Stable Disease Research Articles

Regorafenib in patients with pretreated advanced melanoma: a single-center case series.

Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF V600 mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab ( n = 5), trametinib ( n = 8), binimetinib ( n = 2), encorafenib ( n = 1), dabrafenib/trametinib ( n = 9), or encorafenib/binimetinib ( n = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF V600mut patient treated with REGO plus anti-PD-1, and a NRASQ61mut patient treated with REGO plus a MEK inhibitor. Common grade 3-4 treatment-related adverse events included arterial hypertension ( n = 7), elevated transaminase levels ( n = 5), abdominal pain ( n = 3), colitis ( n = 2), anorexia ( n = 1), diarrhea ( n = 1), fever ( n = 1), duodenal perforation ( n = 1), and colonic bleeding ( n = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1-14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0-33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF V600mut patients.

Thrombin Generation Is Associated With Extracellular Vesicle and Leukocyte Lipid Membranes in Atherosclerotic Cardiovascular Disease.

Clotting, leading to thrombosis, requires interactions of coagulation factors with the membrane aminophospholipids (aPLs) phosphatidylserine and phosphatidylethanolamine. Atherosclerotic cardiovascular disease (ASCVD) is associated with elevated thrombotic risk, which is not fully preventable using current therapies. Currently, the contribution of aPL to thrombotic risk in ASCVD is not known. Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples. Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics. External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients. The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. Targeting EV formation/clearance and developing strategies to prevent the aPL surface of EV interacting with coagulation factors represents a novel antithrombotic target in ASCVD.

Computed Tomography-Derived Fractional Flow Reserve Versus Usual Care Strategy to Guide the Management of Patients With Stable Coronary Artery Disease: A Meta-Analysis and Systematic Review

Computed Tomography-Derived Fractional Flow Reserve Versus Usual Care Strategy to Guide the Management of Patients With Stable Coronary Artery Disease: A Meta-Analysis and Systematic Review

Treatment outcomes of elective neck dissection in intrathoracic esophageal carcinoma.

In the present study, the outcomes of elective neck dissection in patients with intrathoracic esophageal squamous cell carcinoma were investigated. From January 2016 to December 2022, 21 patients who underwent esophagectomy and elective neck dissection (both neck level IV) for intrathoracic esophageal squamous cell carcinoma were enrolled. Of these 21 patients, 19 patients were male and 2 were female. A total of 11 patients received concurrent chemoradiotherapy (CCRT) as preoperative treatment. As a result of elective neck dissection at both neck level IV, occult neck metastasis of esophageal squamous cell carcinoma was diagnosed in 3 cases, all of which involved left neck lymph nodes. The incidence of occult neck metastasis was statistically significant in patients with preoperative CCRT, high T stage and high N stage (P<0.05). In addition, 16 out of 21 patients had been under follow-up without disease recurrence after the completion of treatment. However, 3 out of 21 patients succumbed to esophageal squamous cell carcinoma and 2 out of 21 patients were alive with stable disease of esophageal carcinoma. The follow-up period was 19.2±18.4 months. In conclusion, three-field lymph node dissection for intrathoracic esophageal squamous cell carcinoma may be necessary in patients with certain phenotypes, such that collaboration between thoracic surgeons and otolaryngologists may help reduce surgical complications.

Very-long T2-weighted imaging of the non-lesional brain tissue in multiple sclerosis patients.

The purpose of this study is to demonstrate that T2-weighted imaging with very long echo time (TE > 300 ms) can provide relevant information in neurodegenerative/inflammatory disorder. Twenty patients affected by relapsing-remitting multiple sclerosis with stable disease course underwent 1.5T 3D FLAIR, 3D T1-weighted, and a multi-echo sequence with 32 echoes (TE = 10-320 ms). Focal lesions (FL) were identified on FLAIR. T1-images were processed to segment deep gray matter (dGM), white matter (WM), FL sub-volumes with T1 hypo-intensity (T1FL), and dGM volumes (atrophy). Clinical-radiological parameters included Expanded Disability Status Scale (EDSS), disease duration, patient age, T1FL, and dGM atrophy. Correlation analysis was performed between the mean signal intensity (SI) computed on the non-lesional dGM and WM at different TE versus the clinical-radiological parameters. Multivariable linear regressions were fitted to the data to assess the association between the dependent variable EDSS and the independent variables obtained by T1FL lesion load and the mean SI of dGM and WM at the different TE. A clear trend is observed, with a systematic strengthening of the significance of the correlation at longer TE for all the relationships with the clinical-radiological parameters, becoming significant (p < 0.05) for EDSS, T1FL volumes, and dGM atrophy. Multivariable linear regressions show that at shorter TE, the SI of the T2-weighted sequences is not relevant for describing the EDSS variability while the T1FL volumes are relevant, and vice versa, at very-long TEs (around 300 ms); the SI of the T2-weighted sequences significantly (p < 0.05) describes the EDSS variability. By very long TE, the SI primarily originates from water with a T2 longer than 250 ms and/or free water, which may be arising from the perivascular space (PVS). Very-long T2-weighting might detect dilated PVS and represent an unexplored MR approach in neurofluid imaging of neurodegenerative/inflammatory diseases.

Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1–4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors.

Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.

Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC. TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

Predicting angiographic coronary artery disease using machine learning and high-frequency QRS

AimExercise stress ECG is a common diagnostic test for stable coronary artery disease, but its sensitivity and specificity need to be further improved. In this paper, we construct a machine learning model for the prediction of angiographic coronary artery disease by HFQRS analysis of cycling exercise ECG.Methods and resultsThis study prospectively included 140 inpatients and 59 healthy volunteers undergoing cycling exercise ECG. The CHD group (N=104) and non-CHD group (N=95) were determined by coronary angiography gold standard. Automated HF QRS analysis was performed by the blinded method. The coronary group was predominantly male, with a higher prevalence of age, BMI, hypertension, and diabetes than the non-coronary group (P<0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P<0.001$$\\end{document}), higher lipid levels in the coronary group (P<0.005\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P<0.005$$\\end{document}), significantly longer QRS duration during exercise testing (P<0.005\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P<0.005$$\\end{document}), more positive leads (P<0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P<0.001$$\\end{document}), and a greater proportion of significant changes in HFQRS (P<0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P<0.001$$\\end{document}). Age, Gender, Hypertension, Diabetes, and HF QRS Conclusions were screened by correlation analysis and multifactorial retrospective analysis to construct the machine learning models of the XGBoost Classifier, Logistic Regression, LightGBM Classifier, RandomForest Classifier, Artificial Neural Network and Support Vector Machine, respectively.ConclusionMale, elderly, with hypertension, diabetes mellitus, and positive exercise stress test HFQRS conclusions suggested a high risk of CHD. The best performance of the Logistic Regression model was compared, and a column line graph for assessing the risk of CHD was further developed and validated.

Clinical and molecular insights into A97S variants in hereditary transthyretin amyloid polyneuropathy in South China

Objective This study aims to delineate the clinical profiles of the hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) patients with A97S variant from southern China and the molecular characteristics of this mutant protein. Methods Fifteen ATTRv-PN patients with heterozygous A97S and one patient with homozygous A97S were included in the study. Serum TTR tetramer concentration was quantified through ultra-performance liquid chromatography. Stabilities of A97S-TTR were assessed through in vitro urea-mediated tryptophan fluorescence experiments, and nephelometry was employed in drug response assessment. Results All patients were late-onset (≥50 years) with a mean age of onset at 59.26 ± 5.06 years old. Patients displayed a mixed phenotype featuring sensory-motor neuropathy with autonomic dysfunction and cardiac involvement, such as palpitations and chest pain. Electrophysiological studies showed generally axonal impairment of sensory and motor nerves. Tafamidis-treated patients showed significantly higher TTR tetramer concentrations, approaching healthy controls’ levels. In vitro assessment showed that A97S-TTR was more kinetically stable than the V122I-TTR, and tetramer stabilisers inhibited A97S-TTR amyloid formation by more than 70%. Conclusion This study provides valuable insights into the clinical and molecular characteristics of ATTRv-PN patients with A97S from South China, particularly regarding the differences in disease progression and stability features.

Improving the response to lenvatinib in partial responders using a Constrained-Disorder-Principle-based second-generation artificial intelligence-therapeutic regimen: a proof-of-concept open-labeled clinical trial

IntroductionThe main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability.MethodsA 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib—an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence.ResultsAt 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded.SummaryThe results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach.

Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510).

Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety. A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached). The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.

Results from a Phase I study of 4-L-[131I]iodo-phenylalanine ([131I]IPA) with external radiation therapy in patients with recurrent glioblastoma (IPAX-1)

Abstract Background Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm Phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM. Methods A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radiochemotherapy, were randomized to a single dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; three 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; three 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry. Results All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of 9 patients at 3-month post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval, 3.3–4.5), while median overall survival was 13 months (95% confidence interval, 7.1–27). Conclusions Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.

Efficacy of verdinexor for the treatment of naïve canine epitheliotropic cutaneous T-cell lymphoma: An open-label pilot study.

Verdinexor (Laverdia-CA1; Dechra Veterinary Products), a selective inhibitor of nuclear export, has been utilised for treatment of non-Hodgkin T-cell lymphoma in dogs. However, the efficacy of verdinexor has not been evaluated for cutaneous epitheliotropic T-cell lymphoma (CETL). To evaluate the efficacy of verdinexor for the treatment of CETL. Eight client-owned animals with CETL. Patients received between 1.28 and 1.45 mg/kg verdinexor per os twice weekly with a minimum of 72 h between doses until disease progression or voluntary withdrawal. Adjunctive therapy with lokivetmab or prednisone was permitted after Day (D)14. Assessment of clinical lesions (canine Response Evaluation Criteria in Solid Tumors [cRECIST v1.0] and novel Canine Epitheliotropic Lymphoma Extent and Severity Index [CELESI]), pruritus (Visual Analog Scale) and treatment efficacy (owner global assessment of treatment efficacy [OGATE]) were evaluated every 14 days for 3 months, then monthly thereafter (mean 70 ± 43.4 days). Seventy-five percent of patients achieved complete response, partial response or stable disease. The mean time to disease progression was 56 ± 41 days. There was a significant reduction (p = 0.026) in total CELESI score when the lowest score for each dog was compared to their score at D0. Verdinexor did not significantly reduce pruritus at any time point (p = 0.45), including when given as a monotherapy or concurrently with lokivetmab ± glucocorticoids. On D28, 75% of owners rated response to treatment as 'fair' to 'excellent'. The most common adverse effects included weight loss, inappetence, vomiting and lethargy. Verdinexor could be considered a safe, palliative treatment for canine CETL.

Pentraxin 3 as a marker of development and severity of stable coronary artery disease

Inflammation plays a crucial role in the development of atherosclerotic plaques. Pentraxin 3 (PTX3) is produced at the site of inflammation and has been identified as a specific marker of atherosclerosis, vascular inflammation, and progression of the coronary artery disease (CAD). The aim of the study was to establish if PTX3 has potential relations with classical markers of cardiovascular risk, and if PTX3 may act as an independent risk factor of CAD occurrence and advancement. The study included 98 patients with stable CAD confirmed in coronary angiography (CAD group) (median age 65 interquartile range [IQR] 61-72 years; 72% men). The control group consisted of 40 patients without CAD. The CAD group had significantly higher PTX3 concentration compared to the control group. There was a correlation with age, male gender, lipid profile and intima-media thickness. There was no correlation between PTX3 concentration and the number of coronary vessels with significant atherosclerotic lesions and the advancement of atherosclerotic lesions on the Gensini scoring scale. The cut-off point was determined for 0.89 ng/ml for the exclusion of angiographically significant atherosclerotic lesions. Patients with CAD have significantly higher concentration of PTX3. There was no correlation between PTX3 and the advancement of angiographically significant atherosclerotic lesions in coronary arteries. Low PTX3 concentration may serve as an indicator for the absence of atherosclerosis.

Differential circulating cytokine profiles in acute coronary syndrome versus stable coronary artery disease

Chronic inflammation plays a crucial role in coronary artery disease (CAD), but differences in specific cytokine profiles between acute coronary syndrome (ACS) and stable CAD remain unknown. We investigated cytokine differences between these two manifestations of CAD. The study included 308 patients with angiographically detected, hemodynamically significant CAD: 150 patients undergone angiography for ACS, 158 patients undergone angiography for stable CAD. To assess dynamic changes, 116 patients had index angiogram at least 3 months earlier. We measured the serum concentrations of 48 circulating cytokines. The ACS group had decreased interleukin (IL) 4 (p = 0.005), and increased IL-8 (p = 0.008), hepatocyte growth factor (HGF) (p < 0.001) and macrophage colony-stimulating factor (M-CSF) (p = 0.002) levels compared with the stable CAD group. Multivariable logistic regression revealed increased levels of HGF (OR 18.050 [95% CI 4.372–74.517], p < 0.001), M-CSF (OR 2.257 [1.375–3.705], p = 0.001) and IL-6 (OR 1.586 [1.131–2.224], p = 0.007), independently associated with ACS. In the post-angiography group, only diminished platelet-derived growth factor-BB levels in ACS-manifested patients were observed (OR 0.478, [0.279–0.818], p = 0.007). Cytokine profiles differ between ACS and stable CAD. Such differences seem to be mainly reversible within 3 months after ACS. Thus, targeting one or two cytokines only might not offer one-size fits all-therapeutic approach for CAD-associated inflammation.Trial registration: NCT03444259.

Imaging-Based Disease Assessment and Management Recommendations: Impact of Multidisciplinary Sarcoma Tumor Board

Multidisciplinary tumor boards (MTBs) facilitate decision-making among subspecialists in the care of oncology patients, but the mechanisms by which they enhance outcomes remain incompletely understood. Our aim was to measure the agreement between sarcoma MTBs and radiology reports’ disease assessment and management recommendations. This single-center IRB-approved retrospective study evaluated cases presented at a weekly sarcoma MTB from 1 August 2020 to 31 July 2021. Cases without clinical notes, imaging studies, or radiology reports were excluded. The data collected included the patient’s clinical status at the time of the MTB, the treatment response assessment by the MTB and radiologists (stable disease; partial response; complete response; progressive disease/recurrence), and the recommendations of the radiology reports and of the MTB. The agreement between the initial radiologist review and MTB on disease assessment and recommendations was analyzed using kappa statistics. In total, 283 cases met the inclusion criteria. Radiology reports provided recommendations in 34.3% of cases, which were adhered to by the ordering providers in 73.2% of cases. The agreement between MTBs and radiology reports was moderate in disease assessment (86.2% agreement; κ = 0.78; p &lt; 0.0001) and negligible in recommendations (36% agreement; κ = 0.18; p &lt; 0.0001). Radiologists were more likely to assign progressive disease/recurrence than MTBs (54.4% vs. 44.4%; p &lt; 0.001) and to recommend short-term imaging follow-up more commonly than MTBs (46.4% vs. 21.7%; p &lt; 0.001). At a tertiary care center, radiologists’ isolated interpretations of imaging findings and management recommendations frequently differ from the MTB’s consensus, reflecting the value of multidisciplinary discussions incorporating the patient’s clinical status and the available treatment options into the final radiographic assessment.

Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor

The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic Tcells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates Tcell activity and suppresses tumor growth in mice by enhancing cytotoxic Tcell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma.

Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC). To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC. Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group. Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) (P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) (P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group (P > 0.05). Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation.

Rechallenge immunotherapy after immune resistance in patients with advanced thymic carcinoma.

Immunotherapy is effective for patients with advanced thymic carcinoma (TC). However, the effectiveness of rechallenge immunotherapy in patients who are resistant to immunotherapy has not been investigated. Thirty-five patients with advanced TC using immunotherapy between 2016 and 2023 at Zhejiang Cancer Hospital, The Second Affiliated Hospital of Nanchang University, and Fujian Cancer Hospital were evaluated in this study. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A total of 35 patients were included in this study. The median PFS (mPFS) for all patients was 5.43months and the median OS (mOS) was 16months. After rechallenge immunotherapy, only three patients achieved partial response, resulting in an overall response rate of 16.7%, and nine patients attained stable disease, resulting in a disease control rate of 66.7%. Patients who underwent rechallenge immunotherapy had shorter mPFS compared to chemotherapy (3.53months vs. 6.00months, P = 0.041). In addition, the incidence of Grade 3-4 treatment-related adverse events in these patients was 22.2%. Rechallenge immunotherapy has poor efficacy in immunotolerant TC patients.

A first-in-human phase I clinical study with MVX-ONCO-1, a personalized active immunotherapy, in patients with advanced solid tumors.

Purpose Over two decades, most cancer vaccines failed clinical development. Key factors may be the lack of efficient priming with tumor-specific antigens and strong immunostimulatory signals. MVX-ONCO-1, a personalized cell-based cancer immunotherapy, addresses these critical steps utilizing clinical-grade material to replicate a successful combination seen in experimental models: inactivated patient's own tumor cells, providing the widest cancer-specific antigens repertoire and a standardized, sustained, local delivery over days of a potent adjuvant achieved by encapsulated cell technology. Experimental Design We conducted an open-label, single-arm, first-in-human, phase I study with MVX-ONCO-1 in advanced refractory solid cancer patients. MVX-ONCO-1 comprises irradiated autologous tumor cells co-implanted with two macrocapsules containing genetically engineered cells producing granulocyte macrophage stimulating factor (GM-CSF). Patients received six immunizations over nine weeks without maintenance therapy. Primary objectives were safety, tolerability, and feasibility, while secondary objectives focused on efficacy and immune monitoring. Results Data from 34 patients demonstrated safety and feasibility with minor issues. Adverse events included one serious event (SAE) possibly related to investigational medicinal product (IMP), and two moderate-related adverse events (AE). Over 50% of patients with advanced and mainly non-immunogenic tumors showed clinical benefits, including partial responses (PR), stable diseases (SD), and prolonged survival. In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), one patient achieved a PR, while another survived for more than 7 years without anticancer therapy for over 5 years. Conclusion/Discussion MVX-ONCO-1 is safe, well-tolerated, and beneficial across several tumor types. Ongoing phase IIa trials target advanced R/M HNSCC patients post initial systemic therapy.