Era Of Treatment Research Articles

Impact of immune checkpoint inhibitor-based combination therapy on palliative care utilization for patients with metastatic renal cell carcinoma.

e24086 Background: Palliative care (PC) is a vital tool in the treatment of patients with metastatic cancer, yet its role in metastatic renal cell cancer (mRCC) is poorly defined. These individuals are increasingly treated with immune checkpoint inhibitor-based combination therapies (ICT). While this approach confers a survival advantage, it comes with additional toxicity that may necessitate PC. Yet, little is known about how ICT impacts PC use for mRCC patients. Here we present real-world data from a single center with an embedded PC provider that evaluates the effect of ICT on PC utilization in mRCC and identifies predictors of PC use for these patients in the modern treatment era. Methods: A retrospective sample of patients who received systemic treatment for mRCC at the Jonsson Comprehensive Cancer Center from 2013 to 2023 was studied. With institutional approval, the electronic health record was queried for patient and disease characteristics. PC referral, engagement, and number of visits were compared between patients who did and did not receive ICT as first-line treatment using Pearson’s chi-squared and two-sample T tests. Predictors of PC utilization were identified using multivariable logistic modeling. Results: 146 patients were included. Mean age at mRCC diagnosis was 62.6 (SD 13.1) and 69.2% were male. The diverse patient sample was 6.4% non-Hispanic Black, 16.4% Hispanic, and 11.4% Asian. The majority (78.8%) had clear cell pathology and 20.5% had sarcomatoid features. More than 50% had more than 3 metastatic sites. More patients received ICT (45.2%) than tyrosine kinase inhibitor monotherapy (39.0%) or other single agents (15.7%). Patients travelled 53.2 (SD 98.0) miles for clinic visits. Overall, 48.6% had a PC referral and 43.8% completed a visit. Of the 46.6% of patients who died, 64.7% had a PC referral and 60.3% had a PC visit. There were no statistically significant differences in PC referral (55% vs. 44%, p = 0.19), PC engagement (50% vs. 39%, p = 0.17), or PC visits (mean 4.6 vs. 3.1, p = 0.19) for patients who received ICT compared to other treatments. Controlling for other variables, statistically significant predictors of PC referral were number of metastatic sites (OR 1.57, p = 0.01), distance from clinic (OR 0.99, p = 0.04), and presence of sarcomatoid features (OR 2.85, p = 0.02). Statistically significant predictors of PC engagement included number of metastatic sites (OR 1.61, p = 0.01). Conclusions: Using single institution real-world data, we found that PC referrals and engagement were driven by disease burden and adverse pathology, but not by treatment regimen. Patients receiving first-line ICT did not demonstrate increased need for PC, while patients who lived farther from clinic were slightly less likely to receive a PC referral. Further study of the role and timing of PC in the modern mRCC treatment era are warranted.

Update on the prognostic value of a novel immune-related toxicity grading system (OST score) in patients with advanced solid tumours treated with immune checkpoint inhibitors (ICI).

e14696 Background: Toxicity grading systems have been an asset in managing cancer patients undergoing systemic treatment. In the era of ICI treatment, correlation between toxicity and treatment response is becoming more apparent. A new toxicity score was developed with the aim of better defining the profile of immune-related toxicities (irAEs). Initial analyses also demonstrated its potential in predicting patient outcomes. Here we provide an update on the survival analyses. Methods: Data were collected from the Pathobiology of Adverse Immune Reactions (PAIR) prospective cohort study at Guy’s Hospital from February 2018 until December 2023. Patients with advanced solid tumours naïve to ICI who received at least 1 dose were included. Minimum 6 months of follow-up was required. IrAEs were captured based on the OST score which evaluates the number of affected Organs (O), number of Severe (S) CTCAE (≥G3) toxicities, and Total sum of all grade toxicities (T). OST was calculated as a cumulative score at the end of follow-up or death. Patients were divided in high and low toxicity groups, defined by the median value for each parameter. For the composite OST score analysis, patients were divided in 2 groups based on a point system; 1 point was attributed for each individual OST high parameter; high toxicity OST group included patients with score >1. Descriptive statistics and crude and multivariate survival Cox Proportional Hazards regression analyses were performed accounting for age, tumour type, treatment, and steroid exposure. Results: A total of 148 patients fulfilled the criteria. Median age was 68 years (range 23-87), the majority were white Caucasian (81.8%) and male (56%). Melanoma was the most common tumour type (32.4%) followed by NSCLC (21.6%) and RCC (19.2%). 37.8% of patients received Ipilimumab/Nivolumab, 30.4% Pembrolizumab and 31.8% received other PD(L)-1 monotherapies. Twenty-eight patients (18.9%) had an autoimmune disorder at baseline; hypothyroidism was most common (5.4%). At end of follow-up, 82 deaths (55.4%) had occurred. Across the three OST parameters, Organ (O) was the strongest predictor of survival [HR (95%CI) 0.480 (0.265-0.869)]. After adjustment, multivariate analysis showed that risk of death was significantly lower in the high vs low Organ and Total toxicity groups [HR (95%CI) 0.379 (0.216-0.663) and 0.544 (0.302-0.982) respectively], but not for Severity [0.664 (0.338-1.306)]. In the OST combined score, the high toxicity group had favourable prognosis compared to low groups (mOS 56.6 vs 13 months) [HR (95%CI) 0.439 (0.275-0.702)]. Conclusions: Our new score manages to efficiently capture immune-mediated toxicity profile of patients treated with ICI as well as predict their outcomes. Further prospective evaluation, integration of laboratory markers and external validation is currently ongoing.

Association of Thrombocytopenia With Disease Burden, High-Risk Cytogenetics, and Survival in Newly Diagnosed Multiple Myeloma Patients Treated With Novel Therapies

BackgroundThe effect of thrombocytopenia has not been studied in the era of novel treatments in multiple myeloma (MM). ObjectiveTo evaluate the clinical characteristics and outcomes in MM patients presenting with thrombocytopenia. MaterialsNewly diagnosed MM patients between 2008 and 2018 who received at least 2 novel agents at induction. Thrombocytopenia was defined as a platelet count of less than < 150,000/mm3. ResultsA total of 648 patients were identified. Thrombocytopenia was found in 120 patients (18.5%). Baseline disease characteristics associated with higher rates of thrombocytopenia at baseline included IgA myeloma, P < .01, ISS 3 versus 1 or 2, P < .01, R-ISS 3 versus 1 or 2, P < .01, renal failure (CrCl < 30 mL/min), P < .01, hypercalcemia (Ca > 11.5 mg/dL), P < .01, elevated LDH, P < .03, anemia (Hb < 10 g/dL), P < .01, higher serum monoclonal protein, P < .02, and > 60% plasma cells in the bone marrow, P < .01. Thrombocytopenia was more prevalent across patients with t(4;14) and t(14;16), but was not associated with an overall high-risk fluorescence in situ hybridization (FISH) classification. Median OS was significantly lower among patients with thrombocytopenia (64.4 vs. 145.0 months, P < .01). In multivariable Cox regression, thrombocytopenia was associated with mortality (HR = 2.45, 95% CI, 1.7-3.6) independently of age, sex, high-risk FISH, ISS stage, response at induction, percentage of plasma cells in the BM, and anemia. ConclusionWe found that thrombocytopenia was seen among one-fifth of MM patients and was more common in patients with (t[4; 14] and t[14; 16]). Thrombocytopenia had an independent association with worse survival.

3D imaging in endodontics: a new era in diagnosis and treatment.

3D imaging in endodontics: a new era in diagnosis and treatment.

Treatment Revolution: The New Era Against Hepatitis C

Abstract In recent decades, chronic viral infection C (HCV) has posed a major public health challenge globally, considering the morbidity and mortality associated with this condition, as well as the difficulties related to diagnosis and treatment. Recently, significant advances in medical and pharmaceutical research have led to the development of new direct-acting antiviral therapies (DAAs), marking the beginning of a new era in HCV treatment. These treatments promise cure rates of over 90%, an improved safety profile, and a reduced duration of therapy compared to previous interferon-based regimens. This article aims to examine the evolution of HCV treatment, with a special focus on recent innovations in antiviral therapy. We will analyze the mechanisms of action of DAAs, their efficacy and safety, and their impact on populations with limited access to treatment. Additionally, we discuss the remaining challenges in the path to HCV eradication, including late diagnosis, barriers to treatment access, and the need for long-term monitoring of cured patients. By consolidating data from recent clinical studies and reviewing the specialized literature, this article provides a comprehensive perspective on the current landscape of HCV treatment, highlighting significant progress made and underlining the future directions needed to address remaining challenges. Finally, we reaffirm the importance of an integrated approach, encompassing prevention, early diagnosis, and universal access to innovative treatments, as a cornerstone in the fight against HCV.

Accelerated aging among survivors of childhood leukemia and lymphoma: Estimates of early onset and excess morbidity from the COMPASS model.

10028 Background: Cohort studies have detected an increased risk of accelerated aging among survivors of childhood cancer but the timing and magnitude are not known. Methods: To predict the clinical course of diseases of aging— cancer and cardiovascular disease — among survivors of childhood leukemia and lymphoma compared to the general population, we developed the Cancer Outcomes Microsimulation: Pediatric and Adolescent SurvivorShip (COMPASS) model. The model simulates 8 severe, disabling or life-threatening chronic health conditions (CHCs), including 4 subsequent cancers (breast, colorectal, glial tumors, sarcomas) and 4 cardiovascular diseases (heart failure, myocardial infarction/coronary artery disease, valvular disease, stroke), and excess mortality risks among survivors diagnosed between 1970 and 1999 over the course of their lifetimes. Treatment-related risks varied by patient characteristics (sex, age at diagnosis, diagnosis) and treatment exposures (chemotherapy, radiation dose) and were based on data from the Childhood Cancer Survivor Study (CCSS). Age-related risks and competing mortality were based on national databases (SEER, NHLBI, CDC Wonder). We used model calibration to identify parameter sets that generated outcomes consistent with observed data. Model outcomes included cumulative CHC risk. For comparisons to the general population, age-, sex, and diagnosis year-matched individuals who faced only age-related risks were simulated. Results: Among survivors representative of CCSS participants, the model estimated that 45% of leukemia and 65% of lymphoma survivors will develop at least 1 of the 8 CHCs by age 65. Compared to the estimated 20% cumulative risk for the general population, this represented a two- to three-fold excess morbidity risk among survivors. The age at which 20% of survivors developed at least 1 CHC was 51 years for leukemia and 42 years for lymphoma, suggesting an early onset of 14 and 21 years compared to the general population. Outcomes varied by diagnosis and treatment era due to competing risk changes. Among leukemia survivors diagnosed in the 1990s vs. 1970s, cumulative late recurrence mortality by age 40 (11% to 1%) declined. This combined with a reduction in radiation exposure (79% to 24%) resulted in a greater proportion living into adulthood and developing CHCs by age 65 (38% to 48%). In contrast, among lymphoma survivors, the proportion projected to develop a CHC by age 65 remained stable during the same period (62% to 65%) as late recurrence mortality risk declined (8% to 1%), but almost half still received radiation (90% to 49%). Conclusions: Despite improvements in therapy, leukemia and lymphoma survivors are projected to experience CHC early onset and excess morbidity, underscoring the importance of prevention-focused survivorship care and continued efforts to develop more targeted therapies.

Incidence and prevention of skeletal-related events in multiple myeloma patients: A population-based real-world experience.

Novel treatments in multiple myeloma (MM) could influence the incidence of skeletal-related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real-world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow-up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow-up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26-33) per 100 person years. 48% experienced>1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.

The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study

The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors. This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing. 9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0-31·4) from the date of primary cancer diagnosis (4311 [44.9%] were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9-19·5) compared with 0·9% (0·0-2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23-0·29) events per survivor compared with 0·009 (0·000-0·021) events per community control participant. Increasing cumulative burden of grade 1-4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1-6·0; p<0·0001; two conditions: 6·6, 4·6-9·5; p<0·0001; and three conditions: 7·7, 5·1-11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias [RR 1·5, 95% CI 1·2-2·0; p=0·0017]), grade 2 left ventricular systolic dysfunction (2·2, 1·6-3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2-4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1-2 hypertriglyceridaemia, or grade 1-2 vascular stenosis. Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events. The US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Racial and Ethnic Characteristics and Outcomes of Patients Diagnosed with CLL/SLL in the USA.

This study was designed to compare outcomes among patients by race and ethnicity in the post-covalent Bruton tyrosine kinase inhibitor (cBTKi) treatment era. A nationwide electronic health record (EHR)-derived de-identified database was utilized that included patients diagnosed with CLL from 2013 to 2022 who received systemic therapy for their disease. Use of cBTKi therapy, time to next treatment or death (TTNT-D), and overall survival (OS) were compared by race in unadjusted (Kaplan-Meier method) and adjusted analyses (Cox proportional hazards regression). This study included 4,572 White (71.8%) and 558 Black (8.8%) patients with CLL; 270 were Hispanic or Latino (4.2%). Patients who were Black were significantly younger, more were female, had later stage disease, were of lower socioeconomic status (SES), and were more likely to have unmutated immunoglobulin heavy chain gene (IGHV) and to have received cBTKi therapy than White patients (all p ≤ 0.002). SES was also significantly different by ethnicity. TTNT-D and OS were not different by race in either unadjusted or adjusted analyses (all p &gt; 0.05). In unadjusted and adjusted analyses, TTNT-D and OS were not different by race. These data did not identify racial healthcare disparities in the era following the introduction of cBTKi therapy despite differences in baseline characteristics.

404-error "Disease not found": Unleashing the translational potential of -omics approaches beyond traditional disease classification in heart failure research.

The emergence of personalized medicine, facilitated by the progress in -omics technologies, has initiated a new era in medical diagnostics and treatment. This review examines the potential of -omics approaches in heart failure, a condition that has not yet fully capitalized on personalized strategies compared to other medical fields like cancer therapy. Here, we argue that integrating multi-omics technology with systems medicine approaches could fundamentally transform heart failure management, moving away from the traditional paradigm of 'one size fits all'. Our review examines how omics can enhance understanding of heart failure's molecular foundations and contribute to a more comprehensive disease classification. We draw attention to the current state of medical practice that only relies on clinical evidence and a number of standard laboratory tests. At the same time, we propose a shift towards a universal approach that uses quantitative data from multi-omics to unravel complex molecular interactions. The discussion centres around the potential of the transition as a means to enhance individual risk assessment and emphasizes management within clinical settings. While the use of omics in cardiovascular research is not recent, many past studies have focused only on a single omics approach. In order to achieve a better understanding of disease mechanisms, we explore more holistic approaches using genomics, transcriptomics, epigenomics, and proteomics. This review concludes with a call to action to adopt multi-omics in clinical trials and practice to pave the way for more personalized disease management and more effective heart failure interventions.

Incidence of left ventricle thrombus formation in patients with STEMI in the current era of antithrombotic treatment

Abstract Funding Acknowledgements None. Introduction Left ventricular (LV) thrombus formation is a serious complication of acute ST-segment elevation myocardial infarction (STEMI) which may result in ischemic stroke and systemic thromboembolism. There is limited evidence on the incidence and impact of LV thrombus in STEMI patients in the current era of antithrombotic treatment. Purpose To evaluate the incidence of LV thrombus formation in STEMI patients and to assess clinical predictor factors of LV thrombus formation leading to in-hospital major cardiac events (MACCE). Methods We prospective collected data from 504 STEMI patients treated with primary percutaneous intervention (PCI) in our large volume university hospital from April 2019 to September 2019. All patients underwent echocardiography examination at presentation and at hospital discharge. Results Mean age of the patients was 66.2 years and 78.8% were male. The incidence of LV thrombus formation was 5% in overall cohort and 9.4% in anterior STEMI. Among patients with LV thrombus, the majority had anterior STEMI (96% vs 48.4%; p&amp;lt;0.001), lower LV ejection fraction (LVEF)(35% vs 43%; P&amp;lt;0.001), more increased LV dimension /volume (36%vs7.3%; p&amp;lt;0.001), more apical aneurism/dyskinesia presence (36% vs 9%; p&amp;lt;0.001), longer ischemia time (25 hours vs 14 hours; p&amp;lt;0.002), more increased TPI values (p-0.22) and underwent less coronary angiography (p&amp;lt;0.02) and primary PCI (P=0.021). Increased LV dimension/volume was associated with 3.35 times higher risk of having LV thrombus (p=0.023). Also anterior STEMI was associated with 14 times higher risk of having LV thrombus=0.012. Patients with LV thrombus had a numerically higher incidence of in-hospital MACCE events (20% vs 13.5%; p=0.36). Conclusion The incidence of LV thrombus formation in STEMI still remain high regardless of primary PCI treatment and current antithrombotic treatment, and is higher in patients with anterior STEMI, lower LVEF, adverse ventricular remodeling, apical aneurism/dyskinesia presence, late hospital presentation and longer ischemia time. The presence of LV thrombus was independently associated with in-hospital MACCE events.

Abstract PO1-14-07: Programme of mast cell subsets to potentiate breast cancer immunotherapy: from bed to bench to bed (the phase 2 platform RENAISSANCE trial)

Abstract Background: Immune checkpoint inhibitors (ICIs) have heralded a new era in breast cancer treatment; however, response rates remain limited, making precision immune-oncology a major unmet need. In addition to T cells, effective immune responses to ICIs rely on coordinated interactions between innate and adaptive immune cells. Mast cells are evolutionarily conserved, tissue-resident cells of importance to human health. Specific subsets of mast cells might be endowed with opposite roles in cancer treatment, yet the extent of mast cell heterogeneity and its clinical merit in immunotherapy remain undefined. Objective: We sought to comprehensively characterize mast cells in breast cancer, investigate their association with immunotherapy response with in-depth mechanistic insights, and identify actionable strategies to modulate mast cell functional states, thereby optimizing immunotherapy efficacy. Methods: We employed single-cell profiling on longitudinal breast cancer samples from three independent clinical trials (NCT04613674, NCT03197389 and GSE169246) to delineate mast cell heterogeneity in anti-PD-(L)1 therapy. By integrating multi-omic analyses, tissue characterization, preclinical experiments, transgenic mice, and high-throughput drug screening, we outlined the molecular features, underlying mechanisms, and clinical relevance of distinct mast cells to elicit ICI-responsive microenvironments. Subsequently, we launched RENAISSANCE (NCT05076682), a proof-of-concept, Bayesian adaptive, phase 2 platform trial, to evaluate the efficacy and safety of combining mast cell therapeutics with anti-PD-1 backbone therapy in metastatic triple-negative breast cancer (TNBC) patients who progressed after immunotherapy. The primary endpoint was the objective response rate (ORR) assessed using RECIST v1.1 criteria. Results: We identified a distinct population of mast cells termed antigen-presenting mast cells (APMCs), constituting approximately 30% of intratumoral mast cells and correlating with improved clinical benefit of anti-PD-(L)1 therapy in TNBC. APMCs displayed MHC-II and costimulatory molecules, and indicated the presence of tumor-reactive T cells and tertiary lymphoid structures. Using three immunocompetent mouse models, we confirmed the immunomodulatory capacity of APMCs in immunotherapy. Mechanistically, by employing Cpa3CreERT2Cd74fl/fl mice, we demonstrated that APMCs potentiate anti-PD-1 efficacy and antitumor T cell immunity through their antigen-presentation machinery. Interestingly, we identified cromolyn, an FDA-approved drug for allergy, as a potential therapeutic agent that elicited APMC-dependent CD8+ T cell cytotoxicity to synergize with anti-PD-1 therapy. Between February 2022 and March 2023, 10 patients with immunotherapy-refractory metastatic TNBC were enrolled to receive cromolyn plus camrelizumab backbone treatment. Given Bayesian predictive probability, this arm was “graduated” due to meeting the pre-specified efficacy boundary, with an ORR of 40.0% (4/10). The treatment was well tolerated with similar safety profiles of relevant drugs. Conclusions: Our findings provide crucial insights into the impact of mast cell heterogeneity on the clinical response to ICIs at a single-cell level, and pave the way for APMC-directed therapeutic interventions in cancer treatment. To our knowledge, this is the first prospective study in breast cancer of cromolyn plus anti-PD-1 backbone regimen after anti-PD-(L)1 immunotherapy failure, demonstrating significant antitumor activity and commendable tolerability. Consequently, we suggest a phase 3 randomized study to consolidate this finding, which might be an effective treatment in patients for whom there are few effective treatment options. Citation Format: Song-Yang Wu, Xi Jin, Yin Liu, Wen-Jia Zuo, Li Chen, Xiyu Liu, Lei Fan, Zhong-Hua Wang, Yan-Fei Liu, Yi-Zhou Jiang, Zhi-Ming Shao. Programme of mast cell subsets to potentiate breast cancer immunotherapy: from bed to bench to bed (the phase 2 platform RENAISSANCE trial) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-07.

Pathobiology of Pulmonary Arterial Hypertension

Abstract: Pulmonary Arterial Hypertension (PAH) is a progressive disease associated with occlusive pulmonary arterial remodeling of vessels &lt; 500 μm for which there is no cure. Even in the era of PAH-specific combination therapies, aberrant lung pathology and progressive right ventricular (RV) dysfunction occur, culminating in a median survival of 6.2 years, according to the latest data in the treatment era. While better than a median survival from symptom onset of 2.8 years prior to PAH-specific therapies, it is still poor. Thus, there is an urgent need to move the opportunities forward for meaningful treatment strategies. Clearly, a better understanding of the highly complex pathobiology of PAH is needed if we are to achieve new and novel treatment strategies. This is especially so if we are to pursue a more personalized treatment approach to PAH in light of the multitude of pathobiological abnormalities described in PAH, which likely culminate in a final common pathway for PAH development. : In this State-of-the-Art review, we provide comprehensive insights into the complex pathobiology of PAH to provide understanding and insights for the practicing clinician. We review the pathology of PAH and the cells involved and their impact in driving pathological abnormalities (pulmonary artery endothelial cells, smooth muscle cells, fibroblasts and pericytes) as well as the role of the extracellular matrix. Inflammation and immune dysfunction are considered important drivers of PAH and are comprehensively discussed. Another pathway relates to TGFβ/ bone morphogenic protein (BMP) imbalance, which is highlighted, as well as a new novel agent, sotatercept that impacts this imbalance. Genetic factors underlying heritable PAH (HPAH) are addressed, as well as epigenetic influences. Other important pathways highlighted include growth factor signaling, ion channels/channelopathy, hypoxia signaling pathways, and altered metabolism and mitochondrial dysfunction. We also address the “estrogen paradox”, whereby PAH is more common in women but more severe in men. The basis for drug-induced PAH is discussed, including the new methamphetamine epidemic. We briefly provide insights into DNA damage and senescence factors in pathobiology and highlight commonalities between PAH and cancer pathobiology. Furthermore, we provide concluding insights for the treating physician. In conclusion, we need to pose the right questions to motivate novel and effective treatment strategies for the management of PAH based on pathobiological principles and understanding.

Resource recovery through bioremediation of fuel-synthesis wastewater in a biofilm photobioreactor using purple non-sulfur bacteria: A circular bioeconomy approach

In the current era of wastewater treatment, integrating reusable water production with resource recovery is a key goal. This study aims to treat fuel-synthesis wastewater (FSW), intending to recover various resources, including polyhydroxybutyrate (PHBs), single cell protein, bacteriochlorophylls, carotenoids, and coenzyme Q10 from suspended and biofilm growth to decrease the harvesting costs. The study considered the treatment process, biofilm growth, and resource recovery potential in a mixed-culture system enriched with purple non-sulfur bacteria for treating FSW. Specifically, the effects of four different FSW strengths (25–100 %) and nitrogen sufficiency (N+) or deficiency (N−) were evaluated in eight biofilm photobioreactors. This study observed a direct correlation between the concentration of FSW and PHB content; specifically, as the FSW content decreased from 100 % (undiluted) to 25 % the PHB content decreased. The undiluted condition achieved 17 % dry cell weight as PHB in the suspended growth and 22.6 % in the biofilm growth under N− condition. The protein content ranged between 33 and 44 %, and the presence of nitrogen had a slight positive effect on higher protein content. No trend was observed for carotenoids or bacteriochlorophylls in the N− condition. In contrast, for the N+ condition, the concentration of bacteriochlorophylls increased with decreasing wastewater concentration under suspended growth, while it decreased with decreasing wastewater concentration under biofilm growth. Coenzyme Q10 concentration was enhanced under the most growth-limited condition (25 %, N−). PHB and protein content of these resources seem most promising when using N− and N+ conditions, respectively.

Isolated Limb Perfusion and Immunotherapy in the Treatment of In-Transit Melanoma Metastases: Is It a Real Synergy?

Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape. This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group (p = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group (p = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group (p = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group (p = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS (p = 0.01) and DSS (p = 0.007) but not local DFS (p = 0.13) and distant DFS (p = 0.21). Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.

Imaging in the era of risk-adapted treatment in colon cancer.

The treatment landscape for patients with colon cancer is continuously evolving. Risk-adapted treatment strategies, including neoadjuvant chemotherapy and immunotherapy, are slowly finding their way into clinical practice and guidelines. Radiologists are pivotal in guiding clinicians toward the most optimal treatment for each colon cancer patient. This review provides an overview of recent and upcoming advances in the diagnostic management of colon cancer and the radiologist's role in the multidisciplinary approach to treating colon cancer.

ASO Author Reflections: Is There a Role for Selective Adjuvant Radiotherapy in the Modern Era of Pancreatic Cancer Treatment?

ASO Author Reflections: Is There a Role for Selective Adjuvant Radiotherapy in the Modern Era of Pancreatic Cancer Treatment?

Current Immunotherapy Progress in the Hodgkin Lymphoma

Hodgkin lymphoma, a distinctive cancer affecting the lymphatic system, poses challenges in treatment due to its unique characteristics and the limitations of traditional therapies. This essay delves into the potential of immunotherapy to transform the landscape of treatment for Hodgkin lymphoma. Furthermore, the essay analyses case studies to illustrate the efficacy of these approaches. It presents an overview of the underlying principles, as well as specific immunotherapeutic approaches, such as checkpoint inhibitors, monoclonal antibodies, and CAR-T cell therapy, and their mechanisms. Immunotherapy offers a targeted and personalized alternative to conventional chemotherapy and radiation, presenting promising results in clinical trials. Clinicians manage subtleties in immune-related toxicity and response assessment as the field develops. The goal of immunotherapy research in the initial phases of treatment is to increase cure rates while lowering long-term dangers. Ongoing research and advancements, including checkpoint blockade studies, offer hope for refining treatment approaches and optimizing outcomes in Hodgkin lymphoma. This essay emphasizes the significance of immunotherapy in providing effective and less toxic alternatives, heralding a new era in Hodgkin lymphoma treatment.

MRNA therapies: Pioneering a new era in rare genetic disease treatment

Rare genetic diseases, often referred to as orphan diseases due to their low prevalence and limited treatment options, have long posed significant challenges to our medical system. In recent years, Messenger RNA (mRNA) therapy has emerged as a highly promising treatment approach for various diseases caused by genetic mutations. Chemically modified mRNA is introduced into cells using carriers like lipid-based nanoparticles (LNPs), producing functional proteins that compensate for genetic deficiencies. Given the advantages of precise dosing, biocompatibility, transient expression, and minimal risk of genomic integration, mRNA therapies can safely and effectively correct genetic defects in rare diseases and improve symptoms. Currently, dozens of mRNA drugs targeting rare diseases are undergoing clinical trials. This comprehensive review summarizes the progress of mRNA therapy in treating rare genetic diseases. It introduces the development, molecular design, and delivery systems of mRNA therapy, highlighting their research progress in rare genetic diseases based on protein replacement and gene editing. The review also summarizes research progress in various rare disease models and clinical trials. Additionally, it discusses the challenges and future prospects of mRNA therapy. Researchers are encouraged to join this field and collaborate to advance the clinical translation of mRNA therapy, bringing hope to patients with rare genetic diseases.