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Ethan B Ludmir,1,* Tyler Gutschenritter,1,* Chelsea C Pinnix,1 Jillian R Gunther,1 Loretta J Nastoupil,2 Joseph D Khoury,3 L Jeffrey Medeiros,3 Bouthaina S Dabaja,1 Sarah A Milgrom1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally to this work Abstract: Gastrointestinal stromal tumor (GIST) is an uncommon mesenchymal tumor, and has been shown to be associated with synchronous or metachronous second malignancies. Rare cases of coincident GIST and non-Hodgkin lymphomas (NHL) have been reported previously. Here, we report two cases of GIST and coincident primary breast lymphoma, an uncommon subtype of extranodal NHL. We propose that the exceedingly low likelihood of both these cancers occurring in these two patients by chance warrants examination for possible common oncogenic pathways in these lesions, possibly involving shared anti-apoptotic mechanisms. Further research is vital to elucidate common oncogenic pathways between such rare lesions. Keywords: diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, anti-apoptosis, gastrointestinal stromal tumor, primary breast lymphoma

Despite the concurrent use of haploidentical cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs versus DCTs. Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (OS) (3 years OS 65% DCT versus 63% HCT, P = 1) or relapse-free survival (3 years RFS 62% DCT versus 64% HCT, P = .97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 versus 22 days, P = .021), with no difference in platelet recovery to 20,000/μL (P = .12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (P < .0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients versus 42/70 (60%) HCT recipients (odds ratios 0.37, P value=.001). There was a significant increase in grade 3 to 4 acute graft-versus-host disease (aGVHD) in haplo-cord recipients (P = .007), but no difference in grade 2 to 4 aGVHD (P = .11), all chronic GVHD (cGVHD) (P = .9), or moderate-severe cGVHD (P = .3). Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3 to 4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs., (Copyright © 2024. Published by Elsevier Inc.)

Historically, total body irradiation (TBI) has been delivered using static, parallel opposed photon beams (2D-TBI). Recently, centers have increasingly used intensity-modulated radiation therapy (IMRT) techniques for TBI. Relative to 2D-TBI, IMRT can reduce doses to critical organs (i.e., lungs and kidneys) while delivering myeloablative doses to the rest of the body, so it may decrease the risk of toxicity while maintaining oncologic outcomes. Despite these potential benefits, delivering TBI using IMRT introduces new challenges in treatment planning and delivery. We describe the extensive experience with IMRT-based TBI at Stanford University and City of Hope Cancer Center. These groups, and others, have reported favorable clinical outcomes and have developed methods to optimize treatment planning and delivery. A critical next step is to evaluate the broader adoption of this approach. Therefore, IMRT-based TBI will be incorporated into a prospective, multi-institutional Children's Oncology Group study with careful procedures and safeguards in place., (© 2024 Wiley Periodicals LLC.)

Hodgkin lymphoma (HL) is a treatable cancer with an incidence peak in adolescent and young adult years. Treatment strategies have been developed to balance the intensity of therapy needed to maintain disease-free survival while simultaneously preserving overall survival. Risk-based, response-adapted frontline therapy has long used a combination of chemotherapy and radiotherapy (RT). Successive clinical trials over the past three decades have safely reduced cumulative alkylator, anthracycline, and RT exposures for many patients. The advent of checkpoint inhibitors and the CD30-targeted antibody drug conjugate, brentuximab vedotin, has provided new options for de-escalation of conventional therapies associated with late effects in survivors treated at a young age. The ability to evaluate novel agents has been accelerated in collaborative trials inclusive of children and adolescents within the US National Clinical Trials Network and between the Children's Oncology Group and the EuroNet Pediatric Hodgkin Lymphoma Consortium. With numerous treatment options, patients with HL and their clinicians have an opportunity for shared decision making from diagnosis, through cancer treatment, and into survivorship. Given excellent survival outcomes, decisions about treatment in classic HL should be collaborative and attention to long-term survivorship needs should remain a high priority. Patient-reported outcomes remain an important tool to aid clinicians working with survivors to optimize health status and related quality of life for decades after HL therapy.

Purpose: Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children., Materials & Methods: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method., Results: Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT., Conclusions: This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses <20 Gy in patients <4 years old., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hodgkin lymphoma (HL) occurs throughout the lifespan but is one of the most common cancers in adolescents and young adults (AYA; 15-39 years). HL has become a highly curable disease with survival rates surpassing 90%, including patients with high-risk and advanced stage disease. Unfortunately, intensive treatment carries a risk of short- and long-term toxicity. Given the decades pediatric HL survivors are expected to live after treatment, the pediatric approach to treatment has focused on improving the therapeutic index through response adapted treatment and more recently the incorporation of novel agents. The efforts of pediatric and medical oncologists in research and clinical trial development have long occurred in parallel, but recent efforts have laid the foundation for collaboration with the goal of standardizing AYA care and allowing earlier incorporation of novel therapy for younger patients. This review focuses on the evolution of the management of pediatric HL including epidemiology, biology, and approaches to upfront and salvage treatment regimens., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mallorie B. Heneghan reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Jennifer A. Belsky reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Christopher J. Forlenza reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. If there are other authors, they 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 © 2024 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this document is to develop a summary of recommendations from the "Cardiac Computed Tomographic Imaging in Cardio-Oncology: An Expert Consensus Document of the Society of Cardiovascular Computed Tomography (SCCT)" document and provide commentary on key recommendations that are relevant to radiation oncology., Methods: In July 2019, the SCCT convened a multidisciplinary panel of experts to develop a consensus document based on a literature search and a formal consensus process, which was separately published in 2022. A new panel consisting of the radiation oncologist from the original guideline and additional radiation oncologists was formed to address SCCT recommendations and their implications for radiation oncology., Summary: The SCCT consensus document included 6 core sections. Two of these sections were identified as particularly relevant to radiation oncologists. These include evaluation of shared risk factors and role of cardiac computed tomography in risk stratification of patients with cancer (section 1) and the role of cardiac computed tomography in the evaluation of the effects of radiation therapy (section 4). These recommendations are summarized, with additional commentary on the role of radiation oncologists as individual practitioners and radiation oncology practices as a whole in evaluation of coronary artery calcifications on computed tomography images; assessment of the effects of radiation therapy on cardiovascular risk after treatment; and management of patients at elevated risk of cardiovascular sequelae of treatment. Radiation oncologists should be aware of the recommendations in the SCCT consensus document and consider those elements that relate to their practice. This summary document calls attention to the key roles and limitations of radiation oncologists and radiation oncology practices in managing cardiotoxicity risk and highlights the need for ongoing study on the effects of radiation therapy on the heart, cardiac substructures, and long-term risk of cardiotoxicity related to treatment., Competing Interests: Disclosures Arya Amini: AstraZeneca and Takeda Pharmaceuticals (speaker's bureau), Genentech, RefleXion, and Varian (all research). Jean Wright (chair): American Society for Radiation Oncology (honoraria-APEx surveyor), Oncospace and the Prostate Cancer Foundation (research-site principal investigator). Carmen Bergom and Sarah Milgrom reported no disclosures., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUV max ) and peak SUV (SUV peak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV 2.5 /TLG 2.5 ) and 40% of the tumour SUV max (MTV 40% /TLG 40% ). TLG 2.5 was associated with event-free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut-off for TLG 2.5 was 1841. Four-year EFS was 92% for RER/TLG 2.5  up to 1841, 60% for RER/TLG 2.5  greater than 1841, 74% for SER/TLG 2.5  up to 1841 and 79% for SER/TLG 2.5  greater than 1841. Second EFS for RER/TLG 2.5  up to 1841 was 100%. Thus, RERs with a low baseline TLG 2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG 2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need., Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks., Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s)., Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy., Competing Interests: Matthew M. Mille reports sponsored travel to scientific meetings. Daniel J. Indelicato received a grant from the National Cancer Institute within the past 36 months for participation on the National Cancer Institute Pediatric Clinical Institutional Review Board. Joshua D. Palmer received research grants from Varian Medical Systems, The Kroger Company, Genentech, and the National Institutes of Health, consultant fees from Huron Consulting, a speaker honorarium from Varian Medical Systems, and travel support from Novocure and Varian Medical Systems, and is a Novocure Advisory Board member. Sujith Baliga received a speaker honorarium from Varian Medical Center. Matthew M. Poppe received a speaker honorarium and travel support from Mevion and is an investor in PEEL Therapeutics. Derek S. Tsang is a consultant for Back Alley Film Productions, MD lawyers and received meeting registration support from Mevion Medical Systems. Torunn I. Yock received in-kind research support from MIM Software, Inc. No other disclosures were reported.

Background: Posttherapy imaging studies can provide reassurance or induce anxiety regarding risk of recurrence for patients and their families. In some cases, it is difficult to determine if imaging findings represent posttreatment changes or residual disease. Equivocal radiographic findings can occur due to therapy-related inflammation or residual, inactive soft tissue masses, but it is unknown if such findings indicate an increased likelihood of local recurrence. The aim of this study was to assess the value of initial posttherapy scans for predicting local relapse in patients with Ewing sarcoma (EWS) or rhabdomyosarcoma (RMS) who received radiotherapy (RT) for local control. These findings are critical to inform clinicians' surveillance recommendations and ability to accurately counsel patients and their families., Procedure: The primary endpoint was time to local progression (LP). Patients were classified as having posttherapy scans that were "positive" (residual disease within the RT field), "negative" (no evidence of residual disease within the RT field), or "equivocal" (no determination could be made). The value of initial posttreatment scans for predicting LP was assessed using positive predictive value (PPV) and negative predictive value (NPV)., Results: Negative imaging findings (n = 51) had an NPV of 88%, and positive imaging findings (n = 1) had a PPV of 100%. When equivocal findings (n = 16) were categorized with negative results (i.e., positive vs. equivocal/negative), the NPV was 90%. When equivocal findings were categorized with positive results (equivocal/positive vs. negative), the PPV was 12%., Conclusion: Equivocal findings within the RT field on end-of-therapy imaging studies indicate no higher risk of local recurrence than negative findings. These results may contribute to appropriate surveillance schedules and accurate counseling of patients with RMS and EWS who have received RT for local control., (© 2023 Wiley Periodicals LLC.)

Purpose: : The role of peri-transplant radiation therapy (RT) in children with primary brain tumors is unclear. We characterized our institutional practice patterns and patient outcomes., Methods and Materials: The cohort included all patients treated with high-dose chemotherapy and autologous stem cell transplant for primary brain tumors at our institution from 2011 to 2017. Rates of local control, progression-free survival, overall survival, and radiation-associated injury were assessed., Results: Of the 37 eligible patients, 29 (78%) received peri-transplant RT. Patients treated with RT were more likely to have metastatic ( P  = .0121) and incompletely resected ( P  = .056) disease. Of those treated with RT, 13 (45%) received craniospinal irradiation (CSI) and 16 (55%) received focal RT. The median CSI dose was 23.4 Gy (interquartile range [IQR], 18-36 Gy; boost: median, 54 Gy [IQR, 53.7-55.8 Gy]) and focal RT dose was 50.4 Gy [IQR, 50.4-54.5 Gy]). Compared with the focal RT group, patients treated with CSI were older ( P  = .0499) and more likely to have metastatic disease ( P  = .0004). For the complete cohort, 2-year local control was 82% (95% confidence interval [CI], 70%-96%), progression-free survival 63% (95% CI, 49%-81%), and overall survival 65% (95% CI, 51%-82%). These rates did not differ significantly between patients treated with and without peri-transplant RT. Two cases of fatal myelopathy were observed after spinal cord doses within the highest tertile (41.4 cobalt Gy equivalent and 36 Gy)., Conclusions: Peri-transplant RT was used for high-risk disease. Oncologic outcomes after RT were encouraging. However, 2 cases of grade 5 myelopathy were observed. If used cautiously, RT may contribute to durable remission in patients at high risk of relapse., (© 2022 The Author(s).)

Background: Brachytherapy (BT) delivers highly conformal radiation and spares surrounding tissues, which may limit late effects in pediatric, adolescent, and young adult (AYA) patients. We aimed to characterize trends in BT use for this population in the United States, focusing on patients with rhabdomyosarcoma (RMS)., Methods: The National Cancer Database was queried to identify patients ≤ 21 who were treated for solid tumor malignancies in the United States from 2004 to 2016. We obtained disease, treatment, and outcome data for patients treated with BT, in particular for RMS., Results: 99 506 pediatric and AYA patients met study inclusion. Of these, 22 586 (23%) received radiation therapy (external beam radiation therapy [EBRT] and/or BT) and 240 (0.2%) received BT. Among patients treated with BT, 139 (58%) underwent surgery and 58 (24%) received EBRT. A total of 3836 patients were treated for RMS during this period. Of these, 2531 (66%) received any radiation and 37 (1%) received BT (EBRT + BT in 3, BT in 34). Of patients treated with BT for RMS, 28 (76%) underwent surgery + BT. Survival data were available for 31 patients treated with BT for RMS. With a median follow-up of 63 months, overall survival was 100% for patients with RMS of a favorable site treated with BT., Conclusions: BT is rarely used to treat pediatric and AYA patients in the United States. Patients treated with BT for RMS experienced favorable survival, suggesting that this approach may not compromise oncologic outcomes and warrants further study as a therapeutic option in pediatric and AYA patients, specifically in RMS., (© 2021 Wiley Periodicals LLC.)

Purpose: Cardiotoxicities induced by cancer therapy can negatively affect quality of life and survival. We investigated whether high-sensitivity cardiac troponin T (hs-cTnT) levels could serve as biomarker for early detection of cardiac adverse events (CAEs) after chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC)., Methods and Materials: This study included 225 patients who received concurrent platinum and taxane-doublet chemotherapy with thoracic radiation therapy to a total dose of 60 to 74 Gy for NSCLC. All patients were evaluated for CAEs; 190 patients also had serial hs-cTnT measurements., Results: Grade ≥3 CAEs occurred in 24 patients (11%) at a median interval of 9 months after CRT. Pretreatment hs-cTnT levels were higher in men, in patients aged ≥64 years, and in patients with pre-existing heart disease or poor performance status (P < .05). hs-cTnT levels increased at 4 weeks during CRT (P < .05) and decreased after completion of CRT but did not return to pretreatment levels (P = .002). The change (Δ) in hs-cTnT levels during CRT correlated with mean heart dose (P = .0004), the heart volumes receiving 5 to 55 Gy (P < .05), and tumor location (P = .006). Risks of severe CAEs and mortality were significantly increased if the pretreatment hs-cTnT was >10 ng/L or the Δ during CRT was ≥5 ng/L., Conclusions: Elevation of hs-cTnT during CRT was radiation heart dose-dependent, and high hs-cTnT levels during the course of CRT were associated with CAEs and mortality. Routine monitoring of hs-cTnT could identify patients who are at high risk of CRT-induced CAEs early to guide modifications of cancer therapy and possible interventions to mitigate cardiotoxicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

18 F-fluoro-deoxyglucose positron emission tomography (PET)/computed tomography (CT) scans play an important role in the management of lymphoma patients. They are critical to accurately stage disease and assess its response to therapy. In addition, PET/CT scans enable precise target delineation for radiation therapy planning. In this review, we describe the use of PET/CT scans in lymphoma, with a focus on their role in staging disease, assessing response to therapy, predicting prognosis, and planning RT.

The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings. This review will examine the underlying mechanisms of cardiotoxicity that arise from traditional antineoplastic chemotherapies, radiation therapy, hematopoietic stem cell transplantation, as well as newer cellular therapies and targeted cancer therapies. We will then propose areas for prevention, primarily drawing from the anthracycline-induced cardiotoxicity literature. Finally, we will explore the role of human induced pluripotent stem cell cardiomyocytes and genetics in advancing the field of cardio-oncology.

Background: Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL)., Materials and Methods: Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS)., Results: From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV 2BP was significantly associated with EFS (p = .012)., Conclusion: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV 2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL., (© 2021 Wiley Periodicals LLC.)

Purpose: Primary mediastinal B cell lymphoma (PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is diagnosed predominantly in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiation therapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC) positron emission tomography (PET)/computed tomography (CT) scanning may help to determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients., Methods and Materials: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database. The ARS expert committee, composed of radiation oncologists, hematologists, and pediatric oncologists, developed consensus guidelines using the modified Delphi framework., Results: Nine studies met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5-point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5-point Deauville scale of 1 to 3, 4, or 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion., Conclusions: Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiation therapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The prognostic significance of bulky disease in advanced-stage Hodgkin lymphoma is an area of controversy. Early studies suggested that the presence of bulk was associated with an increased risk of disease relapse. The effect of bulk is less clear in more recent studies. The shift to response-adapted treatment regimens may obscure the prognostic significance of initially bulky disease, as patients with such disease have lower rates of complete metabolic response on early interim scans and thus are more likely to receive intensified chemotherapy. Various definitions of bulk have been used, further complicating interpretation of the available data. Advances in diagnostic imaging enable quantification of the three-dimensional lymphoma volume, which may ultimately become a new routine measure of bulky disease. This review aims to summarize the prognostic significance of bulky disease in advanced-stage HL, the influence of bulk on the choice of therapy, and the changing definition of bulk with advances in diagnostic imaging.

Non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) comprise 4% of childhood cancers and consist of numerous histologic subtypes. Prognostic factors associated with poor outcome include high histologic grade, large tumor size, presence of metastases, and unresectability. Complete surgical resection is critical for the best oncologic outcomes and is prioritized in treatment algorithms. The use of radiation therapy (RT) and chemotherapy is based upon factors such as resectability, histologic grade, tumor size, and stage. North American and European trials are defining a risk-based approach to NRSTS to limit treatment-related toxicity and to maximize therapeutic efficacy. In this paper, we summarize the current roles of surgery, RT, and chemotherapy in NRSTS and describe ongoing research that is advancing the care of NRSTS patients., (© 2021 Wiley Periodicals LLC.)

This guideline for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) by the American Radium Society was developed by a multidisciplinary expert panel of medical, pediatric, and radiation oncologists convened to formulate guidelines for evaluation and treatment. The guideline development was based on an in-depth literature review and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of the recommendations by the panel. Given the scarcity of compelling data for strong recommendations for a rare lymphoma that has been shown to be more indolent than classical Hodgkin lymphoma, in instances where evidence is not available or equivocal, expert opinion guided the recommendations. Four clinical variants exemplify common scenarios and represent the consensus recommendations for patients with nodular lymphocyte Hodgkin lymphoma. A summary of the available published literature is also presented.

Purpose: Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods., Methods and Materials: A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children., Results: Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality., Conclusions: Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiation necrosis is a potentially debilitating side effect of therapy necessary to treat pediatric central nervous system tumors. Clinical signs of cerebral radiation necrosis (CRN) are similar to symptoms of disease progression and require close monitoring. The case of an infant diagnosed with a malignant rhabdoid tumor is presented to describe the medical and rehabilitation interventions implemented to address CRN. Rehabilitation providers should routinely be consulted in children with CRN as they fill a critical role in treatment, neurological symptom monitoring, and intervention planning to address family-centered functional goals., (© 2020 Wiley Periodicals LLC.)

Importance: Response-adapted randomized trials have used positron emission tomography-computed tomography to attempt to identify patients with early-stage favorable Hodgkin lymphoma (ESFHL) who could be treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) without radiation therapy (RT). While maximal efficacy is demonstrated with combined modality therapy, RT is often omitted in fear of late adverse effects; however, the application of modern RT could limit these toxic effects., Objective: To determine the radiation doses delivered to organs at risk with modern involved-site RT among patients with ESFHL treated with 20 Gy after 2 cycles of ABVD., Design, Setting, and Participants: This case series included 42 adult patients with ESFHL (according to the German Hodgkin Study Group criteria) who were treated between 2010 and 2019, achieved complete response by positron emission tomography-computed tomography (1-3 on 5-point scale) following 2 cycles of ABVD, and then received consolidative RT. The study was conducted at a single comprehensive cancer center., Exposures: 2 cycles of chemotherapy followed by 20-Gy involved-site RT., Main Outcomes and Measures: The medical records of patients with ESFHL were examined. Organs at risk were contoured, and doses were calculated. Progression-free survival, defined from date of diagnosis to disease progression, relapse, or death, and overall survival were estimated using the Kaplan-Meier method., Results: The cohort comprised 42 patients with ESFHL (median [range] age at diagnosis, 35 [18-74] years; 18 [43%] women; 24 [57%] with stage II disease). At a median follow-up of 44.6 (95% CI, 27.6-61.6) months, the 3-year progression-free survival and overall survival rates were 91.2% (95% CI, 74.9%-97.1%) and 97.0% (95% CI, 80.4%-99.6%), respectively. The mean heart dose was less than 5 Gy (mean, 0.8 Gy; SD, 1.5 Gy; range, 0-4.8 Gy) in all patients. The mean (SD) breast dose for both breasts was 0.1 (0.2) Gy (left breast range, 0-1.0 Gy; right breast range, 0-0.9 Gy)., Conclusions and Relevance: In this study, combined modality therapy with 2 cycles of ABVD and 20 Gy for ESFHL was highly effective and avoided excess doses to organs at risk, which may limit long-term toxic effects.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments., (© 2020 by The American Society of Hematology.)

Patients with early-stage nodal follicular lymphoma (FL) may be rendered free of detectable disease by a diagnostic excisional biopsy. We reviewed the management and outcomes of 48 patients with FL, diagnosed from 2003-2013, treated at a single institution. The primary endpoints were local control (LC) and progression-free survival (PFS).Median age at diagnosis was 54.5 years (range 15-74 years). Forty-seven patients were stage I (97.9%); 15 patients (31.3%) had grade 3 disease. Initial management consisted of observation (12 patients; 25.0%), radiation therapy (RT) alone (12 patients; 25.0%), systemic therapy alone (9 cases; 18.8%), or both (15 patients; 31.3%). Median follow-up was 4.92 years (range 0.5-13.83 years). 4-year PFS and OS were 80.9% and 97.1%, respectively. Patients treated with additional therapy experienced significantly better 4-year LC (100% vs. 81.8%; p  = .012) and 4-year PFS (86.7% vs. 63.6%; p  = .006).Patients with completely resected limited-stage FL would benefit from therapy beyond excisional biopsy alone.

Background: Radiation exposure increases the risk of coronary artery disease (CAD). We explored the association of CAD with coronary artery dose-volume parameters in patients treated with 3D-planned radiation therapy (RT)., Methods: Patients who received thoracic RT and were evaluated by cardiac computed tomography ≥ 1 year later were included. Demographic data and cardiac risk factors were retrospectively collected. Dosimetric data (mean heart dose, d max , d mean , V 50 - V₅) were collected for the whole heart and for each coronary artery. A coronary artery calcium (CAC) Agatston score was calculated on a per-coronary basis and as a total score. Multivariable generalized linear mixed models were generated. The predicted probabilities were used for receiver operating characteristic analyses., Results: Twenty patients with a median age of 53 years at the time of RT were included. Nine patients (45%) had ≥ 3/6 conventional cardiac risk factors. Patients received RT for breast cancer (10, 50%), lung cancer (6, 30%), or lymphoma/myeloma (4, 20%) with a median dose of 60 Gy. CAC scans were performed a median of 32 months after RT. CAC score was significantly associated with radiation dose and presence of diabetes. In a multivariable model adjusted for diabetes, segmental coronary artery dosimetric parameters (d max , d mean , V₅₀, V₄₀ V₃₀, V₂₀, V₁₀, and V₅) were significantly associated with CAC score > 0. V₅₀ had the highest area under the ROC curve (0.89, 95% confidence interval, 0.80-0.97)., Conclusions: Coronary artery radiation exposure is strongly correlated with subsequent segmental CAC score. Coronary calcification may occur soon after RT and in individuals with conventional cardiac risk factors., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019 Korean Society of Echocardiography.)

Controversy exists regarding the optimal management of limited stage grade 3 follicular lymphoma (FL3). We assessed the treatment outcomes of 190 consecutive patients with stage I-II FL. Fifty two patients had FL3 disease, in whom the median age was 55 years. At a median follow-up of 65 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 76.6% and 87.6%, respectively. Patients receiving systemic therapy followed by radiation therapy (RT) had a significantly better PFS ( p =.003) than those treated with RT alone, but similar OS ( p  = .476). Patients treated with RT had 100% local control. Compared to 132 patients with grade 1-2 FL, those with FL3 had similar PFS ( p  = .493) and OS ( p   =  .330). Patients with FL3 can experience favorable outcomes when treated with a combination of systemic therapy and RT, comparable to low grade FL.

Purpose: To characterize local relapse after surgical fixation and postoperative radiotherapy (RT) for multiple myeloma (MM) with cortical involvement of long bones., Patients and Methods: We retrospectively identified patients with MM involving cortical long bones treated with surgical fixation followed by postoperative RT at our institution. Local failures, defined as radiographic recurrence along the surgical hardware, were documented, and potential associations of independent variables (RT dose, fractionation, and extent of hardware coverage) with local failure were assessed by univariate Cox regression., Results: We identified 33 patients with 40 treated sites with a median follow-up of 25.7 months; 68% of treatments were for pathologic fracture, and 32% were for impending fracture. The most common dose and fractionation were 20 to 25 Gy in 8 to 12 fractions. On average, 76% of the surgical hardware was covered by the postoperative RT field (median, 80%; range, 28%-100%). Local failure was observed in 5 cases (12.5%), 2 within the RT field and 3 out of field. None of the relapses resulted in hardware failure, and 2 were retreated with RT. The extent of hardware coverage predicted disease relapse along the hardware (hazard ratio = 6.44; 95% confidence interval, 1.09-37.97; P = .04); however, total RT dose, biologically effective dose, and number of fractions did not., Conclusion: After internal fixation of long bones with MM, full hardware coverage with the RT field could reduce the risk, though small, of disease developing in the future in the proximate hardware. Postoperative RT doses of 20 to 25 Gy in 8 to 10 fractions can achieve excellent local control., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) generally exhibits an aggressive disease course with poor outcomes. Despite inherent radiosensitivity, radiation therapy (RT) is not commonly used for MCL. This study assesses the role of low-dose RT (LDRT) with concurrent chemotherapy in relapsed, multiply refractory MCL. From 2014 through 2018, 19 patients with relapsed, refractory MCL had 98 sites treated with 4 Gy. Median follow-up from initial LDRT was 15.4 months. Patients had received a median 7 courses of chemotherapy since diagnosis, and 58% were ibrutinib-refractory. Of the 98 sites, 76% were refractory to ongoing chemotherapy, and LDRT was delivered with concurrent chemotherapy for 76%. The complete response (CR) rate was 81% at a median 2.7 months post-LDRT. There were no differences in CR despite ibrutinib-refractory disease, prior chemotherapy courses (>5), or tumor size (>3 cm). There were no RT-related toxicities. Overall survival at 1 year following initial LDRT was 90%, and 1-year progression-free survival following last course was 55%. In summary, LDRT is effective for relapsed, multiply refractory MCL, and may be safely delivered with chemotherapy, to multiple sites, and repeatedly without issue. By treating active sites of disease, LDRT can provide durable local control, help achieve remission, and potentially bridge patients to subsequent novel therapies., (© 2019 by The American Society of Hematology.)

Radiation therapy (RT) for the management of lymphoma has evolved over the past few decades. Large, extended, or involved fields have been replaced by smaller involved sites or nodal volumes. Currently, customized plans are created for each individual patient, and these plans encompass only the areas involved by disease. A critical factor that has enabled this shift in practice is the evolving use of imaging studies. Imaging plays a key role in patient selection and RT planning and delivery. The objective of this manuscript is to provide guidelines for best practice of use of imaging in pretreatment evaluation, treatment choice, RT target volume definition, and RT treatment verification and delivery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: In patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, the standard radiation therapy (RT) dose is ≥30 Gy. We report the outcome of patients treated with reduced dose 24 Gy compared with those treated with ≥30 Gy., Methods and Materials: We reviewed results from 32 patients who received a diagnosis of gastric MALT lymphoma between 2007 and 2017 who were treated with involved site RT using intensity modulated radiation therapy (IMRT). Response to therapy was based on post-RT endoscopic biopsy. Freedom from local treatment failure (FFLTF), freedom from treatment failure (FFTF), and overall survival (OS) outcomes were determined., Results: The median age of patients at diagnosis was 58 years. Therapy for MALT was given prior to RT in 14 patients with residual biopsy proven disease documented in all cases (anti-microbial, n=11; rituximab, n=2; rituximab, cyclophosphamide, doxorubicin, vincristine, n=1). One patient received RT (36 Gy) and concurrent rituximab. The median RT dose was 30 Gy; it was 30 to 36 Gy in 66% of patients (n = 21) and 24 Gy in 34% of patients (n = 11). Post-RT biopsy documented a complete response in all patients. Failures occurred in the stomach and duodenum, respectively, at 3.6 and 4.5 years, after 30 Gy. At a median follow-up of 55.2 months (73.8 for ≥30 Gy compared with 28.7 for 24 Gy; P < .001), the 2-year FFLTF, FFTF, and OS were 100%, 100%, and 97%, respectively. No association was found between the lower (24-Gy) dose and FFLTF (P = .819), FFTF (P = .819), or OS (P = .469)., Conclusions: Contemporary RT with involved site targeting using IMRT is associated with high complete response rates for patients with gastric MALT lymphoma, even using reduced doses of 24 Gy. Additional follow-up and increased patient numbers are required to confirm equivalent disease control., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Radiation fields for limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have shrunk over time; involved-site radiation therapy (ISRT) has replaced extended-field radiation therapy (EFRT) and involved-field radiation therapy (IFRT), but this has not been validated. The role of systemic therapy is unclear. We reviewed 71 stage I/II NLPHL patients and assessed progression-free survival (PFS), overall survival (OS), locoregional disease-free survival, and distant disease-free survival (DDFS). Median patient age was 39 years, and 61% had stage II disease. Thirty-six (51%) received radiation therapy (RT) only, 6 (8%) received systemic therapy only, and 29 (41%) received both. More patients receiving combined therapy had B symptoms ( P = .035) and stage II disease ( P = .001). In the RT-only group, 9 (25%) received EFRT, 13 (36%) received IFRT, and 14 (39%) received ISRT; in the combined-modality group, 3 (10%) received EFRT, 7 (24%) received IFRT, and 19 (66%) received ISRT. After a median follow-up of 6.2 years, 15 patients relapsed (13 distant, 2 locoregional). Five-year PFS and OS rates were 86% and 96% and did not differ by treatment. In the RT-only group, follow-up was shorter in the ISRT cohort (2.6 years vs 17.9 years [EFRT] and 8.5 years [IFRT], P < .01), but 5-year PFS did not differ by field size ( P = .20). Locoregional control rates were 100% for the RT-only and combined groups, and corresponding 5-year DDFS rates were 93% and 95% ( P = .95). Eight patients (11%) experienced a second malignancy (1 within RT field). Six patients died (1 from lymphoma). Use of limited ISRT fields does not appear to increase the risk of locoregional relapse, even when RT is given as single-modality therapy., (© 2019 by The American Society of Hematology.)

Introduction: We report our experience in treating patients with primary breast extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) to better elucidate the natural history and optimal treatment approach for these patients., Patients and Methods: Patients with localized primary breast MALT lymphoma treated between 1995 and 2016 were included. Disease-related endpoints including progression-free survival (PFS) were analyzed., Results: Eleven patients met inclusion criteria; all patients were women with a median age of 62 years (range, 42-75 years). Most (73%) patients presented with stage I disease, and most (73%) patients were treated initially treated with radiation therapy (RT). Local control following RT was 100%; all patients with progression following RT experienced distant relapse. Additionally, none of the 3 patients treated with ultra-low-dose RT (4 Gy) experienced subsequent progression (local or distant). Six (55%) patients progressed after initial therapy, of whom 5 received initial RT; the 5-year PFS after initial therapy was 60%. Salvage systemic therapy was utilized in all patients with progression, with 5 of 6 patients receiving single-agent rituximab. Of the patients treated with salvage therapy, only 1 experienced second relapse, with a 5-year PFS of 100% after salvage systemic therapy. With a median follow-up of 8 years, there were no deaths in the cohort., Conclusions: Patients with primary breast MALT lymphoma achieve excellent outcomes. Initial RT affords local control, and although subsequent distant progression is common, salvage rituximab yields high rates of PFS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

First-order radiomic features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are associated with disease progression in early-stage classical Hodgkin lymphoma (HL). We hypothesized that a model incorporating first- and second-order radiomic features would more accurately predict outcome than MTV or TLG alone. We assessed whether radiomic features extracted from baseline PET scans predicted relapsed or refractory disease status in a cohort of 251 patients with stage I-II HL who were managed at a tertiary cancer center. Models were developed and tested using a machine-learning algorithm. Features extracted from mediastinal sites were highly predictive of primary refractory disease. A model incorporating 5 of the most predictive features had an area under the curve (AUC) of 95.2% and total error rate of 1.8%. By comparison, the AUC was 78% for both MTV and TLG and was 65% for maximum standardize uptake value (SUV max ). Furthermore, among the patients with refractory mediastinal disease, our model distinguished those who were successfully salvaged from those who ultimately died of HL. We conclude that our PET radiomic model may improve upfront stratification of early-stage HL patients with mediastinal disease and thus contribute to risk-adapted, individualized management.

Background and Purpose: A lower proportion of CD8+ tumor infiltrating lymphocytes in mycosis fungoides (MF) patients is associated with worse survival. However, it is not known whether circulating CD4:CD8 ratio is a prognosticator of response to total skin electron beam therapy (TSEBT)., Methods and Materials: We identified 126 MF patients treated with TSEBT from 2001 to 20014 at two high-volume academic centers. Circulating CD4:CD8 ratio was obtained within 1 week before TSEBT. TSEBT was delivered with 6-9mEV electrons with low (12 Gy) or conventional (≥12 Gy) doses. Treatment response was assessed with the modified Severity Weighted Assessment Tool (mSWAT). Post-treatment mSWAT decrease of ≥75% was classified as near complete response (CR) while mSWAT decrease of <75% was considered partial response (PR). Receiver operating characteristic analysis determined an optimal CD4:CD8 threshold value to predict TSEBT response in the derivation cohort and was applied to an external validation cohort., Results: 71.4% and 28.6% of patients achieved CR and PR after TSEBT. Higher CD4:CD8 ratio predicted poorer response: median CD4:CD8 in patients with PR vs. CR was 4.84 vs. 1.97 (p = 0.002). A threshold CD4:CD8 of 4.42 optimally discriminated in the discovery cohort patients with PR vs. XR (sensitivity 90%, specificity 59%, area under curve (AUC) = 0.71; p = 0.002). Within an independent test cohort (n = 32), 73.9% of patients with CD4:CD8 <4.42 achieved CR vs. 33.3% of those with CD4:CD8 ≥4.42 (p = 0.033). Among all patients with CD4:CD8 <4.42 (n = 73), 74% achieved CR with low-dose TSEBT vs. 93% with conventional dose TSEBT (p = 0.02). On multivariable logistic regression, CD4:CD8 remained a significant independent predictor of TSEBT response in all patients (OR = 0.107, 95% CI 0.395-0.290, p < 0.001)., Conclusion: Peripheral blood CD4:CD8 ratio was a significant independent predictor of TSEBT response of MF patients as validated in an independent cohort at separate academic center. The potential for CD4:CD8 ratio as a biomarker to inform radiation treatment dosing warrants further investigation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)