Favorable Disease Research Articles

Sialoadenosis caused by spirocercosis in two dogs from Sri Lanka

AbstractSpirocercosis is a common parasitic disease in dogs in tropical and mediterranean regions of the world caused by the nematode Spirocerca lupi. Some dogs with spirocercosis develop sialoadenosis, a condition identified by non‐inflammatory, painless, bilateral enlargement of the mandibular salivary glands. Development of sialoadenosis in dogs infected with S. lupi occurs as a consequence of neurological stimulation caused by larval migration and oesophageal parasitic nodule formation. This report describes the clinical signs, diagnosis, treatment and the treatment outcome of two dogs diagnosed with sialoadenosis caused by spirocercosis. Phenobarbital therapy is useful to control clinical signs shown by the dogs with sialoadenosis secondary to spirocercosis presented at an early stage of the disease. A more favourable disease outcome is possible when phenobarbital therapy is combined with anti‐parasitic medication effective against S. lupi.

Idarubicin-loaded drug-eluting microspheres transarterial chemoembolization for intermediate stage hepatocellular carcinoma: safety, efficacy, and pharmacokinetics.

Transarterial chemoembolization (TACE) is the treatment of choice for the intermediate stage hepatocellular carcinoma (HCC). Doxorubicin remains the most used chemotherapeutic agent in TACE, although in vitro screening has demonstrated that idarubicin exhibits greater cytotoxicity against HCC. This study aimed to evaluate safety, efficacy, and pharmacokinetics of idarubicin-loaded drug-eluting microspheres TACE (DEMIDA-TACE) in intermediate stage HCC patients. Between September 2019 and December 2021, 31 consecutive intermediate stage HCC patients (96.8% cirrhotic) were included to this study. 2 mL of LifePearl™ microspheres (100 μm) loaded with 10 mg of 1 mg/mL idarubicin were used for treatment. The adverse events, objective response rate (ORR), progression free survival (PFS), time to TACE untreatable progression (TTUP), median overall survival (mOS), and pharmacokinetics were evaluated. There were 68 TACE procedures performed. Adverse events grade ≥ 3 were noted after 29.4% procedures. The ORR was 83.9%, median PFS and TTUP were 10.5 months (95% CI: 6.8-14.3 months) and 24.6 months (95% CI: 11.6-37.6 months), respectively. Median OS was 36.0 months (95% CI: 21.1-50.9 months). Significant differences between patients achieving objective response (OR) and those with progressive disease were observed regarding idarubicinol and combined idarubicin-idarubicinol plasma concentrations at 72 hours post-procedure, higher plasma concentrations were observed in patients achieving OR (p = 0.014 and 0.014; cut-off values 1.2 and 1.29 ng/mL, respectively). DEMIDA-TACE emerges as a safe and effective method of treatment for the intermediate stage HCC with low rates of adverse events alongside high tumor response, favourable disease control and overall survival. Idarubicinol and combined idarubicin-idarubicinol plasma concentrations at 72 hours post-procedure may serve as prognostic factors for achieving OR.

Utilization of Partial Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma.

Cytoreductive nephrectomy for metastatic renal cell carcinoma (mRCC) is a standard of care. Partial nephrectomy (PN) in the setting of metastatic disease is an uncommon occurrence, and we aimed to characterize its utilization in a modern cohort. The National Cancer Database was reviewed for patients with mRCC from 2010 to 2017. Patients with cTanyNanyM1 who underwent cytoreductive surgery in the form of PN or radical nephrectomy (RN) were compiled. Our primary outcome was survival outcome for patients who underwent PN compared to RN. Secondary outcomes included 30-day readmission, length of stay, and survival outcomes. A total of 13,896 patients with mRCC who underwent cytoreductive surgery were identified. In total, 13,242 underwent RN and 654 underwent PN. The RN population was more likely to have cN positive disease, while the PN population was more likely to have cT1 disease. Length of stay, readmission and 30-day mortality were not significantly different between PN and RN, but overall mortality and 90-day mortality favored PN (p < 0.001). Cox regression for death showed PN with improved overall survival (HR 0.782, p < 0.001). Logistic regression for predictors of cytoreductive PN revealed cT1 and cN0 as significant factors. Overall survival, as seen on KM analysis, identified that PN exhibited improved 2-year (67.1% vs. 52.0%) and 5-year (40.7% vs. 29.2%) overall survival relative to RN (p < 0.001). PN is an infrequent treatment with mRCC and its utilization is stable from 2010 to 2017. Overall survival is significantly better for those undergoing PN, likely due to their favorable oncologic disease characteristics.

Menopausal Hormone Therapy in Breast Cancer Survivors.

Menopausal symptoms negatively impact quality of life in breast cancer survivors. The paucity of data on the impact of Menopausal Hormone Therapy (MHT) on oncological outcomes in these patients limits informed clinical discussion. Defining the risk of cancer recurrence with MHT is central to the appraisal of risk/benefit, particularly with low-risk disease (based on genomic profile). The aim of this review is to summarize the current data evaluating MHT in breast cancer patients. A systematic review of the literature was performed to evaluate the impact of MHT on oncological outcomes in breast cancer survivors. Three major databases (PubMed, EMBASE and Medline) were searched. The review included all prospective studies published in English. Four randomized control trials and four non-randomized prospective studies were identified. An increase in breast cancer recurrence with MHT was observed in the early randomized trials whilst no increased risk of recurrence was reported in the observational studies. There remains a need to quantify MHT-related recurrence risk in patients with molecularly favorable disease.

Abstract A039: Joint roles of proteomics and neighborhood-level social determinants of metastatic prostate cancer

Abstract Introduction: Striking racial disparities in prostate cancer (PCa) outcomes among American Black men warrant significant efforts to identify early predictors of lethal PCa, to avoid over- treatment of clinically favorable disease with minimal risk of progression. Building on prior work, this study examined independent and joint roles of proteomic markers and social determinants of health (SDOHs) in predicting prostate disease aggressiveness in a racially diverse cohort of men undergoing prostate biopsy. Methodology: A retrospective cohort of 300 men biopsied for prostate cancer was assembled at University Hospitals (UH) Seidman Cancer Center in Cleveland, Ohio between January 1, 2005-May 2022. An extensive medical chart review was performed to identify Black and White men undergoing transrectal ultrasound- guided biopsy that resulted in: (i) a negative biopsy in patients with a history of 1+ prior negative biopsy and no PCa history (“NEG”); (ii) a biopsy-detected PCa of Gleason sum 6 (“GL6”); and (iii) biopsy-detected PCa with nodal and/or distant metastases at initial cancer detection (“METS”). Prostate biopsy tissues were obtained on each patient, balancing 100 men per biopsy group, and balanced on race (1:1) within each biopsy group. Informed by findings from an untargeted analysis of the entire proteome of 60 patients (“Discovery cohort”), we conducted a targeted proteomics analysis of 16 protein markers generated from prostate biopsy tissue, using mass spectrometry, on n=240 patients (“Verification cohort”). Chi-square testing and Analysis of Variance (ANOVA) were used to assess associations between protein expression, neighborhood-level SDOHs, and biopsy group. Race-stratified analyses were performed to examine statistical interactions between study associations. Principal components (PC) analysis was used to identify protein markers that predicted the greatest variance in biopsy group. Multivariable logistic regression (MLR) was used to predict METS (vs. NEG and GL6, combined), as a function of PC-selected protein markers and census block-group level area deprivation index (ADI). Bonferroni correction was used to establish the threshold for the decision rule of statistical significance (alpha error 0.05/16 markers: p&amp;lt; 0.0031). Results: Median patient age was 68 years. Protein expression distributions were transformed into quintiles due to non-normality. Of 16 protein markers, 14 were significantly correlated with biopsy group, including PARP 1 and TGFB1, for which METS patients had the highest expression. ADI was strongly correlated with race but not protein expression. ADI was significantly higher in METS patients, followed by GL6 and lowest in NEG group; however no associations were seen for ADI with protein expression. Eight proteins were found to predict METS in PC and MLR analysis. Conclusions: These data support use of proteomics markers to predict a metastatic versus non-metastatic biopsy result. Next steps include deep exploration of proteome findings generated in the Discovery cohort, such as biological pathways. Citation Format: Jennifer Cullen, Tao Liu, Holly Hartman, Fangzhou Liu, Anood Alfahmy, Rini Ghosh, Ayesha Shafi, Julia Payne, Randy Vince, Lee Ponsky, Gregory MacLennan. Joint roles of proteomics and neighborhood-level social determinants of metastatic prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A039.

Molecular Transducers of Physical Activity Consortium (MoTrPAC): human studies design and protocol.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Dose Deintensified 3-Day Photon, Proton, or Brachytherapy: A Nonrandomized Controlled Partial Breast Irradiation Trial

BackgroundThe optimal approach for partial breast irradiation (PBI) is unknown. We investigated a novel de-intensified 3-fraction PBI regimen for photons, protons, and brachytherapy. MethodsA multicenter nonrandomized controlled trial with primary outcome of adverse cosmesis at 3 years versus pre-PBI. Eligibility criteria were ≥ age 50 years treated with breast-conserving surgery for node-negative estrogen receptor positive (ER+) invasive breast cancer or any ductal carcinoma in-situ (DCIS) measuring ≤ 2.5 cm. Photon and proton PBI were prescribed 21.9 Gy (RBE) and brachytherapy 21 Gy in 3 fractions. Radiotherapy technique and use of adjuvant endocrine therapy was selected at physician and patient discretion. ResultsBetween June 17, 2015 and July 13, 2017, 161 eligible patients were treated with photons (56), protons (49), or brachytherapy (56). Median patient age was 66.8 years. 126 (78.3%) had invasive breast cancer (all ER+) and 35 (21.7%) had DCIS (88.6% ER+). 54.0% of patients with invasive breast cancer and 25.8% of patients with ER+ DCIS initiated and adhered to prescribed endocrine therapy. The proportion of patients with adverse cosmesis (by trained nurse assessment) was 14.5% at baseline, 2.3% at 3 years (difference -12.2%, 95% CI (-100%, -6.4%)). Adverse cosmesis at last-follow-up, with median follow-up 5 years, was 5.7% by nurse assessment, 5.6% by panel assessment of digital photographs, and 5.2% by patient self-report. There were no observed clinically meaningful changes in other patient reported outcomes, and just two grade 2 or higher adverse events, both grade 2, in the brachytherapy cohort. 5-year local recurrence-free and progression-free survival were 98.0% and 95.5%, respectively. There were no local recurrences amongst 60 patients with invasive breast cancer and Ki67 ≤ 13.25%. ConclusionsDe-intensified 3-day PBI provided favorable disease control, tolerability, and cosmetic outcomes, meeting the pre-specified criteria for acceptability. This approach is an attractive option for small node-negative ER+ BC and DCIS patients. Trial registrationClinicalTrials.gov identifier NCT02453737

Clinical characteristics and long-term disease course in patients with Crohn's disease as diagnosed by video capsule endoscopy: a multicenter retrospective matched case-control study.

Video capsule endoscopy is rarely used to diagnose Crohn's disease in patients with negative ileocolonoscopy or cross-sectional image findings. We evaluated clinical characteristics and long-term outcomes of these rare cases. This multicenter study included patients with Crohn's disease from 3 tertiary hospitals from January 2007 to October 2022. Patients with normal findings on ileocolonoscopy and computed tomography (CT)/magnetic resonance (MR) enterography but had ulcerations at the small bowel detected by video capsule endoscopy were included. The controls were patients with abnormal findings on endoscopy or CT/MR enterography. Controls were case-matched in a ratio of 3:1 for sex, calendar year of diagnosis, and age at diagnosis. Among 3,752 patients, 24 (0.6%) were diagnosed with Crohn's disease using video capsule endoscopy findings. The disease location (P< 0.001) and behavior at diagnosis (P= 0.013) of the cases significantly differed from that of controls. The perianal fistula modifier (25.0% vs. 33.3%, P= 0.446) did not differ significantly between the 2 groups. Initial disease activity and C-reactive protein and fecal calprotectin levels were significantly lower in cases versus controls. The median Lewis score was 838 (interquartile range, 393-1,803). Over 10 years of follow-up, the cases showed significantly lower cumulative risk of complicated behavior, biologics use, Crohn's disease-related hospitalization, and surgeries (log-rank test P< 0.05). Patients with Crohn's disease whose lesions were observed only by video capsule endoscopy were rare, and exhibit different clinical characteristics and a more favorable long-term disease course compared to those who were conventionally diagnosed.

6 Durable response to immunotherapy-based regimens for IMDC favorable risk patients with metastatic clear cell renal cell carcinoma: a pooled analysis of four published randomized control phase 3 trials

Abstract Background An immune checkpoint inhibitor (ICI) backbone of either ICI doublet (ipilimumab-nivolumab [ipi-nivo]) or tyrosine kinase inhibitor (TKI) with ICI (such as axitinib-pembrolizumab [axi-pembro], cabozantinib-nivolumab [cabo-nivo], or lenvatinib-pembrolizumab [len-pembro]) is the current standard of care for previously untreated, metastatic clear cell renal cell carcinoma (mccRCC). The phase 3 trials that evaluated these four regimens were compared to sunitinib, with no direct head-to-head clinical trial data available. With at least 4-year follow up data available, we compared the long-term responders of the IMDC favorable risk patients enrolled in the four phase 3 trials (CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR). Methods Pseudo individual patient data (IPD) was obtained from the Kaplan-Meier (K-M) curves using the graph digitizer software IPDfromKM R package to extract coordinates of points on the curves and applied the numerical algorithm to reconstruct survival results. The hazard ratios (HRs) of the favorable risk group for both progression-free survival (PFS) and overall survival (OS) comparing the experimental arms to sunitinib were extracted. Responses were measured at 24 (durable response [DR]) and 36 months (extreme durable response [EDR]) and long-term OS as OS ≥48 months. K-M method using the extracted IPD was used to estimate the survival rates at 24-month PFS, 36-month PFS, and 48-month OS. Then, we compared the survival rates at each time point using the generalized linear model for the survival rates at fixed time points obtained from the K-M method. Results Len-pembro was associated with the highest DR (57.2%) and EDR (44.5%), while ipi-nivo had the lowest DR (36.0%), and cabo-nivo had the lowest EDR (18.8%). There was no difference in 48 month-OS among regimens (p=0.11), ranging between 58.3% (cabo-nivo) and 70.6% (len-pembro). Comparing the sunitinib control arms among the four studies, a numerically higher PFS at 24 months (59%) and 36 months (40%) was observed in the CheckMate 214 trial compared to the ICI-TKI trials (25-35% and 15-20%, respectively). The 48-month OS for the sunitinib arms ranged from 55-70%, and no differences were observed among trials (p=0.55). Comparisons of survival rates for the immunotherapy arm on fixed time-points for IMDC favorable risk subset of patients Conclusions ICI-based regimens provided durable responses to a significant number of patients with favorable risk mccRCC. While TKI-ICI were associated with higher DR and EDR, no differences in OS at 48 months were observed compared to ipi-nivo or sunitinib for favorable risk disease. Longer follow-up is necessary to evaluate long-term outcomes given the favorable prognosis of these patients. We acknowledge the limitations and caveats of cross-trial comparisons.

Association of Clinical Relapses With Disease Outcomes in Multiple Sclerosis Patients Older Than 50 Years.

Relapse and MRI activity usually decline with aging but are replaced by progression independent of relapse activity (PIRA) in patients with multiple sclerosis (PwMS). However, several older PwMS continue to experience clinical relapses, and the impact on their disease remains undetermined. We aimed to determine the impact of an index relapse on disease outcomes in patients older than 50 years and to identify risk factors of disadvantageous outcomes. We performed a secondary analysis from 3 prospective cohorts in Germany. We evaluated all PwMS 50 years and older with a relapse ≤60 days before a baseline visit and at least 18 months of follow-up compared with a control cohort of PwMS without a relapse. Patients were stratified according to age ("50-54" vs "55-59" vs "60+") or disease outcomes ("stable" vs "active" vs "progressive," according to the Lublin criteria). We analyzed relapses, MRI activity, relapse-associated worsening, and PIRA. Regression analysis was performed to evaluate the association of specific baseline risk factors and treatment regimen changes with disease outcomes at month 18. A total of 681 patients were included in the "relapse cohort" (50+: 361; 55+: 220; 60+: 100). The "control cohort" comprised 232 patients (50+: 117; 55+: 71; 60+: 44). Baseline epidemiologic parameters were balanced among cohorts and subgroups. We observed increased abundance of inflammatory activity and relapse-independent disability progression in the "relapse" vs "control" cohort. In the "relapse" cohort, we identified 273 patients as "stable" (59.7%), 114 patients as "active" (24.9%), and 70 patients as "progressive" (15.3%) during follow-up. Cardiovascular risk factors (CVRFs) and older age at baseline were identified as risk factors of progressive, whereas disease-modifying treatment (DMT) administration at baseline favored stable disease. DMT during follow-up was associated with stable over active, but not over progressive disease. A relapse-suggesting underlying active disease-in PwMS older than 50 years was associated with continued disease activity and increased risk of PIRA. Presence of CVRF and absence of DMT at baseline appeared as risk factors of disadvantageous disease courses. An escalation of DMT switch was associated with stable over active but not progressive disease.

Identification of risk factors and construction of a nomogram predictive model for post-stroke infection in patients with acute ischemic stroke.

Post-stroke infection is the most common complication of stroke and poses a huge threat to patients. In addition to prolonging the hospitalization time and increasing the medical burden, post-stroke infection also significantly increases the risk of disease and death. Clarifying the risk factors for post-stroke infection in patients with acute ischemic stroke (AIS) is of great significance. It can guide clinical practice to perform corresponding prevention and control work early, minimizing the risk of stroke-related infections and ensuring favorable disease outcomes. To explore the risk factors for post-stroke infection in patients with AIS and to construct a nomogram predictive model. The clinical data of 206 patients with AIS admitted to our hospital between April 2020 and April 2023 were retrospectively collected. Baseline data and post-stroke infection status of all study subjects were assessed, and the risk factors for post-stroke infection in patients with AIS were analyzed. Totally, 48 patients with AIS developed stroke, with an infection rate of 23.3%. Age, diabetes, disturbance of consciousness, high National Institutes of Health Stroke Scale (NIHSS) score at admission, invasive operation, and chronic obstructive pulmonary disease (COPD) were risk factors for post-stroke infection in patients with AIS (P < 0.05). A nomogram prediction model was constructed with a C-index of 0.891, reflecting the good potential clinical efficacy of the nomogram prediction model. The calibration curve also showed good consistency between the actual observations and nomogram predictions. The area under the receiver operating characteristic curve was 0.891 (95% confidence interval: 0.839-0.942), showing predictive value for post-stroke infection. When the optimal cutoff value was selected, the sensitivity and specificity were 87.5% and 79.7%, respectively. Age, diabetes, disturbance of consciousness, NIHSS score at admission, invasive surgery, and COPD are risk factors for post-stroke infection following AIS. The nomogram prediction model established based on these factors exhibits high discrimination and accuracy.

Systemic treatments in favorable and very favorable risk metastatic renal cell carcinoma (mRCC): Real world evidence from the International mRCC Database Consortium (IMDC).

4514 Background: The role of immunotherapy combinations in mRCC with IMDC favorable risk is controversial. A very favorable subgroup of favorable risk patients (primary diagnosis to systemic therapy ≥3yr, Karnofsky Performance Status 90 or 100% and absence of brain, liver, or bone metastasis) has been described by Schmidt A. et al., which require characterization in the immuno-oncology combination era. Methods: Using the IMDC, we selected mRCC patients with IMDC favorable risk who started systemic therapy during 2016-2023 and examined the favorable risk group and the subset of very favorable risk patients. First line systemic therapy was divided into 3 groups: Ipilimumab + Nivolumab (IPI/NIVO), combination of anti PD1/PDL1 and VEGF (IO-VEGF) (Pembrolizumab and Axitinib or Lenvatinib, Avelumab and Axitinib, or Nivolumab and Cabozantinib), and Vascular endothelial growth factor (VEGF) inhibitors (Pazopanib or Sunitinib). The primary outcomes were 2-year overall survival (2y OS) in the favorable and very favorable risk population. Secondary outcomes included Response Rate (RR), treatment duration (TD) and time to next treatment (TTNT). We used unadjusted survival rates at 2 years, with Cox regression model with TKI mono as reference. Results: 611 favorable risk patients were eligible for analysis, of which 165 (26.9%) had very favorable risk disease. Median age at diagnosis was 62 years, 73.8% were male, 87.1% had clear cell histology, 5% had sarcomatoid features, and 97,2% had a prior nephrectomy. With a median follow up of 33 months, outcomes are summarized in the table. Conclusions: No significant difference in survival between different treatment regimens in the favorable risk population was detected yet. In the very favorable risk population, there was a statistically significant decrease in 2 year overall survival with IPI-NIVO (HR 3.19) which, if validated, could underline the necessity of targeting the VEGF pathway in this population. Further prospective trials and longer follow-up are required to confirm these findings. [Table: see text]

International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]

Sequential chemoradiotherapy versus induction chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: A multicentre, open-label, non-inferiority, randomised, phase 3 trial.

6075 Background: Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) has been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable disease control. Now, distant metastasis was the main cause of failure. However, concurrent cisplatin is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and chemotherapy before or after radiotherapy decreases the risk of distant failure, it is worth exploring whether sequential chemoradiotherapy (SCRT) regimen could replace IC+CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from January 2018 to September 2021 in 6 centers in China. Patients aged 18–65 years with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive 2 cycles of IC with GP regimen (gemcitabine 1000mg/m2 d1,8 + cisplatin 25 mg/m2 d1-3, q21d) plus IMRT, followed by 2 cycles of adjuvant chemotherapy (AC) with the same regimen or IC with GP regimen for 2 cycles followed by IMRT plus concomitant weekly cisplatin (30 mg/m²). The primary endpoint was 3-year failure-free survival (FFS) with non-inferiority margin of 10% (HR&lt;1.6) and the incidence of grade ≥3 acute mucositis during radiotherapy. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 420 patients were randomly assigned to SCRT group (n = 210) or IC+CCRT group (n = 210). With a median follow-up of 47.0 months (IQR: 35.0-57.8), the 3-year FFS was 84.0% in SCRT group versus 79.8% in IC+CCRT group (log rank P=0.344), with an HR of 0.804 (95% CI, 0.510 to 1.266) and absolute difference of 4.2% (95% CI, -3.2 to 11.6). No significant differences were observed between groups in 3-year overall survival (97.4% vs. 94.5%; HR 0.413; 95% CI, 0.159 to 1.076; log rank P=0.061), locoregional control (91.7% vs. 88.8%; HR 0.767; 95% CI, 0.420 to 1.401; log rank P=0.386), or distant metastasis-free survival (93.6% vs. 91.5%; HR 0.756; 95% CI, 0.376 to 1.520; log rank P=0.430). Compared with IC+CCRT group, the SCRT group had significantly lower incidences of grade ≥3 acute nonhematological AEs due to the omission of concurrent chemotherapy (including acute mucositis 29.0% vs. 41.9%, P&lt;0.001; nausea 9.5% vs. 18.1%, P=0.011; and vomiting 3.8% vs. 9.5%, P=0.019), and higher incidences of grade ≥3 acute hematological AEs (including thrombocytopenia and leukopenia) due to the additional AC. Conclusions: For LA-NPC, SCRT was not inferior in 3-year FFS to IC+CCRT. It might be an alternative treatment for LA-NPC patients with fewer sever nonhematological AEs during IMRT. Clinical trial information: NCT03366415 .

Clinical features and prognosis of idiopathic inflammatory myopathies with coexistent multiple myositis-specific antibodies.

This study aimed to evaluate the clinical significance of the coexistence of 2 or more myositis-specific antibodies (multiple MSAs) in adult patients with idiopathic inflammatory myopathies (IIM). We assessed a cohort of 202 consecutive patients with IIM. Clinical features and survival rates were compared between patients with and without multiple MSAs. Of those 202 patients, 44 (21.8%) were found to have multiple MSAs. 63.6% of the 44 patients tested positive for anti-aminoacyl-tRNA synthetase antibodies (anti-ARS+) and 52.3% positive for anti-melanoma differentiation-associated protein-5 antibody (anti-MDA5+). The presence of multiple MSAs was associated with less rapidly progressive interstitial lung disease (RP-ILD), fever, rash, periungual erythema, more muscle involvement and dysphagia, higher albumin level, and higher positive rate of ANA antibody in anti-MDA5+ population. In anti-ARS+ population with multiple MSAs, there were more V-neck sign, skin ulcers, dysphagia and peripheral edema. No differences in survival rates were observed between patients with or without multiple MSAs in the overall and anti-ARS+ populations. However, the survival rate in anti-MDA5+ population with multiple MSAs was significantly higher than those without multiple MSAs (p = 0.003). Moreover, multiple MSAs remained an independent protective factor against mortality in multivariable Cox regression analysis of anti-MDA5+ population [HR 0.108 (95% CI 0.013, 0.908), p=0.041]. Multiple MSAs coexist in some IIM patients and their existence indicates mixed features from concomitant MSAs in anti-MDA5+ population and anti-ARS+ population. Identifying multiple MSAs could help to discover a more favourable disease phenotype with decreased mortality in anti-MDA5+ population.

Racial and Ethnic Variation in Receipt and Intensity of Active Surveillance for Older Patients With Localized Prostate Cancer.

The use of active surveillance (AS) for prostate cancer is increasing, and racial disparities have been identified in its implementation. We investigated differences by race and ethnicity in the utilization and intensity of AS by race and ethnicity among older men with low- and favorable intermediate-risk prostate cancer, with particular focus on the integration of multiparametric MRI (mpMRI) into AS protocols. Using the Surveillance, Epidemiology, and End Results and Medicare fee-for-service linked database, we identified a cohort of men diagnosed between 2010 and 2017 with low- or favorable intermediate-risk prostate cancer. The odds of receiving AS were compared by patient race and ethnicity using multivariable logistic regression models, while the rates of usage of PSA tests, biopsy, and mpMRI within 2 years of diagnosis among men on AS were assessed using multivariable Poisson regression models. Our cohort included 33,542 men. The proportion of men with low-risk disease who underwent AS increased from 29.5% in 2010 to 51.7% in 2017, while the proportion among men with favorable intermediate disease grew from 11.4% to 17.2%. Hispanic (odds ratio [OR] = 0.68, 95% CI 0.58-0.79) and non-Hispanic Black men (OR = 0.78, 95% CI 0.68-0.89) were less likely to receive AS than non-Hispanic White men for low-risk disease, while non-Hispanic Black men were more likely to receive AS for favorable intermediate disease (OR = 1.21, 95% CI 1.04-1.39). Non-Hispanic Black men receiving AS underwent prostate MRI at a lower rate compared to non-Hispanic White men, regardless of whether they had low-risk (incidence rate ratio = 0.77, 95% CI 0.61-0.97) or favorable intermediate-risk (incidence rate ratio = 0.61, 95% CI 0.44-0.83) disease, respectively. The overall adoption of AS for low-risk prostate cancer increased among Medicare fee-for-service beneficiaries. However, a significant disparity exists for non-Hispanic Black men, as they exhibit lower rates of AS utilization. Moreover, non-Hispanic Black men are less likely to have access to novel technologies, such as mpMRI, as part of their AS protocols.

P090 Real-world data on immuno-modulation therapies and body mass index in children and young people with juvenile idiopathic arthritis

Abstract Background/Aims There is some evidence that children and young people (CYP) with Juvenile Idiopathic Arthritis (JIA) who are overweight/obese have less favourable disease control and treatment outcomes. The aim of this study was to investigate any association between BMI and total number of immune modulation therapies used in CYP with JIA. Methods This was a retrospective observational study at a tertiary paediatric rheumatology centre. Cross-sectional data was captured in April 2022 from CYP receiving immunomodulation therapies for JIA. Data on diagnosis, treatments and weight/height at last routine follow-up was included. BMI was calculated for each patient and centile assigned using Royal College of Paediatrics and Child Health electronic BMI charts as follows: BMI ≥85th to 94th centile - overweight, ≥95th centile - obese, as per population monitoring British 1990 growth reference (UK90). Results 187 CYP were identified and 180 included (seven were excluded due to missing BMI data). Baseline demographic, disease and treatment data are summarised in Table A. 67% were female. Median (interquartile range (IQR)) age in years at diagnosis and follow-up was 4.3 (2.7, 8) and 11.9 (8.5, 14.4) respectively. At follow-up, 41.1% of CYP were either obese or overweight. The median (IQR) number of total immunomodulation therapies per patient according to BMI categories were: under/normal weight 2 (1, 3); overweight 3 (2, 3) and obese 3 (2, 5). The median (IQR) years of follow-up in under/normal weight, overweight and obese groups were 4.77 (2, 8.74); 5.27 (1.86, 7) and 5.5 (3, 9.1) respectively. Conclusion CYP that were overweight/obese received more therapies compared to under/normal weight. The high proportion (41%) of CYP in this study who were either overweight or obese is similar to prevalence (44.2%) for children in year six at school in this region. Corticosteroid use and limited physical activity is associated with inadequate control of joint inflammation and increased BMI but this data was not collected and is an important limitation, in addition to cross-sectional and retrospective study design. The overweight/obese group had longer follow-up and may have accumulated more therapies. Future research to evaluate optimal dosing of immunomodulation in CYP with high BMI is warranted. Disclosure K. Hartley: Grants/research support; NIHR BRC Internship. S. Jandial: None. F. McErlane: None. E. Sen: None. S. Sampath: None.

Serum Free Light Chain Kinetics Is Predictive of Renal Response in Myeloma Patients With Renal Impairment—An ALLG Trial of Carfilzomib-Dexamethasone Therapy in Frontline and Relapse

Background and PurposeRenal impairment (RI) confers adverse prognosis in myeloma; its reversal and avoidance of dialysis are crucial. We investigated whether serum free light chain (SFLC) measurements can predict renal outcome, to enable change in therapy to optimize prognosis and avoid dialysis. Patients and MethodsWe investigated 36 myeloma patients (17 newly diagnosed [ND]; 19 relapsed refractory [RR]; with median of 5 prior lines) with eGFR 15-40 ml/min treated with carfilzomib (Cfz)-dexamethasone to determine whether SFLC kinetics can predict renal outcomes, and assess efficacy and tolerability. ResultsThe change in involved SFLC at Cycle 2 Day 1 was significantly correlated with renal function; for every one log10 reduction in involved SFLC, eGFR increased by 9.0-15.0 mL/min at cycles 2-4, with SFLC reduction of 54%-78%. At a median follow-up of 30.6 months, renal outcomes were favorable—CRrenal 25%, MRrenal 36%. Disease responses (ND 100%, RR 75%), progression-free survival (ND 32.2 months, RR 11.1 months) and overall survival (ND not reached, RR 42.0 months) were comparable to patients without RI. There was significant toxicity, including Cfz-related cardiac impairment of 20% within a cohort with high co-morbidity, and a high incidence of infections. ConclusionWe propose that one log10 reduction in involved SFLC at Cycle 2 Day 1 is an appropriate target for reducing the risk of dialysis in myeloma patients with RI; below this threshold patients may benefit from a change in therapy. While Cfz-dexamethasone achieved favorable renal and disease outcomes, toxicity can be significant in this vulnerable cohort.

Efficacy of targeted therapy in patients with non-small cell lung cancer harboring very rare mutations in EGFR exon 18.

Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27-4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040-0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083-1.80, p .032). MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.