First-line Treatment Research Articles

RADT-42. DISSEMINATED TUMORAL AMYLOIDOSIS OF THE CRANIAL NERVES IN THE ABSENCE OF SYSTEMIC DISEASE: CASE REPORT

Abstract Tumoral amyloidosis, characterized by tumor-like deposits without systemic disease, is rare in the central nervous system. Most often located in the periventricular white matter, tumoral amyloidosis typically consist of immunoglobulin light chains (AL). While prior reports describe cases of tumoral amyloidosis isolated to the trigeminal nerve, we report herein a first known case of diffuse cranial nerve involvement. The patient is a 43-year-old man who presented with left trigeminal dysesthesias, which led to self-excoriation and erosion of the left naris. On exam, he had absent sensation in the V1-V3 distributions, left trochlear nerve palsy, and bilateral abducens nerve palsies. Imaging demonstrated significant thickening of the left trigeminal nerve and diffuse cisternal contrast enhancement of the other cranial nerves, including the oculomotor, abducens, facial, and glossopharyngeal nerves. Work-up began with a lumbar puncture that found elevated protein with otherwise benign results, including flow cytometry. He was therefore recommended to undergo open biopsy of the left trigeminal nerve and cavernous sinus. Pathology from this surgery demonstrated congo red- positive AL amyloid deposits. Following this pathologic diagnosis, he subsequently underwent a full workup for systemic amyloidosis including bone marrow biopsy, abdominal fat pad biopsy, and a PET CT scan. Biopsy of a long nodule was negative for amyloidosis. Systemic amyloid testing did not demonstrate non-CNS sites of amyloid deposition. Medical therapy with daratumumab, cyclophosphamide, bortezomib, and dexamethasone was started but then discontinued due to ineffectiveness. He underwent radiation treatment of 4500 cGy to the left cavernous sinus where the tumoral amyloidosis was most severe. He has had no further progression of his disease. Tumoral amyloidosis of the cranial nerves remains a rare and poorly-understood disease. Prior reports have described the disease isolated to the trigeminal nerve. This report raises attention to this diagnosis in cases of rare multi-nerve involvement and suggests that radiation may be a useful first-line treatment.

CTNI-38. SINGLE-CENTER COMPARATIVE ANALYSIS ABOUT OUTCOMES OF MULTI-AGENTS CHEMOTHERAPY FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA; R-MPV SHOWED A FAVOR RESULT

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a malignant tumor in the brain, spinal cord, and eyes. Radiotherapy may cause delayed leukoencephalopathy so that the first-line treatment is methotrexate (MTX)-based multi-agent chemotherapy. We had used the Bonn protocol based on MTX and cytarabine, but since 2020, we have adopted the R-MPV protocol. This study analyzes the outcomes of patients treated initially at our institution. METHODS AND RESULTS We reviewed 57 out of 88 newly diagnosed PCNSL patients treated with chemotherapy alone between December 2005 and January 2023. Initial treatments included the Bonn protocol in 25 patients (12 with rituximab, forming R-Bonn) and R-MPV in 26 patients. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) was given as consolidation in 4 Bonn and 9 R-MPV patients. The Bonn protocol was completed by 20 patients (80%) with a complete response (CR) in 19 (76%). The R-MPV protocol was completed by 23 patients (88%) with CR in 22 (85%). Post-treatment outcomes were compared using survival analysis. Median progression-free survival (mPFS) had not been reached in the R-MPV group and was significantly better than 33.1 months in the Bonn protocol and 58.6 months in the R-Bonn protocol (log-rank test; p=0.0296, 0.0036). Overall survival (OS) did not show significant differences. PBSCT’s impact on outcomes suggested improvement in PFS and OS after R-MPV, but this was not statistically significant. DISCUSSION We examined the efficacy of different chemotherapy regimens for PCNSL at our institution. The R-MPV protocol showed superior completion rates, response rates, and treatment efficacy. Consolidation with PBSCT may improve outcomes, though further investigation with more cases and longer observation is necessary.

Sorafenib-induced macrophage extracellular traps via ARHGDIG/IL4/PADI4 axis confer drug resistance through inhibiting ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common as well as leading causes of mortality worldwide, and sorafenib is the first-line treatment in HCC patients. Unfortunately, drug resistance to sorafenib often develops. However, the underlying mechanism remains unclear. Here, we reveal the important role of macrophage extracellular traps (METs)-mediated crosstalk between macrophages and tumor cells in sorafenib resistance. METs in HCC tumor tissues were detected using immunofluorescence. The concentrations of MPO-DNA, elastase and cytokines were measured using ELISA. The mRNA expression levels of genes were confirmed by qRT-PCR. The siRNAs were conducted to knock ARHGDIG in Hepa1-6 and Hep3B cells. Western Blot assay was performed to determine protein expression of Rho GDP dissociation inhibitor gamma (ARHGDIG, or RHOGDI-3), PADI2, and PADI4. Cell viability and migration were evaluated by CCK-8 assay and transwell assay, respectively. Cell ferroptosis was assessed by measurement of Fe2+ concentration, flow cytometry assay of lipid ROS, and western blot assay of GPX4. The functions of sorafenib, DNase I, IL4 neutralization antibody and GPX4 in tumor growth were explored through in vivo experiments. Sorafenib induced MET formation in M2 macrophages rather than M1 macrophages derived from both human and mice. In Hepa1-6 HCC mice, METs clearance by DNase I improved response to sorafenib therapy, detected by tumor weight, tumor growth curve, tumor volume, and survival. By screening candidate cytokines that affect macrophage function, we found that sorafenib-promoting IL4 secretion by HCC cells plays a crucial role in sorafenib-induced MET formation. Understanding the critical role of IL4 in sorafenib-induced MET formation led us to find that IL4 neutralization significantly improved the efficiency of sorafenib in HCC models. Mechanistically, we discovered that sorafenib increased the expression of ARHGDIG in HCC cells, which led to the release of IL4. In M2 macrophages, IL4 triggered MET formation by elevating the mRNA and protein expression of peptidyl arginine deiminase 4 (PADI4) rather than PADI2. In HCC models, GSK484 inhibition of PADI4 could consistently weaken sorafenib resistance and improve sorafenib efficiency. Importantly, we discovered that METs contribute to sorafenib resistance by inhibiting the ferroptosis of HCC cells. Meanwhile, PADI4 inhibition or DNase I could reverse the sorafenib resistance caused by METs-inhibiting ferroptosis of HCC cells. Our study concludes that sorafenib-induced METs inhibit the ferroptosis of tumor cells, suggesting that targeting the IL4/PADI4/METs axis in HCC could reduce or prevent sorafenib resistance.

Comparative analysis of efficacy and safety of combined immunotherapy and immune targeted therapy in the first-line treatment of advanced renal cell carcinoma: a real-world study

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice. Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS). Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified. Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

CTIM-17. INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) FOR ADULTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE HEMISPHERIC GLIOMA

Abstract Diffuse Midline Glioma (DMG, H3K27 mutant) and Diffuse Hemispheric Glioma (DHG, H3G34 mutant) are rare malignant CNS tumors with dismal prognosis. We retrospectively searched in our database for adults (>18y) with molecularly define DMG/DHG, treated between May 2015 and 2024 with IMI as part of first-line treatment. Amongst 157 IMI-treated malignant glioma patients, four patients fit these restrictions, pointing to scarce experience of IMI for DMG/DHG adult patients. HM (M, 29y) was diagnosed with a DMG in the pons. He received radiochemotherapy, and continued after 2x TMZm with BRAF-MEK-inhibition therapy. He received one IO-Vac® dendritic cell vaccine but showed fast progression thereafter. He died 9 months after diagnosis. GJE (F, 28y) had a DMG at the corpus callosum. She received radiochemotherapy and 6x TMZm, followed by 2x IO-Vac® and 3x maintenance immunogenic cell death (ICD) immunotherapy (NDV injections, sessions of modulated electrohyperthermia), combined with WT1 and H3K27M long-peptide vaccines. She progressed after 20 months, for which a new IO-Vac® and an H3K27M short- and long-peptide vaccine were given. She died 5 months later. Overall Survival (OS) was 26 months after initial diagnosis. JD (F, 27y) was diagnosed with a DMG in C2-C6. She received radiochemotherapy followed by IMI alone, including 2x IO-Vac®, one ICD immunotherapy, and four doses of anti-PD1. She died 17 months later, making OS 27 months after diagnosis. VJ (F, 21y) had a DHG in the left cerebrum. She received radiochemotherapy and 12 cycles of maintenance TMZ (TMZm), between which ICD immunotherapy was inserted each time. Afterwards, she received two IO-Vac®. Finally, she received ICD immunotherapy (6x) combined with checkpoint inhibitors (4x anti-CTLA4, 10x anti-PD1). Thirty months after diagnosis, she is in remission with a stable Health Utility Index of 0.72. IMI might have contributed to a better OS in three out of four DMG/DHG patients, and should be explored further as part of the treatment for these patients.

CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.

Inflammatory stress determines the need for chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma receiving targeted and immunotherapy.

Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma (EGA), but long-term survival remains limited. Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% CI: 41%-71%) in the Ipi arm and 70% OS (95% CI: 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analysis demonstrated elevated levels of normetanephrine, cortisol, and interleukin 6 (IL-6) in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil-to-lymphocyte ratio (NLR) that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low NLR characterized patients benefiting from immune- and targeted therapy without the need for additional chemotherapy. This data suggests that patient selection based on inflammatory stress-driven immune changes could help to customize first-line treatment in patients with advanced HER2-positive EGA to potentially improve long-term survival.

Do Women with Urinary Incontinence and Pelvic Organ Prolapse Receive Optimal First-Line Treatment?

There is scant knowledge on previous pelvic floor muscle training (PFMT) in women with urinary incontinence (UI) and pelvic organ prolapse (POP) referred to hospitals. We hypothesized that women with predominately UI and POP had not received optimal primary care conservative management. This was a descriptive, cross-sectional survey among women attending a gynecological outpatient's clinic. The questionnaire included questions about demographics, PFMT dosage, whether ability to contract had been assessed and whether the patients had used precontraction before increase in intra-abdominal pressure ("the knack"). One hundred two women, mean age 52.5 (SD 13.4) years, responded; 37.3% had never been treated previously. There was no statistically significant difference in age, BMI, level of education, parity, time since last birth, SUI, or POP between the women who had been treated conservatively or not before the hospital visit. Thirty-three percent had trained with a physiotherapist and > 35% reported that their ability to contract had not been assessed or were unsure whether it had been assessed; 37% were not able to stop their urine stream; 52% reported that they performed "the knack," with 15.7% reporting it to be effective. Reasons for not having trained the PFM before visiting the hospital included not being motivated, not knowing how to do PFMT, not being told/advised to do PFMT and not believing PFMT would help. The results of this study indicated that there is a need for improvement within first-line health care service for women with predominately UI and POP.

CTNI-13. 18-FET-PET ENHANCED DIAGNOSIS OF PSEUDOPROGRESSION IN GLIOBLASTOMA IS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL

Abstract INTRODUCTION Detecting pseudoprogression (PSP) in glioblastoma during first-line treatment remains challenging and has significant clinical implications for patient management. The detection of PSP has been shown feasible using FET-PET. The prognostic impact of FET-PET diagnosed PSP on overall survival is still uncertain, as retrospective studies provide limited insights due to the substantial differences in the distribution of prognostic factors between tumor progression (TP) and PSP groups. This study aims to address these uncertainties by leveraging advanced analysis techniques. METHODS Patients with newly diagnosed glioblastoma (WHO 2021) who underwent chemoradiation and contrast-enhanced MRI suspected for TP and subsequent FET-PET scan at Essen University Hospital were retrospectively evaluated. The modified Response Assessment in Neuro-Oncology (RANO) criteria were used to diagnose PSP. FET-PET analysis included mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax). The two groups (TP/PSP) were balanced using a propensity score analysis including age at diagnosis, extent of resection, Karnofsky-Performance-Status Scale (KPS) and MGMT methylation status. Overall survival was predicted using Kaplan-Meier and multivariate analysis as well as conventional FET-PET parameters, PET/MRI volumetry, and FET/MRI-derived radiomics. An independent cohort was used for validation. RESULTS Out of the 165 patients analysed in this study, 38 were diagnosed with PSP. Following balancing analysis, our study cohort consisted of 40 patients (20 TP/20 PSP). Patients with PSP had a significantly longer mean overall survival (mOS) compared to those with TP (mOS TP 20.24 months; mOS PSP 33.25 months; p=0.0023). The multivariate Cox-Regression analysis confirmed PSP as a significant prognostic marker for overall survival (p=0.0153). Confirmation of these results on an independent validation cohort is pending and will be presented at the meeting. CONCLUSION This study shows that PSP is an independent prognostic factor for overall survival in newly diagnosed glioblastoma patients.

Management of opioid use disorder: 2024 update to the national clinical practice guideline.

In an evolving landscape of practices and policies, reviewing and incorporating the latest scientific evidence is necessary to ensure optimal clinical management for people with opioid use disorder. We provide a synopsis of the 2024 update of the 2018 National Guideline for the Clinical Management of Opioid Use Disorder, from the Canadian Research Initiative in Substance Matters. For this update, we followed the United States Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines and used the Appraisal of Guidelines Research and Evaluation-Recommendation Excellence tool to ensure guideline quality. We carried out a comprehensive systematic literature review, capturing the relevant literature from Jan. 1, 2017, to Sept. 14, 2023. We drafted and graded recommendations according to the Grading of Recommendations, Assessments, Development and Evaluation approach. A multidisciplinary external national committee, which included people with living or lived experience of opioid use disorder, provided input that was incorporated into the guideline. From the initial 11 recommendations in the 2018 guideline, 3 remained unchanged, and 8 were updated. Specifically, 4 recommendations were consolidated into a single revised recommendation; 1 recommendation was split into 2; another recommendation was moved to become a special consideration; and 2 recommendations were revised. Key changes have arisen from substantial evidence supporting that methadone and buprenorphine are similarly effective, particularly in reducing opioid use and adverse events, and both are now considered preferred first-line treatment options. Slow-release oral morphine is recommended as a second-line option. Psychosocial interventions can be offered as adjunctive treatment but should not be mandatory. The guideline reaffirms the importance of avoiding withdrawal management as a standalone intervention and of incorporating evidence-based harm reduction services along the continuum of care. This guideline update presents new recommendations based on the latest literature for standardized management of opioid use disorder. The aim is to establish a robust foundation upon which provincial and territorial bodies can develop guidance for optimal care.

NIMG-34. CXCR4-TARGETED PET IMAGING OF CENTRAL NERVOUS SYSTEM LYMPHOMA AND GLIOMA USING [68GA]GA-PENTIXAFOR

Abstract BACKGROUND Initial results suggest that PET imaging of the chemokine receptor CXCR4 is of considerable interest for differential diagnosis and theranostic approaches. Here, we summarized findings of CXCR4 PET imaging in an institutional series of lymphoma of the central nervous system (CNSL) and glioma. METHODS Twenty-three patients with CNSL and 16 patients with glioma (IDH-wildtype, n=9) underwent PET imaging using the CXCR4-directed tracer [68Ga]Ga-Pentixafor. In 18 patients, serial PET imaging was performed (range, 2-14 scans), resulting in a total of 104 PET scans. For evaluation, PET scans were classified as [68Ga]Ga-Pentixafor-positive and -negative visually, and the maximum standardized uptake value (SUVmax) was obtained from [68Ga]Ga-Pentixafor-PET. RESULTS Twenty-four of all 39 patients (62%) had at least one [68Ga]Ga-Pentixafor-positive PET (CNSL, 57%; glioma, 69%). [68Ga]Ga-Pentixafor-positive PET scans were more common in patients with IDH-wildtype gliomas (89%) than in IDH-mutant gliomas (43%). In patients with [68Ga]Ga-Pentixafor-positive PET, the average SUVmax was 6.4±4.0 in CNSL, and 3.4±1.0 in gliomas (P=0.155). Besides visualization of tumors, [68Ga]Ga-Pentixafor uptake was observed in two patients with radionecrosis. In four CNSL patients who had undergone methotrexate/cytarabine-based first-line therapy, serial PET revealed a significant reduction of SUVmax after chemotherapy completion (average decrease of SUVmax from 4.5±3.8 to 0.6±0.7; P=0.044). In three of those four patients, tumor progression has not been reached (range of time after the follow-up PET, 4-55 months); one patient deceased 44 months after the follow-up PET. In contrast, another patient with an increase in SUVmax from 6.9 to 11.0 after first-line treatment died one month after the follow-up PET. DISCUSSION [68Ga]Ga-Pentixafor PET seems to be of value for non-invasively visualizing and quantifying CXCR4 receptor binding. In CNSL, changes in [68Ga]Ga-Pentixafor uptake following therapy may indicate potential for response assessment. CXCR4-targeting radioligand therapies might be more promising in CNSL than in glioma.

Cost-effectiveness analysis of lorlatinib and crizotinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer

ABSTRACT Objectives To assess the economic value of lorlatinib and crizotinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer at medical insurance negotiation prices from the viewpoint of China’s health system. Methods Based on data from the phase III clinical trial, a three-state partitioned survival model was established. In combination with parameters such as treatment costs, utility values, incidence of adverse reactions, and discount rates, the total incremental cost-effectiveness ratio (ICER) was simulated. Results The results of the fundamental analysis indicated that the patients in the lorlatinib group expended 709,671 yuan more than did the patients in the crizotinib group did but gained 3.09 quality-adjusted life years (QALYs). The ICER value was 229,782.6 yuan/QALY, which was lower than three times the per capita gross domestic product (GDP) of China. Conclusions Compared with crizotinib, lorlatinib may be a cost-effective first-line treatment choice for advanced ALK-positive NSCLC in China.

A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first-line treatment for patients with melanoma in-transit metastases.

Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in-transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first-line ILI/ILP, ICI, and TVEC. Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first-line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM. A total of 551 patients were treated, with ILI/ILP (n=356), ICI (n=125), and TVEC (n=70) with median follow-up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p =.002). Breslow thickness was lowest with TVEC (p =.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p =.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p =.029) and a longer local progression-free survival (PFS) (hazard ratio [HR], 0.40; p =.003). ILI/ILP had shorter local PFS (HR, 1.72; p =.012), PFS (HR, 1.79; p <.001), distant metastasis-free survival (DMFS) (HR, 1.75; p =.014), overall survival (HR, 1.82; p =.009), and melanoma-specific survival (HR, 2.29; p =.004). Stage IIIB disease had longer DMFS (HR, 0.24; p <.001) compared to IIIC/D. TVEC as first-line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first-line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Profiles of Nonpharmacologic Treatment Receipt in the First 10 Weeks Following a New Back Pain Diagnosis Among Active Duty Soldiers: A Latent Class Analysis.

US service members experience high rates of back pain. Guidelines prioritize nonpharmacologic treatment (NPT) as first-line pain treatments; however, NPT utilization patterns research is limited. This study examined NPT patterns of care within the first 10 weeks following an index back pain diagnosis. Data were from the Substance Use and Psychological Injury Combat Study and included 222,427 active duty soldiers with an index back pain diagnosis following return from Afghanistan/Iraq deployment in 2008-2014. We fit a series of latent class analysis models to identify homogenous subgroups of soldiers with NPT utilization during the 10-week period and measured associations with soldier characteristics and clinical characteristics within 90 days before the back pain diagnosis, with the distinct NPT utilization classes. Approval for this study was granted by the Brandeis University Committee for Protection of Human Subjects (Institutional Review Board #14153) and the Uniformed Services University Institutional Review Board. Only half of the soldiers received any NPT within their 10-week early treatment window. Latent class analysis identified 4 classes over the 10-week early treatment window: Class 1 (None/Low NPT, 65%); Class 2 (High and Decreasing NPT, 15%); Class 3 (Low and Increasing NPT, 13%), and Class 4 (Sustained NPT, 7%). Soldier clinical characteristics from the 90-day preperiod window were most important in distinguishing class membership in relation to Class 1, particularly comorbid pain conditions, diagnosis of traumatic brain injury, receipt of prescription opioids, and receipt of invasive surgery. Patterns of weekly NPT utilization during an early treatment window following a new back pain diagnosis varied temporally, with approximately half of soldiers using NPT. Half of the soldiers did not receive any NPT within their 10-week early treatment window, which highlights opportunities for increasing use of NPT utilization among military members with a new back pain episode. Future research is needed in the Military Health System to examine the extent to which NPT patterns are associated with pain management outcomes.

Efficacy and Safety of a Therapy Combining Sintilimab and Chemotherapy With Cryoablation in the First-Line Treatment of Advanced Nonsquamous Non-Small Cell Lung Cancer: Protocol for a Phase II, Pilot, Single-Arm, Single-Center Study.

Immunotherapy has significantly advanced lung cancer treatment, particularly in nonsquamous non-small cell lung cancer (NSCLC), with overall response rates between 50% and 60%. However, about 30% of patients only achieve a stable disease state. Cryoablation has shown potential to enhance immunotherapy by modifying the tumor's immune microenvironment through the release of antigens and immune factors. Addressing how to boost the immune response in these patients is critical. This study aims to investigate the efficacy and safety of immunochemotherapy in combination with cryoablation as a first-line treatment for advanced NSCLC. This is a phase II, pilot, open-label, single arm, single center, interventional study. Patients with stage IIIB to IIIC or IV NSCLC with T staging ranging from T1 to T2b will receive sintilimab (200 mg/m2 every 3 weeks) and chemotherapy. After 2 cycles, the feasibility of cryoablation will be considered for those with stable disease by a multidisciplinary team. Cryoablation with 3 freeze-thaw cycles will be performed for the main lesion. The third cycle of systemic therapy will begin 7 (SD 3) days after cryoablation. A total of 20 patients will be enrolled. Treatment will continue until the disease progresses, there is unacceptable toxicity, a participant withdraws consent, other discontinuation criteria are met, or the study reaches completion. The primary objective is to assess progression-free survival (PFS). The secondary objective is to assess efficacy through duration of response, disease control rate, overall survival (OS), and the safety profile. The exploratory objective is to investigate and compare immune factor changes after 2 cycles of immunochemotherapy and at 1, 3, and 7 days after cryoablation. Survival time will be estimated using the Kaplan-Meier method to calculate median PFS and OS. Any adverse events that occur during the trial will be promptly recorded. The project was funded in 2024, and enrollment will be completed in 2025. The first results are expected to be submitted for publication in 2027. This study will provide evidence for the efficacy and safety of the combination of immunochemotherapy and cryoablation as a first-line treatment for advanced NSCLC. Although it has a limited sample size, the findings of this study will be used in the future to inform the design of a fully powered, 2-arm, larger-scale study. ClinicalTrials.gov NCT06483009; https://clinicaltrials.gov/study/NCT06483009. PRR1-10.2196/64950.

Diving into hot topics of salivary gland carcinoma management—an EORTC young and early career investigator survey

IntroductionRecently, the ASCO and ESMO guidelines on salivary gland carcinomas (SGCs) have been released. However, several crucial points lack strong recommendations due to low or intermediate quality of evidence. To better address these “grey zones” in the guidelines, we conducted a survey among the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group (HNCG) members on behalf of the EORTC young and early career investigators.Materials and methodsThe survey included 29 questions addressing diagnostic and therapeutic issues related to SGC patients and was shared among 539 members of the EORTC HNCG. Responses were collected from December 2022 to March 2023. The primary aim was to evaluate the decision-making criteria guiding physicians in areas with low evidence in SGC guidelines.ResultsWith a response rate of 19%, the survey received input from 102 respondents, mainly medical oncologists (45%). Among those with pathological high-risk features, 35% and 30% of respondents opted for chemoradiotherapy (CRT) in the definitive and adjuvant settings, respectively. For patients with R0 resection of highly aggressive SGC at the pT1–2 stage, 37% proposed a close follow-up, while 38% proposed adjuvant lymph-node field RT. In cases of pT3–4 stage, 48% proposed adjuvant lymph-node field RT in all cases, and 44% proposed it based only on risk factors. The most important factors guiding the decision to give adjuvant RT after salvage surgery for locoregional relapse include previous radiotherapy, margin status, and the presence of extranodal extension. When faced with combined positivity to HER2 and AR, responses regarding the choice of first-line palliative treatment were heterogeneous.ConclusionsInternational guidelines lack strong recommendations in several fields of SGC diagnosis and treatment due to insufficient high-quality data, resulting in heterogeneity in physicians’ treatment decision (e.g., adjuvant lymph-node field RT and their low concordance with guidelines, such as the use of concomitant CRT). The survey demonstrated the need for prospective clinical trial data to address these gaps in the future.

Fatigue and Sleep-related Impairment as Predictors of the Effect of Nonpharmacological Therapies for Active duty Service Members With Chronic Pain: A Secondary Analysis of a Pragmatic Randomized Clinical Trial.

First-line treatments for chronic pain include selected complementary and integrative health therapies, including spinal manipulation, acupuncture, yoga, and massage; and standard rehabilitative care, including physical and occupational therapies. This study aimed to uncover critical factors that contribute to pain impact and the effectiveness of complementary and integrative health therapies and standard rehabilitative care among people with chronic pain, with a focus on the role of sleep-related impairment. We conducted a secondary analysis of data from a pragmatic randomized clinical trial of 280 U.S. active duty service members with chronic pain. Our study's multiple mediation analysis examined the indirect effect of complementary and integrative health therapies on pain impact through fatigue (β = - 0.43; 95% CI, -0.99 to -0.07). When stratified by sleep-related impairment, participants with T scores above the median of 62 demonstrated a significant negative indirect effect of complementary and integrative health therapies through fatigue (β = - 0.80; 95% CI, -2.31 to -0.14). This negative indirect effect was not significant for participants with sleep-related impairment T scores below the median (β = - 0.64; 95% CI, -1.48 to 0.07). These findings suggest that complementary and integrative health therapies are particularly effective in reducing pain impact for individuals with higher levels of sleep-related impairment, and that the effect of complementary and integrative health therapies is supported primarily by reducing fatigue.

How do people use community pharmacies to manage sleep problems? A cross-sectional survey of pharmacy customers in England, UK

Abstract Introduction Insomnia and sleep problems have become increasingly common in the UK population, with research indicating a rise in the prevalence of sleep issues and the use of hypnotic medications1. Poor sleep can severely affect overall health and has been linked to cardiovascular disease, type 2 diabetes, and other conditions2. Community pharmacies are ideally positioned to advise people about sleep, but there is limited information about how people currently utilise them for sleep problems. Aim To understand how people use community pharmacies to manage problems with sleep Methods A researcher-administered questionnaire with customers at 16 community pharmacies in the East Midlands from the 6th to 25th of March 2023. People aged 18 and older were approached to take part. Survey questions included demographic information, general pharmacy use, and specific questions related to health-seeking advice for sleep problems. Responses were recorded using the Qualtrics survey platform and descriptive statistics derived using MS Excel. Ethical approval was given by the School of Pharmacy Research Ethics Committee at the University of Nottingham (2017-017er). Results 13,127 customers were approached to take part, and 4,985 consented and completed the questionnaire (response rate = 38.0%). Two thirds of participants were female (66.3%), half were above the age of 50 years (51.1%), and the majority identified as white ethnicity (79.8%). Just under one-third of participants reported purchasing a medicine, herbal remedy, or other product to help with sleep in the past (28.2%), of which 81.8% had purchased from a community pharmacy. The most common medicines purchased were anti-histamines (43.7%), followed by herbal remedies (34.1%). Only 19.1% of participants had previously sought advice for a sleep problem, of which 64.9% had sought advice from a GP/other healthcare professional, and 29.2% had sought advice from a community pharmacy. The most common advice received from a community pharmacy was to use a medicine (32.2%), with the second most common being sleep hygiene/lifestyle advice (22.8%). The most common advice received from a GP was also to use a medicine (36.4%). Discussion / Conclusion A significant proportion of survey participants reported purchasing a medicine, herbal remedy, or other product to help with sleep from a community pharmacy, highlighting the significant role of pharmacies in managing sleep issues. However, considerably fewer customers had sought advice for their sleep problem, identifying a potential gap in care. Current national guidelines do not recommend medication as first-line treatment for insomnia, emphasising sleep hygiene and behavioural therapy, with no role for sedative anti-histamines3. Despite this, our survey indicated the most common advice focused on medicines. This suggests an opportunity for enhancing the education of healthcare professionals and improving public awareness of managing sleep problems. Whilst this survey involved a large number of participants, we recognise it may not be fully representative of the wider UK population or practice. Further analysis of this survey and interviews with customers and pharmacists would help understand how the role of community pharmacies in managing sleep could be further developed to improve care.

The Interplay Between the MYC Oncogene and Ribosomal Proteins in Osteosarcoma Onset and Progression: Potential Mechanisms and Indication of Candidate Therapeutic Targets

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65–70%, dropping down to 20% when metastases are present at diagnosis. Therefore, curing OS is a clinical challenge, particularly for patients that do not respond to standard treatments. MYC has frequently been reported to be involved in the pathogenesis of OS and its high expression may be associated with drug resistance and patients’ worse prognosis. Moreover, MYC is a master regulator of ribosomal proteins (RPs) synthesis and ribosome biogenesis (RiBi), which is often up-regulated in human tumors. In recent years, RPs have been recognized not only for their traditional role in ribosome assembly but also for their extra-ribosomal functions, many of which are linked to the onset and progression of cancer. In this review we focus on the role and possible interplay of MYC and RPs expression in association with drug resistance and worse prognosis in OS and discuss therapeutic options that target de-regulated MYC, RiBi, or RPs, which are already clinically available or under evaluation in clinical trials.

Sex-related differences in the presentation, management and response to treatment of eosinophilic esophagitis: Cross sectional analysis of EoE CONNECT registry.

Eosinophilic esophagitis (EoE) predominantly affects males across all ages; however, little is known about sex differences for other aspects of EoE. To investigate associations between sex and clinical presentation, endoscopic features, treatment choice and response in EoE patients in real-world practice. Cross-sectional analysis of the multicenter EoE CONNECT registry. The independent contribution of patients' sex and other relevant variables were statistically assessed by multivariate models. A total of 2976 patients (76% male) were evaluated. Males were diagnosed at a younger age compared to females (32.7±14.8 vs. 34.8±15.6years, respectively; p=0.002) with similar diagnostic delay. EoE symptoms varied significantly between sexes, with food impaction predominating in males and dysphagia, heartburn, regurgitation and abdominal and epigastric pain in females. However, female sex contributed to higher symptom severity at diagnosis as measured with Dysphagia Symptom Score (R2=0.57; p=0.013) and presented higher peak eosinophil count in esophageal biopsies (p=0.005). Males showed increased risk of stricturing or mixed phenotypes (adjusted OR 1.43, 95%CI:1.05-1.96; p=0.024). No association was found between patients' sex and first-line treatment modality: proton pump inhibitors (PPI) were preferred over topical corticosteroids in patients with inflammatory phenotypes instead of stricturing or mixed phenotypes, and in patients who did not present food impaction. Both topical corticosteroids and dietary interventions were preferred over PPI in pediatric patients regardless of sex. Sex is associated with clinical and phenotypical presentation of EoE at diagnosis, with more fibrotic findings in males but higher symptom score in females.