level of physical function than "watch and wait" group (90% vs. 65%, P=0.03). The proportion of patients with cognitive problems was significantly higher in female patients than in male patients (93.8% vs. 52.9%, P=0.004). According to QLQ-CLL17, patients with symptom burden, physical condition and worries about health were 94% (47/50), 86% (43/50), 98% (48/50). Patients under 60 years old had higher scores for worries about health than patients older than 60. According to DASS-21 questionnaire, 86% of the patients had depression symptomatic scores (mild grade: 2%, medium grade: 52%, severe grade: 20%, very severe grade: 12%). 84% of the patients had anxiety symptomatic scores ( mild grade: 6%, medium grade: 14%, severe grade: 30%, very severe grade: 34%). 64% of the patients had stress symptomatic scores ( mild grade: 18%, medium grade: 22%, severe grade: 16%, very severe grade: 8%). And these psychosocial issues had no significant correlation with gender, age, household income and treatment . The same questionnaires were completed by 5 patients for the second time after median 8（2-18）months. Compared to the initial assessment, they scored significantly worse on the emotional scales (P=0.0237). No significant difference regarding physical functioning, role functioning, cognitive functioning and social functioning were observed between the former and the latter. Conclusions: The majority of CLL patients had impaired QoL and psychosocial issues. Active-treatment patients had worse physical condition than "watch and wait" patients. Male patients had better cognitive functioning. Younger patients had more worries about health than the elderly. Greater efforts should be made in management of CLL patients. Disclosures No relevant conflicts of interest to declare.

Histopathological and Histochemical Study of Human Cholecystitis

In our study the following inferences were made. Chronic calculous cholecystitis was seen in the age group of 41 to 50 years. A female preponderance was noted with male to female ratio of 2:3. The most common signs and symptoms were upper abdominal tenderness and right hypochondria pain. The mucosa showed ulceration in 63%, hyperplastic mucosa in 34% and metaplasia in 5%. 22% of cases showed mild (Grade-I) inflammation while 41 % of cases and 27% of cases showed moderate(Grade-2) and severe (Grade-3) inflammation respectively. 44 % of cases showed mild (Grade-I) fibrosis while 22% of cases and 15% of cases showed moderate (Grade-2) and severe (Grade-3) fibrosis. With increase 1n severity of inflammation and fibrosis, the total acid mucin content decreased while the neutral mucin content increased. Similar changes were observed in cases of metaplasia too.

HIFU Varicose Vein Treatment Using Veinsound Device Feasibility Study On Sheep

The purpose of this nonclinical study was to evaluate the performance (in terms of vein occlusion) and the local tissue effects of echo-guided HIFU (High Intensity Focused Ultrasound) treatments in sheep’s saphenous veins.HIFU treatments were used to treat 4 saphenous veins. Two HIFU doses were evaluated 4s/60J and 7s/105J with and without tumescence injection in perivenous tissues. Before and after treatment, ultrasound scans were performed (at Day 0, 3, 7 and 21). Sheep were then euthanized at D21. Local tissue effects were evaluated based on the macroscopic observations, while the evaluation of the device performance was based on ultrasonic scan.Macroscopically throughout the study duration, for dose of 4s/60J and with tumescence, significant lumens diameter reduction of 84% was observed without skin burns. For doses of 4s/60J without tumescence and 7s/105J skin burns of slight to severe grade was observed along the vein, while no thrombus nor lumen reduction were observed.

Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial

Background Lymphopenia may lead to worse outcomes for glioblastoma patients. This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on lymphopenia, and effects of lymphopenia on overall survival (OS). Methods CCTG CE.6 randomized elderly glioblastoma patients (≥ 65 yrs) to short course radiation alone (RT) or short course radiation with temozolomide (RT + TMZ). Lymphopenia (mild-moderate: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0, and measured at baseline, 1 wk and 4 wks post-RT. Pre-selected key factors for analysis included age, sex, ECOG, resection extent, MGMT methylation, MMSE, and steroid use. Multinomial logistic regression and multivariable Cox regression models were used to identify lymphopenia-associated factors and association with survival. Results 562 patients were analyzed (281 RT vs 281 RT+TMZ). At baseline, both arms had similar rates of mild-moderate (21.4% vs 21.4%) and severe (3.2% vs 2.9%) lymphopenia. However, at 4 weeks post-RT, RT+TMZ was more likely to develop lymphopenia (mild-moderate: 27.9% vs 18.2%; severe: 9.3% vs 1.8%; p<0.001). Developing any lymphopenia post-RT was associated with baseline lymphopenia (p<0.001). Baseline lymphopenia (HR 1.3) was associated with worse OS (HR: 1.30, 95% C.I. 1.05-1.62; p = 0.02), regardless of MGMT status. Conclusions Development of post-RT lymphopenia is associated with addition of TMZ and baseline lymphopenia and not with RT alone in patients treated with short-course radiation. However, regardless of MGMT status, only baseline lymphopenia is associated with worse OS, which may be considered as a prognostic biomarker for elderly glioblastoma patients.

Tricuspid regurgitation in ischemic mitral regurgitation patients – prevalence, predictors for outcome and long-term follow-up

Background Functional tricuspid regurgitation (FTR) is common in left-sided heart pathology involving the mitral valve. The incidence, clinical impact, risk factors, and natural history of FTR in the setting of ischemic mitral regurgitation (IMR) are less known. Method We conducted a cohort study based on data collected from January 2012 to December 2014. Patients diagnosed with IMR were eligible for the study. The median follow-up was five years. The primary outcome is defined as FTR developing at any stage. Results Among the 134 IMR patients eligible for the study, FTR was detected in 29.9% (N=40, 20.0% mild, 62.5% moderate, and 17.5% severe). In the FTR group, the average age was 60.7±9.2 years (25% females), the mean LV ejection fraction (LVEF) was 37.3±6.45 [%], LA area 46.4±8.06 [mm2], LV internal diastolic diameter (LVIDD) 59.6±3.94 [mm], RV fractional area change (RVFAC) 22.3±4.36 [%], systolic pulmonary artery pressure (SPAP) 48.4±9.45 [mmHg]. Independent variables associated with FTR development were age ≥65y [OR 1.2], failed revascularization, LA area ≥42.5 [mm2] [OR 17.1], LVEF ≤24% [OR 32.5], MR of moderate and severe grade [OR 419.4], moderate RV dysfunction [OR 91.6] and pulmonary artery pressure of a moderate or severe grade [OR 33.6]. During follow-up, FTR progressed in 39 (97.5%) patients. Covariates independently associated with FTR progression were lower LVEF, RV dysfunction, and PHT of moderate severity. LA area and LVIDD were at the margin of statistical significance (p=0.06 and p=0.05, respectively). Conclusion In our cohort study, FTR development and progression due to IMR was a common finding. Elderly patients with ischemic MR following unsuccessful PCI are at higher risk. FTR development and severity are directly proportional to LV ejection fraction, to the extent of mitral regurgitation, and SPAP. FTR tends to deteriorate in the majority of patients over a mean of 5-y follow-up. FUNDunding Acknowledgement Type of funding sources: None.

Acute-on-Chronic Liver Failure in Cirrhosis

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated chronic liver disease. It is characterised by high 28-day mortality, the presence of one or more organ failures (OFs) and a variable but severe grade of systemic inflammation. Despite the peculiarity of each one, every definition proposed for ACLF recognizes it as a proper clinical entity. In this paper, we provide an overview of the diagnostic criteria proposed by the different scientific societies and the clinical characteristics of the syndrome. Established and experimental treatments are also described. Among the former, the most relevant are directed to support organ failures, treat precipitating factors and carry out early assessment for liver transplantation (LT). Further studies are needed to better clarify pathophysiology of the syndrome and discover new therapies.

A Clinician-Free Method Using Top-View Photography for Screening and Monitoring Hallux Valgus

Background Hallux valgus is a progressive foot deformity that commonly affects middle-aged women. The aim of this study was to develop a novel method using only top-view photographs to assess hallux valgus severity. Methods A top-view digital photograph was taken of each foot of 70 female participants. Two straight lines were drawn along the medial edge of the great toe and forefoot, and the included angle (termed bunion angle) was measured using a free software program. Each foot was also assessed by a clinician using the Manchester scale as no (grade 1), mild (grade 2), moderate (grade 3), or severe (grade 4) deformity. Results The mean bunion angles of the 140 feet were 6.7°, 13.5°, and 16.2° for Manchester grades 1, 2, and 3, respectively (no foot was in grade 4). The reliability was excellent for both intrarater (intraclass correlation coefficient [ICC] = 0.93–0.95) and interrater (ICC = 0.90) assessments. Receiver operating characteristic curves determined the optimal bunion angle cutoff value for screening hallux valgus to be 9°, which gives 89.2% sensitivity and 74.2% specificity. Conclusions The bunion angle is a reliable, clinician-free method that can potentially be integrated into a smartphone app for easy and inexpensive self-assessment of hallux valgus.

FREQUENCY OF EXACERBATIONS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AS ONE OF THE FACTORS OF PROGRESSION OF NON-ALCOHOLIC FATTY LIVER DISEASE

This article presents the results of studies obtained by observing patients with non-alcoholic fatty liver disease (NAFLD) on the background of chronic obstructive pulmonary disease (COPD). As a result of the analysis it was found that the frequency of exacerbations of COPD with hospitalization in overweight patients in the presence of NAFLD leads to increased imbalance of adipose tissue hormones in the form of decreased adiponectin and increased leptin, and correlates with impaired lipid metabolism and severe grade of hepatic steatosis. In patients with frequent exacerbations, there is a significant positive correlation between leptin levels and TNF-a factor, which may be associated with an increase in overall inflammation. The revealed imbalance of adiponectin and leptin content in patients with COPD with overweight is a factor in the progression of NAFLD.

Toxicity and Tolerability of 177Lu-DOTA-TATE PRRT with a Modified Administered Activity Protocol in NETs of Variable Origin – A Phase 2 Registry Study

Background: Peptide receptor radionuclide therapy (PRRT) has been recently approved for advanced, metastatic, or progressive neuroendocrine tumors (NETs). Objectives: This study reports the adverse events (AEs) observed with patient-tailored administered activity. Methods: Fifty-two PRRT naive patients were treated with 177Lu-DOTATATE. The administered activity ranges between 2.78 and 5.55 GBq/cycle using the patient's unique characteristics (age, symptoms, blood work, and biomarkers). Results: The protocol was well tolerated with the overwhelming majority of participants being forty-six (88%), completing all 4 induction therapy cycles. The median cumulative administered activity was 19.6 GBq (ranged 3.8-22.3 GBq). A total of 42/52 (81%) reported at least one symptom, and 43/52 (83%) had evidence of biochemical abnormality at enrollment that would meet grade 1 or 2 criteria for AEs. These symptoms only slightly increase with treatment to 50/52 (96%) and 51/52 (98%), respectively. The most common symptoms were mild fatigue (62%), shortness of breath (50%), nausea (44%), abdominal pain (38%), and musculoskeletal pain (37%). The most common biomarker abnormalities were mild anemia (81%), reduced estimated glomerular filtration rate (eGFR) (58%), increased alkaline phosphatase (ALP) (50%), and leukopenia (37%). Of critical importance, no 177Lu-DOTATATE related grade 3 or 4 AEs were observed. Conclusion: Tailoring the administered activity of 177Lu-DOTATATE to the individual patient with a variety of NETs is both safe and well-tolerated. No patient developed severe grade 3 or 4 AEs. Most patients exhibit symptoms or biochemical abnormality before treatment and this only slightly worsens following induction therapy.