Radiosensitive Tumors Research Articles

Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.

Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.

Ku80-Targeted pH-Sensitive Peptide-PNA Conjugates Are Tumor Selective and Sensitize Cancer Cells to Ionizing Radiation.

The development of therapeutic agents that specifically target cancer cells while sparing healthy tissue could be used to enhance the efficacy of cancer therapy without increasing its toxicity. Specific targeting of cancer cells can be achieved through the use of pH-low insertion peptides (pHLIP), which take advantage of the acidity of the tumor microenvironment to deliver cargoes selectively to tumor cells. We developed a pHLIP-peptide nucleic acid (PNA) conjugate as an antisense reagent to reduce expression of the otherwise undruggable DNA double-strand break repair factor, KU80, and thereby radiosensitize tumor cells. Increased antisense activity of the pHLIP-PNA conjugate was achieved by partial mini-PEG sidechain substitution of the PNA at the gamma position, designated pHLIP-αKu80(γ). We evaluated selective effects of pHLIP-αKu80(γ) in cancer cells in acidic culture conditions as well as in two subcutaneous mouse tumor models. Fluorescently labeled pHLIP-αKu80(γ) delivers specifically to acidic cancer cells and accumulates preferentially in tumors when injected i.v. in mice. Furthermore, pHLIP-αKu80(γ) selectively reduced KU80 expression in cells under acidic conditions and in tumors in vivo. When pHLIP-αKu80(γ) was administered to mice prior to local tumor irradiation, tumor growth was substantially reduced compared with radiation treatment alone. Furthermore, there was no evidence of acute toxicity associated with pHLIP-αKu80(γ) administration to the mice. These results establish pHLIP-αKu80(γ) as a tumor-selective radiosensitizing agent. IMPLICATIONS: This study describes a novel agent, pHLIP-αKu80(γ), which combines PNA antisense and pHLIP technologies to selectively reduce the expression of the DNA repair factor KU80 in tumors and confer tumor-selective radiosensitization.

Leptomeningeal disease after surgical resection and radiosurgery for brain metastases and neurologic death: A multi-institutional analysis.

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

Treatment of primary Merkel cell carcinoma: Radiotherapy can be an effective, less morbid alternative to surgery

The standard treatment approach for localised Merkel cell carcinoma (MCC) is wide surgical excision followed by adjuvant radiotherapy. However extensive surgery for locally advanced MCC may cause morbidity and disfigurement, compromise function and delay adjuvant therapy. Since MCC is a highly radiosensitive tumour, an alternative treatment option for advanced MCCs, especially those in anatomically challenging locations, is radiotherapy. Complete and durable control is achieved in up to 90% of cases if the definitive treatment of primary MCC is with radiotherapy. It is generally less morbid than surgery and can produce excellent cosmetic and functional outcomes.

Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine.

BackgroundWhereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenografts.MethodsWe generated zebrafish xenografts using colorectal cancer cell lines and patient biopsies without in vitro passaging, and developed a fast radiotherapy protocol consisting of a single dose of 25 Gy. As readouts of the impact of radiotherapy we analyzed proliferation, apoptosis, tumor size and DNA damage.FindingsBy directly comparing isogenic cells that only differ in the KRASG13D allele, we show that it is possible to distinguish radiosensitive from radioresistant tumors in zebrafish xenografts, even in polyclonal tumors, in just 4 days. Most importantly, we performed proof-of-concept experiments using primary rectum biopsies, where clinical response to neoadjuvant chemoradiotherapy correlates with induction of apoptosis in their matching zebrafish Patient-Derived Xenografts-Avatars.InterpretationOur work opens the possibility to predict tumor responses to radiotherapy using the zebrafish Avatar model, sparing valuable therapeutic time and unnecessary toxicity.

BT-10 A RARE CASE OF RADIATION-INDUCED GLIOBLASTOMA 29 YEARS AFTER TREATMENTS OF GERMINOMA

BACKGROUNDGerminoma is one of the most radiosensitive tumors. Although radiotherapy (RT) can lead to long term-survival, it has the possibility to cause adverse effects. One of the more serious side effects include radiation-induced tumors that can contribute to a life-long prognosis.Case presentationA 40-year-old man was diagnosed with left basal ganglia germinoma at the age of 11 years old. Postoperatively, he received whole-brain radiotherapy 40Gy, focal radiotherapy 9.26Gy, and craniospinal irradiation. After these treatments, he was free from tumor recurrence or a secondary tumor during the long-term follow up. However, after 29 years, he began experiencing aphasia. A Magnetic Resonance Imaging (MRI) showed a developing 4.5cm round mass in the left parietal lobe with marked surrounding edema. He underwent surgical resection of the tumor at the left partial lobe. Pathological examination showed the tumor to consist of unclear pleomorphism, and the diffuse proliferation of heterocyst. Therefore, the pathologic diagnoses concluded as glioblastoma (Ki-67 labeling index was 50%). Conclusion: The tumor developed in the previously irradiated field, and it was not present prior to the RT. He did not suffer from pathologies favoring the development of the tumor. The interval between the radiation exposure and the onset of the second tumor was approximately 29 years, and the histotype of the tumor differed from the original tumor. Considering these clinical features, we diagnosed the glioblastoma as a radiation-induced tumor. Radiation-induced malignant glioma occurs frequently in patients after the treatment for acute lymphoblastic leukemia. Therefore, the radiation-induced malignant glioma after the treatment for germinoma is rare. Regardless of age, histology, and RT dosages, the patient has the possibility to develop radiation-induced malignant glioma. In conclusion, it is necessary to have careful monitoring even after 20–30 years of RT.

Tumor mutation burden, immune checkpoint crosstalk and radiosensitivity in single-cell RNA sequencing data of breast cancer

IntroductionWe analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells. Materials and methodsscRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand–receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells. ResultsMost RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand–receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand–receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells. ConclusionsRR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer.

Abstract AP25: TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE

Abstract OBJECTIVE: Ovarian cancer is the most common cause of gynecologic cancer-related death in the United States. The majority of patients diagnosed with ovarian cancer present with stage III or IV disease in which the tumor has disseminated beyond the ovaries and pelvic organs to the peritoneum and mesothelial lining of abdominal organs. Despite advances in ovarian cancer treatments including maximal cytoreductive surgery, chemotherapy and checkpoint-blockade immunotherapy, recurrence is common and prognosis remains poor. Ovarian cancer is a radiosensitive tumor; however, use of total abdominal irradiation (TAI) has fallen out of favor in the past 15 years due to high toxicity, particularly of the gastrointestinal (GI) tract. In prior studies, ultra-rapid FLASH radiation spares normal tissues, such as the lung and skin, from toxic effects of radiation. This suggests that FLASH may be an effective strategy to reduce complications of radiotherapy while maintaining antitumor control. We developed a FLASH irradiation system for mice using a linear accelerator that generates 16 MeV electrons at a high beam current and delivers large doses of radiation in a single beam in <500ms. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while FLASH radiotherapy delivers a dose-rate of >40 Gy/second. Our objective is to develop a method for delivering TAI using FLASH and assess toxicity. METHODS: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation in increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Normal tissue toxicity was determined by measuring total body weights, stool counts, histological analysis, and survival. RESULTS: Seven cohorts of mice were analyzed: five unirradiated controls, eight received 8.5Gy, five received 10.5Gy and five received 12 Gy of either TAI-FLASH or TAI-CONV. Stool counts were unchanged from controls in TAI-FLASH mice 5 days post-irradiation at all doses. In the TAI-CONV cohort, a 50% stool quantity decrease was noted after 8.5Gy and a 63% stool quantity decrease was noted after 12Gy at 5 days post-TAI. Histological analysis of the duodenum post-irradiation demonstrated that TAI-FLASH has a protective effect on the mucosal architecture. Weights remained unchanged across all groups. The survival analysis was most notable for all of the TAI-CONV mice having died by day 9 whereas all of the TAI-FLASH mice survived. CONCLUSIONS: These data demonstrate FLASH protects against death from TAI and improves the epithelial integrity of the lower GI tract following TAI compared to conventional radiation in a preclinical model. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize TAI-FLASH for treatment of ovarian peritoneal metastases. Citation Format: Karen Levy MD, Joshua Eggold BA, Marjan Rafat PhD, Emil Schuler PhD, Hussein Shehade PhD, Daniel Fregoso BS, Jose Vilches-Moure DVM PhD, Albert Koong MD PhD, Peter Maxim PhD MSc, Billy W Loo MD PhD, Erinn Rankin PhD. TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP25.

A Phase 2 Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases

In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates after conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of postoperative stereotactic body RT (SBRT) in patients who have undergone surgical intervention for spine metastases. We hypothesize that postoperative SBRT to the spine would be associated with higher local control than historical rates after conventional RT. Thirty-five adult patients with a Karnofsky Performance Status score ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. Thirty-three patients were treated. Two patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurological examinations and computed tomography and/or magnetic resonance imaging every 3 months. Neurologic function was assessed at the same time points using the American Spinal Injury Association (ASIA) impairment score. Pain was rated according to the 10-point visual analogue scale and MD Anderson Cancer Center brief pain index. Toxicity was recorded according to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4. The primary objective was the rate of radiographic local recurrence at 12 months after completion of SBRT. Patient characteristics were as follows: 34.3% had radioresistant primaries; 71.4% were ASIA E and the remainder ASIA D; and the median baseline Karnofsky Performance Status score was 70 (range, 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval, 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range, 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure, or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range, 0-9.4 months). This prospective study of postoperative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared with conventional RT; however, a formal comparative study is warranted.

Immune dysregulation underpins radioresistance in nasopharyngeal carcinoma (NPC).

52 Background: Radiotherapy (RT) is a primary modality in the treatment of NPC. However, 30% of patients present with disease recurrence following RT of this radiosensitive tumor. Here, we investigated the molecular and immune profiles associated with radioresistant (RR) NPC. Additionally, we investigated for aberrant molecular pathways in paired recurrences of patients to uncover new drivers underpinning radioresistance. Methods: We prospectively recruited a cohort of 100 NPC patients who completed definitive RT/chemoRT; including 30 cases who were recruited at recurrence. Whole exome sequencing (WES) at 200x was performed to identify low frequencies ( < 1%) of true somatic nucleotide variants (SNVs) and copy number alterations (CNAs). Transcriptomic profiles from RNAseq were interrogated using supervised and unsupervised statistical approaches to determine aberrant pathways that were significantly associated with RR. Results: Genomic instabilityas characterized by percentage genome alteration (PGA) was comparable in our cohort. Additionally, we did not observe any common or exclusive CNAs between RR- and nr-NPC cases. Based on a constellation of immune-related signatures, we observed an “immune-cold” profile that is associated with RR-NPC compared to nr-NPC controls, which is characterized by low expression of CD8+ T cell infiltration and interferon-γ response. Expectedly, pathways relating to angiogenesis, hypoxia and NOTCH signaling were upregulated in the RR-NPC cohort. Interestingly, we observed a reversal of the immune phenotype from “cold” to an enrichment of effector T cell infiltration in the paired recurrences. Conclusions: Here, we present a comprehensive mutational landscape of RR-NPC, which revealed the potential role of the immune environment in modulating RR. The longitudinal immune dysregulation of the tumor microenvironment between the de novo tumors and recurrences could be a driver or passenger event during the onset of recurrence.

A Near-Infrared Phosphorescent Nanoprobe Enables Quantitative, Longitudinal Imaging of Tumor Hypoxia Dynamics during Radiotherapy.

Hypoxia plays a key role in tumor resistance to radiotherapy. It is important to study hypoxia dynamics during radiotherapy to improve treatment planning and prognosis. Here, we describe a luminescent nanoprobe, composed of a fluorescent semiconducting polymer and palladium complex, for quantitative longitudinal imaging of tumor hypoxia dynamics during radiotherapy. The nanoprobe was designed to provide high sensitivity and reversible response for the subtle change in hypoxia over a narrow range (0-30 mmHg O2), which spans the oxygen range where tumors have limited radiosensitivity. Following intravenous administration, the nanoprobe efficiently accumulated in and distributed across the tumor, including the hypoxic region. The ratio between emissions at 700 and 800 nm provided quantitative mapping of hypoxia across the entire tumor. The nanoprobe was used to image tumor hypoxia dynamics over 7 days during fractionated radiotherapy and revealed that high fractional dose (10 Gy) was more effective in improving tumor reoxygenation than low dose (2 Gy), and the effect tended to persist longer in smaller or more radiosensitive tumors. Our results also indicated the importance of the reoxygenation efficiency of the first fraction in the prediction of the radiation treatment outcome. In summary, this work has established a new nanoprobe for highly sensitive, quantitative, and longitudinal imaging of tumor hypoxia dynamics following radiotherapy, and demonstrated its value for assessing the efficacy of radiotherapy and radiation treatment planning. SIGNIFICANCE: This study presents a novel nanoagent for the visualization and quantification of tumor hypoxia.

Predictors of Leptomeningeal Disease after Hypofractionated Stereotactic Radiotherapy for Intact and Resected Brain Metastases

Hypofractionated stereotactic radiotherapy (HSRT) for patients with resected or large intact brain metastases is increasing in clinical practice; however, reporting on patterns of failure, specifically leptomeningeal disease (LMD) is lacking. In this study we identify patterns of LMD and determine predictors for developing LMD in patients with intact or resected brain metastases treated with 5-fraction HSRT. A single-institution retrospective review of a prospective database identified patients receiving HSRT for intact brain metastases or surgical cavities. Patient, tumor, and treatment factors were extracted. Patterns of LMD were stratified into four groups based on their radiographic presentation: focal classical, diffuse classical, focal nodular and diffuse nodular. Univariate and multivariable analyses were conducted to determine potential predictors for developing LMD. HSRT was delivered to 320 intracranial lesions (57% intact and 43% surgical cavities) in 235 patients with a median follow-up of 13.4 months (range, 0.8 to 60 months). The most common dose regimen was 30Gy in 5 fractions (65%). Overall, the incidence of developing LMD was 19% and the most common radiographic presentation of LMD was a diffuse nodular pattern (44%). The 6-month and 1-year rates of LMD were 7.5% and 12%, respectively. On multivariable analysis for the entire cohort, cavity lesions were statistically significant predictors of LMD compared with intact metastases (24% vs. 7%; hazard ratio=0.47; p=0.01). For cavities alone, radiosensitive tumors (including non-small cell lung, small cell and breast cancer) were the only statistically significant predictor of LMD (p=0.030), with a trend towards significance observed for increasing maximum tumor diameter (p=0.050). From the date of LMD diagnosis, the median overall survival (OS) for the entire cohort was 3.8 months (range, 0.2 to 20.8 months). The 6-month and 12-month OS rates were 42% and 15%, respectively. No statistically significant difference in OS was observed between the four patterns of LMD (p=0.203) or between nodular and classical patterns (p=0.267). For patients treated with HSRT, surgical cavities are at increased risk of developing LMD compared to intact brain metastases. Our findings suggest that despite the ability of HSRT to safely escalate tumor dose compared with single-fraction SRS, it may still be insufficient to mitigate the heightened risk of LMD observed with surgical cavities. Further research is required to determine optimal strategies to reduce LMD rates.

P49. Treatment preferences for patients with metastatic spine disease with indeterminate spinal instability neoplastic scores (SINS 7-12)

BACKGROUND CONTEXT As the survival of cancer patients increases, so has the incidence of metastatic spine disease (MSD). While surgical stabilization has demonstrated improved outcomes for some patients, there is also increased perioperative morbidity. The Spine Instability Neoplastic Score (SINS) assigns values to clinical and radiographic findings, providing recommendations for surgical stabilization. Scores 12 are best treated with surgical stabilization. Unfortunately, there are no clear recommendations for patients with instability (SINS of 7-12). The purpose of this exploratory study is to examine treatment preferences among surgeons and radiation oncologists involved in the care of patients with MSD of indeterminate instability. PURPOSE To better understand decision-making principles in the treatment of MSD patients with indeterminate SINS. STUDY DESIGN/SETTING Multi-institutional survey study. PATIENT SAMPLE No actual patients were reviewed for this study, only representative clinical vignettes. OUTCOME MEASURES Survey participant results regarding treatment decision-making in MSD patients with indeterminate SINS. METHODS Spine surgeons and radiation oncologists from five academic, tertiary care institutions were sent an online survey using a secure REDcap database. Participants were asked about their practice characteristics and presented seven cases, including clinical vignettes and relevant imaging studies. They were asked to answer questions regarding treatment recommendations, as well as the hierarchy of factors influencing these recommendations. Five cases highlighted patients with indeterminate SINS and no neurologic deficits, while two additional cases presented patients with a SINS >12 and a SINS RESULTS Seventeen physicians from 5 institutions completed the survey, including 10 orthopaedic surgeons, 5 neurosurgeons, and 2 radiation oncologists. A total of 64.7% of participants have practiced for >10 years and 76.5% treat >10 MSD patients yearly. Eighty-five responses for 5 indeterminate cases were recorded. Surgical stabilization was recommended 43.5% of the time. Dividing indeterminate cases into low (SINS 7-9) vs high (SINS 10-12) categories, there was a trend toward surgical intervention in the high SINS cases (49.0% vs 35.3%). Pain control was the most common indication for surgical intervention (67.6% of responses), while the mechanical nature of pain (32.4%) and degree of epidural spinal cord compression (27.0%) were the most commonly cited anatomic factors for surgical stabilization. Primary cancer type more commonly influenced nonsurgical management (31.3%), which most often consisted of radiation therapy (77.0%). Radiation was more commonly selected in patients presenting with radiosensitive tumors (94.1%) vs. more radioresistant tumors (60.8%). There was an increase in surgical stabilization of radioresistant tumors compared to radiosensitive tumors (49.0% vs 35.3%). CONCLUSIONS As our survey responses demonstrate, there is uncertainty in the surgical decision-making for patients with indeterminate SINS, even among experienced, high-volume physicians. Although pain control was identified as the most common patient factor in determining treatment, surgical stabilization was more often performed when pain was mechanical, relating to patient movement and function. However, physicians were more likely to recommend non-surgical treatment, most commonly radiation, when patients had radiosensitive tumors, regardless of their SINS. Based on survey responses, MSD patients with indeterminate SINS of 10-12, presenting with mechanical pain and radioresistant tumors, are more likely to have surgical stabilization recommended. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Predictors of leptomeningeal disease following hypofractionated stereotactic radiotherapy for intact and resected brain metastases

The objective was to evaluate the risk and predictors of developing leptomeningeal disease (LMD) in patients with brain metastases treated with 5-fraction hypofractionated stereotactic radiotherapy (HSRT). Patients treated with HSRT for intact brain metastases and/or surgical cavities were reviewed from a prospectively maintained database. Radiographic patterns of LMD were classified as focal classical, diffuse classical, focal nodular, and diffuse nodular. HSRT was delivered, most commonly 30 Gy in 5 fractions, to 320 intracranial lesions (57% intact and 43% surgical cavities) in 235 patients. The median follow-up was 13.4 months (range, 0.8 to 60 mo). LMD developed in 19% of patients with a 1-year LMD rate of 12%. From the diagnosis of LMD, the median overall survival (OS) was 3.8 months (range, 2-20.8 mo). The most common LMD pattern was diffuse nodular (44%). No difference in OS was observed between LMD patterns (P = 0.203). Multivariable analysis identified surgical cavities at significantly higher risk of LMD compared with intact lesions (odds ratio [OR] = 2.30, 95% CI: 1.24, 4.29, P = 0.008). For cavities, radiosensitive tumors (OR = 2.35, 95% CI: 1.04, 5.35, P = 0.041) predicted for LMD, while, for intact metastases, patients receiving treatment with targeted agents or immunotherapy (TA/I) were at lower risk (OR = 0.178, 95% CI: 0.04, 0.79, P = 0.023). Patients who had a brain metastasis resected were at an increased risk of LMD. OS was poor despite treatment of LMD, and no differences in OS based on the pattern of LMD was observed. Treatment with TA/I was observed to be protective against LMD and requires further study.

Mismatch Repair System Deficiency Is Associated With Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer

Defective mismatch repair system (dMMR) has been shown to have a favorable impact on outcome in patients with colorectal cancer treated with surgery or immunotherapy, with adjuvant chemotherapy being discouraged unless there is nodal involvement. Its impact on radiosensitivity is unknown in patients with colorectal cancer. Patients treated for locally advanced rectal cancer between 2000 and 2016 were studied. Reported points included age, sex, clinical and radiologic tumor stages at diagnosis, modalities of neoadjuvant treatment, posttreatment pathologic staging, tumor regression score, and local, distant relapse-free, and overall survival. An inverse probability of treatment weighting propensity score analysis was performed to evaluate the association of mismatch repair proficiency with surgical and clinical outcomes. Among the 296 patients included, 23 (7.8%) had dMMR. Median follow-up was 43.0 months (interquartile range, 27.9-66.7). Patients with dMMR were significantly younger than the others. After inverse probability of treatment weighting propensity score matching, dMMR patients had higher pathologic downstaging rate (P < .0001), higher tumor regression grade (P = .024), and a longer recurrence-free survival (P < .0001). dMRR was associated with significant tumor downstaging after neoadjuvant chemoradiation and with increased recurrence-free survival. dMMR patients may have more radiosensitive tumors.

Volumetric changes of intracranial metastases during the course of fractionated stereotactic radiosurgery and significance of adaptive planning.

Fractionated Gamma Knife surgery (FGKS) has recently been used to treat large brain metastases. However, little is known about specific volume changes of lesions during the course of treatment. The authors investigated short-term volume changes of metastatic lesions during FGKS. The authors analyzed 33 patients with 40 lesions who underwent FGKS for intracranial metastases of non-small-cell lung cancer (NSCLC; 25 patients with 32 lesions) and breast cancer (8 patients with 8 lesions). FGKS was performed in 3-5 fractions. Baseline MRI was performed before the first fraction. MRI was repeated after 1 or 2 fractions. Adaptive planning was executed based on new images. The median prescription dose was 8 Gy (range 6-10 Gy) with a 50% isodose line. On follow-up MRI, 18 of 40 lesions (45.0%) showed decreased tumor volumes (TVs). A significant difference was observed between baseline (median 15.8 cm3) and follow-up (median 14.2 cm3) volumes (p < 0.001). A conformity index was significantly decreased when it was assumed that adaptive planning was not implemented, from baseline (mean 0.96) to follow-up (mean 0.90, p < 0.001). The average reduction rate was 1.5% per day. The median follow-up duration was 29.5 weeks (range 9-94 weeks). During the follow-up period, local recurrence occurred in 5 lesions. The TV showed changes with a high dose of radiation during the course of FGKS. Volumetric change caused a significant difference in the clinical parameters. It is expected that adaptive planning would be helpful in the case of radiosensitive tumors such as NSCLCs or breast cancer to ensure an adequate dose to the target area and reduce unnecessary exposure of normal tissue to radiation.

Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers because it is highly resistant to every available therapeutic strategy, in particular conventional chemotherapy or radiotherapy (RT). Sensitizing tumor cells to existing treatments remains a good option to obtain fast and applicable results. Considering that ionizing radiations induce radiolysis-derived reactive oxygen species (ROS), we hypothesized that ROS-inducing bioactive food components (BFCs) could exacerbate ROS-related cell damages, including DNA double stranded breaks (DSBs), leaving the cellular ROS scavenging systems overwhelmed, and precipitating tumor cell death. Combination of resveratrol and capsaicin radiosensitized radiosensitive tumor cells, but RT did not increase BFC combination toxicity in radioresistant tumor cells. BFC addition to RT increased ROS production and led to significant tumor volume reduction in xenografted mouse preclinical model. Strikingly, BFCs inhibited RT-induced DNA damage molecular response by strongly limiting the first steps of DSB repair, and by keeping cells in cell cycle, provoking exacerbated intrinsic apoptosis. This study positions BFCs as potent radiosensitizers when combined, and identifies an actionable molecular pathway by resveratrol and capsaicin combination.

Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma.

Stereotactic body radiotherapy is utilized to treat lung cancer. The mechanism of tumor response to high-dose radiotherapy (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing versus indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of ataxia-telangiectasia mutated gene (Atm; KPAFL/+ or KPAFL/FL), whereas adeno-FlpO-infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of Atm in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVAFL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPAFL/FL mice. Primary tumor cell lines lacking Atm expression also demonstrated enhanced radiosensitivity as determined via a clonogenic survival assay. These findings indicate that tumor cells, rather than endothelial cells, are critical targets of HDRT in primary murine lung cancer. SIGNIFICANCE: These findings establish radiosensitizing tumor cells rather than endothelial cells as the primary mechanism of tumor response to high-dose radiotherapy, supporting efforts to maximize local control by radiosensitizing tumors cells.See related commentary by Hallahan, p. 704.

Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome.

SummaryIntracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background.Learning points:Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism.The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation.Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.

Renal Cancer is Not Radioresistant: Slowly but Continuing Shrinkage of the Tumor After Stereotactic Body Radiation Therapy.

Purpose:To evaluate the safety and efficacy of stereotactic body radiation therapy for primary lesion of renal cell carcinoma with long-term and regular follow-up of tumor size and renal function.Methods:This prospective study included 13 patients treated with stereotactic body radiation therapy for primary lesion of stage I renal cell carcinoma between August 2007 and June 2016 in our institution. Diagnosis of renal cell carcinoma was made by 2 radiologists using computed tomography or magnetic resonance imaging. A dosage of 60 Gy in 10 fractions or 70 Gy in 10 fractions was prescribed. The higher dose was selected if dose constraints were satisfied. Tumor response on imaging examination, local progression-free rate, overall survival, and toxicity were assessed.Results:The mean follow-up period was 48.3 months (range: 11-108 months). The tumors showed very slow but continuous response during long-term follow-up. Three cases (23.1%) showed transient progression during the short follow-up. The mean duration until the day on which partial response was confirmed among the partial or complete response cases was 22.6 months (95% confidence interval, 15.3-30.0 months). Local progression-free rate was 92.3% for 3 years and overall survival rate 91.7% for 2 years and 71.3% for 3 years. Twelve cases (92.3%) had impaired renal function at baseline. Renal function decreased slowly and mildly in most of the cases, but 2 cases of solitary kidney showed grade 4 or 5 renal dysfunction.Conclusion:All renal tumors decreased in size slowly but continuously for years after stereotactic body radiation therapy. Renal cancer can be treated radically with stereotactic body radiation therapy as a radiosensitive tumor, but careful attention should be given in cases with solitary kidney.