Abstract Introduction: The molecular pathways involved in the response to radiation therapy (RT) in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. Attempts to combine RT with immunotherapies in PDAC have yielded inconsistent outcomes, highlighting a critical gap in our understanding of immune dynamics and mechanisms influencing RT response. Our study aims to uncover molecular pathways and cellular subtypes associated with radioresponse. To do so, we developed a novel cell-cell interaction platform, "SpaCCI", to map ligand-receptor (LR) interactions, essential for understanding cellular communication within the TME and its contribution to therapeutic resistance. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on 16 matched pre- and post-treatment PDAC biopsies from a Phase I/II dose-escalation clinical trial of stereotactic body radiation therapy. Additionally, spatial transcriptomics (ST) was conducted on resected PDAC (20 treated with neoadjuvant chemoradiation, 8 untreated). We integrated scRNA-seq and ST datasets using cell type decomposition and developed SpaCCI to enhance LR interaction detection in tissues with complex cell mixtures. Results: ScRNA-seq identified five molecular subpopulations of cancer cells associated to RT response, with PDAC_3 enriched post-RT and marked by genes involved in lipid metabolism and ferroptosis defense. Post-RT depleted subpopulations, such as PDAC_0 and PDAC_prolif, saw upregulation of pathways related to rapid proliferation and oxidative phosphorylation. In a murine model, PDAC_3 was similarly enriched in post-RT tumors, with persister cell lines from these tumors showing overexpression of ferroptosis defense genes and resistance to ferroptosis inducers including Erastin and RSL3. ST analysis also revealed spatial immune changes post-RT, with increased cytotoxic and effector memory T cells balanced by regulatory T cells and M2-like macrophages, indicating immune escape. NK and memory B cells correlated with improved survival post-RT, while plasma IgG cells localized outside the tumor bed, suggesting compartmentalized immune responses. Using SpaCCI, we observed differential enrichment of ligand-receptor interactions in RT-treated tumors, particularly among lipid-associated tumor macrophages, cancer cells, myofibroblast-like cancer-associated fibroblasts, and endothelial cells. Persister PDAC_3 subpopulations showed enriched LR SEMA3 signaling with CAFs, myeloid cells, and endothelial cells consistent with axon guidance pathways. Conclusions: This study presents a molecular and cellular atlas of PDAC response to RT, revealing persister cells populations with adaptations in lipid metabolism and ferroptosis defense that could be targeted to enhance RT efficacy. ST highlighted complex immune dynamics within the TME demonstrating a balance between inflammatory and immunosuppressive populations. Our findings provide a foundation for combinatorial therapeutic strategies and suggest that axon guidance pathways may also play an important role in the response to RT in PDAC. Citation Format: Vincent Bernard, Li-Ting Ku, Tianyu Wang, Kimal Rajapakshe, Dadi Jiang, Galia Jacobson, Jimin Min, Ching-Wei Tzeng, Manoop S. Bhutani, Paola A. Guerrero, Ethan B. Ludmir, Albert C. Koong, Cullen M. Taniguchi, Anirban Maitra, Ziyi Li, Eugene J. Koay.Mapping cellular and microenvironmental determinants of persister populations in pancreatic cancer following neoadjuvant chemoradiation.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P018

Background Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. Methods This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external- beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. Findings Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 655 years (IQR 583-718), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). Interpretation Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. Funding Gateway for Cancer Research and the Israel Cancer Association.

Abstract Background The molecular pathways involved in the response to radiation therapy (RT) in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. Despite extensive molecular stratification efforts, improvements in molecularly informed RT-based therapeutic strategies in the neoadjuvant setting have been limited. This study aims to elucidate the adaptive mechanisms and interactions within PDAC to identify new combinatorial therapeutic targets with RT. MethodsWe constructed a high-resolution molecular landscape of the cellular subtypes and spatial communities that constitute PDAC. Single-cell RNA sequencing (scRNA- seq) was performed on 16 PDAC biopsies of matched pre- and post-treatment samples from a Phase I/II dose-escalation clinical trial of pancreatic stereotactic body radiation therapy (SBRT). Additionally, Visium spatial transcriptomics (ST) was conducted on biopsies from primary PDAC patients collected at the time of surgery. These patients received either no neoadjuvant therapy (n = 8) or neoadjuvant chemoradiation (chemoRT) (n = 20). Cell type profiles were determined from scRNA-seq to compare changes in cell type proportions and signatures before and after RT. From these profiles, we employed robust cell type decomposition to analyze cell type signatures in our ST dataset. ResultsChemoRT induced several significant effects compared to controls within the tumor microenvironment, including an increase in the proportion of myofibroblasts, specifically senescent cancer-associated fibroblasts (CAFs), with signatures consistent with immune cell dysfunction. We observed an increase in CD8 and CD4 effector memory cells with RT; however, this occurred alongside a rise in immunosuppressive alternatively activated tumor-associated macrophages. Additionally, RT upregulated pathways related to HIF, cytokine production, B cell proliferation, and negative regulation of lymphocytes. Patients with increased infiltration of NK, memory B, and CD8 effector memory cells demonstrated improved overall survival outcomes. Inference of copy number variations enabled us to identify cancer subclones as either responsive or resistant in matched pre and post RT biopsies. Resistance was characterized by augmented hypoxia, KRAS activation, epithelial- mesenchymal transition, and interferon-gamma response signaling. Conversely, responders exhibited increased oxidative phosphorylation signaling and pathway enrichment associated with cell proliferation and cell cycle progression. Interestingly, RT induced a decrease in cancer cells characterized as harboring a chemoresistant basal-like molecular subtype. ConclusionThrough both longitudinal and therapy stratified tumor biopsies, we were able to observe significant selection pressures on stromal and cancer cells following RT. This includes upregulation of innate and adaptive immune pathways with a compensatory immunosuppressive response driven by myeloid cells and CAFs. This may provide opportunities for development of clinical trials to therapeutically target specific cellular phenotypes and their interactions. Citation Format: Vincent Bernard, Galia Jacobson, Kimal Rajapakshe, Jimin Min, Guangsheng Pei, Daniel Lin, Ayush Suresh, Dadi Jiang, Ching-Wei Tzeng, Manoop S Bhutani, Linghua Wang, Paola A Guerrero, Ethan B Ludmir, Albert C Koong, Anirban Maitra, Cullen M Taniguchi, Eugene J Koay. A comprehensive spatial atlas of neoadjuvant chemoradiation therapy in resected pancreatic cancer identifies cellular & microenvironmental determinants of persister populations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B078.

Diagnostic imaging has gained prominence as potential biomarkers for early detection and diagnosis in a diverse array of disorders including cancer. However, existing methods routinely face challenges arising from various factors such as image heterogeneity. We develop a novel imaging-based distributional data analysis (DDA) approach that incorporates the probability (quantile) distribution of the pixel-level features as covariates. The proposed approach uses a smoothed quantile distribution (via a suitable basis representation) as functional predictors in a scalar-on-functional quantile regression model. Some distinctive features of the proposed approach include the ability to: (i) account for heterogeneity within the image; (ii) incorporate granular information spanning the entire distribution; and (iii) tackle variability in image sizes for unregistered images in cancer applications. Our primary goal is risk prediction in Hepatocellular carcinoma that is achieved via predicting the change in tumor grades at post-diagnostic visits using pre-diagnostic enhancement pattern mapping (EPM) images of the liver. Along the way, the proposed DDA approach is also used for case versus control diagnosis and risk stratification objectives. Our analysis reveals that when coupled with global structural radiomics features derived from the corresponding T1-MRI scans, the proposed smoothed quantile distributions derived from EPM images showed considerable improvements in sensitivity and comparable specificity in contrast to classification based on routinely used summary measures that do not account for image heterogeneity. Given that there are limited predictive modeling approaches based on heterogeneous images in cancer, the proposed method is expected to provide considerable advantages in image-based early detection and risk prediction.

Purpose. - Continuous positive airway pressure (CPAP) ventilation hyperinflates the lungs and reduces diaphragmatic motion. We hypothesized that CPAP could be safely combined with deep inspiratory breath hold (CPAP-DIBH) during lung stereotactic radiotherapy (SBRT). Material and methods. - Patients with stage-1 lung cancer or lung metastasis treated with CPAP-DIBH SBRT between 3/20175/2021 were analyzed retrospectively. Patient characteristics, treatment parameters, duration of breath holds in all sessions and tolerance to CPAP-DIBH were recorded. Local control (LC) was assessed from CT or PET-CT imaging. The distances between the tumor and mediastinal organs at risk (OAR) in centrally located tumors using either free breathing (FB) or CPAP-DIBH were compared. Toxicity was graded retrospectively. Results. - Forty-five patients with 71 lesions were treated with CPAP-DIBH SBRT. Indications for CPAP-DIBH were prior radiation (35/71, 65%), lower lobe location (34/71, 48%), multiple lesions (26/71, 36.6%) and proximity to mediastinal OAR (7/71, 10%). Patient characteristics were: F:M 43%: 57%; mean gross tumor volume 4.5 cm3 (SD 7.9), mean planning target volume 20 cm3 (SD 27), primary: metastatic lesions (7%:93%). Mean radiation dose was 52.5 Gray (SD3.5). Mean lung volume was 5292 cm3 (SD 1106). Mean duration of CPAP-DIBH was 41.3 s (IQR 3146.8). LC at 2 years was 89.5% (95% CI 7695.5). In patients with central lesions, the distance between the tumor and mediastinal OAR increased from 0.84 cm (SD 0.65) with FB to 1.23 cm (SD 0.8) with CPAP-DIBH (p = 0.002). Most patients tolerated CPAP well and completed all treatments after starting therapy. Three patients did not receive treatment: 2 were unable to tolerate CPAP and 1 had syncope (pre-existing). Toxicity was grade 2 in 4/65 (6%) and grade 3 in 1/65 (1.5%). There was no grade 2 or higher esophageal or tracheal toxicities. Conclusion. - CPAP-DIBH assisted lung SBRT was tolerated well and was associated with minimal toxicity and favorable LC. This technique may be considered when treating multiple lung lesions, lesions located in the lower lobes or adjacent to mediastinal OAR. (c) 2022 Societe francaise de radiotherapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.

Background: Refractory epigastric/midback pain is associated with locally advanced abdominal malignancies, especially pancreatic cancer. The pain is caused by tumor infiltration of the celiac plexus, a nerve network attached to the abdominal aorta. Contemporary palliative approaches are often inadequate. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate this pain. Methods and Materials: We performed a single-arm prospective clinical trial (ClinicalTrials.gov identifier: NCT02356406). Eligible and evaluable patients had celiac pain of at least 5 out of 10 on the Numerical Rating Scale, completed treatment per protocol, and had at least 1 posttreatment visit. The entire retroperitoneal celiac plexus was irradiated with a single 25-Gy fraction. The primary endpoint was change in the Numerical Rating Scale 3 weeks posttreatment. Toxic effects and pain interference (as measured with the Brief Pain Inventory) were secondary endpoints. Results: For our study, 31 patients signed consent, and, of these, 18 patients were treated and evaluable. Median age was 68 years (range, 51-79); 89% of the patients had pancreatic cancer; the median Eastern Cooperative Oncology Group performance status was 1; and the median interval from initial diagnosis to treatment was 9 months (range, 1-36), and, in this interval, patients received a median of 1 systemic treatment line (range, 0-3). Acute toxicity was limited to grade 1 to 2. Three weeks after treatment, 16 patients (84%) reported decreased celiac pain, with median pain level falling from 6 out of 10 (interquartile range [IQR], 5.0-7.5) at baseline to 3 out of 10 (IQR, 1.0-4.3); six weeks after treatment, the Numerical Rating Scale number fell further to 2.8 out of 10 (IQR, 0-3.3; both P <.005 vs baseline), including 4 patients who reported complete eradication of their celiac pain. Total daily morphine milligram equivalents decreased from 59 pretreatment to 50 at 3 weeks, and from 50 to 45 at 6 weeks. Significant improvement was seen in pain-interference scores. Conclusions: Celiac plexus radiosurgery appears to alleviate cancer-related pain. An international multicenter phase 2 trial is currently accruing. (C) 2022 Elsevier Inc. All rights reserved.

Introduction Pancreatic cancer is characterised by severe mid-back and epigastric pain caused by tumour invasion of the coeliac nerve plexus. This pain is often poorly managed with standard treatments. This clinical trial investigates a novel approach in which high-dose radiation (radiosurgery) is targeted to the retroperitoneal coeliac plexus nerve bundle. Preliminary results from a single institution pilot trial are promising: pain relief is substantial and side effects minimal. The goals of this study are to validate these findings in an international multisetting, and investigate the impact on quality of life and functional status among patients with terminal cancer. Methods and analysis A single-arm prospective phase II clinical trial. Eligible patients are required to have severe coeliac pain of at least five on the 11-point BPI average pain scale and Eastern Cooperative Oncology Group performance status of two or better. Non-pancreatic cancers invading the coeliac plexus are also eligible. The intervention involves irradiating the coeliac plexus using a single fraction of 25 Gy. The primary endpoint is the complete or partial pain response at 3 weeks. Secondary endpoints include pain at 6 weeks, analgesic use, hope, qualitative of life, caregiver burden and functional outcomes, all measured using validated instruments. The protocol is expected to open at a number of cancer centres across the globe, and a quality assurance programme is included. The protocol requires that 90 evaluable patients" be accrued, based upon the assumption that a third of patients are non-evaluable (e.g. due to death prior to 3-weeks post-treatment assessment, or spontaneous improvement of pain pre-treatment), it is estimated that a total of 120 patients will need to be accrued. Supported by Gateway for Cancer Research and the Israel Cancer Association. Ethics and dissemination Ethic approval for this study has been obtained at eight academic medical centres located across the Middle East, North America and Europe. Results will be disseminated through conference presentations and peer-reviewed publications. Trial registration number NCT03323489.

Purpose/Objective(s)Gastro-intestinal (GI) side effects are dose limiting for pelvic & abdominal radiation therapy (RT). Advanced-age is hypothesized to be an aggravating factor in severe radiation toxicity, but this has not been well defined. We sought to quantify the effect of age on grade IV / V gastro-intestinal complications of RT by combining information from two US population-based databases.Materials/MethodsThe absolute number of complications was obtained by querying the National Inpatient Database (NIS) of the Healthcare Cost and Utilization Project, which contains discharge data from a 20% stratified sample of all US non-federal hospitals. Inclusion criteria were inpatient episodes between 2015-18, with listed diagnoses of both ‘Malignant neoplasm of rectum' (ICD-10-CM Code C20), and ‘Gastroenteritis and colitis due to radiation' (ICD-10-CM Code K52.0). A grade IV complication was defined as a hospitalization, alive on discharge; whereas grade V was defined as a hospitalization culminating in death. The relative age-distribution of patients with rectal cancer treated with RT was obtained from the SEER database. Relative toxicity incidence by age group was obtained by normalizing the absolute number of toxic events obtained from NIS with the age-distribution treatment data from SEER. Statistical techniques included best-fit linear regression and multivariate logistic regression.ResultsWithin the NIS database there were 31,878 hospitalizations with a listed diagnosis of rectal cancer (median age 63 years), of whom 290 had grade IV (median age 66) and 10 grade V (median age 76.5) radiation gastroenteritis / colitis. There were no grade 4 toxicities under the age of 20, and no grade 5 toxicities under the age of 70. After adjusting for the baseline age distribution of rectal cancer patients receiving radiation derived from SEER data, the relative risk (RR) of grade IV toxicity was 0.44 for subjects aged 20-39, and 0.53 for subjects aged 40-59 and 1.0 for 60-79 (the comparator). The RR for grade V toxicity was zero for <60, 1.0 for 60-79 (the comparator), and 1.26 for subjects aged 80-99. Best-fit linear regression line for grade IV toxicity was defined by [0.0084* age(yrs)* + 0.2], and for grade V toxicity by [0.024* age(yrs)* - 0.87]. On multivariate logistic regression, amongst all those with grade 4-5 radiation gastroenteritis / colitis, age was the only clinical predictor of death (dosimetric factors were not available).ConclusionWe demonstrate that the risk of acute severe radiation-induced bowel toxicity in rectal cancer patients rises linearly with age. Modelling demonstrates that the gradient is far steeper for grade V toxicity than grade IV toxicity. Importantly, our results facilitate the incorporated of age into existing NTCP models of bowel toxicity. Age-adjusted radiation dose constraints for the bowel should be adopted.

PURPOSE:Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response. METHODS AND MATERIALS:Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m2) with concurrent capecitabine and RT in cohort sizes of 3 starting at the lowest dose. Dose limiting toxicity was defined as grade 3 or higher toxicity. Patients were restaged 4 to 6 weeks post-CRT completion, and surgical resection was offered to those with stable/responsive disease. We scored the tumor interface response (IR) postchemotherapy and post-CRT into type I (remained/became more defined) and type II (became less defined). Overall survival (OS) and progression-free survival (PFS) from time of CRT were estimated using Kaplan-Meier method. P ≤ .05 was considered significant. RESULTS:Twenty-three patients started and finished on protocol (LAPC = 14, BRPC = 9). No grade 3 and 4 toxicities were reported in level 1 (n = 3) or level 2 (n = 3) initial groups. Two patients in the initial level 3 group developed dose limiting toxicity, establishing level 2 dose as the maximal tolerated dose. Level 2 group was expanded for additional 15 patients (for a total of 23 on trial), 5 of whom developed grade 3 toxicities. Seven patients underwent surgical resection. Median OS and PFS were 21.2 and 8.1 months, respectively. Type I IR was associated with better OS (P = .004) and PFS (P = .03) compared with type II IR. CONCLUSIONS:We established the maximum tolerated dose for nab-paclitaxel in a consolidative CRT regimen for pancreatic ductal adenocarcinoma. Preliminary efficacy results warrant phase 2 trial evaluation. IR may be used for personalized treatment.

Protein mislocalization is a frequent, yet underappreciated, characteristic of cancer, 1 Wang X Li S. Protein mislocalization: Mechanisms, functions and clinical applications in cancer. Biochim Biophys Acta. 2014; 1846: 13-25 PubMed Google Scholar leading to both gain and loss of function; tumor suppressor proteins such as p53 and adenomatous polyposis coli are ineffective when mislocated out of the nucleus. The eukaryotic protein exportin 1 (XPO1) plays a critical role in regulating the export of proteins and RNAs from the nucleus to the cytoplasm. 2 Azmi AS Uddin MH Mohammad RM. The nuclear export protein XPO1—from biology to targeted therapy. Nat Rev Clin Oncol. 2021; 18: 152-169 Crossref PubMed Scopus (88) Google Scholar XPO1 dysregulation plays a pivotal role in both the development of various malignancies and their resistance to many chemotherapeutic agents. Selinexor (KPT-330, Xpovio) is an oral, first-in-class, selective inhibitor of XPO1-mediated nuclear export compound. Selinexor leads to nuclear retention of both tumor suppressor proteins and oncoprotein mRNAs (eg, c-myc, Bcl family proteins), promoting cancer cell apoptosis (Fig. 1) 2 Azmi AS Uddin MH Mohammad RM. The nuclear export protein XPO1—from biology to targeted therapy. Nat Rev Clin Oncol. 2021; 18: 152-169 Crossref PubMed Scopus (88) Google Scholar and augmenting the activity of many chemotherapeutic agents. 3 Turner JG Dawson JL Grant S et al. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors. J Hematol Oncol. 2016; 9: 73 Crossref PubMed Scopus (57) Google Scholar ,4 Quintanal-Villalonga A Taniguchi H Hao Y et al. Inhibition of XPO1 sensitizes small cell lung cancer to first- and second-line chemotherapy. Cancer Res. 2022; 82: 472-483 Crossref PubMed Scopus (13) Google Scholar Moreover, selinexor acts as a radiosensitizer across diverse cell types, including rectal cancer; proposed mechanisms include impaired DNA damage repair, 5 Kashyap T Argueta C Unger T et al. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents. Oncotarget. 2018; 9: 30773-30786 Crossref PubMed Scopus (39) Google Scholar possibly due to a global inhibition of gene translation 6 Wahba A Rath BH O'Neill JW Camphausen K Tofilon PJ The XPO1 inhibitor selinexor inhibits translation and enhances the radiosensitivity of glioblastoma cells grown in vitro and in vivo. Mol Cancer Ther. 2018; 17: 1717-1726 Crossref PubMed Scopus (29) Google Scholar and promotion of apoptosis. 7 Ferreiro-Neira I Torres NE Liesenfeld LF et al. XPO1 inhibition enhances radiation response in preclinical models of rectal cancer. Clin Cancer Res. 2016; 22: 1663-1673 Crossref PubMed Scopus (36) Google Scholar Selinexor has yet to be combined with radiation in humans. The drug was recently approved by the Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma.

Introduction: Breast cancer patients and survivors frequently report fatigue, emotional, and cognitive disturbances, which reduce performance at all levels of occupation and make life quality issues a considerable clinical concern. The aim of this study is to evaluate attention and emotion regulation across radiotherapy period and the possible effects of complementary alternative medicine (CAM). Methods: Fifty-seven patients with unilateral breast cancer underwent surgery and systemic chemotherapy before participating in this double-blind randomized study. Two thirds were given CAM (n = 38) while the rest received placebo (carrier only, n = 19). Patients’ attention and anxiety were physiologically tested at baseline, 2 and 4 weeks during the radiation period as well as 1-month after the end of radiation session. Results: Both groups showed similar levels of anxiety with no significant differences at baseline nor post-radiotherapy. Long-term significant recovery of attention performance was observed in the CAM patients, accompanied by a similar tendency in anxiety level, measured by the eye-blink probability. Conclusions: This study physiologically validates the attention impairment reported among breast cancer survivors; also, it depicted a beneficial late-effect of a routine CAM on attention dysregulation. The suggested non-invasive physiological measures can physiologically monitor patients’ psychological and cognitive well-being as well as evaluate the beneficial effect of CAM in breast cancer patients by assessing their coping ability to support the treatment plan. Thus, the results have potential clinical implications on patients’ and survivors’ quality of life. Trial Registration: NIH, NCT02890316. Registered July 2016, http://www.ClinicalTrials.gov

PurposeThis study aimed to study the impact of continuous positive airway pressure (CPAP) on chest anatomy and tumor motion in patients receiving radiation therapy.Methods and MaterialsPatients with primary or secondary lung tumors, left-sided breast cancer, or liver metastases referred for radiation therapy were trained to breathe with a CPAP device using a face mask to a maximal pressure of 15 cm H2O. Three- and 4-dimensional computed tomography simulation was performed twice for each patient: once with free breathing (FB) and again using CPAP. Volumetric and dosimetric parameters of treatment plans were compared.ResultsForty-nine patients were enrolled, of whom 6 withdrew consent before simulation and 3 withdrew because of discomfort. Thus, a total of 40 patients were analyzed. Twenty-seven patients (67.5%) were treated with CPAP based on confirmation of the volumetric or dosimetric benefit of CPAP. Mean lung volume increased by 37% (P < .001). The mean augmentation was 1283 ± 1128 cm3 (CPAP vs FB; P = .0006) in patients with normal lung function tests and 719 ± 341 cm3 (P = .003) in patients with a restrictive pattern. Increased lung volume was independent of age, body mass index, sex, chronic obstructive pulmonary disease, smoking status, and heart disease. Tumor motion in the lung was decreased as reflected in a mean reduction of planning target volume by 19% (P < .001). The greatest reduction of tumor trajectory and planning target volume occurred in tumors in the lower lung, particularly in the range of up to 6 cm above the dome of the diaphragm. The mean lung dose was reduced by 15%, lung V20 by 20%, lung V5 by 11%, and heart V5 by 16% (P < .01).ConclusionsIn this prospective trial, the use of CPAP was associated with significant volumetric and dosimetric benefits compared with FB. CPAP was safe, simple to implement, and well tolerated by most patients, and it should be studied further as a method to reduce the risk of lung and heart toxicity.

PURPOSE: Neutropenia is a serious complication of chemotherapy in patients with solid tumors. The influence of hospital volume on outcomes in patients with neutropenia has been little investigated. We hypothesized that large-volume hospitals would have reduced mortality rates for neutropenic patients compared with small-volume institutions. METHODS: We used the Nationwide Inpatient Sample database of the Healthcare Cost and Utilization Project, for the years 2007-2011. All adult inpatient episodes with a diagnosis of both neutropenia and solid-tumor malignancy were included. Hospital volume was defined as the number of neutropenic cancer episodes per institution per year. Mortality was defined as death during admission. A multilevel mixed-effects logistic regression model was applied. RESULTS: Twenty thousand three hundred and ten hospitalizations were included in the study, from 1,869 different institutions. Median age was 62 years. The overall inpatient mortality was 2.3%, and was dependent on age (age 50-59 years—1.6% and age 80-89 years—5.3%). The median number of neutropenic inpatient episodes in each institution per year was 14 (range, 1-168). Mortality was 3.3%, 2.7%, 2.2%, 2.2%, and 1.2% for each quintile of hospital volume (from lowest to highest volume, P < .001). Likewise, the proportion discharged home was 85.7%, 90.3%, 91.5%, 92.7%, and 95.4% ( P < .001). The association between hospital volume and mortality remained significant after adjustment for patient-level and hospital-level variables. DISCUSSION: Patients with neutropenia hospitalized in large-volume institutions have a substantially lower mortality compared with those hospitalized at low-volume institutions. Further study is required to validate our findings or overcome potential biases, understand mechanism, and investigate how smaller institutions can improve outcomes.

Purpose: There is a paucity of data on the rates of ipsilateral breast tumor recurrence (IBTR) in BRCA1/2-associated breast cancer (BC). Scarcer yet are outcomes data in BRCA1/2 mutation carriers in the setting of newer mastectomy techniques, such as skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM). Methods: Data were extracted from the medical records of BRCA1/2 carriers who were diagnosed with BC and treated at a single institution between 2006 and 2020. The data extracted included patient demographics, tumor characteristics, disease stage, surgical treatment, use of radiation therapy (RT), and disease outcome. Results: Overall, 255 BC patients with BRCA1/2 germline mutations were identified. Of these, 128 (50.2%) underwent a mastectomy (SSM or NSM in 82% of them), 76 (59.4%) without postmastectomy RT (non-PMRT) and 52 (40.6%) with PMRT, whereas 127 (49.8%) elected for breast-conserving treatment (BCT). The non-PMRT group had earlier disease stages (82.3% were Tis and T1N0) compared with the PMRT and BCT groups (3.6% and 48.1%, respectively; P<.05). The IBTR cumulative rate was 9 of 76 (11.8%) in the non-PMRT cohort compared with 0 of 52 in the PMRT group (P=.01) and 6 of 127 (4.7%) in the BCT group (P=.06). The cumulative incidences of IBTR at 5 and 10 years were 9.8% and 27.4%, respectively, in the non-PMRT group versus 2% and 11.3%, respectively, in the BCT group (P=.0183). No significant difference in overall survival was observed at the time of follow-up. Conclusions: BRCA1/2 mutation carriers treated with mastectomy without PMRT had higher rates of IBTR than those who underwent mastectomy and PMRT or BCT, despite earlier stages of disease. The safety of SSM/NSM should be evaluated in a prospective trial. (C) 2020 Elsevier Inc. All rights reserved.

In this study, we evaluated the effectiveness of palliative breast radiation therapy (RT), with single fraction RT compared with fractionated RT. Our study showed that both RT fractionation schemas provide palliation. Single fraction RT allowed for treatment with minimal interference with systemic therapy, whereas fractionated RT provided a more durable palliative response. Due to equivalent palliative response, at our institution we have increasingly been providing single fraction RT palliation during the COVID-19 pandemic.

Sir, The rates of mastectomy and immediate breast reconstruction (IBR) are increasing.1 Cosmetic outcomes are probably an important factor driving these trends, but the surgical procedure has also become less prone to morbidity with increased experience.2 IBR fulfills the patients’ desire for a reconstructed breast and the surgeons’ wish to perform a successful single-stage procedure.2 Nevertheless, these operations should be planned with the patient’s cancer diagnosis in mind, and not all patients are suitable for IBR, skin-sparing mastectomy, and/or nipple-sparing mastectomy (NSM). Figure 1 shows a magnetic resonance image of early postoperative recurrence after implant-based IBR. A 40-year-old patient presented with cT2 multicentric left invasive ductal carcinoma (7 tumor foci, between 7 and 32 mm, per magnetic resonance image), grade 3, triple negative disease, and cN1, including a tumor focus underneath the breast skin, without skin involvement (Fig. 1A). She was treated with preoperative chemotherapy, leading to only partial response per imaging. She underwent NSM and axillary dissection and IBR at a different institution. The final pathologic finding was positive for extensive multicentric disease in the breast, ypT1 (7 foci, largest 10 mm) with free margins, lymphovascular invasion, and tumor thrombi around the masses. Axillary residual disease included 2 out of the 8 positive lymph nodes. After surgery, the patient suffered from a wound infection and needed prolonged antibiotic treatment. She subsequently underwent additional surgery due to wound complications. Two months after the surgery, she was referred to our center to continue oncologic treatment, including postmastectomy irradiation. She suffered from painful palpable masses within the reconstructed breast and was referred for a biopsy, which confirmed loco-regional recurrence at multiple sites (Fig. 1B).Fig. 1.: Breast magnetic resonance image (MRI). A, Preoperative MRI showing a foci adjacent to the skin but not involving it. B, Local subcutaneous early recurrence after an implant-based reconstruction.There are many issues to discuss in this specific case, but we would like to highlight the main concern that led to this letter. This patient had triple-negative disease and responded poorly to a full course of preoperative systemic therapy. Such patients have a higher rate of local recurrence and early systemic failure and tend to recur early within 2 years from primary surgery. Skin-sparing mastectomy and NSM are considered oncologically safe procedures based on retrospective studies, and both procedures tend to leave a larger amount of residual breast tissue (at least 5 mm of subcutaneous tissue) after mastectomy to allow for IBR,3 and in this specific case, a possible unnoted residual tumor foci.4 Importantly, current evidence suggests that these patients may benefit from additional postoperative therapy (postmastectomy irradiation, systemic therapy), and IBR might interfere with postoperative treatment.5 Therefore, this patient should have been referred for modified total mastectomy without IBR to allow for complete glandular tissue removal and for immediate postoperative oncologic treatment. More studies are needed to identify the patients who are not suitable for IBR and skin-sparing with or without nipple-sparing procedures. In the meantime, the possibility of residual breast tissue after these procedures should be kept in mind and fully discussed with the patient. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article.

Oncology is an evidence-driven specialty, in which clinical practice is based upon the outcome of randomized trials. The phase III trials performed today determine the care that will be delivered tomorrow. However, this objective evidence-based model is biased based on what clinical trials are performed. To predict future oncology practice, we investigated trends in oncology Phase III clinical trials over the past 20 years. We hypothesize that the performance of Phase III trials is increasingly dominated by the pharma industry, with long term consequences for the future of radiation oncology. We performed an analysis of randomized oncology trials in clinicaltrials.gov. Inclusion criteria were interventional phase III cancer trials with a start date between 2000 and 2019; hematological malignancies were excluded. Trials were classified based on a text analysis of database entries, performed using Stata/IC 16.0 (Statacorp, College Station, TX). A 'radiation trial' (RT) was defined as one in which radiation therapy was an intervention. A total of 4,271 trials, both RT and non-RT, were included in the analysis, with a planned total enrollment of 2,628,932 patients. 40% were completed, 20% recruiting, the remainder were either active but not recruiting, unknown status, or terminated. The number of new cancer trials per year has incrementally increased from 101 in 2000 to 284 in 2019. Although there has been an increase in absolute numbers of RT trials (from 24 in 2000 to 36 in 2019), the proportion of trials involving radiation as an intervention dropped from 24% in 2000 to 9% in 2011, latterly recovering to 13% in 2019. The proportion of RT trials being performed in metastatic patients has increased from 9% in the early 2000s to 16% in 2019. Since 2012 there has been a big increase in the number of radiation trials involving some form of immunotherapy, rising from none to 14% in 2019. There are 9 proton or carbon ion trials, all of which were initiated since 2009; no trials are testing MRI-guided irradiation. Government funding of RT trials has decreased in both absolute and relative terms: from 10 new trials (42% of RT trials) in 2000 to 6 new trials (17%) in 2019. Over the past 20 years, there has been a steep decrease in the proportion of Phase III cancer trials involving RT, somewhat reversed by recent interest in the combined use of RT with immunotherapy. Furthermore, there has been a shift from government-funded RT only trials, to those funded by pharmaceutical companies focusing on drug-RT combination. New RT technologies are being little investigated. The large discrepancy between the frequent use of radiation in cancer therapy and the limited number of trials being performed bodes poorly for the future: either the use of radiation will decrease, or we will cease to be an evidence-based specialty.

Purpose: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM. Methods and Materials: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with >= 5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined. Results: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma. Conclusions: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers. (C) 2020 Elsevier Inc. All rights reserved.