Administration Of Radiotherapy Research Articles

Management of Unresectable Cholangiocarcinoma Using Modern Radiation Therapy Techniques

AbstractCholangiocarcinoma (CCA) is a malignancy of epithelial cells in the bile duct, categorized based on its anatomical location as intrahepatic, perihilar, or extrahepatic. It has a low prevalence of ∼1.6 cases per 100,000 people in the United States, but has a poor prognosis. All stages included, CCA has a 5-year survival rate of less than 10%. The preferred curative treatment for intrahepatic, perihilar, and extrahepatic CCA is surgical resection combined with systemic chemotherapy. However, resection is not always a viable option for many patients, as the disease is often discovered at the time of diagnosis to be either metastatic or locally advanced precluding surgical resection. In this setting, a variety of options can be used, one of which is radiation therapy (RT). The administration of RT has evolved tremendously over the past decades. Total doses given can be limited by a tumor's proximity to regional normal organs such as the liver, stomach, bile duct, and small and large bowel. When a CCA is unresectable, it is often in close proximity to radiosensitive organs. Delivering RT in this setting therefore requires precise delivery techniques. An emerging technique known broadly as stereotactic body radiation therapy (SBRT) or stereotactic ablative body radiation therapy gives a highly focused, often ablative, form of RT to a defined and specific target. Categorically, SBRT offers a quick and efficient management option, in some cases only one to three total treatments. This narrative reviews various applications of SBRT for cholangiocarcinoma including SBRT alone, SBRT with chemotherapy, SBRT with chemotherapy followed by a liver transplantation (orthotopic liver transplantation), and finally novel combinations of SBRT with immunotherapy.

Assessment of Use of Subcutaneous Mastectomy with Silicon Prostheses as Treatment of Early Breast Cancer

Abstract Background Breast cancer is the most common cancer among women and the second most common cause of cancer death in the United States. Approximately 268,600 new breast cancer diagnoses and 41,760 cancer- related deaths in the U.S. were estimated for 2019. SSM (skin sparing mastectomy) is defined as a simple or radical surgery with modified minimal incisions that retain the widest possible coverage and sub-cutaneous breast groove but dry the NAC, flaws of previous biopsies and/or scarring caused by diagnostic percutaneous biopsies. Access to the armpit for a possible sentinel-node biopsy or axillary dissection is obtained through the same incision. An additional incision may be necessary to perform the reconstructive procedure (e.g., microsurgical axillary anastomosis). Objective To study the risks and benefits of use subcutaneous mastectomy with silicon prosthesis as treatment of early breast cancer: as regards the impact of radiotherapy administration on implant, psychological impact, operative time and post-operative complications including complication of silicon, effect on wound healing. Patients and Methods This prospective interventional study was conducted at tertiary care hospital at the general surgery department in Ain Shams University hospitals and Misr University for Science and Technology (MUST) hospital and from November 2021, till July 2022 and performed on total 15 females suffering from stage I-II infiltrating breast carcinomas. Results The current study revealed that mean ±SD of age of the studied cases was 46.3±7.4. Regarding tumor site, LOQ was the most frequent (40.0%), followed by UIQ (33.3%), then UOQ (20.0%) and lastly LIQ (6.7%). Concerning T grades, T1 was in (46.7%), while the remaining (53.3%) were T2. Concerning N grades, N0 was in (73.3%), while the remaining (26.7%) were N1. Sentinel lymph nodes done in 73.3% of cases. As regards operative characteristics, Axillary clearance done in less than half of cases (46.7%), while nipple sparing achieved in less than quarter of cases (20.0%). As regards post-mastectomy treatment, majority of cases (86.7%) received hormonal therapy, adjuvant radiotherapy to axilla was (46.7%), chemotherapy (33.3%), while immunotherapy was (6.7%). As regards postoperative side effects, Pain was the most frequent postoperative side effect; detected in (33.3%) of cases, followed by seroma (20.0%), then flap necrosis (13.3%), and the least frequent was hematoma (6.7%). As regards postoperative patients’ satisfaction, mean ±SD of Postoperative patients’ satisfaction was 7.3±1.5 with range 5.0 − 10.0. Near half of the studied cases (46.7%) had 7.0 − 8.0 satisfaction grade. Conclusion Skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) with immediate subcutaneous silicon implantation are an acceptable and safe method for breast reconstruction. It offers a number of advantages including ease of dissection for surgeons, improved symmetry, and low complication rates. With improvements in surgical techniques in preserving mastectomy skin flap viability, the traditionally higher rates of complications in subcutaneous implants may be outdated. The present study can burden the knowledge and shed some light on future prospective studies with larger sample sizes to evaluate a cost benefit analysis and patient and surgeon assessment of outcomes to directly compare with traditional submuscular single- or 2- stage implant-based reconstruction.

Clinical characteristics and prognosis of lung metastases from unknown primary cancer sites

Abstract Objectives Limited knowledge exists regarding lung metastases from cancer of unknown primary (CUPL), particularly concerning young patients. This study aims to investigate the clinicopathologic features and prognostic factors of CUPL patients, with a specific focus on comparing the survival outcomes across different age groups. Methods We conducted a retrospective analysis of patients diagnosed with CUPL between 2010 and 2020, utilizing the SEER database. Clinical characteristics among different age groups were compared. Prognostic factors influencing overall survival (OS) in CUPL patients were assessed through Cox regression analysis, while competing risks analysis was employed to evaluate cancer-specific survival (CSS) prognostic factors. A comparison of survival differences between age groups was conducted utilizing the Kaplan–Meier and Cumulative Incidences Function. Results A total of 2,474 patients with CUPL were included in this study, predominantly in the middle-aged and elderly demographic. The median survival time was a mere 1 month, with a one-year OS rate of 11 % and a one-year CSS rate of 13.8 %. Age, tumor histological typing and grading, liver metastasis, bone metastasis, radiotherapy, and chemotherapy were identified as independent prognostic factors affecting both OS and CSS. Despite the small representation of young patients (<40 years old) at 3 %, their OS and CSS rates significantly surpassed those of middle-aged (40–70 years old) and elderly patients (>70 years old). This advantage persists among patients undergoing radiation and chemotherapy. Conclusions While exceedingly uncommon among young patients, the prognosis for survival is more favorable than in middle-aged and elderly patients. Administration of radiotherapy and chemotherapy emerges as a potential avenue to enhance the survival prognosis for CUPL patients.

Inhibition of DNMTs increases neoantigen-reactive T-cell toxicity against microsatellite-stable colorectal cancer in combination with radiotherapy

The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically “cold” microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an ∼50 % complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.

Fractionated external-beam radiation therapy in elderly patients.

e13764 Background: To review the outcome of elderly patients treated with fractionated external-beam radiation therapy (RT) at a privately-owned, multi-disciplinary cancer center. Methods: From January 7, 2019, to August 22, 2023, 63 elderly patients were treated with fractionated RT at California Cancer Associates for Research and Excellence (“cCARE”), a privately-owned, multi-disciplinary cancer center in Fresno, California. The median age at the time of RT was 90 y/o (range, 85-98 y/o). Twenty-three patients were female and 40 were male. Forty-six patients identified as white and 17 as non-white. Treatment sites/histologies included primary lung 10, non-melanomatous skin 6, bone metastases 6, breast 5, esophagus 5, H&N 5, prostate 4, primary CNS 3, brain metastases 3, rectum 3, bladder 2, Merkel tumor 2, sarcoma 2, anus 1, liver 1, melanoma 1, multiple myeloma 1, NHL 1, pancreas 1 and stomach 1. Results: Thirty-two of the patients (51%) were treated with curative intent. The remaining 31 patients were treated for palliation. All patients were treated with fractionated RT. However, 4 patients also received a separate course of single-fraction RT. Twenty-seven patients received more than one course of RT. The median RT course was 10 fractions (range, 1-35 fractions). Most patients had previously been treated with systemic therapy. Nearly one third (31%) received systemic therapy concurrent with their RT. The majority of the patients (73%) completed their prescribed course(s) of RT. Many patients (61%) required one or more treatment breaks. The median duration of a treatment break was 1 day (range, 1-29 days). There were no grade 3 or higher RT toxicities recorded. The median follow-up since RT was 5 months (range, 1-59 months). Twenty-four patients have expired. The mediation duration from RT to death was 5 months (range, 1-32 months ). Of the remaining 39 patients, 92% were scored as clinically stable at the time of their last f/u visit. Conclusions: In our experience at cCARE, fractionated RT was administered to elderly patients and the majority completed their prescribed treatment courses. None of the patients in our review experienced clinically significant side effects (Grade 3 or higher) during their RT even in the cohort (31%) who were treated with concurrent systemic therapy. Clearly, careful patient selection and state-of-the-art RT administration is paramount. It is also highly advantageous for patients to be treated in a multi-disciplinary setting such as cCARE where seamless coordination of cancer care among radiation oncologists, medical oncologists and surgeons excels. A companion study is in process comparing the outcome of similarly matched elderly patients from our center who were treated with systemic therapy alone. We anxiously await the outcome of this vital comparison review.

Linking an early access program (EAP) to the National Health Data System (NHDS) in France and assessing its performances and potential biases.

11137 Background: Early access programs (EAP) are a unique opportunity to document first use of innovative treatments in real-world settings. The French HTA body requires mandatory patients’ clinical data collection for EAP and since July 2021, has recommended anticipating linkage EAP to the National Health Data System (NHDS). Prior to drug initiation, the collected data is almost complete contrary to follow-up data. To the best of our knowledge, no other study has proposed a methodology to link EAP to the French Cancer cohort (FCC), an extract of the NHDS of over 8 million persons diagnosed or at high risk of cancer, and to assess its assets and downsides. Methods: This cohort study has reused data of informed French EAP patients treated with durvalumab from October 1st, 2017 to December 31st, 2018 (n=457) in locally advanced unresectable NSCLC and of patients who received durvalumab at the time of the EAP in the FCC (n=666). The linkage methodology consists in harmonizing available data across sources, defining matching, control and study variables, testing several indirect deterministic linkage algorithms and assessing their performances. Consistency and differences between data sources were described for the best performing algorithm. Results: Proposed linkage algorithms required matches on a combination of data among sex, birth year and month, treating hospital ID and department. Performance started at 80.9% (370/457) patients from the EAP cohort linked to eligible patients from FCC up to 85.3% (390/457) for the best performing algorithm. The consistency of linkage variables between the two sources was substantial (Cohen’s kappa > 0.8) or excellent (intraclass correlation > 0.9). It was the same for control variables. Comparisons between linked patients and unlinked patients from the EAP cohort showed no statistically significant difference on matching and control variables, except for few cases on history of chemotherapy and history of radiation therapy prior to durvalumab. Similarly, no statistically significant difference was found on matching and control variables between linked patients and unlinked patients from FCC, except for history of radiation therapy and treating hospital department. Median of time difference between foreseen date of first durvalumab administration in EAP versus the effective date in FCC was -1 (IQR = [-9 ; 0]) day. Lack of reported diagnosis related to prior radiation therapy administration in out-of-hospital settings refrained from using them as matching or control variables. Conclusions: The study illustrates the feasibility of matching EAP patients to the French NDHS with indirect deterministic linkage. Additional EAP linkages will be required to ensure the validation and reproducibility of such methodology. Further works in progress will document the adequacy of French NHDS data to address effectiveness.

Neoantigen-augmented iPSC cancer vaccine combined with radiotherapy promotes antitumor immunity in poorly immunogenic cancers

Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.

Administration of intratumoral GD2-directed interleukin-2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma.

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8 Gy fraction (arm A) or three 8 Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral-immunocytokine at 12 mg/m 2 on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral-immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use. The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS). 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone. Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Abstract PO3-22-06: Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in patients with metastatic HER2-positive breast cancer

Abstract Background Trastuzumab deruxtecan (T-DXd) currently represents the standard of care for the treatment of patients with metastatic HER2-positive (HER2+) breast cancer (BC) after disease progression in the first line, which includes taxanes and trastuzumab. This recommendation is based on the results of the DESTINY-Breast03 trial, which demonstrated improved efficacy compared to trastuzumab emtansine (T-DM1). Radiation therapy (RT) is frequently required in the metastatic setting, either for palliative purposes or with ablative intent in cases of oligometastatic or oligoprogressive disease. The aim of our study is to evaluate the safety of using T-DXd and concomitant radiation therapy (RT) in a consecutive series of HER2+ BC patients. Methods We conducted a retrospective evaluation of patients diagnosed with metastatic HER2+ BC who initiated treatment with T-DXd between May 2021 and May 2023 at our institution, with or without receiving RT. We collected clinical data pertaining to the diagnosis of metastatic disease, T-DXd treatment, acute toxicities, survival data, and biological characteristics of both the primary tumor and metastases. The primary objective of this study was to assess the association between RT and any adverse events greater than grade (G) 2. Results We retrospectively evaluated data from 30 consecutive patients who were treated with T-DXd, with or without RT. Among these patients, ten received RT either immediately before (within a month) or during T-DXd treatment, while the remaining 20 did not. The median age of the patients was 72 years (range 34-88), and the median follow-up period was 9 months. Thirteen patients received T-DXd as the fourth or subsequent line of systemic anti-HER2 treatment, eight patients received it as the third line, and seven patients received it as the second line. Two patients, who experienced early metastatic disease relapse (&amp;lt; 6 months after completion of adjuvant anti-HER2 therapy), received T-DXd as their first-line treatment. The median prescribed total dose of RT was 34 Gy (range 20-48), with a median number of fractions of 4 (range 2-10). The median equivalent dose in 2 Gy fractions (EQD2) was 64 Gy (range 23.3-104), and the median biologically effective dose (BED) was 76 Gy (range 28-125). The most commonly treated sites were bone (70% of cases), followed by brain (20%) and liver (10%). A chi-square test of independence was conducted to examine the relationship between the administration of RT and the development of toxicity exceeding G2. However, this analysis did not reveal a significant relationship (p = .27). Regarding the specific toxicities of interest associated with T-DXd, three cases of grade 3 fatigue were reported in the group that did not receive RT, while one case was observed in the RT group. Overall, only one case of grade 3 nausea was reported, and it occurred in the group that did not receive RT. G2 interstitial lung disease, which led to discontinuation of T-DXd, was observed in one case in the RT group and one case in the no-RT group. Conclusions Our initial data is promising regarding the potential safety of this combination, as it indicates that concurrent RT did not lead to an increase in severe acute toxicity. However, larger series of data are required to validate and confirm these findings. Citation Format: Luca Visani, Carlotta Becherini, Niccolo' Bertini, Ilaria Bonaparte, Luca Burchini, Carolina Orsatti, Marianna Valzano, Marco Banini, Viola Salvestrini, Erika Scoccimarro, Vieri Scotti, Isacco Desideri, Giulio Francolini, Lorenzo Orzalesi, Marco Bernini, Cinzia Tommasi, Jacopo Nori, Simonetta Bianchi, Icro Meattini, Lorenzo Livi. Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in patients with metastatic HER2-positive breast cancer [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 PO3-22-06.

Abstract PO1-03-05: Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer

Abstract BACKGROUND AND PURPOSE: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiotherapy and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast radiotherapy has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab (P) with adjuvant radiotherapy (RT) in locally advanced TNBC patients. METHODS: This bicentric ambispective study included the first prospectively registered patients with non-metastatic TNBC treated with the KEYNOTE-522 regimen in our institution. They received P in combination with carboplatin and paclitaxel chemotherapy and a second chemotherapy with doxorubicin and cyclophosphamide, followed by surgery and locoregional RT with or without P as adjuvant treatment. RT was normo- or hypofractionated, for the breast or chest wall, with or without lymph node irradiation according to institutional guidelines. Adjuvant P was administered at a total dose of 1800 mg at 200 mg once every 3 weeks or 400 mg once every 6 weeks. The safety profile was evaluated during and after the end of RT (until the last contact) with CTCAE V.5 scale. RESULTS: A total of 55 patients (pts) were prospectively included between July 2021 and March 2023. The median age was 49 years (29-69). The median follow-up was 12 months ( range, 10-26). Of them, 27 (49%) did not receive P concomitantly with RT (RT-only group) because of neo-adjuvant treatment related toxicities, and 28 (51%) received P concomitantly with RT (P-RT group). There was no statistical difference in population and toxicity between the RT-only group and the P-RT group. Nine patients were diagnosed with cardiac toxicities before the beginning of the RT and did not receive P during the RT. No RT-induced grade ≥4 toxicities were observed. Early toxicities were mainly grade 1-2. Two grade 3 toxicities occurred (1 case of axillary pain in the P-RT group and 1 radiodermatitis in the RT-only group). No cardiac or pulmonary toxicities ≥grade 2 were observed with adjuvant therapy. The toxicity profile is given in table 1. DISCUSSION: In these series, the main cause of discontinuation of pembrolizumab was related to suspicion of cardiac adverse events occurring during the neoadjuvant treatment and related to the injection of pembrolizumab or of the chemotherapy. All myocarditis happened before radiotherapy and did not affect the administration of radiotherapy. In this context, the optimal radiotherapy technique and cardiac dose constraints after ICI-induced myocarditis is unknown and late cardiotoxicity studies will be needed to precise these points. Cardiac sparing techniques, such as deep-inspiration breath hold, proton therapy, or alternative positioning (such as isocentric lateral decubitus) could be considered. CONCLUSION: Adjuvant radiotherapy can be combined with pembrolizumab for TNBC patients without increasing the risk of radiation-induced adverse events, allowing maintaining a systemic treatment in these high-risk patients. Longer follow-up and prospective studies are needed to validate these results. Adjuvant treatment-related adverse events Citation Format: Youlia Kirova, Thaïs Tison, Pierre Loap, Emilie ARNAUD, Kim Cao, Solène Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Salomon, Mariana Mirabelle, Delphine Loirat, Francois-Clement Bidard. Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer [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 PO1-03-05.

Degenerated (Ancient) Schwannomas: Unraveling Unusual Locations and Treatment Management

Background/Aims:Schwannomas, originating from Schwann cells in peripheral nerve sheaths, exhibit diverse clinical manifestations and unpredictable behavior. Among them, ancient schwannomas, with distinctive degenerative features, present in atypical locations and pose diagnostic challenges. This study explores their unique characteristics and implications for diagnosis and management. Material and Methods: The study was designed as a retrospective analysis of 7 adult patients aged ≥18 years, diagnosed with paraspinal, presacral, sacral, or para-aortic tumors, all confirmed histologically as ancient schwannomas. Data for analysis were collected from patients treated and followed up at Ankara City Hospital between April 2017 and December 2022. Ethical approval and informed consent were obtained before inclusion in the study. Results: The most common symptoms included the presence of a local lump (71,4%) and localized or radiating pain (57,1%). Notably, 1 patient (14,2%) was incidentally diagnosed during the evaluation process. Surgical intervention played a crucial role in the management of these tumors, with 71,4% of patients undergoing complete resection, while 28,5% underwent subtotal resection. Tumor recurrence occurred in 42,8% of cases, prompting the administration of radiotherapy as part of the treatment strategy. Imaging findings, particularly on MRI, played a crucial role in the accurate identification of ancient schwannomas. These tumors displayed isointensity on T1-weighted images and heterogeneous hyperintensity on T2-weighted images, along with distinctive heterogeneous contrast enhancement. Conclusion: Ancient schwannomas exhibit unique histological features and distinctive MRI characteristics, differentiating them from other nerve sheath tumors. Early diagnosis and complete surgical resection offer favorable outcomes. Awareness of this entity is essential for managing peripheral nerve sheath tumors effectively.

Abstract 3585: DNA-PK inhibition to enhance radiation sensitivity in metastatic pancreatic neuroendocrine cancer

Abstract Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are neoplasms originating from the gastrointestinal track and pancreas. Unfortunately, most patients at the time of diagnosis have extensive metastatic disease and are not candidates for curative surgical resection of metastatic tumors. In such cases, targeted radiation therapy (RT) can slow the progression of metastatic disease, but eventually tumors develop resistance to radiation therapy. In this study, we examined whether DNA-PK inhibition could sensitize pancreatic NETs to radiation therapy and enhance the radiation therapy effect in a preclinical model of pNET metastasis. Methods. We used 96-well clonogenic assays to evaluate the efficacy of the DNA-PK inhibitor peposertib in combination with RT in vitro in QGP-1 and BON pancreatic NET cell lines. Double-strand break-induced DNA repair was visualized with confocal laser scanning microscopy using γ-H2AX immunofluorescence after peposertib treatment alone or in combination with RT. Western blot analysis was used to confirm inhibition of DNA-PKcs (pDNA-PKcs S2056) combination RT. The efficacy of peposertib in combination with RT was evaluated in QGP-1 and BON human xenograft models in athymic nude mice and a BON preclinical lung metastasis model. Results. Clonogenic assays demonstrated absence of cytotoxicity from peposertib alone at doses below 1000 nM and a strong radiosensitizing effect at 200 nM in both QGP-1 and BON cell lines. Pretreatment with peposertib or treatment within 2 h after RT suppressed colony formation; treatment at later timepoints did not enhance radiotherapy. Immunofluorescence analysis revealed high numbers of γH2AX foci with peposertib therapy alone at 96 h or when given 2 h after RT. Western blot analysis confirmed inhibition of DNA-PK Ser2056 after RT in combination with peposertib. DNA-PK inhibition in combination with RT led to remarkable repression of pNET growth both in subcutaneous xenografts (&amp;gt;90%) and in the preclinical lung metastasis model (&amp;gt;90%). Conclusions. Our results showed several advantages of targeting DNA-PK to enhance radiation sensitivity in high-grade pNETs: (1) DNA-PK inhibition alone disrupts DNA damage response in pNETs as demonstrated by strong H2AX phosphorylation. (2) DNA-PK inhibition is most effective at enhancing radiotherapy either right before or after radiation therapy administration. This demonstrates that extended DNA-PK inhibition is not necessary to achieve marked responses during pNET radiotherapy. (3) DNA-PK inhibition 30 min before radiation therapy is sufficient to greatly reduce pNET tumor growth or metastasis progression in pNET preclinical models. In summary, selective DNA-PK inhibition provides a potent therapeutic strategy for disruption of non-homologous end joining DNA double-strand break repair and may offer a novel therapeutic approach in advanced NET radiotherapy. Citation Format: Piotr G. Rychahou, Aman Chauhan, Zeta Chow, Tadahide Izumi, Quan Chen, Eun Y. Lee, Dana Napier, Lowell Brian Anthony, Michael J. Cavnar, Courtney M. Townsend, B. Mark Evers. DNA-PK inhibition to enhance radiation sensitivity in metastatic pancreatic neuroendocrine cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3585.

Long Term Clinical Outcomes of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma: A Single Center Study

Objectives: Few studies have reported long-term follow-up after treatment of gastric mucosaassociated lymphoid tissue (MALT) lymphoma. In this single-center study, we investigated longterm treatment outcomes in patients diagnosed with gastric MALT lymphoma.Methods: The study included 80 patients diagnosed with gastric MALT lymphoma, who were followed up at a single center between January 2005 and December 2019 after &lt;i&gt;Helicobacter pylori&lt;/i&gt; eradication therapy, radiotherapy, or chemotherapy. We evaluated complete remission, improvement, or recurrence of the lesion. Follow-up over &gt;60 months was classified as long-term follow-up, and the progression-free survival rate was recorded.Results: Following &lt;i&gt;H. pylori&lt;/i&gt; eradication treatment, complete remission occurred in 85.9% (55/64) of &lt;i&gt;H. pylori&lt;/i&gt;-positive and 50.0% (3/6) of &lt;i&gt;H. pylori&lt;/i&gt;-negative patients. All patients with gastric MALT lymphoma who did not respond to &lt;i&gt;H. pylori&lt;/i&gt; eradication therapy (100.0% [6/6]) achieved complete remission following administration of local radiotherapy. We observed no deaths on long-term follow-up (&gt;60 months), and the progression-free survival was 101 months.Conclusions: In this study, patients with gastric MALT lymphoma showed excellent survival rates, progression-free survival, and prognosis on long-term follow-up. Prospective studies are warranted to determine the long-term prognosis of gastric MALT lymphoma after treatment.

Clinical Outcomes in Patients With DLBCL Treated With R-CHOP According to Radiotherapy and Interim PET Response.

Interim positron emission tomography/computed tomography (PET/CT) scan is a valuable tool for assessing the early metabolic response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). Although radiotherapy is an effective treatment for lymphoma, especially for local tumor control, the role of consolidative radiotherapy in diffuse large B-cell lymphoma (DLBCL) remains controversial. This study analyzed the clinical outcomes of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), stratified by interim PET response and the administration of radiotherapy. We conducted a retrospective review of 107 patients with DLBCL treated with R-CHOP chemotherapy between January 2012 and December 2016. Overall survival (OS), recurrence-free survival (RFS), and freedom from disease progression (FFDP) were calculated using the Kaplan-Meier method and compared using the log-rank test. Forty-six patients were included in this analysis, with a median follow-up time of 65.9 months (range=4.7-125.3 months). The metabolic CR (mCR) group exhibited superior OS, RFS, and FFDP compared with the metabolic PR (mPR) group (p=0.003, p=0.001, and p=0.008, respectively). The 1-, 2-, and 5-year FFDP were 92.97%, 89.3%, and 85.6%, respectively, in the mCR group and 78.6%, 61.9%, and 44.2%, respectively, in the mPR group. In subgroup analysis, the FFDP of the mPR group without radiotherapy was significantly lower than that of the other groups (mCR with/without radiotherapy and mPR with radiotherapy, p=0.001). Consolidative radiation therapy using interim PET can benefit patients who do not achieve mCR. Further well-controlled prospective randomized trials are required.

Postoperative Radiotherapy and Survival in Oral Cavity Squamous Cell Carcinoma With Mandibulectomy

Oral cavity squamous cell carcinoma (SCC) tumors with mandibular invasion are upstaged to pT4a regardless of their size. Even small tumors with boney invasion, which would otherwise be classified as pT1-2, are recommended for the locally advanced treatment pathway to receive administration of postoperative radiotherapy (PORT). To evaluate the association of PORT with overall survival according to tumor size among patients who received mandibulectomy for pT4aN0 oral cavity SCC. This was a retrospective analysis using data from the US National Cancer Database from January 1, 2004, through December 31, 2019. All patients who received mandibulectomy for treatment-naive pT4aN0 oral cavity SCC with negative surgical margins were included. Data analyses were performed in January 2023 and finalized in July 2023. PORT vs no PORT. Entropy balancing was used to balance covariate moments between treatment groups. Weighted multivariable Cox proportional hazards regression was used to measure the association of PORT with overall survival associated with tumor size. Among 3268 patients with pT4aN0 oral cavity SCC (mean [SD] age, 65.9 [12.1] years; 2024 [61.9%] male and 1244 [38.1%] female), 1851 (56.6%) received PORT and 1417 (43.4%) did not receive PORT. On multivariable analysis was adjusted for age, insurance status, Charlson Comorbidity Index score, tumor site, tumor grade, tumor size, and PORT. Findings indicated that PORT was associated with improved overall survival and that this relative survival advantage trended upwards with increasing tumor size. That is, the larger the tumor, the greater the survival advantage associated with the use of PORT. For the 1068 patients with tumors greater than 4 cm, the adjusted hazard ratio (aHR) in favor of PORT was 0.63 (95% CI, 0.48-0.82); for the 1774 patients with tumors greater than 2 cm but less than or equal to 4 cm, the aHR was 0.76 (95% CI, 0.62-0.93); and for 426 patients with tumors less than 2 cm, the aHR was 0.81 (95% CI, 0.57-1.15). In this retrospective analysis of patients who received mandibulectomy for pT4aN0 oral cavity SCC, PORT was associated with improved overall survival, the benefit of which improved relatively with increasing tumor size. These findings suggest that tumor size should be considered in guidelines for PORT administration in this patient population.

Pleomorphic dermal sarcoma of the scalp - A single-centre experience

BackgroundPleomorphic dermal sarcoma (PDS) of the scalp is a rare tumour which is usually slow growing, but occasionally displays rapid growth and has a low rate of local recurrence. Surgical resection is the mainstay of treatment, with or without radiotherapy. The aim of this study is to describe the surgical approach and the additional benefit of radiotherapy to the treatment of these patients. MethodsRetrospective, single-centre analysis of patients with PDS of the scalp that underwent surgical resection between 2007 and 2021 (n = 24). Treatment variables including depth of resection (superficial or deep to the galea aponeurotica) and adjuvant radiotherapy were investigated. ResultsTwenty-four patients were included in this study. Median age was 80 (range, 52–95), with a median ASA score of 3 (2–3). Sixteen (66.6 %) patients underwent surgical resection including the galea, while the rest (n = 8) did not or was not known. Radiotherapy was given in 7 (29 %) patients in which only 3 (12.5 %) were in the galeal resection group. Reasons for radiotherapy administration were concomitant SCC found at the same area of resection and close margins. In a median follow-up of was 26.2 months (range, 13.6–102.5) there was only one recurrence event. ConclusionsPDS of the scalp can be safely managed with a surgical resection if clear surgical margins are achieved without radiotherapy with good oncological outcomes.

Regulatory role of RGMb in lung injury promoted by the combination of carbon ion irradiation and anti-PD-1 antibody through Erk1/2 and p38 MAPK pathways

The combination of carbon ion radiotherapy and anti-PD-1 antibody represents a new approach to treating thoracic tumors. However, the lung damage caused by this combination therapy may limit its use, and the potential mechanisms for this are worthy of investigation. The objective of this research was to examine the potential involvement of repulsive guidance molecule b (RGMb) in lung damage promoted by the utilization of carbon ion irradiation combined with an anti-PD-1 antibody. The C57BL/6 mice have been randomly separated into four distinct groups: control, anti-PD-1, whole thorax carbon ion irradiation, and irradiation in combination with anti-PD-1 treatment groups (combination group). Detection of pathological changes in lung tissue using HE staining. Detection of pulmonary fibrosis by Masson staining and the hydroxyproline assay. ELISA to detect TNF-α, TGF-β, IL-6, and IL-1β expression levels within lung homogenates. The expression of RGMb, p38 MAPK, and Erk1/2 pathways was detected using a fully automated digital Western blotting system WES (ProteinSimple, USA). Flow cytometry was employed to analyze tissue-resident memory T cells (TRM) within the lung. Subsequently, the siRNA gene was employed to induce the downregulation of RGMb in mice in order to validate the involvement of RGMb in radiation-immune lung injury. The present study observed a significant increase in both inflammatory and fibrotic indicators within the mice group's lung tissue that received the combination treatment. The combination group exhibited elevated levels of TGF-β, TNF-α, IL-6, and IL-1β in lung homogenates. Anti-PD-1 antibody and carbon ion irradiation, upregulated RGMb, phospho-p38 MAPK and phospho-Erk1/2. The results obtained from the flow cytometry analysis indicated that the combination group was significantly higher in the number of clonal expansion TRMs, which were predominantly characterized by the expression of CD8+CD103+CD69-TRMs. The downregulate of RGMb via siRNA in mice resulted in a decrease in phospho-p38 MAPK and phospho-Erk1/2. The combination group exhibited a reduction in TNF-α, TGF-β, IL-6, and IL-1β in their lung tissues, and the number of CD8+CD103+CD69-TRM was significantly reduced. The combination group exhibited a significant improvement in inflammatory and fibrotic indicators within the lung tissues. Anti-PD-1 antibody and carbon ion irradiation synergistically regulate RGMb, leading to strong clonal expansion of lung TRM through the p38 MAPK and Erk1/2 pathways. The present study offers valuable insights into the treatment of lung injury due to the combined administration of carbon ion radiotherapy and anti-PD-1 antibody therapy.

Outcome predictors in a series of 40 patients after surgery for low-grade gliomas

ObjectiveLow grade gliomas (LGGs) account for 15 % of primary brain tumors. The paper has the aim to identifying prognostic factors affecting overall survival (OS) and progression-free survival (PFS), and to evaluate the outcome of patients. MethodsA total of 40 patients undergoing surgery for cerebral LGG (WHO grades I and II) at Our Institute were enrolled in the retrospective study. Inclusion criteria were: histological diagnosis of LGG, availability of complete clinical-instrumental documentation and follow-up data. For each patient, the following were analyzed: the clinical parameters in the preoperative and postoperative phases, the histological variant of the tumor, the extent of surgical resection (EOR) and any use of intraoperative methods, the Mib-1/Ki-67 proliferation index, the administration of adjuvant chemotherapy and/or radiotherapy and the occurrence of any complications. ResultsThe cohort included 14 males and 26 females. The independent predictors of OS at multivariate analysis were: age, pre-operative KPS, Ki67/Mib-1, EOR and adjuvant chemotherapy. With regard to PFS, statistical significance on multivariate analysis was observed for pre-operative KPS, Ki67/Mib-1, EOR, post-operative tumor volume and radiotherapy. An EOR < 80 % was confirmed as negative prognostic factor for both OS and PFS. Lastly, the pre-operative tumor volume and the use of Intra-operative Electrophysiological Monitoring were significantly associated with EOR. ConclusionIn this study, according to the literature, several prognostic factors determining the outcome of LGG patients, both in terms of OS and PFS, were confirmed. Knowing the impact of these parameters in terms of prognosis would guide the choice of treatment, which will necessarily be multidisciplinary and tailored.

Radiotherapy Administration Checklist for Patients Undergoing Radiotherapy: Development and Validation

Background: Radiotherapy is the use of high energy ionizing radiation to treat diseases. With newer technological advancements, the application of radiotherapy in cancer treatment is increasing. Administration of radiation therapy requires great precision and competency, hence tools should be available to implement uniformity of care in the procedure of radiotherapy and to reduce medical errors. This necessitates the need of a checklist to serve as a standard guide for the procedure of radiotherapy. The objective of present study was to develop radiotherapy administration checklist for patients undergoing radiotherapy. Materials and methods: Radiotherapy administration checklist was developed by using methodological research design. The checklist was developed in five phases: i) the preliminary phase (including literature review, focused group discussion, assessment of current practices, generation of item pool and preparation of preliminary draft), ii) the validation phase (content validity by modified Delphi technique and construct validation by factor analysis), iii) pilot testing, iv) final try out followed by establishment of reliability (internal consistency and inter-rater reliability), v) evaluation phase. Results: The final draft of Radiotherapy administration Checklist consisting of 29 items was developed and the validity and reliability of the developed tool were established. In content validity, S-CVI/Avg. and S-CVI/UA were 0.97 and 0.79 respectively. Cronbach’s coefficient alpha, and interrater reliability were 0.64 and 0.76 respectively. All 29 items in final checklist were loaded under 8 factors. The checklist developed was found to be a valid and reliable tool for the procedure of Radiotherapy administration. Conclusion: Radiotherapy administration Checklist is a valid and reliable tool with psychometric properties within expected range. The Radiotherapy administration Checklist can be used as a standard tool to ensure safe, uniform and optimal delivery of radiotherapy.