Stress-testing pelvic autosegmentation algorithms using anatomical edge cases.

Commercial autosegmentation has entered clinical use, however real-world performance may suffer in certain cases. We aimed to assess the influence of anatomic variants on performance. We identified 112 prostate cancer patients with anatomic variations (edge cases). Pelvic anatomy was autosegmented using three commercial tools. To evaluate performance, Dice similarity coefficients, and mean surface and 95% Hausdorff distances were calculated versus clinician-delineated references. Deep learning autosegmentation outperformed atlas-based and model-based methods. However, edge case performance was lower versus the normal cohort (0.12 mean DSC reduction). Anatomic variation presents challenges to commercial autosegmentation.

The Advantage of Proton Therapy in Hypothalamic-Pituitary Axis and Hippocampus Avoidance for Children with Medulloblastoma.

PURPOSE: Craniospinal irradiation (CSI) improves clinical outcomes at the cost of long-term neuroendocrine and cognitive sequelae. The purpose of this pilot study was to determine whether hypothalamic-pituitary axis (HPA) and hippocampus avoidance (HPA-HA) with intensity-modulated proton therapy (IMPT) can potentially reduce this morbidity compared with standard x-ray CSI. MATERIALS AND METHODS: We retrospectively evaluated 10 patients with medulloblastoma (mean, 7 years; range, 4-14 years). Target volumes and organs at risk were delineated as per our local protocol and the ACNS0331 atlas. An experienced neuroradiologist verified the HPA and hippocampus contours. The primary objective was CSI and boost clinical target volume (CTV) covering 95% of the volume (D95) > 99% coverage with robustness. Described proton therapy doses in grays are prescribed using a biological effectiveness relative to photon therapy of 1.1. The combined prescribed dose in the boost target was 54 Gy. Secondary objectives included the HPA and hippocampus composite average dose (Dmean ≤ 18 Gy). For each patient, volumetric modulated arc radiotherapy (VMAT) and tomotherapy (TOMO) plans existed previously, and a new plan was generated with 3 cranial and 1 or 2 spinal beams for pencil-beam scanning delivery. Statistical comparison was performed with 1-way analysis of variance. RESULTS: Compared with standard CSI, HPA-HA CSI had statistically significant decreases in the composite doses received by the HPA (32.2 versus 17.9 Gy; P < .001) and hippocampi (39.8 versus 22.8 Gy; P < .001). The composite HPA Dmean was lower in IMPT plans (17.9 Gy) compared with that of VMAT (21.8 Gy) and TOMO (21.2 Gy) plans (P = .05). Hippocampi composite Dmean was also lower in IMPT plans (21 Gy) compared with that of VMAT (27.5 Gy) and TOMO (27.2 Gy) plans (P = .02). The IMPT CTV D95 coverage was lower in IMPT plans (52.8 Gy) compared with that of VMAT (54.6 Gy) and TOMO (54.6 Gy) plans (P < .001) The spared mean volume was only 1.35% (19.8 cm3) of the whole-brain CTV volume (1476 cm3). CONCLUSION: We found that IMPT has the strong potential to reduce the dose to the HPA and hippocampus, compared with standard x-ray CSI while maintaining target coverage. A prospective clinical trial is required to establish the safety, efficacy, and toxicity of this novel CSI approach.

The Effect of Adjuvant Pelvic Radiotherapy on Distant Metastasis for Uterine Carcinosarcoma.

BACKGROUND: Uterine carcinosarcomas (UCS) are rare tumors that carry a poor prognosis and high recurrence rate. Standard treatment consists of surgical resection and chemotherapy, though the benefit of adjuvant radiotherapy (RT) has yet to be determined. This study assessed survival rates between patients with UCS who underwent surgical resection alone and patients who underwent combinations of surgery, chemotherapy, and RT. MATERIALS AND METHODS: We conducted a retrospective review of all patients who underwent surgical resection for UCS between 1993 and 2011 at a single institution. We assessed 3-year disease-free survival, locoregional recurrence-free survival, distant metastases-free survival (DMFS), and overall survival rates and utilized Kaplan-Meier modeling to analyze differences between UCS treatment modalities. RESULTS: Twenty-four patients underwent UCS surgical resection between 1993 and 2011. The mean age was 61 (range: 39 to 75 y). Of these patients, 100% (n=24) underwent surgical resection, 25% (n=6) underwent surgery and adjuvant chemotherapy, 29% (n=7) underwent surgery and adjuvant RT, and 33% (n=8) underwent surgery and adjuvant chemotherapy and RT. At 3 years median follow, there was no significant difference in overall survival between treatment modalities. The addition of radiation therapy conferred increased DMFS in patients undergoing surgery irrespective of adjuvant chemotherapy (44% vs. 83%, P=0.0211).In patients receiving adjuvant chemotherapy, the significant increase in DMFS persisted with the addition of RT (P=0.0310). Lymph node involvement (n=8) was associated with a lower locoregional recurrence-free survival (38% vs. 92%, P=0.0029). CONCLUSIONS: RT may offer a potential benefit in reducing the rate of distant metastases, though there were no statistically significant improvements in survival metrics.

"Was It Worth It?": A Pilot Study in Patient Perspectives on the Worthwhileness of Radiation Therapy.

OBJECTIVES: Radiation therapy is a core oncologic treatment, but literature detailing patient satisfaction post-treatment is sparse. The authors conducted a pilot study to determine whether a simple survey would be feasible to administer and could elucidate factors predictive of satisfaction with radiotherapy. MATERIALS AND METHODS: Patients with cancer receiving radiotherapy in an academic radiation oncology department from 2014 to 2015 received a 4-item radiotherapy-focused version of the "Was It Worth It?" questionnaire (r-WIWI) on the last day of treatment and at the first follow-up. Univariate analysis and logistic regression modeling were performed on collected patient and treatment characteristics to explore predictors of satisfaction. RESULTS: Two hundred patients completed an r-WIWI questionnaire at treatment completion and 60 at the time of the first follow-up. Seventy-one percent and 90% of patients found radiotherapy worthwhile on the last day of treatment and at first follow-up, respectively. Patients treated during the morning and for a longer duration as measured in elapsed days were more likely to report treatment being worthwhile. Age, sex, race, marital status, employment status, treatment intent or modalities, daily radiation treatment delays, distance traveled, insurance type, site of treatment, and cancer stage were not predictive of patient satisfaction. CONCLUSIONS: The r-WIWI survey was feasible to administer and most patients reported treatment being worthwhile on the last day of treatment and at first follow-up. Morning treatment times and longer treatment duration as measured in elapsed days were predictive of higher satisfaction in this pilot study. A broader study of factors associated with patient satisfaction with radiotherapy using the r-WIWI is indicated.

Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase.

Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.

Outcomes of intraoperative radiotherapy for early-stage breast cancer: Experience from a multidisciplinary breast oncology program.

BACKGROUND: Intraoperative radiotherapy (IORT) was implemented at our institution for early stage breast cancer patients including those with geographic or medical co-morbidity limitations to whole breast radiation therapy (WBRT). METHODS: Retrospective review of patients (n = 127) who underwent IORT from 2009 to 2016 for breast cancer. Demographics, pathology, toxicity, and recurrences were ascertained. RESULTS: The median age was 67 years (interquartile range: 62-73). At median follow-up (49.6 months), 5 patients (4%) had ipsilateral breast tumor recurrence with median time to recurrence of 36.8 months. Acute and late grade ≥3 skin toxicities were observed in 3.1% and 4.7% of patients, respectively. A subset (n = 7) who received prior ipsilateral WBRT was found to have no subsequent local recurrence, one case of acute grade 3 skin toxicity, and no late toxicity. CONCLUSIONS: IORT is a safe and effective alternative to whole breast radiotherapy, and serves as a suitable alternative to completion mastectomy in locally recurrent breast cancer.

Integrating nanomedicine into clinical radiotherapy regimens.

While the advancement of clinical radiotherapy was driven by technological innovations throughout the 20th century, continued improvement relies on rational combination therapies derived from biological insights. In this review, we highlight the importance of combination radiotherapy in the era of precision medicine. Specifically, we survey and summarize the areas of research where improved understanding in cancer biology will propel the field of radiotherapy forward by allowing integration of novel nanotechnology-based treatments.

Underutilization of the CROSS Regimen Among US Radiation Oncologists: A National Survey of Practice Patterns.

AIM: To examine patterns of clinical practice in locally advanced esophageal cancer among US radiation oncologists after publication of the CROSS trial. MATERIALS AND METHODS: US radiation oncologists were surveyed on 13 questions pertaining to the management of esophageal cancer. Respondents' demographics and their clinical rationale were analyzed for statistical association with their treatment recommendations. RESULTS: Few respondents (15%) offered the CROSS regimen to patients considered suitable surgical candidates, while a near-equivalent number (16%) prescribed between 41.4 and 50.4 Gy contingent upon radiation planning parameters. Among respondents who prescribed 50.4 Gy, 50% and 17% reported concurrent administration of carboplatin/paclitaxel and cisplatin/5-FU, respectively. Higher radiation doses, over 50.4 Gy, were utilized by 15% and 38% of respondents for borderline surgical candidates and candidates unfit for surgery, respectively. The majority of respondents believed that higher complete pathological response and R0 resection would be achieved, as well as higher toxicity conferred using 50.4 Gy instead of 41.4 Gy. A clinical trial comparing 41.4 Gy to 50.4 Gy with concurrent carboplatin/paclitaxel was supported by 76% of respondents. CONCLUSION: Despite results from the CROSS trial, the majority of responding US radiation oncologists do not offer 41.4 Gy with concurrent chemotherapy for surgically-fit patients with locally advanced esophageal cancer, believing that a higher dose will translate to improved response.

microRNA-451a regulates colorectal cancer proliferation in response to radiation.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. METHODS: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. RESULTS: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. CONCLUSIONS: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

MicroRNAs in Cancer: challenges and opportunities in early detection, disease monitoring, and therapeutic agents.

PURPOSE OF REVIEW: The goals of this review are to examine the usefulness of miRNAs as diagnostic and prognostic biomarkers for cancer and to evaluate the applicability of miRNAs as cancer therapeutics. RECENT FINDINGS: Examination of miRNA milieu from body fluids offers a new alternative for quick, affordable and easy analysis of disease status in patients. Blood-based exosomal miRNAs have increased stability and are an excellent choice for clinical cancer diagnostics and prognostics. Currently, there are many miRNA signatures associated with cancer and progression but there is no consensus among multiple sera and tumor sample studies. Off-target and immunological effects remains an obstacle for use of miRNAs as novel chemotherapeutics in the clinic. Recent developments in nanotechnology and drug delivery systems which target the tumor microenvironment may provide an alternative therapeutic approach with decreased toxicity. SUMMARY: This review critically evaluates the literature investigating the use of miRNAs as biomarkers and their future as potential therapeutics.

Understanding and Resetting Radiation Sensitivity in Rectal Cancer.

OBJECTIVE: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies. SUMMARY BACKGROUND DATA: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers. METHODS: Forty-five rectal cancer patients, partial responders (PR = 18), nonresponders (NR = 13), and complete responders (CR = 14) to CRT, as defined by a tumor regression score, were examined. miRs differentially expressed, using NanoString microArray profiling, were validated with qPCR. We quantified 1 miR and its downstream targets in patient samples. Chemosensitivity was measured in HCT-116, a human colorectal carcinoma cell line, using inhibitors of SHP2 and RAF. RESULTS: miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5-fold change) in a NanoString profiling miR panel. qPCR revealed a decrease in expression of miR-451a in NRs. EMSY and CAB39, both downstream targets of miR-451a and involved in carcinogenesis (shown in TCGA) were increased in NRs (qPCR). Both targets are associated with worse survival in colorectal cancer. Inhibition of miR-451a in HCT-116 cells significantly decreased cell proliferation with treatment of SHP2 and RAF inhibitors. CONCLUSIONS: An integrated analysis of rectal cancer miRs may yield biomarkers of radioresistance and offer treatment targets for resensitization.

Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions.

In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.

Scholastic activity among radiation oncology residents at US academic institutions: a benchmark analysis.

Objective assessment of academic productivity is useful for residency programs. This study aims to analyze the number of publications and Hirsch index (h index) among radiation oncology residents. Names of residents during the 2010 academic year (n = 607) were collected from the Association of Residents in Radiation Oncology 2010 Directory. Number of publications and h index from Jan. 1996 to Feb. 2012 were collected from a bibliographic database (SCOPUS, Elsevier, BV, Amsterdam, NL). Analysis of h index included stratification by gender, residency size, and postresidency private practice or academic employment. Six hundred seven residents, 67% men and 33% women, had an overall mean h index of 2.5 ± 3.2. Graduates in academia exhibited a higher mean h index (3.9 ± 0.30) compared to private practice (2.0 ± 0.25; p < 0.01). Gender, residency size, and post-graduate position remained correlates of h index (all p ≤ 0.01). Women had lower mean h index and number of publications than men (2.1 ± 2.3 vs 2.7 ± 3.5, 4.5 ± 5.3 vs 6.2 ± 8.0, respectively; both p < 0.05). However, when stratified by current position (resident, private practice, or academic), there were no significant differences in h index by gender. The mean ± SD h indices for institutions comprising the top 10% ranged 4.17 ± 3.2-5.25 ± 5.4 while the bottom 10% ranged 0.0 ± 0.0-0.75 ± 1.4. The h index is a useful metric to assess residents' early dedication to scholarly endeavors. Female radiation oncology residents had fewer total publications and slightly lower h indices, warranting accessible research avenues and environments for future female physician-scientists. The application of the h index provides a reference for medical students, residents, residency program directors, and many others to gauge academic performance and establish appropriate benchmarks.

Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury.

MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that modulate gene translation. Their expression is altered in many central nervous system (CNS) injuries suggesting a role in the cellular response to stress. Current studies in brain tissue have not yet described the cell-specific temporal miRNA expression patterns following ischemic injury. In this study, we analyzed the expression alterations of a set of miRNAs in neurons and astrocytes subjected to 60 minutes of ischemia and collected at different time-points following this injury. To mimic ischemic conditions and reperfusion in vitro, cortical primary neuronal and astrocytic cultures prepared from fetal rats were first placed in oxygen and glucose deprived (OGD) medium for 60 minutes, followed by their transfer into normoxic pre-conditioned medium. Total RNA was extracted at different time-points after the termination of the ischemic insult and the expression levels of miRNAs were measured. In neurons exposed to OGD, expression of miR-29b was upregulated 2-fold within 6 h and up to 4-fold at 24 h post-OGD, whereas induction of miR-21 was upregulated 2-fold after 24 h when compared to expression in neurons under normoxic conditions. In contrast, in astrocytes, miR-29b and miR-21 were upregulated only after 12 h. MiR-30b, 107, and 137 showed expression alteration in astrocytes, but not in neurons. Furthermore, we show that expression of miR-29b was significantly decreased in neurons exposed to Insulin-Like Growth Factor I (IGF-I), a well documented neuroprotectant in ischemic models. Our study indicates that miRNAs expression is altered in neurons and astrocytes after ischemic injury. Furthermore, we found that following OGD, specific miRNAs have unique cell-specific temporal expression patterns in CNS. Therefore the specific role of each miRNA in different intracellular processes in ischemic brain and the relevance of their temporal and spatial expression patterns warrant further investigation that may lead to novel strategies for therapeutic interventions.

Stathmin 1: a novel therapeutic target for anticancer activity.

Stathmin 1 (STMN1), also known as p17, p18, p19, 19K, metablastin, oncoprotein 18, LAP 18 and Op18, is a 19 kDa cytosolic protein. It was the first discovered member of a family of phylogenetically related microtubule-destabilizing phosphoproteins critically involved in the construction and function of the mitotic spindle. A threshold level of STMN1 is required for orderly progression through mitosis in a variety of cell types. STMN1 is overexpressed across a broad range of human malignancies (leukemia, lymphoma, neuroblastoma; ovarian, prostatic, breast and lung cancers and mesothelioma). It is also upregulated in normally proliferating cell lines but is only rarely upregulated in nonproliferating cell lines with the exception of neurons, anterior pituitary cells and glial cells. Its expression is also upregulated in hepatocytes during regeneration and in lymphoid cells when they are signaled to proliferate. In this review, we summarize available data as rationale for the therapeutic manipulation of STMN1 in cancer patients.