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Dimitri Maamari1 ,* Habib El-Khoury1 ,* Omran Saifi,1 Samar A Muwakkit,2 Nathalie K Zgheib3 1Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3Department of Pharmacology and Toxicology, American University of Beirut, Faculty of Medicine, Beirut, Lebanon*These authors contributed equally to this workCorrespondence: Samar A Muwakkit; Nathalie K Zgheib Email sm03@aub.edu.lb; nk16@aub.edu.lbAbstract: Despite major advances in the management and high cure rates of childhood acute lymphoblastic leukemia (ALL), patients still suffer from many drug-induced toxicities, sometimes necessitating dose reduction, or halting of cytotoxic drugs with a secondary risk of disease relapse. In addition, investigators have noted significant inter-individual variability in drug toxicities and disease outcomes, hence the role of pharmacogenetics (PGx) in elucidating genetic polymorphisms in candidate genes for the optimization of disease management. In this review, we present the PGx data in association with main toxicities seen in children treated for ALL in addition to efficacy, with a focus on the most plausible germline PGx variants. We then follow with a summary of the highest evidence drug-gene annotations with suggestions to move forward in implementing preemptive PGx for the individualization of treatment regimens for children with ALL.Keywords: pharmacogenetics, childhood ALL, implementation

Contemporary cooperative group lymphoma trials have developed smaller radiation (RT) fields based on interim (i) or end-of-systemic therapy (EST) PET scans. These fields are used as a "boost" following standard-of-care involved site RT (ISRT) or to replace ISRT entirely. These fields lack standardized nomenclature, complicating comparison of RT approaches across studies. The NRG hematologic working group convened a forum of radiation oncology lymphoma leaders from the National Clinical Trials Network (NCTN) groups (NRG Oncology, COG, SWOG, Alliance for Clinical Trials in Oncology (Alliance), ECOG-ACRIN, CCTG). The forum's objective was to establish standardized nomenclature for contemporary lymphoma RT target volumes. This nomenclature was developed through a comprehensive review of RT volumes utilized in 6 NCTN group lymphoma protocols after 2012 that included non-standard ISRT fields. A classification was developed based on the different fields described in the protocols and nomenclature was chosen to represent the fields. Analysis of the protocols (Table) revealed 5 non-mutually exclusive RT volumes, defined by our group as: ISRT, residual site radiotherapy (RSRT), and 3 PET-directed radiotherapy (PD-RT) types. ISRT considers post-chemo anatomic changes in the axial dimension only, and generally includes the full cranial-caudal extent of pre-chemo disease. RSRT targets only the post-chemo CT-anatomical mass, regardless of its PET avidity and irrespective of pre-chemo disease extent. ISRT and RSRT are independent of EST PET imaging. Conversely, PD-RT is only feasible with EST PET or iPET, and exclusively targets PET-positive disease. The 3 PD-RT types include: PET-directed involved site radiotherapy (pISRT), PET-directed residual site radiotherapy (pRSRT), and PET-directed residual PET radiotherapy (pRPRT). The pISRT target volume includes and follows the superior-inferior aspect of the pre-chemo involved disease site(s) that remain(s) PET-avid on post-treatment imaging. pRSRT target volume includes only the post-systemic therapy CT-anatomical residual mass that contains the PET-avid lesion on EST ± iPET imaging, without including sites that achieved complete metabolic response. pRPRT target volume includes only the PET-avid focus, irrespective of the corresponding adjacent non-PET-avid CT-anatomical disease surrounding it. Detailed target delineation and concept illustrations will be presented at the meeting. NRG Oncology, COG, SWOG, Alliance, ECOG-ACRIN, and CCTG propose a consensus nomenclature for contemporary RT target volumes to be used on lymphoma protocols. Recommendations for using these target volumes are beyond the scope of this work and require comparative studies and/or in-depth analysis of patterns of relapse. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is an important modality in the management of lymphoma. However, there has been a significant decrease in the use of RT in clinical practice and research studies. This may be due to underrepresentation of radiation oncology (RO) in lymphoma leadership positions. The NRG Hematologic Malignancies Working Group (NRG heme) aimed to assess the inclusion of RO among other specialties in the various lymphoma academic leadership positions. We conducted a comprehensive review of the official websites of National Comprehensive Cancer Network (NCCN), lymphoma cooperative research groups (ECOG, SWOG, NCTN, NRG, EORTC, COG, GHSG, LYSA, CIBMTR), lymphoma research foundations (Leukemia & Lymphoma Society, AACR, EHA, LRF) and hematology journals (Blood, Lancet Heme, AJH, Blood Cancer J, Haematologica, HemaSphere, BJH, Blood Adv; date of access 12/7/2023). The evaluation of participation from various specialties, including RO, hematology/oncology (HO), pathology/molecular biology (PM), diagnostic radiology (DR), and other fields such as patient advocacy, public health, pharmacy, biostatistics, dermatology, and research coordinators, was assessed. Median percentages were then calculated and reported for each specialty. Detailed breakdown of committees and research groups by specialty is provided in the Table. Among the 8 NCCN lymphoma guidelines' committees, HO had a median involvement of 77%, while RO, PM and DR had 6%, 7.5% and 0%, respectively. Of the 9 identified lymphoma research cooperative groups, HO had a median involvement of 50%, compared to RO's 11%, PM's 5% and DR's 3%. Among the 4 lymphoma research foundations, HO had a median involvement of 80%, with 15% for PM and 0% for RO and DR. The editorial boards of the 8 highest impact hematology journals had a median involvement of 82% for HO, 14.5% for PM and 0% for RO and DR. HO holds a predominant role in the clinical and research domains of lymphoma, whereas the representation of RO and DR is notably limited. Acknowledging the indications and the significance of therapeutic and diagnostic RT in hematology/lymphoma research and multidisciplinary care, the NRG heme is actively dedicated to augmenting its representation for the benefit of patients. [ABSTRACT FROM AUTHOR]

Unirradiated relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) patients who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized pre-CART disease. This study is the first to report on the role of bridging radiotherapy (BRT) for patients with limited (< 5 involved sites) disease prior to CART. Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 centers was performed and identified 150 patients with r/r B-cell NHL who received CART and had < 5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. Bridging radiation (BRT) was defined as comprehensive, treating all PET-avid disease sites, or focal. Local relapse was defined as disease recurring at the same site(s) (with or without new sites) on PET imaging prior to CART infusion. Relapse-free survival (RFS) was defined from CART infusion to any disease relapse/progression. Event-free survival (EFS) was defined from CART infusion to any disease relapse/progression, initiation of post-CART consolidative/salvage therapy, or death. Prior to CART infusion, 48 (32%) patients received BRT and 102 (68%) did not. The median number of involved disease sites prior to leukapheresis was 2 (range = 1-4). Female gender and extranodal involvement were more common in the BRT group. The median equivalent 2 Gy BRT dose was 25.5 (range = 9.3-43) Gy. There were no grade ≥ 3 BRT-related toxicities. The median follow-up was 21 months. Following CART infusion, BRT patients had better objective response rate (92% vs 78%, P = 0.046). Sustained complete response without subsequent relapse was higher with BRT (54% vs 33%, P = 0.016). Local relapse in sites present prior to CART was lower in the BRT group (21% vs. 46%, P = 0.003). BRT patients had improved 2-year RFS (53% vs 44%, P = 0.023) and 2-year EFS (37% vs 34%, P = 0.039) compared to no BRT patients. Further improvement in 2-year RFS (57% vs 44%, P = 0.003) and 2-year EFS (44% vs 32%, P = 0.008) was seen in patients who received comprehensive BRT to all active disease sites (n = 37) compared to those who did not (n = 113). The impact of BRT was most prominent in patients who had ≤ 2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared to 42% in those who did not (P = 0.002). This improvement in RFS was not seen in patients who had > 2 pre-CART involved disease sites. BRT prior to CART for patients with limited (< 5 involved disease sites) r/r NHL improves response rate, local control, RFS, and EFS without causing significant toxicities. Larger prospective studies are needed to confirm our findings, and clinical predictors of which patients will benefit most from BRT are needed. [ABSTRACT FROM AUTHOR]

Contemporary lymphoma radiation target volumes that rely on post-systemic therapy imaging do not have standardised nomenclature. A forum of radiation oncology lymphoma leaders from the National Clinical Trials Network groups (NRG Oncology, Children's Oncology Group, SWOG Cancer Research Network, Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group, and the Canadian Cancer Trials Group) was convened and established standardised nomenclature for these volumes in the autumn of 2024. Involved-site radiotherapy includes the full cranial-caudal extent of prechemotherapy disease and takes into account axial anatomical changes only. Residual site radiotherapy targets only the postchemotherapy CT-anatomical mass. PET-directed radiotherapy exclusively targets PET-positive disease and includes three types: PET-directed involved site radiotherapy using the superior-inferior aspect of prechemotherapy involved disease sites that remain PET-avid on post-treatment imaging; PET-directed residual site radiotherapy using only the postchemotherapy CT-anatomical residual mass that contains the PET-avid lesion on post-treatment imaging, without excluding sites that had complete metabolic response; and PET-directed residual PET radiotherapy using only the PET-avid focus, irrespective of the corresponding adjacent non-PET-avid CT-anatomical disease surrounding it., Competing Interests: Declaration of interests LKB declares (in the last 36 months) payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events as visiting professor at University of Pittsburgh and Columbia University; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the American Board of Radiology as Oral Boards chair Hematology. SF declares (in the last 36 months) payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events as visiting professor at University of Kansas; participation on the Proton Collaborative Group Data Safety Monitoring Board; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, as chair of Task Group Number 427 Technical Guidelines for the Use of Proton Therapy in Clinical Trials, for the American Association of Physicists in Medicine. JCG reports (without time limit) research in this publication was supported by the National Cancer Institute of the US National Institutes of Health, under award number U10CA180821 (to the Alliance for Clinical Trials in Oncology). JCG declares (in the last 36 months) grants or contracts from Intra-op Medical as institutional support for clinical trial; honorarium payments from DAVA Oncology and Primo-Oncology; support for travel paid by Alliance for Clinical Trials in Oncology to attend their group meeting as the Publication Committee co-chair; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, as Publications Committee co-chair at Alliance for Clinical Trials in Oncology, president and immediate past president, and a member of the board of directors at the International Society of Intraoperative Radiation Therapy, president and past president; is a councillor at the Ohio Radiological Society, Small Cell Lung Cancer Guideline, and a committee member at National Comprehensive Cancer Network. CSH declares (in the last 36 months) leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, as chair of the Radiation Oncology Committee at SWOG since June, 2023. BSH declares (in the last 36 months) leadership or fiduciary role in other board, society, committee, or advocacy group, unpaid, as NRG Hematologic Working Group co-chair; and travel support to semi-annual meetings from the Children's Oncology Group. SAM declares (in the last 36 months) support for travel to Children's Oncology Group meetings paid for by the Children's Oncology Group, and travel to a National Comprehensive Cancer Network guidelines meeting paid for by the National Comprehensive Cancer Network; leadership or fiduciary role in other board, society, committee, or advocacy group, unpaid, as Children's Oncology Group Hodgkin Lymphoma Committee radiation oncology/imaging lead, American Radium Society Appropriate Use Criteria–Lymphoma chair, and a member of the International Journal of Radiation Oncology, Biology, Physics editorial board. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Radiation therapy assumes a pivotal role in Hodgkin lymphoma management, especially within combined modality therapy. It serves as a cornerstone in early-stage disease and in mitigating high-risk instances of local relapse in advanced stages. Over recent decades, radiation therapy has undergone significant advancements, notably alongside diagnostic imaging improvements, facilitating the reduction of radiation field size and dosage. This progress has notably led to minimized toxicity while upholding treatment efficacy. This comprehensive review extensively evaluates the indications and advancements in radiation therapy for Hodgkin lymphoma, with a primary focus on enhancing treatment efficacy while minimizing radiation-related toxicities. The exploration encompasses a detailed examination of various radiation fields, techniques and delivery modalities employed in Hodgkin lymphoma treatment, including intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy. It delves into the intricacies of optimal dose selection and treatment planning strategies aimed at achieving maximal disease control while concurrently minimizing the risk of long-term side effects., Competing Interests: Declaration of competing interest None of the authors have relevant conflict of interest related to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life-threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre-existing sites of disease present pre-CART. Radiation therapy stands as a promising peri-CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease-free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post-CART disease alters the pattern of relapse and improves local recurrence-free and progression-free survivals. Salvage radiotherapy for relapsed post-CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri-CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART., (© 2023 Wiley Periodicals LLC.)

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

Purpose: The optimal approach to incorporate radiation therapy (RT) in conjunction with chimeric antigen receptor (CAR) T-cell therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (bNHL) remains unclear. This study documented the RT local control rate among patients who received bridging radiation therapy (BRT) before CART and compares it with those who received salvage radiation therapy (SRT) after CART. This article further reports on a promising way to use SRT for post-CART disease and identifies predictors for RT in-field recurrence., Methods and Materials: We retrospectively reviewed 83 patients with r/r bNHL who received CART and RT, either as BRT pre-CART infusion (n = 35) or as SRT post-CART infusion (n = 48), between 2018 and 2021. RT was defined as comprehensive (compRT; ie, treated all sites of active disease) or focal (focRT). Limited disease was defined as disease amenable to compRT, involving <5 active disease sites., Results: At time of RT, patients who received BRT before CART had bulkier disease sites (median diameter, 8.7 vs 5.5 cm; P = .01) and were treated to significantly lower doses (median equivalent 2-Gy dose, 23.3 vs 34.5 Gy; P = .002), compared with SRT post-CART. Among 124 total irradiated sites identified, 8 of 59 (13%) bridged sites and 21 of 65 (32%) salvaged sites experienced in-field recurrence, translating to 1-year local control rates (LC) of 84% and 62%, respectively (P = .009). Patients with limited post-CART disease (n = 37) who received compSRT (n = 26) had better overall survival (51% vs 12%; P = .028), freedom from subsequent progression (31% vs 0%; P < .001), and freedom from subsequent event (19% vs 0%; P = .011) compared with patients with limited disease who received focSRT (n = 11)., Conclusions: BRT followed by CART appears to be associated with improved LC compared with SRT in r/r bNHL. Nonetheless, SRT offers a promising salvage intervention for limited (<5 sites) relapsed post-CART disease if given comprehensively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The role of post-mastectomy radiation therapy (PMRT) following primary systemic therapy (PST) in HER-2 positive breast cancer (Her2 + BC) remains poorly understood. The current study evaluates PMRT based on the pathological response to PST in Her2 + BC., Methods and Materials: TRYPHAENA and NeoSphere are randomized phase II trials that investigated PST for Her2 + BC. Our study is a pooled analysis of both trials, including 312 node-positive patients treated with HER-2 targeted PST followed by mastectomy with or without PMRT. The primary endpoint is loco-regional recurrence-free survival (LRRFS)., Results: Our analysis included 172 (55%) patients who achieved complete nodal pathological response (ypN0) and 140 (45%) patients who did not. Patients with ypN0 had a 5-year LRRFS of 97% in both, the PMRT and no PMRT, groups (p = 0.94). Patients with ypN + had 5-year LRRFS of 89% in the PMRT group and 82% in the no PMRT group (p = 0.17). Patients with ypN1 (n = 62) disease who received PMRT (n = 40) had a 5-year LRRFS of 85% as compared to 89% in those who did not (n = 22); (p = 0.60). A significant LRRFS difference was noted in patients with ypN2-3 (n = 78) disease who received PMRT (n = 53) compared to those who did not (n = 25) (5-year LRRFS 92% vs. 75%; p = 0.019). On multivariate analysis, clinical nodal disease at diagnosis and ypN0 were significantly associated with loco-regional recurrence (LRR)., Conclusions: Her2 + BC patients who achieve ypN0 after PST have excellent locoregional-control which supports de-escalation of PMRT. In contrast, patients with ypN2-3 disease derive significant benefit from PMRT. Clinical nodal stage at presentation and ypN0 status are significantly associated with LRR risk in Her2 + BC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Severe excessive dynamic airway collapse (EDAC) is defined as airway narrowing due to posterior wall protrusion into the airway lumen, >90%. We aimed to establish an overall severity score to assess severe EDAC and the need for subsequent intervention., Methods: A retrospective study of patients who underwent dynamic bronchoscopy for evaluation of expiratory central airway collapse between January 2019 and July 2021. A numerical value was given to each tracheobronchial segmental collapse: 0 points (<70%), 1 point (70% to 79%), 2 points (80% to 89%), and 3 points (>90%) to be added for an overall EDAC severity score per patient. We compared the score among patients who underwent stent trials (severe EDAC) and those who did not. Based on the receiver operating characteristics curve, a cutoff total score to predict severe EDAC was calculated., Results: One hundred fifty-eight patients were included. Patients were divided into severe (n = 60) and nonsevere (n = 98) EDAC. A cutoff of 9 as the total score had a sensitivity of 94% and a specificity of 74% to predict severe EDAC, based on an area under the curve 0.888 (95% CI: 0.84, 0.93; P < 0.001)., Conclusion: Our EDAC Severity Scoring System was able to discern between severe and nonsevere EDAC by an overall score cutoff of 9, with high sensitivity and specificity for predicting severe disease and the need for further intervention, in our institution., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

Background: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas., Objective: To investigate the relationship between neuroanatomic structure distances from the radiation target and anterior pituitary function preservation after SRS through multicenter study., Methods: We retrospectively reviewed the International Radiosurgery Research Foundation database from January 2002 to December 2021 for adult patients undergoing SRS for pituitary adenomas with >6 months of follow-up. Distances between centers or edges of hypothalamic-pituitary axis structures and SRS target volumes were measured using MRI. The primary outcome was anterior pituitary function preservation. Predictors were analyzed using multivariable logistic regression and area under the receiver operating curve (AUROC) curve analyses., Results: Four hundred eighty-seven patients were categorized by preservation (n = 384) and no preservation (n = 103) of anterior pituitary function. The mean margin dose was 19.1(6.2) Gy. Larger distance from the center of the stalk to the tumor margin isodose was a positive predictor (adjusted odds ratio [aOR] = 1.162 [1.046-1.291], P = .005), while pre-SRS hypopituitarism (aOR = 0.646 [0.405-1.031], P = .067) and larger treatment volume (aOR = 0.965 [0.929-1.002], P = .061) were near negative predictors of the primary outcome. An interaction between the treatment volume and center stalk to margin isodose distance was found (aOR = 0.980 [0.961-0.999], P = .045). Center stalk to margin isodose distance had an AUROC of 0.620 (0.557-0.693), at 3.95-mm distance. For patients with treatment volumes of <2.34 mL, center stalk to margin isodose distance had an AUROC of 0.719 (0.614-0.823), at 2.95-mm distance., Conclusion: Achieving a distance between the center of the pituitary stalk and the tumor margin isodose ≥3.95 mm predicted anterior pituitary function preservation. For smaller treatment volumes <2.34 mL, the optimal distance was ≥2.95 mm. This may be modifiable during trans-sphenoidal resection to preserve pituitary function., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Purpose: Compare overall survival (OS) and breast cancer-specific survival (BCSS) outcomes of breast conservative therapy (BCT) and mastectomy in a large cohort of patients with early-stage triple negative breast cancer (TNBC), using a propensity score-based matching approach., Methods: Surveillance, Epidemiology, and End Results (SEER) database was used to study the role of RT in early stage TNBC. Primary end points were OS and BCSS. Cox proportional hazard regression models and Kaplan-Meier plots were used to generate the desired outcomes. Propensity score matching was done to minimize bias., Results: 12,761 patients with T1-2N0M0 TNBC as their first malignancy were retrieved. Of these 7237 had lumpectomy with RT, and 5524 had mastectomy only. Age, race, marital status, tumor laterality, grade and stage, and receipt of chemotherapy were prognostic variables for OS and BCSS. Among 4848 matched subjects, the 5-year OS was significantly higher in patients with lumpectomy and RT (89%) compared to mastectomy alone (84.5%) (p-value <0.001). Similarly, BCSS was significantly higher in patients with lumpectomy and RT (93%) compared to mastectomy alone (91%) (p-value <0.001). On subgroup analysis, patients who are younger than 40 had similar survival outcomes after either mastectomy alone or lumpectomy with RT. However, those who are older than 60, have any grade or T stage had better survival outcomes with lumpectomy and RT., Conclusions: Overall, lumpectomy followed by RT is associated with better OS and BCSS compared to mastectomy in T1-2N0M0 TNBC patients. Further research is needed to determine the optimal treatment strategy for specific patient subgroups., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBVs) has emerged as an important treatment method for patients with severe chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are a frequent complication following BLVR with EBV. However, there is no consensus on the prevention of AECOPD., Objectives: Our study aims to compare the outcomes of different prophylactic measures on the occurrence of AECOPD after BLVR with EBV., Methods: We conducted a multicenter, retrospective study of patients who underwent BLVR with EBV at six different institutions. Emphasis was directed towards the specific practices aimed at preventing AECOPD: antibiotics, steroids, antibiotics plus steroids, or no prophylaxis. Subgroups were compared, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated., Results: A total of 170 patients were reviewed. The rate of AECOPD was 21.2% for the full cohort. Patients who received prophylaxis had a significantly lower rate of AECOPD compared with those who did not (16.7% vs. 46.2%; p = 0.001). The rate was lowest in patients who received antibiotics alone (9.2%). There was no significant difference in the rate of AECOPD between patients who received steroids alone or antibiotics plus steroids, compared with the other subgroups. The OR for AECOPD was 4.3 (95% CI: 1.8-10.4; p = 0.001) for patients not receiving prophylaxis and 3.9 (95% CI: 1.5-10.1; p = 0.004) for prophylaxis other than antibiotics alone., Conclusions: Administration of antibiotics after BLVR with EBV was associated with a lower rate of AECOPD. This was not observed with the use of steroids or in combination with antibiotics., (© 2021 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Purpose: Analyze the pattern of disease failure after anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) for non-Hodgkin lymphoma, assess the local control rate of bridging radiotherapy (bRT) and characterize in-field recurrences., Methods: We retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020. Baseline characteristics and treatment outcomes were compared between patients who received bRT and those who did not (noRT)., Results: Of the 118 patients included, 14 (12%) received bRT, while 104 (88%) did not. bRT group had more localized and extranodal disease. bRT was delivered with a median dose of 20 Gy (range: 15-36) in 5 fractions (range: 3-24). Pattern of failure analysis revealed that progression involving pre-existing sites was the predominant pattern of failure in both the bRT and noRT groups (86% and 88%, respectively). Median duration of response was 128 days (range: 25-547) for bRT group and 93 days (range: 22-965) for noRT group (p = 0.78). In the bRT group, only 2/15 sites irradiated had infield recurrence and where characterized by bulky disease, SUV max >20, elevated LDH at the time of CART infusion, and extranodal involvement. The bRT 1-year LC was 86%. Median duration of local response was 257 days (range: 25-630) for radiation-bridged sites., Conclusion: Majority of progressions after CART infusion involve pre-existing sites. Bridging RT prior to CART provides excellent in-field local control and durable response. Patients with bulky disease, SUV max >20, elevated LDH, and extranodal involvement are likely at higher risk of in-field recurrence after bRT and may benefit from higher curative doses of bRT., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cerebral sinus venous thrombosis (CSVT) is one of the many side effects encountered during acute lymphoblastic leukemia (ALL) therapy. Due to the rarity of cases, lack of data, and consensus management, no recommendations exist to target the population at risk., Methods: This is a retrospective chart review of 229 consecutive patients diagnosed with ALL with an age range of 1-21 years, treated at the Children's Cancer Center of Lebanon between October 2007 and February 2018., Results: The incidence of CSVT was 10.5%. Using univariate analysis, increased risk of CSVT was observed with male gender, age >10 years, T-cell immunophenotype, intermediate/high-risk disease, maximum triglyceride (TG) level of >615 mg/dl, presence of mediastinal mass, and larger body surface area (BSA). With multivariate analysis, the only statistically significant risk factors were maximum TG level, BSA, presence of mediastinal mass, and risk stratification (intermediate/high risk)., Conclusion: Our study was able to unveil TG level of >615 mg/dl, mediastinal mass, and a larger BSA as novel risk factors that have not been previously discussed in the literature., (© 2021 Wiley Periodicals LLC.)

Background: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor that can affect multiple organs. Little is known about the pathophysiology, clinical course and management of this disease. The aim of this study is to determine survival rates and elucidate the role of various prognostic factors and therapeutic modalities as compared to surgery on patients with HEH., Methods: A retrospective analysis on patients diagnosed with HEH between 2004 and 2016 was performed utilizing the SEER database. Kaplan-Meier curves were constructed to determine overall and cancer-specific survival, and the log-rank test was used to compare between groups. To explore prognostic factors and treatment outcomes, univariable and multivariable Cox proportional hazard models were developed., Results: A total of 353 patients with HEH (median age: 50.4 years) were identified. The most common surgery performed was liver resection (90.8%). One-year OS in the surgical group and non-surgical group was 86.6% and 61.0%, respectively, while 5-year OS was 75.2% and 37.4%, respectively. On multivariable analysis, surgery emerged as a favorable prognostic factor [HR (95%CI): 0.404 (0.215-0.758) p value = 0.005]. Age > 65 years [HR (95%CI): 2.548 (1.442-4.506) p value = 0.001] and tumor size > 10 cm [HR (95%CI): 2.401 (1.319-4.37) p value = 0.004] were shown to be poor survival prognostic factors., Conclusion: HEH is a rare disease that is poorly understood. Surgical intervention is associated with improved survival rates. Multicenter prospective collaborations are needed to improve our limited knowledge about this neoplasm and determine the optimal treatment strategy., (© 2021. Société Internationale de Chirurgie.)

Purpose: This study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma)., Methods and Materials: Forty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated., Results: All patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups ( P  = .38, P  = .18, and P  = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group ( P <.001 and P  = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups., Conclusions: Reduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT., (© 2021 The Author(s).)

Consanguineous marriage is a deeply rooted tradition in the Arab world. Such marriages are linked to higher rates of recessive genetic diseases. During the Syrian conflict, which started in 2011, around one million Syrian individuals became refugees in Lebanon. This study assessed the consanguinity rates among Syrian refugees living in Lebanon up to three successive consanguineous generations, and examined refugees' awareness of the possible consequences of consanguineous marriage and their attitudes towards consanguinity. Their knowledge of, and access to, premarital screening was also assessed. The study was conducted between January and May 2018. Several study sites representing refugees' distribution within the country were chosen. The study sample included 1008 interviewees from different families. Of those interviewed, 51.9% were in a consanguineous marriage. Interestingly, 23.9% were the product of consanguineous marriages themselves, and 17.9% were consanguineous for three successive generations. The interviewees generally knew about premarital screening, but the majority (61.9%) had not had the screening. The high rates of consanguinity in these Syrian refugees call for immediate action, including raising genetic awareness and providing appropriate genetic counselling. Despite the respondents' familiarity with premarital screening, there was a low rate of uptake of the test, underscoring the importance of providing better education to these refugees.

Introduction: Armed conflict may influence the size and scope of research in Arab countries. We aimed to assess the impact of the 2011 Syrian conflict on health articles about Syria published in indexed journals., Methods: We conducted a scoping review on Syrian health-related articles using seven electronic databases. We included clinical, biomedical, public health, or health system topics published between 1991 and 2017. We excluded animal studies and studies conducted on Syrian refugees. We used descriptive and social network analyses to assess the differences in rates, types, topics of articles, and authorship before and after 2011, the start of the Syrian conflict., Results: Of 1138 articles, 826 (72.6%) were published after 2011. Articles published after 2011 were less likely to be primary research; had a greater proportion reporting on mental health (4.6% vs. 10.0%), accidents and injuries (2.3% vs. 18.8%), and conflict and health (1.7% vs. 7.8%) (all p < 0.05); and a lower proportion reporting on child and maternal health (8.1 to 3.6%, p = 0.019). The proportion of research articles reporting no funding increased from 1.1 to 14.6% (p < 0.01). While international collaborations increased over time, the number of articles with no authors affiliated to Syrian institutions overtook those with at least one author affiliation to a Syrian institution for the first time in 2015., Conclusion: To our knowledge, this is the first study to examine the impact of armed conflict on health scholarship in Syria. The Syrian conflict was associated with a change in the rates, types, and topics of the health-related articles, and authors' affiliations. Our findings have implications for the prioritization of research funding, development of inclusive research collaborations, and promoting the ethics of conducting research in complex humanitarian settings.

The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Since the relapse rate of DLBCL to frontline chemoimmunotherapy and salvage autologous hematopoietic cell transplant is high, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was adopted. Given the time interval needed for CAR T cells to be manufactured (3-5 weeks) and the aggressiveness of these relapsed/refractory lymphomas, some patients do not make it to the CAR T-cell infusion phase. This calls for a bridging therapy to control, debulk, and sensitize the disease during this period. Radiation therapy can serve this purpose and has shown promising results in some studies. Proton therapy, compared to standard radiation therapy, in some locations, can reduce the radiation dose to the organs at risk, which may lead to fewer side effects for patients with lymphomas. Thus, we hypothesize that proton therapy may serve as a promising bridging strategy to CAR T-cell therapy for some patients., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose., (©Copyright 2020 The Author(s).)

Purpose: Conflict-induced cross-border travel for medical treatment is commonly observed in the Middle East. There has been little research conducted on the financial impact this has on patients with cancer or on how cancer centers can adapt their services to meet the needs of this population. This study examines the experience of Iraqi patients seeking care in Lebanon, aiming to understand the social and financial contexts of conflict-related cross-border travel for cancer diagnosis and treatment., Patients and Methods: After institutional review board approval, 60 Iraqi patients and caregivers seeking cancer care at a major tertiary referral center in Lebanon were interviewed., Results: Fifty-four respondents (90%) reported high levels of financial distress. Patients relied on the sale of possessions (48%), the sale of homes (30%), and vast networks to raise funds for treatment. Thematic analysis revealed several key drivers for undergoing cross-border treatment, including the conflict-driven exodus of Iraqi oncology specialists; the destruction of hospitals or road blockages; referrals by Iraqi physicians to Lebanese hospitals; the geographic proximity of Lebanon; and the lack of diagnostic equipment, radiotherapy machines, and reliable provision of chemotherapy in Iraqi hospitals., Conclusion: As a phenomenon distinct from medical tourism, conflict-related deficiencies in health care at home force patients with limited financial resources to undergo cancer treatment in neighboring countries. We highlight the importance of shared decision making and consider the unique socioeconomic status of this population of patients when planning treatment.

Lower invertebrates' hearts such as those of zebrafish have the capacity for scarless myocardial regeneration which is lost by mammalian hearts as they form a fibrotic scar tissue instead of regenerating the injured area. However, neonatal mammalian hearts have a remarkable capacity for regeneration highlighting conserved evolutionary mechanisms underlying such a process. Studies investigated the underlying mechanism of myocardial regeneration in species capable to do so, to see its applicability on mammals. The epicardium, the mesothelial outer layer of the vertebrate heart, has proven to play an important role in the process of repair and regeneration. It serves as an important source of smooth muscle cells, cardiac fibroblasts, endothelial cells, stem cells, and signaling molecules that are involved in this process. Here we review the role of the epicardium in myocardial regeneration focusing on the different involved; Activation, epithelial to mesenchymal transition, and differentiation. In addition, we will discuss its contributory role to different aspects that support myocardial regeneration. Of these we will discuss angiogenesis and the formation of a regenerate extracellular matrix. Moreover, we will discuss several factors that act on the epicardium to affect regeneration. Finally, we will highlight the utility of the epicardium as a mode of cell therapy in the treatment of myocardial injury.

Background: No accurate evaluation of smoking and water pollution on bladder cancer has been conducted in the Lebanese population. Our aim is to examine the significance of smoking and one of the main water pollutants Trihalomethanes (THM) on bladder cancer risk., Methods: Population Attributable Fraction (PAF) was used to quantify the contribution of the risk factors smoking and THMs on bladder cancer in Lebanon. To calculate PAF for each risk factor, we used the proportion of the population exposed and the relative risk for each risk factor. Relative risks for each risk factor were obtained from published meta-analyses. The population at risk values were obtained from a report on chronic disease risk factor surveillance in Lebanon which was conducted by the World Health Organization between 2008 and 2009 and a national study by Semerjian et al. that conducted a multipathway exposure assessment of selected public drinking waters of Lebanon for the risk factors smoking and THMs, respectively., Results: Bladder cancer cases that were the result of smoking in Lebanon among males and females are 33.4 and 18.6%, respectively. Cases attributed to mid-term exposure to THM contamination of drinking water is estimated at 8.6%., Conclusion: This paper further highlights the negative impact of smoking on bladder cancer risk and adds an overlooked and often underestimated risk that THMs have on this type of cancer. Thus, it is imperative that a national based study which assesses THM exposure by gender and smoking status be implemented to determine the real risk behind this byproduct.