Mediastinal Irradiation Research Articles

Abstract 4144555: Atrial Fibrillation Catheter Ablation among Patients with Mediastinal Radiation; Insight from The National Inpatient Database (2015-2020)

Introduction/Background: Radiation therapy (RT) is one of the most common treatment modalities for mediastinal cancers. RT has multiple adverse cardiovascular effects and it has been identified as an independent risk factor for atrial fibrillation (AF). The efficacy of catheter ablation in AF is well established, however there is limited data on procedural safety and outcomes in patients with mediastinal cancers and history of radiation Methods: The National Inpatient Sample (NIS) was analyzed from 2015-2020 to identify admissions for AF catheter ablation among patients with previous history of mediastinal radiation exposure using the 10-PCS (International Classification of Diseases, procedure coding system) codes. Baseline characteristics were compared between the two groups and multivariate logistic regression was used to analyze hospitalization outcomes. Results: We identified 257,240 admissions for AF catheter ablation of which 1720 patients (0.67%) had a history of mediastinal radiation exposure. In the adjusted analysis, the odds of in-hospital mortality (aOR 0.639, 95% CI 0.34-1.20, p 0.1637), major complications (aOR 0.876, 95% CI 0.73-1.05, p 0.1443), any gastrointestinal or hematological complication (aOR 0.853, 95% CI 0.63-1.15, p 0.3017), renal complications (aOR 1.017, 95% CI 0.88-1.18, p 0.0509) were similar in both cohorts. The odds of any cardiovascular complication (aOR 0.825, 95% CI 0.70-0.97, p 0.0208) was lower and odds of any pulmonary complication (aOR 1.433, 95% CI 1.27-1.62, p<.001) was higher in the mediastinal radiation cohort. Conclusion: AF catheter ablation in patients with history of mediastinal radiation is a safe treatment modality. It is not associated with higher in-hospital mortality or cardiac complications in a nationwide registry.

Abstract 4144542: In-Hospital Outcomes of Open Mitral Valve Repair or Replacement versus Percutaneous Mitral Valve Repair or Replacement in patients with Prior Mediastinal Radiation: Insight from The National Inpatient Database (2015-2020)

Background: Radiation associated heart disease has a wide spectrum of manifestations including pericardial disease, coronary artery disease, and valvular heart disease. Mitral valve regurgitation is the second most common valvular dysfunction in patients with prior mediastinal radiation. Research Question: What are the outcomes of percutaneous or transcatheter mitral valve replacement/repair (T-MVR) versus surgical mitral valve replacement/repair (S-MVR) in patients with prior mediastinal radiation. Methods: The National Inpatient Sample (NIS) was analyzed from 2015-2020 to identify patients with mediastinal tumors and prior exposure to radiation therapy undergoing mitral valve repair/replacement. We subclassified the data into hospitalizations for S-MVR and T-MVR. Baseline characteristics were compared between the two groups and multivariate logistic regression was used to analyze hospitalization outcomes. Results: A total of 1725 patients with prior mediastinal radiation were hospitalized for MVR; 1110 (64.3%) patients underwent S-MVR and 615 (35.6%) patients underwent T-MVR. On a multivariable analysis, the odds of MACCE [aOR: 2.21; 95 % CI: (1.87-4.01); p <0.001)], and in-hospital mortality [aOR: 5.6; 95% CI (2.06-7.35); p=0.008] were higher in patients undergoing S-MVR compared to those undergoing T-MVR. Additionally, patients undergoing S-MVR had higher odds of periprocedural complications including cardiogenic shock [aOR: 7.4; 95% CI: (3.75 -9.20); p <0.001], major bleeding [aOR: 2.9; 95% CI: (1.26-7.09); p=0.01], AKI [aOR: 3.4; 95% CI: (1.33-5.23); p <0.001], stroke [aOR: 5.01; 95% CI: (1.51-6.57); p=0.008], and MCS utilization [aOR: 3.05; 95% CI: (1.31-7.13); p=0.009] compared to the T-MVR cohort. Conclusion: Compared to T-MVR, S-MVR was associated with higher odds of MACCE, in-hospital mortality and periprocedural complications suggesting that T-MVR might be a safer option for MVR among patients with prior mediastinal radiation.

The Triglycerides - Glucose Index: An independent predictor of late subclinical cardiotoxicity in adult survivors of childhood, adolescent and young adult cancer

Abstract Introduction The Triglycerides - Glucose index (TyG index) has been identified as a reliable alternative for estimating insulin resistance (IR). Numerous recent studies have provided strong statistical evidence suggesting that this index is associated with the development and prognosis of cardiovascular pathologies. Objectives The aim of this study was to investigate the predictive role of the TyG index on the decrease in left ventricular longitudinal global strain (GLS) assessed on two-dimensional echocardiography in asymptomatic adult survivors of childhood, adolescent and young adult cancer. Methods The study included patients aged 18 years and older, asymptomatic cardiovascular survivors of childhood, adolescent and young adult cancer treated with anthracyclines with or without mediastinal radiotherapy. Anthropometric characteristics, cardiovascular risk factors and cancer treatment-related characteristics were collected. The TyG index was calculated using the formula: ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. GLS was assessed and expressed as an absolute value. A GLS equal to 17.3% was retained as the threshold value after calculation in a referent group matched to patients according to age and gender. Cardiac biomarkers GDF 15, ultra-sensitive troponin I and NT-proBNP levels were measured in addition to fasting blood glucose and lipid profiles. Multivariate analysis using linear regression was performed to identify associations between these different parameters. Results A total of 105 cancer survivors from childhood, adolescence and young adulthood were included. The sex ratio was 1.3. The mean age of the patients was 25 years, the mean time since completion of cancer treatment was 10.6 years, the mean cumulative doses of anthracyclines and mediastinal radiotherapy were successively 245.75 ± 75.14 mg/m2 and 34.6 ± 6.19 Gy. Mean GLS was 18.5 ± 2.83%, mean LVEF 60.6 ± 5.69%. None of the patients had any known diabetes or treatment to lower blood glucose or triglyceride levels. No patient had a history of cardiovascular disease. In the univariate study, the factors associated with lower GLS were patient age at recruitment (p = 0.03), mean time since completion of cancer treatment when this was greater than ten years (p = 0.005), dyslipidemia (p = 0.012), obesity (p = 0.037) and TyG (p = 0.037). In multivariate analysis, lower GLS was related to mean time since completion of cancer treatment (p = 0.015) and TyG index (p = 0.002). Conclusion Our results suggest that the TyG index, as a simple and inexpensive marker of insulin resistance, could help identify cancer survivors from childhood, adolescence and young adulthood who would be at risk of subclinical cardiac dysfunction. Prospective studies with larger numbers are needed to confirm these findings.

Long-term complete remission in a patient with high-risk primary mediastinal B-cell lymphoma and iatrogenic symptomatic bradycardia after only two courses of DA-EPOCH-R followed by chemo-free treatment.

Most patients with Primary Mediastinal B-Cell Lymphoma (PMBCL) are cured by rituximab and doxorubicin-based immunochemotherapy, with or without radiotherapy. In cases with relapsed and refractory (RR) disease the prognosis was historically poor. Recently, immune checkpoint-based strategies have been shown to be highly effective in patients with RR-PMBCL. We report the case of a 23-year-old woman who, due to recurring episodes of symptomatic chemotherapy-induced sinus bradycardia, was unable to receive the planned six courses of immunochemotherapy, mediastinal radiotherapy, and autologous transplantation, leading to the early initiation of a chemo-free strategy. The patient maintains a continuous complete remission at a four-year follow-up after only two cycles of immunochemotherapy followed by nivolumab plus brentuximab vedotin (BV) and pembrolizumab consolidation. Beyond describing an underreported complication of anticancer treatments, the favorable clinical outcome suggests that in PMBCL, a minimal load of chemotherapy, integrated by early PD-1 blockade, with or without BV, may be sufficient to achieve long-term disease control and cure at least in some patients.

Incidence and Risk Factors for Permanent Pacemaker Implantation After Tricuspid Valve Repair

BackgroundAlthough the likelihood of needing a permanent pacemaker (PPM) after tricuspid valve (TV) repair has been thought to be low compared with TV replacement, the incidence and determinants are controversial. This study aimed to evaluate the incidence and risk factors for PPM implantation after TV repair. MethodsA total of 1237 consecutive patients undergoing TV repair from 1997 to 2019 were reviewed using a prospectively maintained database, and 1058 patients were enrolled. ResultsIncidence of PPM implantation was 10.3% (n = 109). Median time to PPM implantation was 7 (range, 6-9) days. Indications for PPM implantation were heart block (n = 62, 56.9%), junctional or sinus bradycardia (n = 21, 19.3%), and ventricular arrhythmia (n = 17, 15.6%). Likelihood of PPM varied with concurrent procedures: left ventricular assist device (3.4%), mitral repair (11.2%), mitral valve replacement (13.7%), aortic and mitral valve replacement (19.2%), and isolated tricuspid repair (6.5%). Older age (odds ratio [OR], 1.020; 95% CI, 1.003-1.036), prior mediastinal radiation (OR, 4.106; 95% CI, 1.598-10.554), and concomitant mitral and aortic valve replacement (OR, 1.963; 95% CI, 1.046-3.683) were risk factors, and concomitant left ventricular assist device implantation (OR, 0.325; 95% CI, 0.139-0.759) was a protective factor for PPM implantation. PPM implantation did not affect the early outcomes, overall survival (P =.287), or cumulative incidence of recurrent moderate or greater tricuspid regurgitation (P =.890) or TV reoperation (P =.602). ConclusionsThe likelihood of PPM implantation after TV repair is relatively high, but PPM implantation does not affect the early and long-term clinical outcomes. Older age, prior mediastinal radiation, and concomitant mitral and aortic valve replacement are risk factors, and concomitant left ventricular assist device implantation is a protective factor for PPM implantation after TV repair.

A multi-centre retrospective study of long-term outcomes of spinal re-irradiation with SABR.

Stereotactic ablative body radiotherapy (SABR) is a highly conformal technique utilising a high dose per fraction commonly employed in the re-treatment of spinal metastases. This study sought to determine the safety and efficacy of re-irradiation with SABR to previously treated spinal metastases. This was a retrospective analysis of patients at three Australian centres who have undergone spinal SABR after previous spinal radiotherapy to the same or immediately adjacent vertebral level. Efficacy was determined in terms of rates of local control, while safety was characterised by rates of serious complications. Thirty-three spinal segments were evaluated from 32 patients. Median follow-up for all patients was 2.6 years, and median overall survival was 4.3 years. Eleven of 33 (33.3%) treated spinal segments had local progression, with a local control rate at 12 months of 71.4% (95% C.I. 55.2%-92.4%). Four patients (16.7%) went on to develop cauda equina or spinal cord compression. Thirteen out of 32 patients (40.6%) experienced acute toxicity, of which 12 were grade 2 or less. Five out of 30 spinal (16.7%) segments with follow-up imaging had a radiation-induced vertebral compression fracture. There was one case of radiation myelitis which occurred in a patient who had mediastinal radiotherapy with a treatment field which overlapped their prior spinal radiation. The patients in this study experienced long median survival, durable tumour control and high rates of freedom from long-term sequelae of treatment. These results support the use of SABR in patients who progress in the spine despite previous radiotherapy.

Treatment Outcomes in Primary Mediastinal Large B-Cell Lymphoma. Experience of the AF Tsyb Medical Radiological Research Center (Obninsk)

AIM. To assess chemotherapy outcomes in patients with primary mediastinal large B-cell lymphoma (PMBCL) treated at the AF Tsyb Medical Radiological Research Center from 2016 to 2023. MATERIALS & METHODS. The analysis focused on the data from 58 patients with the morphologically verified diagnosis of PMBCL. The patients were aged 17–62 years (median 34 years), there were 39 women and 19 men. The median follow-up was 51.2 months (range 0.4–200.9 months). Depending on drug chemotherapy regimens, patients were divided into 3 groups: R-NHL-BFM-90 (n = 9), R-CHOP (n = 17), and R-MACOP-B (n = 32). Most patients (90 %) received mediastinal radiotherapy of total 30–46 Gy. RESULTS. The 5-year overall survival in the therapy groups was 66.7 %, 88.2 %, and 100 %, respectively (p = 0.007), progression-free survival was 66.7 %, 70.6 %, and 96.9 % (p = 0.006), and event-free survival was 66.7 %, 54.7 %, and 90.6 % (p = 0.038). On the whole, the toxicity profile of chemotherapy was quite acceptable. Neither low blood values nor other adverse events essentially affected a complete implementation of chemoradiotherapy program. The intermediate outcomes were based on PET-CT data after 2–4 therapy cycles in 37 (64 %) patients. PET-CT showed that at the stage of drug chemotherapy, complete response (CR) was achieved in 27 (73 %) patients, and partial response (PR) was achieved in 4 (11 %) patients. With respect to the CR and PR criteria, there were 6 (16 %) non-responders. CONCLUSION. PMBCL is one of extranodal lymphomas with thymic B-cells being primary source of tumor growth. PMBCL is characterized by aggressive course and extreme heterogeneity of clinical manifestations. Up to now, the first-line chemotherapy decision making in PMBCL has remained an issue with practical importance. This paper reports immediate and long-term outcomes of the program chemoradiotherapy regimen R-MACOP-B with subsequent consolidation radiotherapy. The results obtained can be termed quite satisfactory and noninferior to the data from national and international sources. Nevertheless, more effective chemoradiotherapy programs for PMBCL continue to be elaborated. In this context, immune checkpoint inhibitors as part of therapy programs seem to hold promise for the treatment of newly diagnosed PMBCL.

Prevalence and clinical outcomes of acute heart failure among patients with mediastinal radiation exposure: A propensity score matched analysis.

e24029 Background: Radiation therapy (RT) for malignancy in mediastinal region is associated with radiation-induced heart disease in subsequent years, including coronary, valvular, myocardial, pericardial and conduction system disease. Although increased risk of diastolic heart failure (DHF) has been established, there is limited data on the prevalence, trends and outcomes of acute DHF admissions in patients with prior mediastinal RT. Methods: We extracted data from the National Inpatient Sample (NIS) Database from 2016 to 2020. We included all admissions ≥18 years old with a principal diagnosis of acute DHF with and without history of RT for mediastinal cancer using International Classification of Diseases Tenth Revision (ICD-10) codes. Propensity score matching was performed to balance hospital characteristics, patient demographics and comorbidities between the two groups. Univariate logistic regression was performed in the balanced cohorts. The primary outcome was inpatient mortality. Analysis was performed using STATA-MP, version 14.2. Results: A total of 2,356,025 admissions for acute DHF were identified between 2016 to 2020, of which 15,435 (0.65%) had prior mediastinal RT. During the study period, we found an increasing trend in the number of admissions for acute DHF (p trend < 0.01) along with an increased proportion of patients with prior mediastinal RT. (0.55% in 2016 to 0.78% in 2020, p trend < 0.01). After propensity score matching, there was no difference in in-hospital mortality (odds ratio [OR] 1.12, 95% CI 0.79-1.58, p = 0.537), or complications such as cardiogenic shock, respiratory failure, stroke, venous thromboembolism, or acute kidney injury between the two cohorts. There was no difference in length of stay, however, cohort with history of mediastinal RT had higher hospital charges ($26,634 vs $31,511, p < 0.01). Conclusions: Exposure to mediastinal RT represents a minority but growing number of hospital admission with DHF. The mortality and complications of RT associated DHF does not differ significantly from those with traditional etiologies of DHF.

Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF < 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.

Tamoxifen for breast cancer prevention among survivors of pediatric lymphoma previously treated with chest radiation: Clinical benefits, harms and tradeoffs.

10025 Background: Survivors of pediatric lymphoma previously treated with chest radiation are at high risk for subsequent breast cancer. Although early initiation of breast cancer screening is recommended, the clinical benefits and harms of adding tamoxifen to reduce breast cancer deaths among these women are unknown. Methods: We adapted a Cancer Intervention and Surveillance Modeling Network (CISNET) breast model using data from the Childhood Cancer Survivor Study (CCSS) to reflect the elevated risks for breast cancer and competing mortality for 5-year survivors previously treated with chest radiation (RT). Breast cancer risk was based on age, chest RT field, timing of RT relative to menarche, menopause status, anthracycline exposure, and family history. Premature menopause risk varied by cumulative ovarian RT and alkylator dose. Based on the US Preventive Services Task Force 2019 Evidence Summary, we assumed tamoxifen (20mg daily for 5 years) reduced estrogen receptor positive (ER+) breast cancer risk by 42% (RR = 0.58 [0.42-0.81]) for 20 years and increased risks for venous thromboembolism, deep vein thrombosis, coronary heart disease, stroke and endometrial cancer during treatment. Strategies included no screening or tamoxifen, annual screening with mammography and MRI starting at age 25, annual screening with mammography and MRI starting at age 25 with the addition of tamoxifen at ages 25, 30 or 35. Model outcomes included cumulative breast cancer risk, number of childbearing years before age 45 (defined as years menstruating without tamoxifen use or a breast cancer diagnosis or having survived breast cancer for at least 3 years), and number of tamoxifen-related side-effects. Results: Among a cohort of 20-year-old 5-year lymphoma survivors previously treated with mediastinal RT without primary ovarian failure, an estimated 20% were projected to develop breast cancer and 2.6% would die from the disease before age 50 in the absence of screening or tamoxifen use. Survivors would have on average 22 childbearing years before age 45. Early initiation of breast cancer screening at age 25 would reduce breast cancer deaths before age 50 by 56.3%. Depending on age at initiation, tamoxifen would further reduce breast cancer deaths by 8.0 to 9.6 percentage points for an overall 64.3% to 65.9% reduction and reduce the average number of childbearing years by 17% to 21%. For each breast cancer death averted, a reduction of 1950 to 3740 childbearing life years and 11 to 20 side-effects would occur and varied by the tamoxifen start age compared to mammography and MRI screening. Conclusions: Tamoxifen use for primary breast cancer prevention among pediatric lymphoma survivors may further reduce breast cancer deaths but decisions might depend on survivor preferences for side effects vs. avoiding breast cancer and consideration of timing for childbearing.

FEMALE GENDER: AN INDEPENDENT PREDICTOR OF HIGH NORMAL BLOOD PRESSURE IN LONG -TERM ADULT SURVIVORS OF CHILDHOOD, ADOLESCENT AND YOUNG ADULT CANCER

Objective: Determine the blood pressure profile in longterm adult survivors of childhood, adolescent and young adult cancer. Determine predictive factors for abnormal blood pressure figures in these patients. Design and method: 104 patients aged over 18, who had received chemotherapy with or without mediastinal radiotherapy for the treatment of neoplasia diagnosed and treated before the age of 21. High blood pressure was defined by a SBP > = 140 mmHg and/or DBP > = 90 mmHg or by the use of antihypertensive drugs. High normal blood pressure corresponded to a SBP between 130 mmHg and 139 mmHg and/or a DBP between 85 and 89 mmHg. Results: Male predominance (56.7%) with a sex ratio of 1.3. Mean current age 25.12 +/-5.40 years, age at diagnosis 13.4 ±5.13 years, duration since end of treatment of cancer 10.67 +/-5.80 years, BMI 22.77 ±4.66 kg/m2, male waist circumference (WC) 82.7 ±12.6 cm, female (WC) 78.6 ± 10.4 cm, SBP 114.5 ±11.7 mmHg, DBP 74.2 ±7.4 mmHg. Chemotherapy alone 80.8%, chemotherapy + mediastinal radiotherapy 19.2%, anthracyclines 100%, platinum salts 32%, corticoids 9%. Low HDL-cholesterol 44.7%, high normal blood pressure 24.3%, abdominal obesity 15.8%, hypertriglyceridemia 9.7%, obesity 8.7%, prediabetes 6.9%, fasting plasma glucose > = 110 mg/dl 6.9%, metabolic syndrome (MS) 3.8%. Multivariate study: Gender (OR = 3.32 95% CI 1.11 - 9.92 p=0.03) - MS (OR = 0.07 95% CI 0.06 - 0.81 p=0.03). Conclusions: Nearly a quarter of the patients in our study (24%) had a high normal blood pressure, which was associated with female gender and the presence of metabolic syndrome. These results confirm the need for early screening of cardiovascular risk factors, particularly hypertension, in long-term adult survivors of childhood, adolescent and young adult cancer.

3138: Mediastinal irradiation for thymic epithelial tumors: A deep focus on coronary arteries’ exposure

3138: Mediastinal irradiation for thymic epithelial tumors: A deep focus on coronary arteries’ exposure

Long-term cardiac effects of modern treatment for Hodgkin’s lymphoma

BackgroundHodgkin’s lymphoma (HL) is a hematological malignancy that affects both children and young adults. Traditional treatment is associated with a life-time prevalence of cardiac disease exceeding 50%. In the late 1990s protocols were modified to reduce cancer therapy-related adverse cardiac effects. This study aimed to assess the long-term impact of advances in treatment protocols on the cardiac health of HL survivors (HLS).MethodsHLS (n = 246) treated between 1997 and 2007 with anthracycline-based chemotherapy in three centers in Norway were included. Of these, 132 (53%) had also received mediastinal radiotherapy. HLS were compared to controls (n = 58) recruited from the general population and matched for sex, age, smoking status, and heredity for coronary artery disease. All subjects underwent echocardiography, clinical assessment, and blood sampling.ResultsThe HLS were 46 ± 9 years old and had been treated 17 ± 3 years before inclusion in the study. There was no significant difference between HLS and controls in ejection fraction (EF) (58%±5 vs. 59%±4, p = 0.08) or prevalence of heart failure. HLS treated with both anthracyclines and mediastinal radiotherapy (AC + MRT) had slightly worse left ventricular global longitudinal strain than controls (-19.3 ± 2.5% vs. -20.8 ± 2.0%, p < 0.001), but those treated with only anthracyclines did not. HLS treated with AC + MRT had a higher prevalence of valve disease than those treated only with anthracyclines (12% vs. 4%, p < 0.05).ConclusionsHLS treated with anthracyclines after the late 1990s have similar cardiac function and morphology as age-matched controls, apart from higher rates of valvular disease in those who also underwent mediastinal radiotherapy.

Tracheal Tumours

Malignant primary tracheal tumours are rare. The most common histological subtypes are squamous cell carcinoma and adenoid cystic carcinoma. These two entities have different prognoses and growth patterns. Tracheobronchoscopy and thoracic sectional imaging are standard diagnostic tools for tumour staging and local evaluation. Complete surgical resection of the affected tracheal segment is the treatment of choice for limited disease without distant metastases. Incomplete gross tumour resection with additional irradiation is an acceptable therapeutic option for adenoid cystic carcinoma. Interventional endoscopy with tumour debulking or tracheal stenting and/or definitive mediastinal radiotherapy are treatment alternatives in either a locally advanced or palliative setting.

Effects of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in patients with osteosarcoma and their influencing factors.

The objective of this study was to investigate the impact of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in osteosarcoma patients and analyze the factors influencing this effect. A retrospective study was conducted on 165 osteosarcoma patients admitted to our hospital from January 2020 to December 2022. Based on the chemotherapy regimen, the patients were divided into two groups: the control group (n = 62) treated with Cisplatin and cyclophosphamide, and the observation group (n = 103) treated with Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline). The general records of both groups were analyzed, and left ventricular ejection fraction (LVEF) was evaluated through echocardiography before and after chemotherapy. Blood cTnT and CK-MB levels were measured using immunoluminescence. The incidence of adverse reactions during chemotherapy was also analyzed. Univariate analysis was performed to identify patients with cardiotoxic events, and multiple logistic regression analysis was done to study the effects of Doxorubicin, Epirubicin, Liposomal Doxorubicin, and their dosages on cardiotoxicity in patients. The general records between the two groups showed no significant differences (P > 0.05). However, at the fourth cycle of chemotherapy, the observation group exhibited a lower LVEF (P < 0.05), and a higher percentage of LVEF decrease compared to the control group (P < 0.05). Moreover, the observation group had higher levels of blood cTnT and CK-MB (P < 0.05). The incidence of cardiotoxicity in the observation group was also higher (P < 0.05), but no significant differences were seen in other adverse reaction rates (P > 0.05). The occurrence of cardiotoxicity was found to be related to the choice and dosage of chemotherapy drugs (P < 0.05), but not significantly correlated with age, sex, and mediastinal irradiation in patients (P > 0.05). Furthermore, the use of Doxorubicin, Epirubicin, and Liposomal Doxorubicin in chemotherapy, as well as an increase in their dosages, was found to elevate the risk of cardiotoxicity in osteosarcoma patients (P < 0.05). However, age, sex, and mediastinal radiation were not significantly associated with cardiotoxicity in osteosarcoma patients (P > 0.05). We demonstrated that Doxorubicin, Epirubicin, Liposomal Doxorubicin (Anthracycline), and other drugs adversely affected cardiac function in osteosarcoma patients, increasing the risk of cardiac toxicity. Therefore, close monitoring of cardiac function during chemotherapy is crucial, and timely adjustments to the chemotherapy regimen are necessary. In addition, rational control of drug selection and dosage is essential to minimize the occurrence of cardiac toxicity.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children

Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

The Correlation Between Low-Dose Radiotherapy Area of the Mediastinum and CD8+T Cells and the Efficacy of Radiotherapy for Non-Small Cell Lung Cancer.

Radiation therapy (RT) can cause changes in peripheral blood immune cells. The relationship between the efficacy of radiation therapy for non-small cell lung cancer (NSCLC) and immune cell changes and the study of how mediastinal radiation dose parameters affect immune cell changes is still unclear. This study aims to analyze the relationship between immune cell changes induced by radiotherapy and the efficacy of NSCLC radiotherapy, as well as the relationship between radiotherapy dose parameters and immune cell changes. We retrospectively analyzed the data of NSCLC patients receiving mediastinal radiation therapy from 2020 to 2022. Collect lymphocytes and circulating immune cells within one week before and after radiotherapy and collect the dose-volume parameters of the whole mediastinum in the patient's RT planning system. Analyze the changes in lymphocytes and radiotherapy effects after radiotherapy, and explore the relationship between radiotherapy dose parameters and immune cell changes. A total of 72 patients were enrolled. Compared with before radiotherapy, the proportion of CD3+T cells, CD8+T cells, and CD8/Treg in peripheral blood significantly increased after radiotherapy (P<0.05). The increase in CD8+T cells and CD8/Treg after radiotherapy was correlated with Objective response rate (ORR) (P<0.05). Based on binary logistic univariate and multivariate regression analysis, an increase in CD8+T cells after radiotherapy is an independent predictor of objective tumor response after radiotherapy (OR=12.71, 95% CI=3.64-44.64, P=0.01), and Volume of 200 cGy irradiation (V2) is an independent positive predictor of an increase in CD8+T lymphocyte ratio after radiotherapy (high group, OR=3.40, 95% CI=1.13-10.36, P=0.03). The increase in CD8+T cells after radiotherapy can positively predict the short-term efficacy of radiotherapy. Mediastinal low-dose radiation therapy can increase CD8+T cells, thereby improving the short-term efficacy of radiotherapy. These potentially related mechanisms are worth further verification and exploration.

Nelarabine (NEL), Pegylated Asparginase (PEG) and Venetoclax (VEN) Incorporated to HCVAD Chemotherapy in the Frontline Treatment of Adult Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (T-ALL/T-LBL)

Background: The incorporation of novel agents such as NEL and PEG to frontline therapy has been associated with improved outcomes in pediatric patients (pts) with T-ALL/LBL, but has not been extensively studied in the adult pts. BCL-2 upregulation has been demonstrated in T-lymphoblasts, especially of the early T-cell precursor (ETP) ALL and addition of VEN (BCL-2 inhibitor) may be beneficial. Methods: Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, total bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles (C) of HCVAD (C 1,3, 5, 7) alternating with high dose Ara-C and methotrexate (MTX) (C 2, 4, 6, 8) at approximately 3-week intervals. Two cycles of NEL (650 mg/m 2 daily x 5) were initially administered after C8 (cohort 1). Later, after a protocol amendment, they were administered after C4 and C5 (cohort 2). Subsequently, the protocol was amended to add PEG (1500 IU/m 2 capped at 3750 IU; for pts age 60 or older, dose was 1000 IU/m 2, capped at 2000 IU) on day 5 of the NEL cycles (cohort 3) and more recently, VEN 400 mg daily was added on the first 7 days of each of 8 cycles of therapy (cohort 4); this was later modified to be given for 7 days during the induction cycle to all pts and reduced to 3 days per post-induction cycle only in pts with ETP-ALL or those with persistent measurable residual disease (MRD) and all other pts did not receive VEN after C1 (cohort 5). Pts with ETP-ALL were referred for allogeneic stem cell transplant (allo-SCT) in first complete remission (CR). After the completion of the intensive phase; pts in all cohorts received 30 cycles of maintenance therapy with monthly POMP (prednisone, vincristine, MTX, prednisone) and early intensification with NEL/PEG on C6 and 7 and late intensification with MTX/PEG in C18 and HCVAD on C19. All pts received 8 intrathecal chemotherapy with MTX alternating with Ara-C and mediastinal radiation was considered in pts with bulky mediastinal disease. Results: Between 7/2007 and 12/2022, 133 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=21) (Table 1). Eighty pts (60%) had T-ALL, 52 T-LBL (39%) and 1 pt had ETP/myeloid bi-phenotypic leukemia. The median age for the entire cohort was 35 years (yrs) (range 18-78), 102 pts were male (77%), 83 pts (62%) were white and 18 pts (14%) had PS ≥2. Overall, 24 pts (18%) had an ETP phenotype and another 19 pts (14%) had a near-ETP phenotype. Six pts (5%) had central nervous system disease at diagnosis, 72 pts (54%) had mediastinal disease, 49 of 80 (61%) T-ALL pts had extramedullary disease and 20 pts (15%) were in complete remission (CR) at trial enrollment after minimal pre-enrollment therapy. Overall response (CR+CRp+CRi+PR) on trial was attained in 109/113 (95%) pts [CR= 101 (89%), CRi/CRp= 3 (3%), PR=5 (4%)]. CR/CRi/CRp was attained in 36/41 (88%) pts with ETP/near-ETP ALL and 60/64 (94%) of confirmed near-ETP ALL pts ( p=0.31). At a median follow-up of 62 months (mos), the median overall survival (OS) was not reached (NR), 3-yr OS was 71% and 5-yr OS was 64% . The 3-yr OS for pts treated with HCVAD+NEL (cohort 1+2), HCVAD+NEL+PEG (Cohort 3) and HCVAD+NEL+PEG+VEN (Cohort 4+5) were 66%, 88% and 76% respectively (Figure 1). Median OS was not reached for both VEN cohorts, while 3-yr OS was 72% in cohort 4 compared to 88% in cohort 5 ( p=0.51), with significantly shorter follow-up for the latter (33 mos vs. 15 mos). Amongst the 124 pts who had CR/CRp/CRi, the median RFS was NR and 5-yr RFS was 68%. 24 (18%) pts underwent SCT in first remission, including 20 (83%) with ETP or near-ETP ALL. The median OS was shorter in the 44 ETP/near-ETP pts compared to the 77 pts with non-ETP phenotype (71 mos vs. NR, p=0.08). 30 and 60-day mortality was 0% and 1%. 10 pts (7.5%) died in remission (3, 5 and 2 pts in cohorts 1, 2 and 4 respectively) including 1 after SCT, 4 after developing therapy-related acute myeloid leukemia and 5 from infectious complications. Conclusion: The ongoing phase 2 trial of NEL, ASP, VEN added to the HCVAD regimen shows promising long-term survival in adult pts with T-ALL/LBL with 3-yr OS of 76%-88% in pts treated with HCVAD+NEL+PEG +/- VEN. Larger prospective trials and longer follow-up are needed to demonstrate further benefit.

Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-line therapy for PMBL. This study investigates the efficacy and safety of this novel, time-limited, radiotherapy sparing regimen. Methods ALLG-PACIFIC (ANZCTR- ACTRN12621001529831) is a phase II, single arm, open-label study of R-CHOP in combination with Pembrolizumab. The trial is open to recruitment across Australia. Approximately 35 patients with newly diagnosed PMBL, will be enrolled to receive two cycles of Rituximab (375mg/m 2) plus Pembrolizumab (200mg) once every 21 days ('window phase') followed by six cycles of R-CHOP plus Pembrolizumab once every 21 days ('induction phase') followed by five cycles of Pembrolizumab 400mg once every 42 days ('consolidation phase') (Figure 1). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function are eligible. Key exclusion criteria are the presence of active autoimmune disease, requiring recent immunosuppressive therapy, life-threatening or organ-compromising lymphoma symptoms requiring urgent cytoreductive therapy, and other medically significant conditions that preclude eligibility to receive R-CHOP. Patients who require urgent cytoreductive therapy following initiation of window phase treatment may proceed immediately to induction phase chemotherapy. The primary endpoint is 18-month event free survival. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

A Two-Part Study Evaluating the Combination of Tazemetostat and CPX-351 (Part 1) and Palbociclib with CPX-351 (Part 2) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

BACKGROUND AND SIGNIFICANCE Acute myeloid leukemia (AML) is an aggressive cancer of early hematopoietic progenitor cells with only 25-30% of patients (pts) surviving 5 years from diagnosis. For fit pts, conventional chemotherapy with DNA-damaging agents remains the mainstay of treatment. Conventional chemotherapeutic agents cause DNA-damage by targeting cells during DNA replication. Chromatin structure is highly influential in the efficacy of DNA-damaging agents, as areas of compacted chromatin are more resistant to DNA-damaging effects. Areas of DNA marked with histone 3 lysine 27 trimethylation (H3K27me3) are transcriptionally repressed and exhibit reduced accessibility to DNA-damaging agents. Enhancer of Zeste Homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repressive complex 2 which methylates H2K27 to produce a di- or trimethylated state (H3K27me2/3). In preclinical studies, treatment of AML cell lines with the combination of an EZH2 inhibitor (EZH2i) and doxorubicin resulted in an increase in DNA damage and apoptosis compared to those treated with doxorubicin alone. Further, a significant decrease in leukemia burden was seen in mice injected with THP-1 (AML) cells and treated with an EZH2i and doxorubicin and cytarabine compared to doxorubicin and cytarabine alone. This effect was further enhanced by pre-treatment of AML cells with palbociclib (PALB), a CDK4/6 inhibitor, by significantly increasing the number of cells in S phase when exposed to the EZH2i and doxorubicin combination, resulting in an increase in DNA damage and apoptosis compared to cells that were not pre-treated with PALB. These findings were reproduced in in vivo studies with mice injected with the primary AML cells (Porazzi P, et al. Cancer Res., 2021). STUDY DESIGN AND METHODS We will perform a 2-part phase I dose escalation study utilizing EZH2i tazemetostat (TAZ) in combination with CPX-351 induction chemotherapy and of PALB pre-treatment followed by CPX-351 in pts with relapsed or refractory (R/R) AML (NCT05627232). All pts will receive CPX-351 at standard dose on days 1, 3 and 5. Part 1 evaluate the addition of TAZ to CPX-351 via traditional 3+3 design. Pts will be treated with TAZ on days -1 to 6 at a starting dose of 600 mg twice daily to open chromatin concurrent with CPX-351 administration. Part 2 evaluate the pre-treatment with PALB via traditional 3+3 design. Pts will be treated with PALB starting dose of 100 mg daily on days -3 to -1 to induce cell cycle G1. PALB will be held on day 1 to allow cells to then enter S phase prior to administration of CPX-351. ( Figure 1). The study will enroll pts with R/R AML treated at Sidney Kimmel Cancer Center. Pts must be ≥18 years of age with R/R AML (non-acute promyelocytic leukemia) and have received at least 1 prior line of therapy and have adequate performance status and organ function. Pts whose participation would result in a total cumulative dose of daunorubicin greater than 550 mg/m 2 (450 mg/m 2 if they previously received mediastinal radiation) and those with active central nervous system involvement of AML, unstable cardiac disease or other severe concurrent disease will be excluded. The primary endpoints of Parts 1 and 2 will be to determine the maximum tolerated dose of TAZ and of PALB in combination with CPX-351, respectively. Secondary endpoints for Parts 1 and 2 include preliminary assessment of efficacy. Correlative studies to evaluate the on-target effect of TAZ on H3K27me3 and DNA-damage and of PALB on cell cycling will be performed at protocol-specified time points. If these two 2-drug combinations prove to be safe, we will amend the protocol to add Part 3 which will evaluate the safety of the 3-drug combination of pre-treatment with PALB followed by co-treatment with TAZ and CPX-351.