Cardiopulmonary Toxicity Research Articles

CTIM-09. INB-200: FULLY ENROLLED PHASE 1 STUDY OF GENE-MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)

Abstract IN8bio’s DeltEx drug resistant immunotherapy (DRI), comprising TMZ-resistant γδ T cells engineered to express methylguanine-DNA methyltransferase (MGMT), enables γδ T cells to target upregulated NKG2D ligands on tumor cells in real time during alkylating chemotherapy exposure. Updated results from the fully enrolled Phase 1 trial evaluating DRI in adult newly diagnosed GBM subjects with IDH wild type and mutant tumors, adequate organ function and KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107 DRI cells/dose) into the resection cavity with 150 mg/m2 of IV TMZ on Day 1 of each of 6 Stupp maintenance cycles. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. A total of 23 subjects were enrolled and 13 dosed (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS), neurotoxicity (ICANS) or treatment related deaths were reported. The most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder with ≥G3 platelet count decreased in 23% and WBC/ neutrophil/ lymphocyte count decreased in 7.7% each. Peripheral TMZ-based lymphodepletion was maintained for up to 1 year evidenced by near or below normal range T, B, and NK subsets. With median follow-up of 10.8 months, 83% of subjects exceeded the median 7 month Progression Free Survival (PFS) of the Stupp regimen alone, had manageable toxicity with a continued encouraging trend in PFS. Subject with IDH mutant tumor remains progression free for > 35 months. Long-term follow-up for durability of PFS and OS continues.

Involved-field high-dose chemoradiotherapy with respiratory motion management for esophageal squamous cell carcinoma.

We investigated the clinical outcomes of involved-field high-dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath-holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. We enrolled 35 patients with a prescribed dose of 66-70 Gy in 33-35 fractions. The overall response rate within 6 months post-CRT was 94.3%; the median follow-up period for survivors was 43 months. The 2-year overall survival (OS), progression-free survival, and locoregional failure-free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log-rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out-of-field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Involved-field high-dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates.

How Effective is Deep Inspiration Breath Hold in Minimizing Cardiac Doses During Hybrid Radiotherapy Treatment for Left-Sided Breast Cancer with Comprehensive Regional Nodes?

In the context of left breast cancer radiotherapy, long term cardiopulmonary toxicity has been well-documented, significant efforts have been undertaken to mitigate such toxicity by using 4D gating, deep inspiration breath-hold(DIBH) and active breath control(ABC) techniques. To evaluate and compare the cardio-pulmonary radiation doses incurred during postmastectomy radiotherapy (PMRT) in two distinct breathing conditions such as DIBH and Free Breathing (FB), with a specific focus on the left chest wall with comprehensive regional nodal irradiation. A prospective dosimetric study was conducted on 15 patients who received adjuvant loco-regional radiotherapy of chest-wall (CW), supraclavicular fossa(SCF), and internal mammary region(IMC), with or without axilla. Two sets of planning CT scans were taken in DIBH and FB conditions. The dosimetric difference between DIBH CT and FB CT plans analyzed using Wilcoxon signed-rank test, employing SPSS software version 21.0. Comparison of DIBH and FB parameters for target coverage revealed a statistically significant advantage with DIBH in SCF(D95, V90, p<0.017) and IMC(D98, V90 & V95, p<0.03). Dosimetric characteristics of heart and LAD exhibited statistically significant lower doses with DIBH (V20, V25, and Dmean, p<0.001) compared to FB plans. Lung doses were similar with no discernible advantage of one technique over the other. Other OARs such as contralateral breast (p=0.027) and esophagus (p=0.001) received lower doses with the DIBH technique while the spinal cord (p=0.691) and thyroid(p=0.496) showed no significant difference. Maximum heart distance (p= 0.001), central lung distance (p= 0.011) and Haller index (p= 0.001) exhibited statistical significance between the two techniques, whereas chest wall separation showed no significant statistical difference (p=0.629). DIBH demonstrates a substantial reduction in cardiac and LAD doses compared to the FB technique. This study underscores the efficacy of DIBH as a viable strategy for mitigating cardiac and LAD radiation doses in left-sided breast cancer patients undergoing PMRT of chest wall with comprehensive regional nodes.

Comparing the Differences in Adverse Events among Chimeric Antigen Receptor T-Cell Therapies: A Real-World Pharmacovigilance Study.

In this study, we compared the similarities and differences in adverse events (AEs) among CAR T-cell products through signal mining via the FDA Adverse Event Reporting System (FAERS) and identified unknown AEs to provide a reference for safe clinical medication. Data from the FAERS database spanning from the fourth quarter of 2017 to the first quarter of 2024 were extracted. Signals were identified using the reporting odds ratio (ROR) method and the Medicines and Healthcare Products Regulatory Agency (MHRA) method. A total of 11,386 AE reports related to six CAR T-cell products were selected. The top three categories of AEs reported were nervous system disorders, immune system disorders, and general disorders and administration site conditions. However, there were variations in the AE spectra among the different CAR T-cell products. The BCMA-targeting drugs idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) were found to be associated with parkinsonism, which were not observed in CD19-targeting drugs. Tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel) exhibited cerebrovascular accident-related AEs, graft versus host disease, and abnormal coagulation indices. Cilta-cel was associated with cerebral hemorrhage, intracranial hemorrhage, cranial nerve disorder, and facial nerve disorder. Cardiopulmonary toxicity, including hypoxia, tachypnoea, cardiorenal syndrome, and hypotension, exhibited strong signal intensities and considerable overlap with CRS. The number of positive signals for cardiopulmonary toxicity associated with drugs targeting CD-19 is greater. Clinicians should assess patients prior to medication and closely monitor their vital signs, mental status, and laboratory parameters during treatment.

Fentanyl Overdose Causes Prolonged Cardiopulmonary Dysregulation in Male SKH1 Mice.

Fentanyl overdose is a survivable condition that commonly resolves without chronic overt changes in phenotype. While the acute physiological effects of fentanyl overdose, such as opioid-induced respiratory depression (OIRD) and Wooden Chest Syndrome, represent immediate risks of lethality, little is known about longer-term systemic or organ-level impacts for survivors. In this study, we investigated the effects of a single, bolus fentanyl overdose on components of the cardiopulmonary system up to one week post. SKH1 mice were administered subcutaneous fentanyl at the highest non-lethal dose (62 mg/kg), LD10 (110 mg/kg), or LD50 (135 mg/kg), before euthanasia at 40 min, 6 h, 24 h, or 7 d post-exposure. The cerebral cortex, heart, lungs, and plasma were assayed using an immune monitoring 48-plex panel. The results showed significantly dysregulated cytokine, chemokine, and growth factor concentrations compared to time-matched controls, principally in hearts, then lungs and plasma to a lesser extent, for the length of the study, with the cortex largely unaffected. Major significant analytes contributing to variance included eotaxin-1, IL-33, and betacellulin, which were generally downregulated across time. The results of this study suggest that cardiopulmonary toxicity may persist from a single fentanyl overdose and have wide implications for the endurance of the expanding population of survivors.

Optimizing Therapeutic Approaches in Superficial Esophageal Cancer: Reduced-volume Radiotherapy and Dose-dense Chemotherapy After Endoscopic Resection.

Endoscopic submucosal dissection (ESD) followed by chemoradiotherapy (CRT) has become a promising treatment modality in the management of early-stage superficial esophageal squamous cell carcinoma (SESCC). However, radiotherapy often leads to significant adverse events (AEs), including cardiopulmonary toxicity, limiting the delivery of this treatment modality. This study aimed to evaluate the efficacy of reduced-volume radiotherapy and dose-dense chemotherapy in mitigating AEs for high-risk SESCC following ESD. We retrospectively analyzed patients treated with customized CRT after ESD between 2014 and 2023. Thirty-nine consecutive patients were identified. The median follow-up period was 63.4 months (range=8.3-99.8 months). All patients completed CRT, with a low incidence (3%) of grade ≥3 nonhematologic AEs. Thirteen patients (33%) had a recurrence: 10 local, one regional, and two distant. The 5-year overall and disease-free survival rates were 77% and 64%, respectively. A positive vertical resection margin was identified as a prognostic factor associated with survival. Our novel approach of combining ESD with customized reduced-volume radiotherapy and dose-dense chemotherapy shows promise in providing favorable oncologic outcomes and a safer nonsurgical strategy for high-risk SESCC. Specifically, this regimen minimized cardiopulmonary toxicity without compromising therapeutic efficacy. More aggressive adjuvant therapy may be required for patients with positive vertical resection margins after ESD.

Diesel exhaust particle extract elicits an oxPAPC-like transcriptomic profile in macrophages across multiple mouse strains

Air pollution is a prominent cause of cardiopulmonary illness, but uncertainties remain regarding the mechanisms mediating those effects as well as individual susceptibility. Macrophages are highly responsive to particles, and we hypothesized that their responses would be dependent on their genetic backgrounds. We conducted a genome-wide analysis of peritoneal macrophages harvested from 24 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). Cells were treated with a DEP methanol extract (DEPe) to elucidate potential pathways that mediate acute responses to air pollution exposures. This analysis showed that 1247 genes were upregulated and 1383 genes were downregulated with DEPe treatment across strains. Pathway analysis identified oxidative stress responses among the most prominent upregulated pathways; indeed, many of the upregulated genes included antioxidants such as Hmox1, Txnrd1, Srxn1, and Gclm, with NRF2 (official gene symbol: Nfe2l2) being the most significant driver. DEPe induced a Mox-like transcriptomic profile, a macrophage subtype typically induced by oxidized phospholipids and likely dependent on NRF2 expression. Analysis of individual strains revealed consistency of overall responses to DEPe and yet differences in the degree of Mox-like polarization across the various strains, indicating DEPe × genetic interactions. These results suggest a role for macrophage polarization in the cardiopulmonary toxicity induced by air pollution.

INB-200: Fully enrolled phase 1 study of gene-modified autologous gamma-delta (γδ) T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).

2042 Background: γδ T cells can target NKG2D ligands that are upregulated on tumor cells after alkylating chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are genetically engineered γδ T cells expressing methylguanine-DNA methyltransferase (MGMT), which conveys TMZ resistance to enable concomitant therapy and continued surveillance against tumor cells. Updated results from the Phase 1 trial which fully enrolled adult newly diagnosed GBM patients with adequate organ function, KPS ≥ 70% follow. Methods: Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107 DRI cells/dose) into the resection cavity with 150 mg/m2 of IV TMZ on Day (D) 1 of each Stupp maintenance cycle. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 23 patients were enrolled, with 11 dosed and 2 awaiting dosing (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) are reported. Most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder. Conclusions: γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. The majority of dosed patients who received DRI exceeded the expected median PFS of 7 months (5.8-8.2 months) with Stupp alone and had manageable toxicity with a continued encouraging trend in PFS. Long-term follow-up for durability of PFS and OS continue. Clinical trial information: NCT04165941 . [Table: see text]

Esophageal Cancer Outcomes After Definitive Chemotherapy With Intensity Modulated Proton Therapy

PurposeThe effectiveness of intensity-modulated proton therapy (IMPT) for esophageal cancer treated with definitive concurrent chemoradiation therapy remains inadequately explored. We investigated long-term outcomes and toxicity experienced by patients who received IMPT as part of definitive esophageal cancer treatment. Patients and MethodsWe retrospectively identified and analyzed 34 patients with locally advanced esophageal cancer who received IMPT with concurrent chemotherapy as a definitive treatment regimen at The University of Texas MD Anderson Cancer Center from 2011 to 2021. The median IMPT dose was 50.4 GyRBE in 28 fractions; concurrent chemotherapy consisted of fluorouracil and/or taxane and/or platinum. Survival outcomes were determined by the Kaplan-Meier method, and toxicity was scored according to the Common Terminology Criteria for Adverse Events version 4.0. ResultsThe median age of all patients was 71.5 years. Most patients had stage III (cT3 cM0) adenocarcinoma of the lower esophagus. At a median follow-up time of 39 months, the 5-year overall survival rate was 41.1%; progression-free survival, 34.6%; local regional recurrence-free survival, 78.1%; and distant metastasis-free survival, 65.0%. Common acute chemoradiation therapy-related toxicities included hematologic toxicity, esophagitis (and late-onset), fatigue, weight loss, and nausea (and late-onset); grade 3 toxicity rates were 26.0% for hematologic, 18.0% for esophagitis and 9.0% for nausea. No patient had grade ≥3 wt loss or radiation pneumonitis, and no patients had pulmonary fibrosis or esophageal fistula. No grade ≥4 events were observed except for hematologic toxicity (lymphopenia) in 2 patients. ConclusionLong-term survival and toxicity were excellent after IMPT for locally advanced esophageal cancer treated definitively with concurrent chemoradiation therapy. When available, IMPT should be offered to such patients to minimize treatment-related cardiopulmonary toxicity without sacrificing outcomes.

Phenolic-rich fraction of green tea attenuates histamine-mediated cardiopulmonary toxicity by inhibiting Cox-2/NF-κB signaling pathway and regulating oxidant/antioxidant balance

BackgroundHistamine (HIS) has a substantial impact on the development of numerous allergic disorders including asthma. Antihistamines mostly target histamine receptor-1 alone, so it is not entirely effective in the treatment of allergic diseases. In the current investigation, we examine the growing evidence for novel therapeutic strategies that aim to treat histamine-mediated cardiopulmonary toxicity with the phenolic-rich fraction of green tea (PRFGT).ResultsOur findings demonstrated that weekly ingestion of HIS to rats induced oxidant/antioxidant imbalance in both lung and heart homogenates. The histopathological examination demonstrated extensive interstitial pneumonia with progressive alveolar and bronchial damage in HIS receiving groups. Heart sections showed severe myocardial necrosis and hemorrhage. All lesions were confirmed by the immunohistochemical staining that demonstrated strong caspase-3, cyclooxygenase-2 (Cox-2), and tumor necrosis factor-α (TNF-α) protein expressions along with upregulation of the pulmonary m-RNA expression of TNF-α, nuclear factor kappa-B (NF-κB), and interleukin-1β (IL-1β) genes and cardiac levels of many apoptotic genes. Otherwise, the pretreatment of rats with PRFGT had the ability to alleviate all the aforementioned toxicological parameters and return the microscopic picture of both lung and heart sections to normal histology.ConclusionsWe concluded that PRFGT’s powerful antioxidant, anti-inflammatory, and anti-apoptotic properties can reduce cardiopulmonary toxicity caused by HIS. We recommended daily intake of green tea as a beverage or adding it to foods containing elevated levels of HIS to prevent its possible toxicity.

Selenium and zinc supplementation mitigates metals-(loids) mixture- mediated cardiopulmonary toxicity via attenuation of antioxidant, anti-inflammatory and antiapoptotic mechanisms in female Sprague Dawley rats.

This study evaluated the cardiopulmonary protective effects of essential elements (Zn and Se) against heavy metals mixture (HMM) exposure. Twenty five female Sprague Dawley albino rats, divided in to five groups: controls were orally treated only with distilled water; next, group 2 was exposed to HMM with the following concentrations: 20mg/kg of Pb body weight, 0.40mg/kg of Hg, 0.56mg/kg of Mn, and 35mg/kg of Al. Groups 3, 4 and 5 were exposed to HMM and co-treated with zinc chloride (ZnCl2; 0.80mg/kg), sodium selenite (Na2SeO3;1.50mg/kg) and both zinc chloride and sodium selenite, respectively. The experiment lasted for 60days. Afterwards animals were sacrificed, and we conduced biochemical and histopathological examination of the heart and lungs. HMM only exposed animals had an increased levels of malondialdehyde (MDA) and nitric oxide (NO), increased IL-6 and TNF-α, attenuated SOD, GPx, CAT and GSH and caspase 3 in the heart and lungs. HMM affected NF-kB and Nrf2 in the heart muscle with histomorphological alterations. Zn and Se attenuated adverse effects of HMM exposure. Essential element supplementation ameliorated heavy metal cardiopulmonary intoxication in rats.

CTIM-42. INB-200: PHASE 1 STUDY OF GENE MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)

Abstract γδ T cells target NKG2D ligands that are upregulated on tumor cells after chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are γδ T cells genetically engineered to express MGMT, conveying TMZ resistance to allow concomitant therapy. We present updated results from this Phase 1 trial, which enrolled adult newly diagnosed glioblastoma patients with adequate organ function, KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107) of DRI cells intratumorally with 150 mg/m2 of TMZ on Day (D) 1 of Stupp maintenance. The primary endpoint is safety and secondary endpoints include survival; immunologic and genomic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. 21 patients were enrolled, with 11 dosing (57% male; median age 68 (range: 21-76); 86% IDH-WT, 52% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) reported. Most common adverse events were WBC/platelet count decreased, asthenia, headache, hydrocephalus, decreased appetite and balance disorder. C1 pts had PFS of 8.3, 11.9, 7.4 months (m) and OS of 15.6, 17.7 and 9.6m, respectively. In C2, 1 pt remains progression free at 26.4m, while one progressed at 22m and another died without relapse at 8.7m. C3 pt had a PFS of 7.1 and OS of 13.11m with other pts in dosing. γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. DRI T cells have manageable toxicity with encouraging trend in PFS with enriched γδ T cell remaining despite peripheral lymphodepletion.

Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial

IntroductionPrior attempts to escalate radiation dose for non–small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs). MethodsPatients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint. ConclusionPACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

Is there role of adjuvant radiotherapy after complete resection of locally advanced nonsmall cell lung cancer?

This review aims to provide a timely and relevant overview of the role of postoperative radiotherapy (PORT) in completely resected stage IIIA-N2 nonsmall cell lung cancer (NSCLC). Given the controversy surrounding the use of PORT and the emergence of advanced radiation techniques and therapies, this review provides valuable insight into current and potential treatment strategies. The Lung ART and PORT-C trials have provided valuable insights into the efficacy of PORT in stage IIIA-N2 NSCLC. While the results have been mixed, studies have shown that advanced radiation techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy, can reduce cardiopulmonary toxicities associated with PORT. Molecular targeted therapies and immunotherapies have also shown potential in improving NSCLC treatment outcomes. The role of radiotherapy becomes smaller and smaller in new era. However, it is too early to abolish radiotherapy for all the patients after complete resection of locally advanced NSCLC. Nowadays, it is recommended to adopt individualized treatment approaches guided by multidisciplinary team consultations. The integration of IMRT, proton therapy, and emerging therapies offers the potential to enhance treatment efficacy while minimizing toxicity. Further research is needed to optimize the use of PORT and explore the method to identify the patients who can really benefit from PORT.

Ameliorative effects of propolis and coenzyme Q10 against short-term paclitaxel associated cardiopulmonary toxicity: histopathological and immunohistochemical evaluation.

Ameliorative effects of propolis and coenzyme Q10 against short-term paclitaxel associated cardiopulmonary toxicity: histopathological and immunohistochemical evaluation.

Cardiopulmonary Toxicity from Intensity Modulated Proton Therapy for Thymic Malignancies

Use of radiation therapy for thymic malignancies is limited by excess dose to organs at risk (OARs) including heart, lung, and esophagus. Intensity Modulated Proton Therapy with Pencil Beam Scanning (IMPT/PBS) allows the conformality benefits of volumetric modulated arc therapy (VMAT) combined with dosimetry benefits of protons making it an exciting tool to treat thymic tumors. Very limited clinical data are reported with the use of IMPT/PBS to treat thymic malignancies. This study evaluates the incidence of acute and delayed toxicities among patients who underwent IMPT/PBS for thymic tumors. Our single center retrospective study identified 27 patients with diagnosis of either thymic carcinoma or thymoma who received IMPT/PBS between 2015 and 2022. Patient demographics, IMPT treatment details and clinical outcomes (toxicity, recurrence, and survival) were recorded. Frequency distributions are described for primary endpoints of acute (≤ 90 days) and late (>90 days) toxicity graded using CTCAE version 5.0. Specific toxicities assessed were dermatitis, esophagitis, pneumonitis, pulmonary fibrosis, and cardiac toxicity. Recurrence and survival data were analyzed as secondary endpoint using Kaplan-Meier method. Median follow-up was 22 months. Median age of the patients was 59 years (range, 30-87), predominantly female (55%), and white (66%), and stage ¾ (72%). Histologically showed mainly thymoma (59%) and Masaoka stage ¾ (70%). Surgery prior to IMPT was performed in 19 (70%) patients; of whom 5 patients had positive margins. Chemotherapy was used in 12 (44%) patients. Median IMPT dose was 50.4 GyE. Patients were primarily planned with 2 or 3 fields (81%), coplanar distribution (74%), using SFO technique (70%). Robust planning was performed accounting for 5 mm margin and 3.5-5% range uncertainty. All patients required use of range shifter ranging from 2-5 cm. Median of Heart-mean (10.3 GyE), Heart-max (54 GyE), Lung-mean (8.1 GyE), Lung V20 Gy (16.1%), Lung-V30 Gy (11.4%), Esophagus-mean (10.3 GyE) and Cord-Max (1.4 GyE). QACT was performed in 21 (77%) patients with replan needed in 5 of them. Only 1 (3.7%) patient had a grade 3+ acute toxicity (dermatitis) and only 2 (7.4%) patients had a grade 3+ late toxicity (both pulmonary). No patients had any acute or delayed cardiac-related adverse effects following PBT treatment. One (3.7%) patient had an infield recurrence of malignancy and 6 had out-of-field metastatic failure. Local control and overall survival were 74.1% and 85.2%, respectively. In this largest single-institution analysis of IMPT/PBS experience, we note extremely low incidence of grade 3+ acute or late toxicity with excellent local control and overall survival. No marginal failures were noted. In a patient population at high risk of cardiopulmonary radiation toxicities, IMPT/PBS should be strongly explored as a possible treatment option.

Cardiopulmonary Protection for Bilateral Breast Irradiation: A Dosimetric Comparison between Proton and Photon Plans

Recent advances in cancer treatment improve cancer survivorship. Cardiovascular disease has become the leading cause of non-cancer death in breast cancer survivors. Therefore, risk of cardiopulmonary toxicities during multimodality treatment should be assessed carefully. It remains to be defined the best scenario for proton therapy to confer meaningful cardiovascular protection in the setting of breast irradiation. We hypothesized proton therapy plan provides optimal cardiopulmonary protection during bilateral breast irradiation. The study aimed to compare cardiopulmonary dosimetric parameters of proton and photon radiotherapy plans. We conducted a retrospective study and patients with bilateral breast cancer indicated for radiotherapy between January 01, 2010 and December 31, 2020 were included. All patients received whole breast or chest wall irradiation with or without regional nodal irradiation. The dose scheme was 50-50.4 Gy in 25-28 fractions. Boost was allowed if patients receiving breast conserving surgery or known risk factors. The dosimetric parameters included planning target volume, mean dose to the heart, the volume of whole lung receiving 5 Gy, 10 Gy, and 20 Gy. For photon therapy, volumetric modulated arc therapy using double partial arc plans was generated with Pinnacle 9.8, Elekta Synergy and tomotherapy helical plan was generated with Tomo Hi-Art planning system. For proton therapy, treatment planning was generated with Ray station 9A. All data was managed using SAS v.9.4 software. Analysis of variance (α = 0.05) was used to compute the dosimetry of different treatment modalities. The statistical significance was considered with a p-value <0.05. Thirty-one patients with bilateral breast cancer were included, including 12 bilateral breast irradiation patients and 6 bilateral chest wall irradiation patients. The mean dose of heart was 53.0±43.3 cGy in proton therapy while 736.6±225.1 cGy and 869.67±241.0 cGy in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 5 Gy was 15.4±7.91% in proton therapy while 46.1±10.8% and 46.3±2.5% in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 20 Gy was 7.7±4.3% in proton therapy while 15.4±5.6% and 19±3.5% in Tomotherapy and volumetric modulated arc therapy respectively. The effects of cardiopulmonary protection were more significant for chest wall irradiation over breast irradiation. Proton radiotherapy provided significant dose reduction for bilateral breast irradiation. The benefit is more significant is patients receiving bilateral chest wall irradiation. Further clinical validations will be warranted to confirm the clinical relevance of the finding.

Definitive concurrent chemoradiotherapy with docetaxel plus cisplatin versus 5-fluorouracil plus cisplatin in patients with esophageal squamous cell carcinoma: long-term follow-up results of a phase II randomized controlled trial

BackgroundDefinitive radiotherapy plus concurrent chemotherapy has been a standard treatment for esophagus patients who are unfit to undergo surgery. However, there are a variety of concurrent chemotherapy regimens with varying efficacy. In this phase II prospective study, we compared the efficacy and toxicity of DP (docetaxel and cisplatin) and PF (cisplatin and 5-fluorouracil) regimens with concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC) and analyzed the 5-year overall survival (OS) and progression free survival (PFS). We also summarized the salvage treatments and late toxicities.MethodsWe enrolled 86 patients with clinical stage II-IVA from the Sun Yat-sen University Cancer Center. The patients were divided into two groups: PF group (41) and DP group (45). Statistics were analyzed using SPSS version 19.0.ResultsThe 5-year OS rates were 62.9% ± 7.6% in PF group, and 52.7% ± 7.5% in DP group (P = 0.131), respectively. The 5-year PFS rates were 43.9% ± 7.8% for PF group, and 40.0% ± 7.3% for DP group (P = 0.398), respectively. Sixteen patients in the DP group and thirteen in the PF group received salvage treatment. For those patients with local residual or local recurrent disease, the median survival time after salvage treatment was 13.5 months and the 1, 2, and 3-year survival rates were 79.0%, 50.3%, and 43.1%, respectively. For all patients, thirteen (15.1%) had Grade 2 late cardiac toxicities. One patient had Grade 2 pleural effusion and required diuretic. Most patients with pneumonia are mild, and only one patient in PF group had Grade 2 pneumonia. One patient in the DP group developed tracheoesophageal fistula.ConclusionsThe 5-year follow-up confirmed that definitive CCRT with the DP regimen did not improve the treatment response, OS, or PFS in patients with ESCC compared to the PF regimen. The PF regimen remains the standard regimen for definitive CCRT for patients with locally advanced ESCC. Long-term follow-up also suggested that appropriate and active salvage treatment has a survival benefit for some patients, and late cardiopulmonary toxicities should be noticed during follow-up.Trial registrationThe trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT 02969473, October 2010).

Metformin ameliorates cardiopulmonary toxicity induced by chlorpyrifos

Chlorpyrifos (CPF) is a widely used pesticide that can impair body organs. Nonetheless, metformin is known for its protective role against dysfunction at cellular and molecular levels led by inflammatory and oxidative stress. This study aimed to investigate the modulatory impacts of metformin on CPF-induced heart and lung damage. Following the treatment of Wistar rats with different combinations of metformin and CPF, plasma, as well as heart and lung tissues, were isolated to examine the level of oxidative stress biomarkers like reactive oxygen species (ROS) and malondialdehyde (MDA), inflammatory cytokines such as tumor necrosis alpha (TNF-α), high mobility group box 1 (HMGB1) gene, deoxyribonucleic acid (DNA) damage, lactate, ADP/ATP ratio, expression of relevant genes (TRADD, TERT, KL), and along with histological analysis. Based on the findings, metformin significantly modulates the impairments in heart and lung tissues induced by CPF.

INB-200 phase I study of gene modified autologous gamma-delta (γδ) T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).

2007 Background: MHC unrestricted γδ T cells target NKG2D ligands upregulated on tumor cells. IN8bio’s DeltEx chemotherapy resistant cell therapy (CRCT), is a novel γδ T cell genetically engineered to express MGMT to convey temozolomide (TMZ) resistance and allow combination therapy. NCT04165941, a Phase 1 trial assessing the safety of single and multiple infusions of autologous CRCT cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis were infused through a Rickham catheter placed during surgery. Cohorts (C) 1, 2 and 3 each receive 1, 3 and6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally with 150 mg/m2 of TMZ intravenously on D1 of maintenance with the standard Stupp maintenance regimen on D2-5. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 15 patients (53% male; median age 69 (range: 21-76); 80% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 8 dosed (N=3 in C1, 4 in C2, 1 in C3). No patients experienced DLTs, cytokine release syndrome (CRS), or neurotoxicity (ICANS). The most common adverse events (AEs) were Grade 1/2 events including fever, fatigue, nausea, headache, platelet count decreased, incision site pain attributable to TMZ, radiotherapy or disease. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, four patients have been dosed, with no DLTs in 3 evaluable patients; 2 remain progression free at 18.9 and 14.8 months, while a third died without relapse due to pulmonary embolus at 8.7 months. One C3 patient has completed 5 of 6 planned doses without DLT. Patient recruitment continues with anticipated completion in 2023. Conclusions: Data demonstrates that single, repeat doses of CRCT gamma delta T cells have manageable toxicity with continued encouraging trend in PFS and warrants further assessment. Clinical trial information: NCT04165941 .