Long-term Control Research Articles

Tumor integrin-targeted glucose oxidase enzyme promotes ROS-mediated cell death that combines with interferon alpha therapy for tumor control.

While heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive anti-tumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor expressed integrins both as a tumor-agnostic therapeutic approach, but also as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro, and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other pro-oxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control, and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.

Efficacy and Safety of Ruxolitinib Cream in Atopic Dermatitis Based on Previous Medication History.

For some patients with atopic dermatitis (AD), topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), and systemic therapies are inadequate to control disease or are associated with adverse events (AEs). Ruxolitinib cream monotherapy demonstrated anti-inflammatory and anti-pruritic effects among patients enrolled in two pivotal phase 3 studies (TRuE-AD1/TRuE-AD2); most patients had long-term disease control with as-needed use during the 44-week long-term safety (LTS) period. This post hoc analysis explored efficacy and safety of 1.5% ruxolitinib cream by previous medication use. Patients aged ≥ 12years enrolled in TRuE-AD1/TRuE-AD2 were randomized 2:2:1 to twice-daily 0.75% or 1.5% ruxolitinib cream or vehicle cream for 8 weeks, followed by a 44-week LTS period; patients initially on vehicle were re-randomized 1:1 to either ruxolitinib cream strength. Within 12months of enrollment (N = 1249), previous AD therapies were used by 89.4% of efficacy-evaluable patients applying vehicle or ruxolitinib cream (n = 725); of these, 80.4% received TCS (n = 583), 22.2% TCI (n = 161), 20.3% TCS + TCI (n = 147), and 18.9% systemic therapies (n = 137). Across previous medication subgroups, achievement of Investigator's Global Assessment (IGA)-treatment success (IGA 0/1 with ≥ 2-grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index from baseline, and ≥ 4-point improvement in Itch numerical rating scale score from baseline at Week 8 did not substantially differ among patients who applied ruxolitinib cream. Outcomes were similar to those in the overall study population. At all study visits during the LTS period, > 70% of patients in each subgroup had IGA 0/1 and a low percentage (generally < 3%) of affected body surface area. Treatment-related AEs across subgroups were reported in 7.3% (n = 35/481)to17.4% (n = 19/109) of patients. Continuous-use ruxolitinib cream monotherapy for 8weeks followed by as-needed use was effective and well tolerated, regardless of previous topical or systemic therapy, with outcomes similar to those achieved in the overall study population. ClinicalTrials.gov Identifier, NCT03745638/NCT03745651.

Injectable Intravitreal Fluocinolone Acetonide Implant for Chronic Postoperative CME in the Presence of Silicone Oil Tamponade

Purpose: This report describes the use of the injectable intravitreal fluocinolone acetonide 0.18mg implant (FAI) for chronic postoperative cystoid macular edema (CME) in an eye with a silicone oil-filled vitreous cavity. Methods: A retrospective chart review was performed including surgical, clinical, and imaging data. Results: The patient had multiple complicated vitreoretinal surgical procedures including long-term silicone oil tamponade. The eye developed chronic CME, which responded to intravitreal steroid therapies and subsequently received FAI for longer-term control. The eye had no complications related to FAI. Conclusion: FAI is a long-acting steroid that may be beneficial in controlling chronic CME. It can be considered for use in eyes with silicone oil tamponade, but further studies are required to better understand the pharmacokinetics and utility of the FAI when injected into silicone oil-filled vitreous cavities.

Is There a Correlation Between Preoperative HbA1c Change, Long-Term Weight Loss and Glycaemic Control in Patients With Type 2 Diabetes Undergoing Metabolic Surgery?

Introduction Optimisation of patients with type 2 diabetes mellitus (T2DM) prior to metabolic surgery aims to achieve tight glycaemic control by the time of surgery. Little is known about the influence of altering preoperative glycated haemoglobin (HbA1c) on postoperative weight loss and glycaemic control. The aim of this study was to determine whether a change in HbA1c during the preoperative period correlated with long-term weight maintenance and HbA1c in patients undergoing metabolic surgery. The quantity of glucose-lowering medication used prior to and following surgery was also examined. Methods A retrospective analysis was conducted on patients with T2DM who underwent metabolic surgery between 2013 and 2017. Preoperative HbA1c change was measured as a change in glycaemic control during the one-year pre-surgery. The primary outcomes were % excess weight loss (EWL) and HbA1c at five-year post-surgery. Secondary outcomes were % EWL and HbA1c at one-year post-surgery and the use of glucose-lowering medications post-surgery. The Pearson correlation coefficient (r) was used to determine the relationship between the pre-surgery HbA1c change and postoperative % EWL and HbA1c. A chi-squared test was used to calculate the statistical impact of changes in medication use post-surgery. Results Sixty-nine patients with complete data were included in the study. The mean change in HbA1cin the one-year pre-surgery, the one-year post-surgery and five-year post-surgery was -0.9% (1.5), -0.7% (1.2) and 0% (0 1.8), respectively. A change in HbA1cin the one-year pre-surgery did not correlate with % EWL at one-year and five-year post-surgery or with HbA1cat one-year and five-year post-surgery. At one-year and five-year post-surgery, there was a significant decrease in the proportion of patients requiring glucose-lowering medications compared to patient use prior to surgery (p < 0.001). Conclusion This study demonstrated a significant reduction in the proportion of glucose-lowering medication required long-term following metabolic surgery. Altering preoperative glycaemic control was not associated with long-term weight maintenance or glycaemic control.

7236 Long Term Extension of Osilodrostat Therapy in Canadian Patients with Cushing’s Disease Benefiting from the LINC 3 and LINC 4 Studies

Abstract Disclosure: L.M. Martel: Other; Self; LMD receives partial fellowship salary support though educational grants from Recordati Rare Disease Canada Inc and Pfizer Canada. G. Houde: Other; Self; GH served as a consultant for Novartis. C. Chik: Other; Self; grants and/or consulting fees from Pfizer, Ipsen, Novartis and Novo Nordisk Canada. S.A. Imran: Other; Self; consulting fees from Pfizer, Recordati and Novartis. E. Paron: Other; Self; employees of Recordati Rare Disease Canada Inc. F. Lebel: Other; Self; employees of Recordati Rare Disease Canada Inc. A. Lacroix: Other; Self; reports grants and personal consulting fees from Novartis, Recordati and Pfizer. Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid, sustained cortisol normalization in Cushing’s disease (CD) patients in two Phase III trials (LINC 3, NCT02180217; LINC 4, NCT02697734); persistent biochemical and clinical improvement of CD were reported after 72 and 96 weeks of therapy, respectively (10.1530/EJE-22-0317; 10.3389/fendo.2023.1236465). After study completion and continued clinical benefit with osilodrostat, patients could transition in a roll-over study (CLCI699C2X01B , NCT03606408). As osilodrostat is now approved for therapy of CS in Europe and CD in USA, but not in Canada, seven Canadian patients who had benefited from osilodrostat were transitioned to an investigator initiated study ((ISS-CA-2023, NCT06131580). Objective: To analyze the course of therapy with osilodrostat which allowed long-term biochemical and clinical control of CD since initiation of LINC 3 and LINC 4 core studies for up to 105 months. Methods: Retrospective review of clinical, biochemical and imaging data were collected through chart review of 11patients enrolled in four Canadian centers in LINC 3 and 4 in LINC 4 parent studies. Seven patients remained in the roll-over study until termination and initiation of the Canadian study on October 24 2023. Data from initiation of therapy until October 24 2023 were analyzed. Results: Of the eleven enrolled patients, four discontinued treatment due to muscle cramps, repeat transsphenoidal surgery (TSS) for corticotroph adenoma progression in 2 cases, and hyperandrogenism and opting for bilateral adrenalectomy in one case. Seven cases (5 LINC 3 and 2 LINC 4) pursued therapy in the extension study: 2 men and 5 women, mean age 46 y.o. (range 28-72). All but one had previous TSS, one Gamma Knife and 4 received previous medical therapy. The median 24 hour urinary free cortisol (UFC) before starting osilodrostat was 334 nnmol/d (2.4 x ULN; range 133-414). The median treatment duration was 82 months (range 67-105) and median time to normalize UFC was 36 days. The median maximal dose required to normalize UFC was 10 mg/day (4-60); dose was frequently reduced because of symptoms of relative cortisol withdrawal or adrenal insufficiency (n: 5) to 6.5 mg/day (range: 1 mg every 6 days to 30 mg/d) currently. Last median UFC was 60 nmol/d (range 22-154; 6/7 in normal range &amp;lt; 138nmol/d). Tumor growth occurred in 1 patient (2mm). All patients presented partial to complete improvement of CD features, whereas one patient developed moderate clinical hyperandrogenism, hypertension and borderline prolongation of QTc that normalized after a dose reduction. Conclusions: Osilodrostat can provide sustained biochemical and clinical control of hypercortisolism in patients with CD for up to 9 years; however drug efficacy and dose requirement varies greatly between patients and must be adjusted carefully and regularly during course of therapy. Presentation: 6/3/2024

7373 CAM2029, Octreotide Subcutaneous Depot, Provides Sustained Biochemical Control of Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Grant Recipient; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. F. Gatto: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. P. Kadioglu: None. P. Maffei: Research Investigator; Self; Camurus AB. J. Seufert: Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. E. Isaeva: None. A. Dreval: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is characterized by excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production. A key treatment goal is long-term biochemical control to minimize adverse effects of prolonged excess GH. CAM2029 is a novel, subcutaneous, octreotide depot, designed for convenient monthly self-administration using a pre-filled injection/pen. In a 24-week Phase 3 trial (ACROINNOVA 1, NCT04076462), CAM2029 achieved superior IGF-1 control vs placebo (IGF-1 ≤ upper limit of normal [ULN]: 72.2 vs 37.5%; P=0.0018) in acromegaly patients previously controlled with standard-of-care (SoC; octreotide long-acting repeatable/lanreotide Autogel). On trial completion, patients could roll over to a Phase 3, 52-week, open-label, long-term safety trial (ACROINNOVA 2, NCT04125836). Here, we report data from an interim analysis of roll-over patients in ACROINNOVA 2. Methods: Roll-over patients received monthly CAM2029 20 mg for 28 weeks in ACROINNOVA 2. Primary endpoint: occurrence of adverse events (AEs). Key secondary endpoints: proportion of patients with available assessments who had (i) IGF-1 ≤1x ULN (mean of weeks 50/52 measurements) and (ii) both IGF-1 ≤1x ULN (weeks 50/52 mean) and mean GH &amp;lt;2.5 µg/L (week 52). Data are reported according to prior treatment in ACROINNOVA 1. Safety data from the whole trial period are reported. Results: Fifty-four of the 64 patients completing ACROINNOVA 1 (prior CAM2029 n=36; prior placebo n=18) entered ACROINNOVA 2. At data cut-off (May 23, 2023) 28 and 15 patients in the prior CAM2029 and prior placebo groups, respectively, had completed treatment week 52; 7 and 3 were ongoing; 1 and 0 had discontinued. The medication was well tolerated with a safety profile comparable to SoC treatment; no new safety signals were observed. One treatment-related serious AE (cholelithiasis, moderate severity, resolved) occurred in the prior placebo group. Injection site treatment-emergent AEs (Grade ≤2) occurred in 50% of patients in the prior CAM2029 (18/36) and prior placebo (9/18) groups. Of evaluable patients in the prior CAM2029 and prior placebo groups, 89.3% (25/28) and 100% (15/15) had IGF ≤1x ULN at weeks 50/52; 88.5% (23/26) and 100% (14/14) had both IGF ≤1x ULN (week 50/52) and GH &amp;lt;2.5 µg/L (week 52). Mean IGF-1 levels remained &amp;lt;ULN throughout the 52-week study period for the prior CAM2029 group; in the prior placebo group, mean IGF-1 increased above 1x ULN during placebo treatment, returning to &amp;lt;ULN after switching to CAM2029 for 28 weeks. All patients previously treated with placebo regained IGF-I control upon switching to CAM2029. Conclusions: The safety profile of CAM2029 was consistent with SoC, with no new or unexpected safety signals during extended treatment. CAM2029 provided persistent control of IGF-1 and GH during 52 weeks of treatment. All patients in the prior placebo group regained biochemical control of acromegaly after switching to CAM2029. Presentation: 6/1/2024

12199 Uncontrolled Graves Disease Leading To The Development Of Pulmonary Hypertension

Abstract Disclosure: A. Agrawal: None. N. Shaykh: None. C. Marsalisi: None. L. Lam: None. C. Harrison: None. G.Y. Gandhi: None. Introduction: Graves’ disease can cause cardiorespiratory complications by increasing cardiac output, inducing endothelial dysfunction, and increasing the metabolism of intrinsic pulmonary vasodilating substances. Case: A 26-year-old female with a one-year history of Graves’ disease presented with chest pressure, shortness of breath, worsening orthopnea, a 40-pound weight loss, and subjective fevers. Her home methimazole dose was 10 mg daily, which she had missed for four days before admission. Her BP was 153/90 mmHg, heart rate 117 bpm, and temperature 100.7° F. She had mild bilateral proptosis and an enlarged but non-tender thyroid, which caused her difficulty swallowing. TSH was undetectable less than 0.005 mIU/L (0.27-4.2 mIU/L), and thyroid hormone levels were significantly elevated free T4 greater than 7.77 ng/dL (0.8-1.7 ng/dL) and free T3 29.1 pg/mL (2-4.4 pg/mL). TSI was high at 5.66 IU/L (0-0.55 IU/L) as was BNP at 1,642 pg/mL (0-125 pg/mL). Cardiac troponin was 105 ng/dL (less than 14 ng/dL) with a peak of 106 ng/dL. A Burch-Warsofsky score of 50 was highly suggestive of thyroid storm. She initially received 1 mg of IV propranolol, 1,000 mg of PTU, and 4 mg of dexamethasone followed by hydrocortisone 100 mg, methimazole 20, propanol 20 mg, and two doses of SSKI. A transthoracic echocardiogram was remarkable for severe right atrial and ventricular enlargement, and pulmonary artery pressure measured 55 mmHg (normal 20-30 mmHg). Autoimmune testing, including ANA, c-ANCA, p-ANCA, rheumatoid factor, anti-CCP, anti-SS-A, anti-SS-B antibodies, ultrasound for deep vein thrombosis, and ventilation-perfusion scan were negative. There was no history of congenital heart defects or valvulopathy. The patient reached a euthyroid state and was discharged home on methimazole 20 mg daily. Discussion: Although frequently underappreciated, pulmonary hypertension is present in 30 to 65% of Graves’ disease patients when systematically ascertained. Elevated thyroid hormones can increase heart rate, contractility, venous return, and cardiac output. An imbalance between vasoconstriction and vasodilation, along with endothelial dysfunction, can cause pulmonary vascular effects of hyperreactivity, remodeling, and thrombosis. An autoimmune mechanism is plausible due to an association between antithyroid antibodies and pulmonary hypertension. Right heart catheterization remains the gold standard for diagnosis, though in this case, it was not pursued in the acute setting. This case reinforces the importance of screening for pulmonary hypertension in patients with Graves’ disease and possibly normalizing pulmonary hypertension, thereby avoiding irreversible complications. Clinicians should consider reassessing for pulmonary hypertension even after long-term control of the thyrotoxic state, as about 30% of these patients have persistent pulmonary hypertension. Presentation: 6/3/2024

12199 Uncontrolled Graves Disease Leading To The Development Of Pulmonary Hypertension

Abstract Disclosure: A. Agrawal: None. N. Shaykh: None. C. Marsalisi: None. L. Lam: None. C. Harrison: None. G.Y. Gandhi: None. Introduction: Graves’ disease can cause cardiorespiratory complications by increasing cardiac output, inducing endothelial dysfunction, and increasing the metabolism of intrinsic pulmonary vasodilating substances. Case: A 26-year-old female with a one-year history of Graves’ disease presented with chest pressure, shortness of breath, worsening orthopnea, a 40-pound weight loss, and subjective fevers. Her home methimazole dose was 10 mg daily, which she had missed for four days before admission. Her BP was 153/90 mmHg, heart rate 117 bpm, and temperature 100.7° F. She had mild bilateral proptosis and an enlarged but non-tender thyroid, which caused her difficulty swallowing. TSH was undetectable less than 0.005 mIU/L (0.27-4.2 mIU/L), and thyroid hormone levels were significantly elevated free T4 greater than 7.77 ng/dL (0.8-1.7 ng/dL) and free T3 29.1 pg/mL (2-4.4 pg/mL). TSI was high at 5.66 IU/L (0-0.55 IU/L) as was BNP at 1,642 pg/mL (0-125 pg/mL). Cardiac troponin was 105 ng/dL (less than 14 ng/dL) with a peak of 106 ng/dL. A Burch-Warsofsky score of 50 was highly suggestive of thyroid storm. She initially received 1 mg of IV propranolol, 1,000 mg of PTU, and 4 mg of dexamethasone followed by hydrocortisone 100 mg, methimazole 20, propanol 20 mg, and two doses of SSKI. A transthoracic echocardiogram was remarkable for severe right atrial and ventricular enlargement, and pulmonary artery pressure measured 55 mmHg (normal 20-30 mmHg). Autoimmune testing, including ANA, c-ANCA, p-ANCA, rheumatoid factor, anti-CCP, anti-SS-A, anti-SS-B antibodies, ultrasound for deep vein thrombosis, and ventilation-perfusion scan were negative. There was no history of congenital heart defects or valvulopathy. The patient reached a euthyroid state and was discharged home on methimazole 20 mg daily. Discussion: Although frequently underappreciated, pulmonary hypertension is present in 30 to 65% of Graves’ disease patients when systematically ascertained. Elevated thyroid hormones can increase heart rate, contractility, venous return, and cardiac output. An imbalance between vasoconstriction and vasodilation, along with endothelial dysfunction, can cause pulmonary vascular effects of hyperreactivity, remodeling, and thrombosis. An autoimmune mechanism is plausible due to an association between antithyroid antibodies and pulmonary hypertension. Right heart catheterization remains the gold standard for diagnosis, though in this case, it was not pursued in the acute setting. This case reinforces the importance of screening for pulmonary hypertension in patients with Graves’ disease and possibly normalizing pulmonary hypertension, thereby avoiding irreversible complications. Clinicians should consider reassessing for pulmonary hypertension even after long-term control of the thyrotoxic state, as about 30% of these patients have persistent pulmonary hypertension. Presentation: 6/3/2024

Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control

BackgroundImmune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines...

Analysis of short- and long-term controls on the variability of event-based runoff coefficient

Study regionThis study focuses on the Ohio Region, which spans 11 states in the eastern United States. Study focusRunoff coefficients are crucial in hydrology, indicating the relationship between rainfall and runoff. Understanding their controls and variability is essential for water resource assessment, management strategies, and land use planning. This research examines factors influencing runoff coefficients and their trends in the Ohio region using data from the North American Land Data Assimilation System phase-2 (NLDAS-2) Mosaic Land Surface Model, covering 2000–2020. The analysis considers short-term controls, such as climatic features (rainfall intensity, amount, and duration), hydrological factors (antecedent soil moisture, drainage density, and curve number), topographic factors (drainage area, land use, slope, elevation), and watershed shape. Additionally, the study investigates trends in runoff coefficients and their long-term controls, including climatic factors and land use changes. New hydrological insights for the regionThe findings indicate that runoff coefficients increase with antecedent soil moisture and rainfall intensity. Higher elevations show lower runoff coefficients due to forested land use. Larger watersheds have lower runoff coefficients at low rainfall intensity but higher ones when intensity is high. Long-term trends reveal soil moisture as the primary control, with land cover changes as a secondary factor. This research deepens understanding of runoff coefficient dynamics and controls in the Ohio region. Future studies could explore the impacts of urbanization, reservoirs, evapotranspiration, and snowmelt on runoff coefficients.

A Prospective Cross-Sectional Study on the Correlation of Adenosine Deaminase and HbA1c With Microvascular Complications in Type 2 Diabetes Mellitus at a Tertiary Care Hospital in Central India.

Background Type 2 diabetes mellitus (T2DM) is a prevalent chronic condition characterized by hyperglycemia, which can lead to various microvascular complications, including diabetic nephropathy, neuropathy, and retinopathy. Identifying reliable biomarkers for early detection and risk stratification of these complications is crucial for improving patient outcomes. Adenosine deaminase (ADA) and HbA1c have emerged as potential markers associated with immune function, inflammation, and long-term glycemic control. This study investigates the correlation between ADA and HbA1c levels and microvascular complications in patients with T2DM. Material and methods This prospective observational cross-sectional study involved 150 patients diagnosed with T2DM, focusing on those with diabetic nephropathy, neuropathy, and retinopathy. Clinical data were collected through patient interviews, clinical examinations, and laboratory tests, including measurements of fasting blood glucose, HbA1c, serum creatinine, ADA levels, and urine protein creatinine ratio (UPCR). Fundus examinations and nerve conduction velocity (NCV) tests were performed to assess diabetic retinopathy and neuropathy, respectively. Data were analyzed using SPSS version 25.0 (IBM Corp., Armonk, New York), with statistical tests to evaluate the correlation between ADA and HbA1c levels and microvascular complications. Results The study found a significant correlation between elevated ADA and HbA1c levels and microvascular complications in patients with T2DM. Higher ADA levels were particularly associated with diabetic nephropathy (p=0.003), while HbA1c levels showed a positive correlation with all three complications: nephropathy, neuropathy, and retinopathy. The findings suggest that ADA and HbA1c levels can serve as valuable biomarkers for identifying patients at higher risk of developing these complications. Conclusion This study highlights the potential of ADA and HbA1c as biomarkers for early detection and risk assessment of microvascular complications in T2DM patients. Routine monitoring of these markers could improve the management and prognosis of diabetic patients by enabling timely interventions to prevent or mitigate the progression of complications. Further research is needed to explore the underlying mechanisms linking ADA with diabetic complications and to validate its clinical utility.

Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers.

Predictors of Local Control With Palliative Radiotherapy for Multiple Myeloma

IntroductionWe performed a retrospective analysis of patients with multiple myeloma (MM) receiving palliative radiotherapy (RT) and assessed factors associated with local control, with a focus on dose/fractionation and cytogenetics. Materials and MethodsWe included patients who received palliative RT for MM at our institution. Cytogenetics were collected via fluorescence in situ hybridization. Follow-up imaging was used to assess local control. ResultsA total of 239 patients with 362 treated lesions were included. Eighty-six (36.0%) patients had high-risk cytogenetics. Most lesions received 20 Gray (Gy) in 5 fractions (131, 36.2%), 8 Gy in 1 fraction (93, 25.7%), or 30 Gy in 10 fractions (48, 13.3%). At a median follow-up of 4.3 years, 4-year local progression was 13.4% (95% confidence interval [CI]: 10.3-17.5). No cytogenetic abnormalities were correlated with local progression, nor were double- and triple-hit status. There was a nonsignificant trend toward association between number of treated lesions and local progression (HR for >3 vs. 1: 2.43 [95% CI: 0.88-6.74], P = .059). Among patients with >3 treated lesions, equivalent dose in 2 Gy fractions ≥20 Gy reduced progression (HR: 0.05 [95% CI: 0.01-0.23], P = .0001). ConclusionIn this large study of patients with MM, modern palliative RT achieved excellent rates of long-term local control. Although there was no dose-response observed in the overall cohort, patients with high volume symptomatic disease may benefit from EQD2 ≥20 Gy. High-risk cytogenetics did not appear to influence radioresponsiveness, and standard radiation doses appear to be effective for all MM patients regardless of cytogenetics.

Follow Up Care After Penile Sparing Surgery for Penile Cancer: Current Perspectives.

Penile cancer (PeCa) is a rare urologic tumor worldwide. In 2024, 2100 new cases and 500 deaths are estimated in the United States. Radical surgery via total penectomy has historically been the cornerstone of treatment, since it provides excellent long-term oncological control. The rationale of surgery for penile cancer was to achieve a 2 cm macroscopic surgical margin that is historically advocated to reduce recurrences. Over time, numerous studies have demonstrated that resection margin status does not affect patients' survival. Different penile-sparing techniques are currently recommended in the European Association of Urology-American Society of Clinical Oncology (EAU-ASCO) guidelines for the treatment of localized primary PeCa. Centralization of care could yield multiple benefits, including improved disease awareness, higher rates of penile-sparing surgery, enhanced detection rates, increased utilization of less invasive lymph node staging techniques, enhanced quality of specialized histopathological examinations, and the establishment of specialized multidisciplinary teams. Compared to more aggressive treatments, the higher recurrence rates after penile-sparing surgery do not hamper neither the metastasis-free survival nor the overall survival. Repeated penile-sparing surgery could be considered for selected cases. The psychological impact of penile cancer is not negligible since the perceived loss of masculinity might adversely affect mental health and overall well-being. Quality of life may be compromised by sexual and urinary dysfunction which may be the result either of the loss of penile tissue or the psychological status of the patient. It is of utmost importance to offer rehabilitative treatment as sexual therapy, physical therapy, occupational therapy, family and peer counseling.

Long-term outcomes of more than a decade treating patients with stereotactic body radiation therapy for hepatocellular carcinoma

Purpose/Objective(s)To evaluate if stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) has a durable effect on tumor control and can be delivered safely. Materials/MethodsPatients included in this retrospective study have been treated at our institution from January 2008 to December 2022. Eligibility criteria were diagnosis of HCC, BCLC stage 0-A-B, non-cirrhotic liver or liver with cirrhosis Child-Pugh class A, and a maximum of three lesions with a cumulative diameter of ≤ 6 cm. Patients with relapses after surgery, thermal ablation or TACE or patients awaiting transplant were also candidates for SBRT. SBRT was delivered in 6 fractions of 8 or 9 Gy. The primary endpoint was local (target) control (LC). Secondary endpoints were time to progression (TTP), overall survival (OS), response rate (RR) and toxicity. ResultsA total of 52 patients received SBRT at our institution and 51 were included in this study. One patient objected and was excluded. Median follow-up was 2.1 years for LC and 2.3 years for OS. Median tumor size was 26 mm. LC rates at 1, 2, and 5 years were 100 %, 95 % and 95 % respectively. Median TTP was 45.6 months. Median OS was 7.1 years. RR was 96 %. No patients in this study have experienced SBRT related CTC AE grade ≥ 3 toxicity. ConclusionSBRT resulted in excellent long-term local control rates and absence of severe toxicity in a group of HCC patients. The reported outcomes compare favorably with other local therapies. SBRT should be considered as one of the available local treatment options for HCC.

Metastatic-Site Radiation Therapy for Ewing Sarcoma and Rhabdomyosarcoma: Consensus Guidelines From the National Pediatric Cancer Foundation

BackgroundDespite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities. MethodsWe gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address five key questions: 1) the role of whole lung irradiation (WLI) in treating lung metastases 2) number of metastatic sites warranting radiotherapy and the radicality of such an approach; 3) radiation techniques, including stereotactic body radiation therapy (SBRT); 4) the timing of metastatic-site radiation therapy; and 5) the utility of metastatic site radiation therapy for relapsed metastatic disease. ResultsAfter a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation with the goal of improving long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred. ConclusionsA consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy.

Hyperactive Dendritc Cells Redirect Aged Antitumor Immunity.

Aging is one of the biggest risk factors for cancer development. More than 85% of all cancers occur in individuals above 55 years old, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in antitumor immunity, particularly with regard to T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting antitumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL1β production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving antitumor immunity and achieving long-term tumor control in older mice.

CAR T-cell therapy combined with autologous hematopoietic cell transplantation in patients with refractory/relapsed Burkitt Lymphoma

Burkitt lymphoma (BL) is a highly aggressive type of non-Hodgkin lymphomas that have a high likelihood of relapse and are highly refractory to initial treatment. While high-intensity chemotherapy has improved the outcomes, many adult patients still experience treatment failure, and effective salvage therapies are limited. This study retrospectively analyzed the outcomes of 21 relapsed or refractory (R/R) adult BL patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, combined or not with hematopoietic cell transplantation (HCT), across four Chinese hospitals. Patients were grouped based on treatment strategies: autologous HCT followed by CAR T-cell therapy (auto-HCT+CART group, n=8), and CAR T-cell therapy alone (CART group, n=13). The auto-HCT+CART group demonstrated superior outcomes, with an overall response rate (ORR) of 87.5% and significantly higher 1-year overall survival (OS) and progression-free survival (PFS) rates compared to the CART group (p=0.014 and p=0.045, respectively). These findings suggest that combining auto-HCT with CAR-T therapy may enhance long-term disease control in R/R BL patients. These encouraging results highlight the need for further prospective studies to validate our data.

Impaired Long-Term and Short-Term Control of Sympathetic Nerve Activity in Nonhypertensive Dahl S Salt-Sensitive Rats

Impaired Long-Term and Short-Term Control of Sympathetic Nerve Activity in Nonhypertensive Dahl S Salt-Sensitive Rats

Assessing the Burden of Atopic Dermatitis in Portugal through Patient-Centered Experiences

Introduction: Adult patients and caregivers of children with atopic dermatitis experience high physical, mental, and financial burden in Portugal. We outline the experience of atopic dermatitis management and how the current medical care model impacts patient-centered concerns such as financial burden, quality of life, disease burden, and treatment satisfaction. Methods: We conducted a survey of 419 Portuguese adults and caregivers of children to capture the experience of managing atopic dermatitis in Portugal. Results: Respondents reported average satisfaction with treatment, with a mean satisfaction rating of 3.15/5.00 (SD = 0.77). Adults reported slightly better control of atopic dermatitis symptoms (mean = 56.6) than pediatric patients (mean = 55.9, caregiver reported). Nearly 34% of adults and 39% of caregivers of children and adolescents indicated that their healthcare providers asked about their priorities at the last medical visit. Additionally, only 40% of adult patients and 32% of caregivers reported that patient training was offered to them. Respondents seeing dermatologists reported higher satisfaction than those seeing other healthcare providers (p = 0.01) but there were no differences in long-term control of symptoms by provider type (p = 0.85) when controlling for severity. Portuguese adult patients scored 0.86/1.00 on the EQ-5D (where 0 = death and 1 = perfect health). Financial concern was high as nearly 80% of patients and caregivers reported using savings, borrowing money, and/or reducing spending to cover atopic dermatitis-related costs.Conclusion: Portuguese patients with atopic dermatitis and caregivers experience financial burden, lower health-related quality of life, higher disease burden, and treatment satisfaction issues with their current medical care. These factors often deteriorate as the disease’s severity increases. Providers, researchers and policymakers should focus on better addressing patient-centered concerns for individuals suffering from atopic dermatitis to improve care and health outcomes.