Systemic Treatment Research Articles

Remodeling the tumor immune microenvironment through hydrogel encapsulated G-Rh2 in situ vaccine and systemic immunotherapy

Ginsenoside Rh2 (G-Rh2) is a vital bioactive compound in Traditional Chinese Medicine, celebrated for its strong pharmacological properties, particularly its potent antitumor effects. However, its poor water solubility and limited bioavailability have necessitated the development of a novel drug delivery method. In this study, we utilized an indocyanine green carboxylic acid-hydroxypropyl cellulose-abietic acid-bovine serum albumin hydrogel (ICG-HPC-AA/BSA hydrogel) as a tumor in situ vaccine to enhance the permeability, retention, and tumor-targeted therapeutic efficacy of G-Rh2. We examined the therapeutic impact of a G-Rh2-loaded hydrogel combined with systemic PD-1 antibody treatment in murine models of H22 liver cancer and CT26 colon cancer. Additionally, we explored the immune microenvironment of the tumors influenced by this in situ vaccination strategy.

The meaning-making process in the re-entry phase: A qualitative focus group study with patients treated for breast cancer or melanoma

Purpose After completion of curative cancer treatment patients enter the re-entry phase, which is characterized by the task to pick up life again. While having to resume their former roles, patients experience the loss of normality and face existential concerns. A sense of meaning and purpose may help in dealing with changes in life and existential concerns. The aim of this study is to gain insight in the meaning-making process of patients treated for breast cancer or melanoma in the re-entry phase in order to develop an intervention to support picking up life after a long treatment process including systemic treatment. Methods We conducted six focus groups with 16 patients (11 breast cancer and five melanoma) to explore their experiences, challenges, and sources of meaning during the re-entry phase. The re-entry phase was defined as the point from completion of surgical and systemic treatment (except for hormonal therapy) up to 18 months in remission. A thematic content analysis was performed by two researchers. Results We identified four themes pertaining to patients’ use of sources of meaning in the meaning-making process: (1) use of existing, helpful sources; (2) distress due to impacted sources; (3) search for new sources; and (4) use of adapted or new sources. When patients drew upon existing sources of meaning that had been impacted by cancer and the aftermath of treatment, they experienced distress. This could instigate a search resulting in adapted, strengthened, or new sources of meaning. Conclusions Meaning-making in the re-entry phase is a versatile process involving the use of existing sources of meaning, and a search for, or use of new, strengthened, or adapted sources of meaning. An intervention increasing patients’ awareness of their sources of meaning might strengthen the meaning-making process of patients treated for breast cancer or melanoma.

Non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts.

Efficacy of botulinum neurotoxin A in persistent idiopathic dentoalveolar pain: a case series.

Persistent idiopathic dentoalveolar pain (PIDP) is a challenging clinical entity associated with both physical and emotional consequences. Currently, the management is symptom-based and includes both topical and/or systemic treatments. More recently, botulinum neurotoxin-A (BONT-A) has been suggested as a treatment option. We present a case series of 9 patients (5 female) with mean age 56 ± 15 diagnosed with PIDP. All patients reported prior experience with systemic drugs without a sufficient pain-relieving effect. BONT-A (BOTOX, Allergan) 100 U diluted with saline solution was used and the dose ranged from 20U to 50U distributed in 3 sites (intraoral and/or extraoral) per session. Patients underwent further injections (50U) monthly if pain severity measured using a Numerical Rating Scale (NRS 0-10) was still > 3 for 3 months. Pain severity and characteristics were recorded at baseline (T0), after 1 month (T1), 2 months (T2) and 3 months (T3). Mean pain intensity at baseline was NRS 6 (4-10). Latency before analgesic effect was at least 5-10 days after injection. Minor adverse effects were sickness and muscular hypotonia. Pain significantly reduced to NRS 4 (0-8) at T1, to NRS 2 (0-8) at T2 and to NRS 2 (NRS 0-8) at T3. Patients' functional variables (discomfort while chewing, talking, swallowing) were also recorded. BONT-A is widely used and although the exact mechanism of action remains unclear, it can be used effectively in reducing pain for a variety of conditions including PIDP. Our results suggest that BONT-A seems to be an alternative therapeutic approach for patients with PIDP.

Oligometastatic non-small cell lung cancer: Impact of local and contemporary systemic treatment approaches on clinical outcome.

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

HER3 is widely expressed across diverse subtypes of NSCLC in a retrospective analysis of archived tissue samples.

Aim: This noninterventional study (NCT05769764) aimed to characterize human epidermal growth factor receptor 3 (HER3) expression in non-small cell lung cancer (NSCLC) by patient, clinical or tumor characteristics.Methods: HER3 immunohistochemistry was performed in archival tissue samples from patients with advanced or metastatic NSCLC. Samples were scored for membrane percent positivity and intensity. Membrane H-scores were calculated.Results: Of 203 evaluable samples, HER3 expression was observed in 98.5%, including all histologies, genomic subtypes and regardless of prior systemic anticancer treatments. The median H-score was 140, and 70.4% had a HER3 intensity of 3+.Conclusion: HER3 is widely expressed in NSCLC, indicating that HER3-directed therapy may be broadly applicable across diverse subtypes of NSCLC.

Prediction of High Nodal Burden in Patients With Sentinel Node–Positive Luminal ERBB2-Negative Breast Cancer

In patients with clinically node-negative (cN0) breast cancer and 1 or 2 sentinel lymph node (SLN) macrometastases, omitting completion axillary lymph node dissection (CALND) is standard. High nodal burden (≥4 axillary nodal metastases) is an indication for intensified treatment in luminal breast cancer; hence, abstaining from CALND may result in undertreatment. To develop a prediction model for high nodal burden in luminal ERBB2-negative breast cancer (all histologic types and lobular breast cancer separately) without CALND. The prospective Sentinel Node Biopsy in Breast Cancer: Omission of Axillary Clearance After Macrometastases (SENOMAC) trial randomized patients 1:1 to CALND or its omission from January 2015 to December 2021 among adult patients with cN0 T1-T3 breast cancer and 1 or 2 SLN macrometastases across 5 European countries. The cohort was randomly split into training (80%) and test (20%) sets, with equal proportions of high nodal burden. Prediction models were developed by multivariable logistic regression in the complete luminal ERBB2-negative cohort and a lobular breast cancer subgroup. Nomograms were constructed. The present diagnostic/prognostic study presents the results of a prespecified secondary analysis of the SENOMAC trial. Herein, only patients with luminal ERBB2-negative tumors assigned to CALND were selected. Data analysis for this article took place from June 2023 to April 2024. Predictors of high nodal burden. High nodal burden was defined as ≥4 axillary nodal metastases. The luminal prediction model was evaluated regarding discrimination and calibration. Of 1010 patients (median [range] age, 61 [34-90] years; 1006 [99.6%] female and 4 [0.4%] male), 138 (13.7%) had a high nodal burden and 212 (21.0%) had lobular breast cancer. The model in the training set (n = 804) included number of SLN macrometastases, presence of SLN micrometastases, SLN ratio, presence of SLN extracapsular extension, and tumor size (not included in lobular subgroup). Upon validation in the test set (n = 201), the area under the receiver operating characteristic curve (AUC) was 0.74 (95% CI, 0.62-0.85) and the calibration was satisfactory. At a sensitivity threshold of ≥80%, all but 5 low-risk patients were correctly classified corresponding to a negative predictive value of 94%. The prediction model for the lobular subgroup reached an AUC of 0.74 (95% CI, 0.66-0.83). The predictive models and nomograms may facilitate systemic treatment decisions without exposing patients to the risk of arm morbidity due to CALND. External validation is needed. ClinicalTrials.gov Identifier: NCT02240472.

On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer

BackgroundPatients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies.MethodsOn-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS).ResultsAmong the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2−), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2−: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2−: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2−: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013–1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963–0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928–0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001–1.047; p = 0.04).ConclusionOn-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures.Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).

‘Ritlecitinib: unveiling hair regrowth for alopecia areata’

Alopecia Areata (AA) is an autoimmune disorder characterized by non-scarring hair loss on the scalp and other parts of the body. It is a complex medical condition associated with an impaired immune response in hair follicles. Various therapies are available for AA, including topical, systemic, and injectable treatments. However, their effectiveness varies, and no treatment consistently achieves and maintains remission. Therefore, this review aims to highlight the breakthrough advancement in treatment of AA i.e., the United State Food and Drug Administration (FDA) approved Ritlecitinib, the first and only oral treatment for moderate to severe alopecia areata in patients aged 12 and older. This approval represents a significant achievement in AA management, offering a targeted and effective treatment for those with more extensive hair loss.

National Registry for Childhood Onset Scleroderma I: Insights from the first 341 juvenile localized scleroderma patients

Objectives: There is an under recognition of juvenile-onset localized scleroderma and its extracutaneous manifestations leading to delay in systemic treatment. Our study aims to address this gap by describing the demographics, presentation, associated family history, concurrent autoimmune disease, extracutaneous manifestations, laboratory evaluation, treatment, and course of disease in juvenile-onset localized scleroderma patients enrolled in the National Registry for Childhood Onset Scleroderma. Methods: Participants for this study were derived from the National Registry for Childhood Onset Scleroderma and included 341 patients with juvenile-onset localized scleroderma. Demographic, and prospectively collected outcome measures, such as the Localized Scleroderma Cutaneous Assessment Tool, physical exam findings, laboratory values, and patient-reported outcomes were reviewed. Results: Most patients were female (71%), Caucasian (94%), had a linear subtype (56%), and had the onset of disease at age 7.5 (±4.2) years, and diagnosis 1.9 (±2.6) years after symptom onset. Most patients experienced at least one extracutaneous manifestation (70%), most commonly musculoskeletal (57%), followed by neurological (46%), and ophthalmological (11%). Those with musculoskeletal extracutaneous manifestation have significantly abnormal inflammatory and antibody laboratory values. Of patients with 1-year follow-up, a majority were treated with systemic therapy and globally improved with significant reduction in both modified Localized Scleroderma Skin Index ( p &lt; 0.001) and Localized Scleroderma Damage Index ( p = 0.001). Conclusion: The study highlights need for earlier recognition of juvenile-onset localized scleroderma after demonstrating the delay in diagnosis and frequent extracutaneous manifestations with significant disease burden in a juvenile-onset localized scleroderma cohort. The benefits of systemic treatment and full extracutaneous manifestation screening in juvenile-onset localized scleroderma is supported.

The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8.

Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants associated with migraine risk. Surprisingly, some of the most common mutations are associated with TRPM8, a non-selective cation channel that is the primary sensor of cold temperatures in primary afferent neurons of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 underlies its role in migraine pathogenesis. To define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor GFRα3, also mediate TRPM8-associated migraine-like pain in the meninges. To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in wildtypes and mice lacking either GFRα3 or TRPM8, we tested the effects of supradural infusions of a mix of inflammatory mediators, artemin, and a TRPM8-specific agonist on migraine-related pain in mice. We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway. Further, we show TRPM8 expression in the meninges and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan. These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to migraine pathogenesis.

Modern surgical strategies in pediatric neuroblastoma: Evolving approaches and treatment principles.

Neuroblastoma, the most common extracranial solid tumor in children under the age of 5, has been described as early as the 19th century, and its complexity has continued to intrigue researchers, as well as medical and surgical specialists. At one end of the phenotypic spectrum, neuroblastoma is self-limiting with minimal to no intervention required, while on the opposite end exists the challenge of refractory disease despite aggressive management and toxic systemic treatments. The goal of this review is to describe a comprehensive surgical perspective and contemporary approach to neuroblastoma.

Chinese expert consensus on the systemic treatment of advanced clear cell renal cell carcinoma (2024 edition)

Renal cell carcinoma (RCC) accounts for approximately 2% to 3% of malignant tumors in adults, with a male-to-female ratio of approximately 1.5∶1 worldwide. It can occur in all age groups, with a peak incidence in the 60-70 age range, and the median age is approximately 64 years. The current causes of kidney cancer are still unclear, but smoking, obesity, hypertension, and some genetic factors are considered risk factors for kidney cancer development. Conducive to the gradual popularization of physical examination and screening, more and more patients with kidney cancer are being detected and treated in the early stages. However, nearly 30% of patients still have locally advanced or metastatic kidney cancer at the time of initial diagnosis. Traditional chemotherapy drugs are generally ineffective for advanced RCC, and currently, advanced RCC is mainly treated with anti-vascular and immunotherapy. At present, first-line treatment is mostly stratified based on clinical characteristics such as International mRCC Database Consortium (IMDC) prognosis risk, and there are multiple options available, including anti vascular therapy, anti-vascular combined immunotherapy, and dual immunotherapy. Subsequently, first-line treatment often selects drugs based on the composition, effectiveness, and safety of first-line treatment plans. In recent years, research has found that the molecular typing and metastasis characteristics of RCC also affect the prognosis of patients, leading to many controversies in the treatment of advanced RCC. This consensus is guided by the controversial clinical issues in the management of advanced RCC. After discussion and voting by multidisciplinary clinical experts, a consensus of 10 clinical issues has been reached. At the same time, experts recommend domestic clinical and research institutions to lead or participate in more large-scale clinical trials, providing more basis for clinical decision-making and the selection of the best beneficiaries.

Improved Topical Delivery of Sorafenib-Meglumine Antimoniate: Elastic Nano-Liposomal Formulation for the Treatment of Cutaneous Leishmaniasis

Background: Cutaneous leishmaniasis (CL) is a widespread parasitic disease with significant health and social impacts. Current systemic treatments have severe side effects, highlighting the need for effective topical alternatives.Objective: This study aimed to develop and evaluate the effectiveness of sorafenib (SF) and meglumine antimoniate (MM) dual-loaded transferosomes (TRs) for topical treatment of CL.Methods: TRs were prepared using a thin film hydration method and incorporated into a carbopol gel. The formulations were characterized for vesicle size, zeta potential, entrapment efficiency, and deformability index. In vivo and ex vivo skin permeation studies were conducted, along with anti-leishmanial efficacy testing on an intramacrophage amastigote model using BALB/c mice.Results: The TRs exhibited a vesicle size of 186.1 ± 65.89 nm, zeta potential of -27.9 mV, and entrapment efficiency of 71.7 ± 3.9% for MM and 78.6 ± 4.2% for SF. Ex vivo studies showed enhanced skin permeation with cumulative permeation of 327.6 ± 29.4 µg/cm² for MM and 291.6 ± 28.3 µg/cm² for SF. In vivo results indicated a significant reduction in lesion size (0.1 ± 0.12 mm) and parasite load (2.7 ± 0.3 log scale).Conclusion: The MM-SF dual-loaded TRs demonstrated effective topical delivery and therapeutic potential for CL, providing a promising alternative to systemic treatments.

Abstract C063: Using a disparities dashboard to identify racial/ethnic differences in breast cancer treatment: Implications for improving cancer care delivery

Abstract Purpose: The use of a cancer dashboard to assess and inform real time assessments of the timing of surgery and systemic treatment by race/ethnicity may be used to address delays in cancer treatment. Yet, the utility of cancer dashboards in cancer settings are unclear as electronic medical record (EMR) stage data are unstructured. We investigated whether a cancer disparities dashboard can be used to assess racial/ethnic differences in the first line of breast cancer treatment and timeliness of breast cancer surgery. Methods: A disparities cancer dashboard was built using data from the tumor registry and the EMR’s Data Warehouse. Key fields assessing patient race/ethnicity, cancer stage, receptor status, surgery type, treatments received and dates of surgery were collected. This retrospective analysis included women diagnosed with a new primary breast cancer who underwent definitive surgery at an urban Hospital (2010-2020). We defined delays as &amp;gt;8 weeks to treatment initiation, and delay to breast surgery as &amp;gt; 6 weeks from diagnosis. Chi-square and t tests were used to assess independent variables (e.g., stage, age) by race/ethnicity. Patient-level multivariable logistic regression was used to evaluate the association between race/ethnicity and delays to initiation of first treatment and surgical delays. Results: Of 8,403 women identified (46.5% non-Hispanic White, 17.7% Black, 16.9% Hispanic), 66% had stage I cancer, 72% had estrogen receptor cancer. 18.6% of the sample had delays to first treatment modality and 42.6% experienced delays to breast surgery. After adjusting for stage, age and receptor status Black patients compared to non-Hispanic White patients had the greatest likelihood of delayed first treatment (OR: 2.09; 95% CI:1.7-2.5) or surgery delays (OR:1.76; 95% CI:1.5-2.0). With regards to clinical/sociodemographic factors younger patients (22-39 vs. 40-64; p&amp;lt;0.001), mastectomy surgery type (vs lumpectomy; p=0.031), higher stage (stage 3 vs.1; p&amp;lt;0.0001), HER2 + and TNBC receptor status (vs. ER+; p&amp;lt;0.0001) were more likely to experience surgery delays. Conclusions: Given persistent breast cancer survival disparities, health IT strategies are needed to help reduce disparities. A disparities dashboard can be used to assess differences in timeliness of care when treatment can still affect outcomes. These data can be used to inform quality initiatives to improve cancer care delivery for at-risk patient populations who experience worse cancer outcomes. Citation Format: Megan Edmonds, Parul Agarwal, Tara Balija, Cardinale Smith, Nina Bickell. Using a disparities dashboard to identify racial/ethnic differences in breast cancer treatment: Implications for improving cancer care delivery [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 C063.

Abstract A075: Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States

Abstract Background: Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer among men in the United States (US). Limited data currently exists regarding inequities in access to androgen deprivation therapy (ADT) which is the backbone of systemic treatment in management of advanced CaP. Gonadotropin-releasing hormone (GnRH) antagonists, first approved in 2008, represent a novel class of ADT drugs with faster onset of action and without initial testosterone surge or symptom flare when compared to GnRH agonists. There is also some evidence that GnRH antagonists, compared to GnRH agonists, may be associated with lower cardiovascular complications. Thus, in this study, we assessed inequities in access to GnRH antagonist (degarelix) by examining the associations of race and ethnicity with initiation of this drug among patients diagnosed with distant CaP. Methods: Using the Surveillance, Epidemiology and End Results (SEER) data linked to Medicare fee-for-service (Parts A, B, and D), we identified a cohort of patients, at least 66 years of age, who were diagnosed with distant CaP between 2008 and 2019 with follow-up through 2020. We defined treatment initiation with a GnRH antagonist (degarelix) or GnRH agonists (leuprolide, goserelin, histrelin, or triptorelin) as starting treatment with the study drug within one year after diagnosis. Poisson regression models were used to estimate adjusted rate ratios (aRR) and 95% confidence intervals (CI) for the association between race and ethnicity and degarelix treatment initiation (vs GnRH agonists, no treatment). All models were adjusted for age and Gleason score and compared Non-Hispanic Black (NHB), Hispanic, Non-Hispanic Asian American and Pacific Islander (NHAAPI), and Non-Hispanic American Indian and Alaska Native (NHAIAN) with Non-Hispanic White (NHW) patients. Results: There were 25,277 patients diagnosed with CaP in our analytic cohort, 3,033 (12.0%) initiated degarelix, and 14,045 (55.6%) initiated GnRH agonists over the study period. Mean (SD) age in the study population was 77.8 (7.8). Among all patients, 19,231 (76.1%) were NHW, 3,013 (11.9%) were NHB, 2,075 (8.2%) were Hispanic, 770 (3.0%) were NHAAPI, and 119 (0.5%) were NHAIAN. In the primary analysis, NHB (aRR: 0.58, 95% CI: 0.51-0.66), Hispanic (aRR: 0.59, 95% CI: 0.51-0.69), NHAIAN (aRR: 0.85, 95% CI: 0.49-1.47), and NHAAPI (aRR: 0.75, 95% CI: 0.59-0.94) were less likely to initiate degarelix compared with NHW patients. Discussion: In this US population-based study of patients diagnosed with distant CaP, we observed lower rates of treatment initiation with degarelix among patients of all other racial and ethnic groups compared to NHW patients, which may suggest lower access to these new class of ADT in these groups. Additional research is needed to elucidate health systems, provider, and patient access barriers that contribute to these inequities. Citation Format: Farzin Khosrow-Khavar, Mingchao He, Elizabeth Handorf, Tina Mayer, Thomas Jang, Saum Ghodoussipour, David Golombos, Biren Saraiya, Elisa V. Bandera, Hari S. Iyer. Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States [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 A075.

Transarterial chemoembolization combined with sintilimab and lenvatinib for the treatment of unresectable hepatocellular carcinoma: a retrospective study

BackgroundThe treatment of unresectable hepatocellular carcinoma (uHCC) challenging due to unfulfilled clinical requirements.ObjectiveTo evaluate the safety and efficacy of combining transarterial chemoembolization (TACE) with sintilimab and lenvatinib in the treatment of uHCC.MethodsWe retrospectively analyzed the data of patients with uHCC who were treated with a combination of TACE, sintilimab, and lenvatinib between May 2019 and December 2021 at the Chinese PLA General Hospital. Systemic treatment was started 1 week after TACE was performed. Sintilimab was administered intravenously at a dosage of 200 mg every three weeks, and lenvatinib was given orally at dosages of 8 mg or 12 mg daily, contingent upon the weight of the patients. The primary endpoint was the objective response rate (ORR) as per the mRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (tr-AEs).ResultsA total of 32 patients were enrolled in the study. Among them, 9 patients were classified as Barcelona Clinic Liver Cancer-B (BCLC-B), 23 patients were classified as BCLC-C, 14 patients diagnosed with portal vein tumors, and 12 patients were diagnosed with extra hepatic metastases. The ORR and DCR were 75% and 90.6% respectively, with 4 patients exhibiting (12.5%) complete response, 20 patients exhibiting (62.5%) partial response, 5 patients exhibiting (15.6%) stable disease, and 3 patients exhibiting (9.4%) progressive disease. With a median follow-up time of 19.6 months, the median PFS was 9.9 months, and the median OS was 33.3 months. A total of 31 patients experienced different degrees of tr-AEs, of which 2 were grade 3 tr-AEs.ConclusionThe combination therapy of TACE, sintilimab, and lenvatinib demonstrates satisfactory efficacy in the treatment of uHCC with manageable tr-AEs.

High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity

AbstractGlioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug–target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma – the DUCT study protocol

BackgroundSalivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients.MethodsThis prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome.DiscussionThe DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial’s findings could be readily applied into clinical practice.Trial registrationClinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022.Protocol versionCurrent protocol version 4.0, February 21, 2024.

Asymptomatic multicentric Castleman disease: a potential early stage of idiopathic MCD

AbstractAccording to the diagnostic criteria for human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD) proposed by Castleman Disease Collaborative Network in 2017, there is a group of HHV-8–negative patients with multicentric Castleman disease (MCD) who do not have symptoms and hyperinflammatory state and do not meet the iMCD criteria. This retrospective study enrolled 114 such patients, described as asymptomatic MCD (aMCD), from 26 Chinese centers from 2000 to 2021. With a median follow-up time of 46.5 months (range, 4-279 months), 6 patients (5.3%) transformed to iMCD. The median time between a diagnosis of aMCD and iMCD in these 6 patients was 28.5 months (range, 3-60). During follow-up, 7 patients died; 3 of them died from progression of MCD. Despite that, 37.7% of patients received systemic treatment targeting MCD; this strategy was neither associated with a lower probability of iMCD transformation nor a lower death rate. The 5-year estimated survival of all patients with aMCD was 94.1% (95% confidence interval, 88.8-99.6). Transformation to iMCD was an important predictor of death (log-rank P = .01; 5-year estimated survival, 83.3%). This study suggests that patients with aMCD may represent a potential early stage of iMCD, who may not require immediate treatment but should be closely monitored.