Purpose:Patients with breast cancer isolated local-regional recurrence (iLRR) can benefit from salvage reirradiation (reRT) to provide durable control and prevent further progression. Conformal radiation techniques like pencil beam scanning (PBS) proton beam therapy (PBT) may improve the reRT therapeutic ratio by limiting cumulative dose and improving target region dose delivery. Materials and methods:Consecutive patients between 8/2019-9/2025 treated with PBS-PBT reRT for breast cancer iLRR with prior dose overlap were identified. Clinicopathologic, treatment, and outcomes details were collected. Associations between clinical/treatment factors and time to recurrence and grade (G) ≥2 adverse events (AEs) were evaluated with Fine-Gray models and logistic regression, respectively. Correlations between DVH metrics and late AEs were assessed using Kruskal-Wallis and Wilcoxon rank sum tests. Results:Seventy patients were identified with median first course (C1), reRT course (C2), and cumulative doses of 53, 50, and 106Gy(RBE), respectively. During C2, 82.2% received comprehensive nodal irradiation. Median follow-up was 30 months. Two- and three-year rates of any recurrence were 14% and 17%, and OS were 100% and 95%, respectively. Maximum acute G2 and G3 AEs occurred in 50% and 7%, and late G2 and G3 AEs in 34% and 10%, respectively. Rib fractures developed in 21.1% and were associated with C1 and C2 chest wall D200cc and C1 rib D10cc. Conclusion:In the largest experience of PBT reRT for breast cancer iLRR to date, we report promising disease control and limited severe AEs despite a high-risk patient cohort. We provide dose metrics that can serve as the foundation for reRT dose constraints and be further refined in future reRT investigations.

PURPOSE:Patients with extensive-stage small cell lung cancer are commonly treated with induction systemic therapy and consolidative thoracic radiotherapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open-label phase I study of concurrent olaparib with TRT. PATIENTS AND METHODS:Patients without progression after induction platinum/etoposide ± atezolizumab were treated with oral olaparib for 3 weeks and concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose started at 50 mg twice daily and escalated in 50 mg/dose increments in cohorts of three patients each. Primary objectives were the safety and maximum tolerated dose (MTD) of olaparib + TRT. Secondary objectives included in-field local recurrence rate, progression-free survival, and overall survival. RESULTS:Between October 2018 and March 2022, 24 patients with a median age of 68 years were treated (median follow-up, 11.4 months) with platinum/etoposide and 30 Gy/10 fractions TRT; 10 patients also received atezolizumab. The MTD of olaparib with TRT was 200 mg twice daily. There were three grade 3 (G3) dose-limiting adverse events (AE), including pneumonitis/pneumonia, esophagitis, and abdominal pain. The most common G2 to G3 treatment-related AE were esophagitis (n = 12) and pneumonitis/pneumonia (n = 2). There were no G4 or G5 AE. The 12-month cumulative incidence of local recurrence was 27%, and the median progression-free survival and overall survival were 3.6 and 17.7 months, respectively. CONCLUSIONS:This study established the MTD and recommended a phase II dose of olaparib at 200 mg twice daily with concurrent low-dose TRT, and the combination seemed safe without unexpected toxicities.

Proteolysis-targeting chimeras (PROTACs) are catalytic protein degraders with promising preclinical activity. The clinical translation of PROTACs has been limited by poor pharmacologic properties and toxicities, in part due to their "non-druglike" characteristics, including large molecular weights. We found that the vast majority of PROTACs can self-assemble into nanoparticles, yielding nanoparticle PROTACs (nanoPROTACs) with ultrahigh drug loadings. While PROTAC molecular features can be deleterious to their pharmacokinetic properties, we found that they can drive nanoencapsulation more efficiently than FDA-approved small-molecule drugs. Using structure-based prediction algorithms, we identified spatial autocorrelation molecular descriptors that defined nanoPROTAC formation with 96% sensitivity at 100% specificity. NanoPROTACs, targeted to the tumor microenvironment via P-selectin, led to significantly enhanced tumor drug uptake, target degradation, tumor growth inhibition, and overall survival in solid tumor xenografts. These findings offer a broad strategy to improve the pharmacologic properties and therapeutic index of PROTACs and potentially other non-druglike experimental therapeutics.

Association of PTV and dosimetry with toxicities.

Correlation of planning target volume (PTV) with development of esophagitis/dysphagia.

Purpose: Antibody drug conjugates (ADCs) are an increasingly important class of therapeutics among patients with breast, lung, urothelial, and other malignancies. Guidelines recommend local therapy and continuation of current systemic therapy among patients with isolated brain relapse. We describe the clinical outcomes of this approach among patients receiving ADCs. Methods and Materials: We queried our institutional database for patients receiving radiation therapy (RT) in the setting of isolated brain progression on ADCs with a plan to continue same-line therapy after radiation. Patients with ≤3 brain metastases at the time of recurrence were categorized as oligoprogressive. Study endpoints included overall survival, progression-free survival (PFS), and the cumulative incidence of next therapy from the start of local therapy. Results: We identified 17 patients receiving ADC therapy with isolated brain progression treated with radiation (stereotactic radiosurgery [SRS]: n = 13, whole brain radiation: n = 4). All patients received concurrent ADC and RT. The median follow-up from local therapy was 29.5 months (95% CI, 21.4-not reached). The median overall survival was 19 months (95% CI, 16-not reached), and the median PFS was 8.1 months (range, 6.7-19 months). One lesion treated with SRS had local failure 21 months after treatment, and the 24-month cumulative incidence of local failure across the entire cohort was 1.6% (95% CI, 0.13%-7.7%). The 6-month cumulative incidence of radiation necrosis was 12% (95% CI, 1.8%-32%). The cumulative incidence of next therapy at 6 and 12 months was 47% (95% CI, 22%-69%) and 71% (95% CI, 41%-87%), respectively, and was significantly lower among patients with oligoprogressive brain recurrence. After SRS, 2 patients were without evidence of disease, discontinued systemic therapy, and were stable on observation at last follow-up. Conclusions: To the best of our knowledge, this is the first clinical report of outcomes using the guideline-recommended approach of local therapy for isolated brain relapse among patients receiving ADCs. Local therapy may delay the need for next line systemic therapy, particularly among patients with oligoprogressive brain relapse.

Overall (possibly, probably or definitely related) treatment-related toxicities by use of prior immunotherapy.

Representativeness of study participants.

Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT). Methods and Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified. Comparative VMAT plans (XRT1) using matched BP dose constraints were developed. A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy. Incidence of brachial plexopathy was also assessed. Results: Ten consecutive patients were identified. Median time between RT courses was 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (range, 42.6-60.0), 50.4 Gy relative biologic effectiveness (RBE) (45.0-64.4), and 102.4 Gy (RBE) (95.0-120.0), respectively. Median follow-up was 15 months (5-33) and 18 months for living patients (11-33) Mean BP max was 37.5 Gy (RBE) for PBT1 and 36.9 Gy for XRT1. Target volume coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were numerically lower for XRT1 versus PBT1. Similarly, axilla I -III and supraclavicular area coverage were significantly higher for PBT2 than XRT2 at dose levels of V55%, V65%, V75%, V85%, and V95%. Only axilla I V55% did not reach significance (P = .06) favoring PBS -PT. Two patients with high cumulative BPmax (95.2 Gy [RBE], 101.6 Gy [RBE]) developed brachial plexopathy symptoms with ulnar nerve distribution neuropathy without pain or weakness (1 of 2 had symptom resolution after 6 months without intervention). Conclusions: PBS -PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high -risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality. (c) 2023 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

COVID-19 is associated with characteristic lung CT findings. Radiotherapy simulation CT scans may reveal characteristic COVID-19 findings and identify patients with active or prior infection. We reviewed patients undergoing CT simulation at a major cancer center in an early epicenter of the COVID-19 pandemic in the United States. Scans were reviewed by radiation oncologists using established radiographic criteria for COVID-19 pneumonia. Radiographic classifications were compared with available COVID-19 PCR test results. A one -tailed t -test was used to compare the rate of positive COVID-19 tests in radiographically suspicious vs. non -suspicious groups. Scans deemed suspicious were re-reviewed by expert diagnostic radiologists. 414 CT simu-lation scans were performed on 400 patients. 119 patients had COVID-19 PCR test results available. Radiation oncologists considered 71 scans (17.1%) suspicious for COVID-19. Of these, 23 had corresponding COVID-19 PCR tests, and 3/23 (15.7%) were positive for COVID. 107 non-suspicious scans had corresponding COVID-19 test results, and 9 were positive (8.4%). The difference in positive test results between suspicious and non -suspicious groups was not significant (p = 0.23). Upon re-review by a diagnostic radiologist, 25 (35%) scans deemed suspicious by radiation oncologists were confirmed to meet criteria, while the rest were re-classified as "atypical" for COVID-19. We conclude that radiotherapy simulation CT scans can be reviewed for signs of COVID-19 pneumonia by radiation oncologists. However, suspicious CT simulation was not associated with a higher incidence of COVID infection compared with non-suspicious CT simulation, and there was low concor-dance between radiation oncologist and diagnostic radiologist classification of scans.

Patients with cancer have a unique susceptibility to coronavirus disease 2019 (COVID-19) [1,2]. Multiple reports have assessed the impact of anti-neoplastic therapies on COVID-19 outcomes in these patients [3–6], and although radiotherapy (RT) has been investigated [1,4,6], the exact impact of RT dose to the cardiopulmonary system on COVID-19 outcomes is largely unknown.

Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and therapeutic responses, including the radiation response. We present combined SP analysis and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant and also distinct effects of radiation on immune cell populations within the tumor microenvironment.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP + exosomes. Moreover, uptake of CEMIP + exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2 , Tnf and Ccl/Cxcl , known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

BDNF promotes the neural and behavioral plasticity induced by cocaine or other stimulant drugs of abuse via actions on the mesolimbic dopamine system, which is composed of dopamine neurons in the ventral tegmental area (VTA) of the midbrain and their anterior projections to the nucleus accumbens (NAc) and other forebrain regions1–3. Previous studies have shown that BDNF-TrkB activity and its downstream signaling cascades are induced in NAc by cocaine exposure4–6. In addition, manipulations that enhance BDNF signaling in the VTA-NAc circuit increase rewarding and locomotor responses to cocaine, whereas suppressing BDNF signaling has the opposite effect5,7–10. In marked contrast, we recently found that chronic morphine suppresses Bdnf gene expression in mouse VTA and that such a blockade enhances rewarding and locomotor responses to morphine by augmenting dopamine neuron activity11. Chronic opiates also induce some unique biochemical and morphological alterations in VTA, such as downregulation of intracellular neurotrophin signaling cascades and reduced soma size of VTA dopamine neurons, which are not seen with stimulants12–15. Notably, some of these changes are reversed by direct administration of BDNF into this brain region. Despite this evidence for an inverse relationship between BDNF activity in VTA and morphine action, the transcriptional mechanisms underlying Bdnf suppression by morphine are largely unknown. We carried out a comprehensive analysis of epigenetic regulation at the Bdnf gene and observed a series of interacting chromatin mechanisms that mediate morphine’s downregulation of Bdnf transcription in rat VTA. We found that unique binding patterns of RNA polymerase II (Pol II), permissive and repressive histone modifications, their histone-modifying enzymes and related regulatory proteins, and key transcription factors at specific Bdnf promoters were associated with morphine-induced Bdnf suppression in this brain region and with enhanced behavioral responses to opiates.

Dose-painting stereotactic body radiation therapy (DP-SBRT) is a valuable tool that can be considered for reirradiation as a means to deliver effective therapy and minimize the risk of toxicity. With recent US Food and Drug Administration approval for immune checkpoint blockade for several metastatic cancers, immunotherapy is changing the landscape of cancer treatment. Radiation therapy (RT) may serve to boost the local and systemic response to immune therapy through immune stimulatory mechanisms. [1] Sharabi AB Lim M DeWeese TL Drake CG Radiation and checkpoint blockade immunotherapy: Radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015; 16: e498-e509 Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar Here we present a case of an exceptional response to combination RT with immunotherapy in a patient with prior RT to the treated region.

Objectives: To evaluate the sites of nodal failure (NF) of nasopharyngeal carcinoma (NPC) treated with intensitymodulated radiation therapy (IMRT).Study Design: Retrospective chart review.Methods: We reviewed the records of 165 patients with nonmetastatic NPC treated with IMRT between July 1998 and April 2011 at our institution. Recurrent nodes were delineated on imaging and coregistered with the original treatment planning computed tomography. Failures were assessed as in-field, out-field, or marginal based on the relative volumes of the recurrent nodes covered by the original dose distribution.Results: Ten patients had NF at a median follow-up of 70.4 months for surviving patients. The 3-and 5-year overall survival and NF rates were 88.7%, 76.0% and 5.8%, 7.7%, respectively. Six of the nodal failures were in-field, of which five occurred in level II; whereas four had out-field failures, all of which were in the protected parotid gland area. There were no recurrences in level 1b despite this region being protected. The cumulative 3-and 5-year failure rates in the parotid gland area were 2.2% and 3.1%, respectively. Three patients with parotid failure initially had subcentimeter, nonspecific nodules in the same locations of the parotid gland as the recurrent nodes.Conclusion: Nodal failure is uncommon after IMRT in NPC. Recurrence in the parotid gland region accounts for all of the out-field failures and 40% of NF in our study. Comprehensive assessment of nodules in or around the parotid gland is therefore a key aspect of treatment planning and follow-up.

Background: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations.Results: We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain.Conclusions: We establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.

Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.