Search

Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC–peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer. Cancer Immunol Res; 2(9); 867–77. ©2014 AACR.

PDF file - 87K, Supplementary Figure 1. Sequence and secondary structure ofVEGF-4-1BB and OPN-4-1BB aptamer conjugates. Supplementary Figure 2. Biodistribution of VEGF-4-1BB aptamer conjugates. Supplementary Figure 3. OPN-targeted costimulation inhibits tumor growth.

BACKGROUND: We evaluated inter-fraction penile bulb (PB) changes in prostate cancer (PCa) patients undergoing MR-guided RT in the post-radical prostatectomy (RP) setting. MATERIALS AND METHODS: 10 patients with PCa status-post RP received MR-guided RT from 2017–2019. Patients received daily setup volumetric MRI scans prior to RT delivery for alignment and target localization. Setup MRI datasets from Fx 1, Fx 19, and Fx 37 were fused for each patient based on soft tissue anatomy. The PB was contoured on each MRI. Data on volume (cc), superior/inferior positional change (cm), and mean dose (Gy) was collected. Differences were assessed by Student’s t-test (sig. p

Biodistribution of VEGF-4-1BB conjugate. Survival assay in MCA induced fibrosarcoma model. Cytokine levels in treated animals. Tumor volume studies with combinatorial therapy in Balb/c model. Histology and morphology for toxicity profiles.

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310–21. ©2017 AACR.

Background and purpose Consensus for defining gross tumor volume (GTV) and clinical target volume (CTV) for limited-field radiation therapy (LFRT) of GBM are not well established. We leveraged a department MRI simulator to image patients before and during LFRT to address these questions. Materials and methods Supratentorial GBM patients receiving LFRT (46 Gy + boost to 60 Gy) underwent baseline MRI (MRI1) and interim MRI during RT (MRI2). GTV1 was defined as T1 enhancement + surgical cavity on MRI1 without routine inclusion of T2 abnormality (unless tumor did not enhance). The initial CTV margin was 15 mm from GTV1, and the boost CTV margin was 5–7 mm. The GTV1 characteristics were categorized into three groups: identical T1 and T2 abnormality (Group A), T1 only with larger T2 abnormality not included (Group B), and T2 abnormality when tumor lacked enhancement (Group C). GTV2 was contoured on MRI2 and compared with GTV1 plus 5–15 mm expansions. Results Among 120 patients treated from 2014-2019, 29 patients (24%) underwent replanning based on MRI2. On MRI2, 84% of GTV2 were covered by GTV1 + 5 mm, 93% by GTV1 + 7 mm, and 98% by GTV1 + 15 mm. On MRI1, 43% of GTV1 could be categorized into Group A, 39% Group B, and 18% Group C. Group B’s patterns of failure, local control, or progression-free survival were similar to Group A/C. Conclusions Initial CTV margin of 15 mm followed by a boost CTV margin of 7 mm is a reasonable approach for LFRT of GBM. Omitting routine inclusion of T2 abnormality from GTV delineation may not jeopardize disease control.

The inhibition of immunosuppressive mechanisms may switch the balance between tolerance and surveillance, leading to an increase in antitumor activity. Regulatory T cells play an important role in the control of immunosuppression, exhibiting the unique property of inhibiting T cell proliferation. These cells migrate to tumor sites or may be generated at the tumor site itself from the conversion of lymphocytes exposed to tumor microenvironment signaling. Because of the high similarity between regulatory T cells and other lymphocytes, the available approaches to inhibit this population are nonspecific and may antagonize antitumor response. In this work we explore a new strategy for inhibition of regulatory T cells based on the use of a chimeric aptamer targeting a marker of immune activation harboring a small antisense RNA molecule for transcriptional gene silencing of Foxp3, which is essential for the control of the immunosuppressive phenotype. The silencing of Foxp3 inhibits the immunosuppressive phenotype of regulatory T cells and potentiates the effect of the GVAX antitumor vaccine in immunocompetent animals challenged with syngeneic tumors. This novel approach highlights an alternative method to antagonize regulatory T cell function to augment antitumor immune responses., Graphical abstract, Here we have generated a chimeric aptamer that binds to 4-1BB receptor that is constitutively expressed in Tregs to vehiculate a transcriptional RNAi silencing molecule targeting FoxP3. Silencing FoxP3 in Tregs may inhibit immunosuppressive phenotype and potentiate antitumor response.

Background One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established. Materials and methods 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS). Results rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01–0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11–0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09–0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06–0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01–0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04–0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02–0.33, p Conclusion rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease.

Molecular profiling facilitates opportunities for personalization of breast cancer management. Increasing availability of germline and somatic sequencing provides insight into predictors of treatment efficacy and treatment tolerance of patients with breast cancer. The presence of pathologic mutations can guide patient selection for breast conserving surgery vs mastectomy. However, our understanding of the interplay between genetic variants and radiotherapy responses and side effects remains incomplete. Here we review the available data on germline mutations and polymorphisms in breast cancer. We also outline their association with treatment tolerance, locoregional outcomes, and ongoing efforts to transform these insights into more effective treatment strategies in combination with radiotherapy.

Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established. WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS). Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins

Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

Tumors can rarely overexpress human chorionic gonadotropin (hCG) resulting in false-positive pregnancy tests. Here, we report a 44-year-old female with a metastatic gastrointestinal stromal tumor (GIST) who presented with a positive urine pregnancy test before radiotherapy. Further workup ruled out pregnancy. Following radiotherapy, her metastatic disease progressed and her hCG level continued to rise. To the best of our knowledge, this is the first report of a GIST tumor overexpressing hCG.

Chemoradiation for patients with laryngeal squamous cell carcinoma (SCC) may achieve organ preservation, but appropriate patient selection remains unknown. This study investigates pre-treatment risk factors associated with functional and survival outcomes after radiation-based therapy in patients with advanced laryngeal SCC.A retrospective cohort study was performed on 75 adult patients with stage III or IV laryngeal SCC receiving definitive radiation-based therapy from 1997 to 2016 at a tertiary care center. Tracheostomy and gastrostomy dependence were the primary functional outcomes. Multivariable logistic regressions were performed to evaluate relationships between pre-treatment factors and tracheostomy and gastrostomy dependence. Time-to-event analyses were performed to determine risk factors associated with overall survival.Among 75 patients included in the analysis, 30 (40%) patients were tracheostomy dependent and 31 (41%) were gastrostomy tube dependent. The median length of follow-up was 31 months (range = 1 to 142 months). Pre-treatment tracheostomy was a significant predictor of post-treatment tracheostomy (aOR = 13.9, 95% CI = 3.35 to 57.5) and moderate-severe comorbidity was a significant predictor of post-treatment gastrostomy dependence (aOR = 2.96, 95% CI = 1.04 to 8.43). The five-year overall survival was 51% (95% CI = 38 to 64%). Pre-treatment gastrostomy tube dependence was associated with an increased risk of death (aHR = 2.45, 95% CI = 1.09 to 5.53).Baseline laryngeal functional status and overall health in advanced laryngeal SCC are associated with poor functional outcomes after radiation-based therapy, highlighting the importance of patient selection when deciding between surgical and non-surgical treatment plans. Laryngoscope, 2022.

Gorham-Stout disease (GSD) is a rare, locally destructive musculoskeletal disorder of unknown etiology. GSD affecting the skull base is a particularly challenging disease entity. Skull base GSD has a high propensity for causing life-threatening complications such as cerebrospinal fluid (CSF) leaks, meningitis, and osteomyelitis. Additionally, skull base GSD is often surgically unresectable. While the primary treatment modality for GSD is surgery, prior series demonstrate that GSD is radiosensitive, and radiotherapy (RT) is indicated for refractory or symptomatic cases not amenable to surgery. Older case series have described the management of skull base GSD with 2D or 3D RT techniques. Recent technological advances such as intensity-modulated RT (IMRT) and image-guided RT (IGRT) have allowed for the delivery of highly conformal RT potentially improving disease outcomes and minimizing toxicity for head and neck cancer. Here we describe a case of GSD of the skull base successfully treated with conformal IMRT and a provide a review of the pertinent literature.

Background : Prostate stereotactic body radiotherapy (SBRT), which delivers high-dose precision treatment in ≤5 fractions, is a shorter, more convenient, and less expensive alternative to conventionally fractionated radiotherapy (CRFT; ∼44 fractions) or moderately hypofractionated radiotherapy (MFRT; 20-28 fractions). SBRT has not been widely adopted but may have radiobiologic advantages over CFRT/MFRT. We hypothesized that SBRT would be associated with improved overall survival (OS) vs. CFRT or MFRT ± androgen deprivation therapy (ADT) for unfavorable-intermediate-risk prostate cancer (UIR-PCa). Methods : Men with UIR-PCa treated with SBRT (35-40Gy in ≤5 fractions) or biologically effective doses (BED) of CFRT (72-86.4Gy in 1.8-2.0Gy/fraction) or MRFT (≥60Gy in 2.4-3.2Gy/fraction; BED ≥120) were identified in the National Cancer Database (NCDB). Unweighted and propensity-weighted multivariable Cox analysis (MVA) was used to compare OS hazard ratios. Results : 28,028 men with UIR-PCa who received CFRT with (n=12,872) or without ADT (n=12,984); MFRT with (n=251) or without ADT (n=281); and SBRT with (n=212) or without ADT (n=1,428) were identified. Relative to CFRT without ADT, CFRT+ADT (HR 0.92, 95%CI 0.87-0.97, P=.002) and SBRT without ADT (HR 0.74, 95%CI 0.61-0.89, P=.002) were both associated with improved OS on MVA. Relative to CFRT+ADT, SBRT without ADT correlated with improved OS on MVA (HR:0.81, 95%CI 0.67-0.99, P=.04). Propensity-weighted MVA demonstrated that SBRT (HR:0.80, 95%CI 0.65-0.98, P=.036) and ADT (HR:0.91, 95%CI 0.86-0.97, P=.002) correlated with improved OS. SBRT was not associated with improved OS vs. MFRT. Conclusion : SBRT, which offers a cheaper and shorter treatment course that mitigates COVID-19 exposure, was associated with improved OS vs. CFRT for UIR-PCa. These results confirm guideline-based recommendations that SBRT is a viable option for UIR prostate cancer. The results from this large retrospective study require further validation in clinical trials. Micro-Abstract : In the era of COVID-19, there has been a large shift toward delivering larger doses of radiation over fewer treatments using stereotactic body radiation therapy (SBRT). There is a strong radiobiologic basis for using SBRT, as prostate cancer cells are more sensitive to higher doses of radiation delivered over fewer treatments. Here we show that men with unfavorable intermediate-risk prostate cancer (UIR-PCa) treated with SBRT lived significantly longer when treated with SBRT relative to longer courses of radiotherapy. While we await results from several ongoing clinical trials, this study lends support to the use of SBRT in men with UIR-PCa.

Purpose The use of prostate fiducial markers and perirectal hydrogel spacers can reduce the acute and late toxic effects associated with prostate radiation therapy. These procedures are usually performed days to weeks before simulation during a separate clinic visit to ensure resolution of procedure-related inflammation. The purpose of this study was to assess whether same-day intraprostatic fiducial marker placement, perirectal hydrogel injection, and computed tomography (CT) and magnetic resonance imaging (MRI) simulation were feasible without adversely affecting hydrogel volume, perirectal spacing, or rectal dose. If feasible, performing these procedures on the same day as simulation would expedite the start of radiation therapy, improve patient convenience, and reduce costs. Methods and Materials Twenty-one patients with clinically localized prostate cancer who were enrolled on a prospective clinical trial (NCT01617161) underwent same-day marker placement, hydrogel injection, and CT and MRI simulation, then underwent T2 MRI verification scans 3 to 4 weeks later. The MRI scans were fused to the CT planning scans by clinical target volumes (CTVs) to generate comparison treatment plans (70 Gy in 28 fractions). Hydrogel volume and symmetry, perirectal spacing, CTV dose, and organ-at-risk dose were evaluated. Results Verification scans occurred a mean of 24.9 ± 4.6 days after simulation and 9.3 ± 4.9 days after treatment start. Prostate volume did not change between scans (median, 67.3 ± 22.1 cm3 vs 64.1 ± 21.8 cm3; P = .64). The median hydrogel change between simulation and verification was −1.8% ± 4.5% (P = .27). No significant differences in perirectal spacing (midgland: 1.33 ± 0.45 cm vs 1.3 ± 0.7 cm; 1 cm superior: 1.25 ± 0.95 cm vs 1.43 ± 0.91 cm; 1 cm inferior: 1.16 ± 0.28 cm vs 1.41 ± 0.49 cm) were identified. No significant differences in rectal V66 (median 2.3 ± 2.18% vs 2.3 ± 2.28%; P = .99), V35 (median 14.79 ± 7.61 vs 14.67 ± 8.4; P = .73), or D1cc (65.7 ± 9.2 Gy vs 68.2 ± 9.0 Gy; P = .80) were found. All plans met CTV and organ-at-risk constraints. Conclusion Same-day placement of intraprostatic fiducial markers, perirectal hydrogel, and simulation scans was feasible and did not significantly affect hydrogel volume, position, CTV coverage, or rectal dose.

Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibody-coated tumor cells. Here we describe an approach to potentiate tumor immunity whereby hapten-specific polyclonal antibodies are recruited to tumors by coating tumor cells with the hapten. Vaccination of mice against dinitrophenol (DNP) followed by systemic administration of DNP targeted to tumors by conjugation to a VEGF or osteopontin aptamer elicits potent FcR dependent, T cell mediated, antitumor immunity. Recruitment of αGal-specific antibodies, the most abundant naturally occurring antibodies in human serum, inhibits tumor growth in mice treated with a VEGF aptamer-αGal hapten conjugate, and recruits antibodies from human serum to human tumor biopsies of distinct origin. Thus, treatment with αGal hapten conjugated to broad-spectrum tumor targeting ligands could enhance the susceptibility of a broad range of tumors to immune elimination.

PURPOSE/OBJECTIVE(S) Electronic medical records (EMR) hold potential for transformative improvements in the quality and efficiency of healthcare delivery. However, the unstructured nature of EMR data often necessitates manual review and is a significant barrier to leveraging it for downstream analysis. Methods to address this challenge include natural language processing (NLP) algorithms such as tokenization, shallow parsing, and boundary/negation detection. Recent radiation oncology (RO) specific attempts to use NLP to structure EMR data have involved identifying common toxicity terms in on-treatment visit (OTV) notes. Classical NLP works well for positive toxicity term identification (i.e., toxicity present) but is suboptimal for negated symptoms (i.e., toxicity absent). Convoluted neural networks (CNN) aid context detection, however, no publicly available RO-specific CNNs which identify toxicity terms exist. We hypothesized that RO-specific CNNs, naively trained on OTV notes, could improve tabulation of positive and negative toxicity information to an accuracy level suitable for automation. MATERIALS/METHODS OTV notes (n = 3789) for prostate cancer (PCa) patients treated at our institution between 2019-2021 were identified and analyzed for inclusion/exclusion/omission of CTCAE toxicity terms. The top 5 terms identified (fatigue, nausea, diarrhea, dysuria, hematuria) were used for further analysis. Each note was manually classified by explicit positive identification, negation, or omission of each toxicity term, and used to train an in-house, toxicity-term-specific CNNs. Algorithms were structured as 3-group multiclass classification problem to distinguish between positive or negative symptom identification and omission of the term. Gold standard accuracy measurements were determined using manual review scores of OTV notes for the presence, absence or omission of toxicity terms in each OTV note. Overall, out of sample accuracy and F1 score were determined using a test/train split of OTV notes. RESULTS The 3-class accuracy of CNNs for the top 5 CTCAE terms present/absent/negated in PCa OTV notes were: fatigue (accuracy = 0.93, F1 = 0.95), diarrhea (accuracy = 0.95, F1 = 0.94), nausea (accuracy = 0.98, F1 = 1.0), dysuria (accuracy = 0.97, F1 = 0.97), hematuria (accuracy = 0.99, F1 = 0.96). CONCLUSION Training naive CNNs with RO-specific training data from OTV notes increased the accuracy of CTCAE toxicity coding. This approach addresses challenges previously encountered using classical NLP from RO EMR data. Therefore, use of CNNs in NLP may reduce barriers to implementation of automated methods to improve data extraction for retrospective and prospective analyses.

Purpose Our purpose was to describe the risk of radiation-induced brachial plexopathy (RIBP) in patients with breast cancer who received comprehensive adjuvant radiation therapy (RT). Methods and Materials Records for 498 patients who received comprehensive adjuvant RT (treatment of any residual breast tissue, the underlying chest wall, and regional nodes) between 2004 and 2012 were retrospectively reviewed. All patients were treated with conventional 3 to 5 field technique (CRT) until 2008, after which intensity modulated RT (IMRT) was introduced. RIBP events were determined by reviewing follow-up documentation from oncologic care providers. Patients with RIBP were matched (1:2) with a control group of patients who received CRT and a group of patients who received IMRT. Dosimetric analyses were performed in these patients to determine whether there were differences in ipsilateral brachial plexus dose distribution between RIBP and control groups. Results Median study follow-up was 88 months for the overall cohort and 92 months for the IMRT cohort. RIBP occurred in 4 CRT patients (1.6%) and 1 IMRT patient (0.4%) (P = .20). All patients with RIBP in the CRT cohort received a posterior axillary boost. Maximum dose to the brachial plexus in RIBP, CRT control, and IMRT control patients had median values of 56.0 Gy (range, 49.7-65.1), 54.8 Gy (47.4-60.5), and 54.8 Gy (54.2-57.3), respectively. Conclusions RIBP remains a rare complication of comprehensive adjuvant breast radiation and no clear dosimetric predictors for RIBP were identified in this study. The IMRT technique does not appear to adversely affect the development of this late toxicity.

e18059 Background: Biological behaviors of cancers are extremely complex and governed via nonlinear interplay of thousands of genes. This complexity has become a major hurdle to generating mechanistic conclusions in rare clinical scenarios, such as treatment resistant HPV+ head and neck squamous cell carcinoma, when observations are limited. Recently, data augmentation algorithms have served to increase the number and diversity of training observations while preserving the underlying structure and nonlinear relationships of data features. Deep learning techniques such as generative adversarial neural networks (GANs) have shown promise as robust tools for data augmentation of nonimage data. This study aims to evaluate the utility of employing separate GANs to highlight gene expression differences between treatment sensitive (TS) vs treatment resistant (TR) HPV+ head and neck squamous cell carcinoma. Methods: We performed RNAseq on 17 patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). We defined TR patients as those with locally advanced OPSCC at presentation, who rapidly recurred following receipt of standard of care therapy (n = 11). In most cases, patients failed to respond to salvage therapies and rapidly died. In contrast, we defined TS patients as those with locally advanced OPSCC at presentation, who received standard of care therapy, and were followed for 5 years without any evidence of recurrence (n = 6). These two cohorts were used to train two separate GANs, which synthesized 500 robust synthetic samples of each phenotype for downstream analysis. Results: Analysis of 17 samples yielded less than 100 differentially expressed (DE) genes passing FDR cutoffs, inhibiting pathway enrichment analysis (PAE). DE testing between synthetic samples yielded 1196 DE genes. Validating our deep learning approach, these genes belong to coherent pathways as determined by PAE. Namely, the VEGFA-VEGFR2 pathway was strongly enriched in the TR population (p = 1.5 x 10-4). Further, the NKT cell signature (p = 3.0x10-62), and the gene library of T-cell receptor induction of apoptosis (p = 5.4 x 10-9), was enriched in the TS population. Lastly, to validate the experimental method, DE testing on GAN augmented cohorts of renal papillary vs renal clear cell samples from The Cancer Genome Atlas, trained on 10 samples per condition, reliably predicted DE genes when comparing the full cohort of renal papillary n = 534 vs renal clear cell n = 295 samples, with an accuracy of 93% and F1 score of 88%. Conclusions: To our knowledge this is the first study to utilize separate GANs to augment structural gene expression changes occurring in rare clinical scenarios such as treatment resistant HPV+ OPSCC. Utilizing this method uncovers changes in angiogenesis and T-cell function between treatment sensitive and resistant HPV+ OPSCC.

Purpose Optimal therapy for clinically node-positive, nonmetastatic (cN1) prostate cancer (PC) patients remains controversial, ranging from aggressive local therapy to palliative systematic therapy alone. Despite guideline support, it is unclear if a brachytherapy (BT) boost should be considered for cN1 patients as these patients were excluded from randomized trials establishing its benefit. Herein, we compare definitive radiation therapy (RT) with or without a BT boost in cN1 PC. Methods and materials The National Cancer Database was used to identify men with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy between 2004 and 2013. Overall survival (OS) was compared between those who received external beam RT (EBRT) or combination EBRT plus BT boost (EBRT + BT) using Kaplan–Meier with propensity score matching and Cox proportional hazards. Results With a median followup of 48.5 months, 1,650 patients were eligible for this analysis, 103 (6.2%) of whom received EBRT + BT. Younger age, no medical comorbidities, and Gleason score of six were associated with higher likelihood of receiving EBRT + BT over EBRT alone. The mean (median) OS for EBRT and EBRT + BT was 99.0 (110.6) months vs 109.2 (not reached) months, respectively (p = 0.048). However, no significance difference in OS was observed between the groups after propensity score matching. On multivariable analysis, EBRT + BT was not significantly associated with improved OS (adjusted HR 0.67, 95% CI, 0.41–1.07, p = 0.098). Conclusions In this retrospective, observational study of patients with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy, EBRT + BT had an unadjusted improvement in OS compared with EBRT alone that lost statistical significance after multivariable adjustment and propensity score matching.

258 Background: Radiation dose escalation with the addition of a brachytherapy boost (BT) to external beam radiation therapy (EBRT) may be associated with improved survival in certain men with Gleason grade 5 (GG5) prostate cancer (PCa). However, low PSA, high-grade PCa has much worse outcomes, is associated with neuroendocrine genomic features, and may be more resistant to androgen suppression. It is unclear whether the addition of a BT boost in men with this disease subgroup is associated with a survival benefit and is the subject of this analysis. Methods: Men diagnosed with node-negative, non-metastatic GG5 PCa and treated with (1) EBRT plus ADT or (2) EBRT plus BT plus ADT between 2004 and 2015 were identified in the National Cancer Database (NCDB). The EBRT cohort received conventionally fractionated ≥ 74 Gy or moderately hypofractionated (2.5-3.0 Gy x 20-28 fractions) EBRT. EBRT plus BT cohort received external beam doses of conventionally fractionated ≥45 Gy or moderately hypofractionated (2.5 Gy x 15 – 18 fractions) radiation, and either LDR or HDR BT. Men receiving chemotherapy, immunotherapy, or any form of surgery were excluded. Patients were stratified into two groups based on whether the presenting PSA was above or below the normal threshold (≤4 and > 4 ng/mL). OS was compared using the Kaplan-Meier and log-rank test. Multivariable analysis (MVA) using Cox proportional hazards regression modeling was performed, accounting for age, race, year of diagnosis, Charlson-Deyo comorbidity score, insurance status, treatment facility type, Gleason Score (9 versus 10), and clinical T-stage. Results: 8,260 men met study inclusion criteria of which 658 (8%) presented with PSA ≤4. 572 (87%) patients were treated with EBRT monotherapy and 86 (13%) patients were treated with EBRT + BT. 5-year OS for EBRT versus EBRT plus BT was 79.7 +/- 2.3% versus 86.9 +/- 5.0%, respectively (P = 0.49). On MVA analysis, EBRT plus BT was not associated with improved OS versus EBRT (adjusted HR 0.90, 95% CI 0.52-1.87; P = 0.62). In comparison, for men with PSA > 4 and GG5 disease [EBRT: 6,780 patients (89.2%) & EBRT plus BT: 822 patients (10.8%)], EBRT plus BT was associated with improved OS versus EBRT (adjusted HR 0.85, 95% CI 0.66-0.99; P = 0.044). Conclusions: Receipt of dose-escalated prostate radiation by means of a BT boost was not associated with improved survival in men with PSA ≤4 ng/mL and GG5 prostate cancer. By contrast, an association with improved survival was observed in men with GG5 disease and higher initial PSA. This low PSA, high-grade subgroup may represent a unique risk tier for which current treatment paradigms need further investigation, including study of escalated systemic therapy.

264 Background: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT). Treatment is frequently intensified by electively treating the pelvic lymph nodes with whole pelvis radiotherapy (WPRT), but practice patterns differ and the benefits of WPRT are not clearly defined, with mixed results from clinical trials. The recent POP-RT trial showed improved biochemical control with WPRT but most patients were staged with PET/CT scan. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy in patients staged using conventional imaging. Methods: Men diagnosed between 2008-2015 with UIR or high-risk prostate cancer were retrospectively reviewed from the National Cancer Database (n = 28,724). Patients with involved nodes or distant metastases were excluded. Men received EBRT to a dose of 72-86.4 Gy and either prostate-only RT ± ADT (n = 13,549) or WPRT plus prostate RT ± ADT (n = 15,175). WPRT was delivered using a dose range of 40-50.4 Gy (1.8 – 2.0 Gy/fraction). The MSKCC nomogram was used to calculate risk of lymph node involvement. Unweighted or inverse probability of treatment weighting (IPTW) was used to perform multivariable analysis (MVA) using Cox regression modeling to compare OS hazard ratios, accounting for age, race, year of diagnosis, Charlson-Deyo comorbidity score, insurance status, education, income, treatment facility type, PSA, Gleason score, clinical T-stage, use of ADT, lymph node risk score, and radiation dose. Results: 53% of men received WPRT, with national utilization of WPRT increasing from 2008 to 2015. For every 1% increase in risk of lymph node involvement, there was a 1% increased risk of death ( P

Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibody-coated tumor cells. Here we describe an approach to potentiate tumor immunity whereby hapten-specific polyclonal antibodies are recruited to tumors by coating tumor cells with the hapten. Vaccination of mice against dinitrophenol (DNP) followed by systemic administration of DNP targeted to tumors by conjugation to a VEGF or osteopontin aptamer elicits potent FcR dependent, T cell mediated, antitumor immunity. Recruitment of αGal-specific antibodies, the most abundant naturally occurring antibodies in human serum, inhibits tumor growth in mice treated with a VEGF aptamer–αGal hapten conjugate, and recruits antibodies from human serum to human tumor biopsies of distinct origin. Thus, treatment with αGal hapten conjugated to broad-spectrum tumor targeting ligands could enhance the susceptibility of a broad range of tumors to immune elimination., Efficient tumor antigen uptake by dendritic cells is facilitated by antibody coating of tumor cells. Here, the authors develop an approach based on hapten vaccination and hapten/tumor targeting ligand conjugates that potentiate anti-tumor immunity by generating and redirecting serum antibodies to tumors.

Purpose/Objective(s) Cancer patients with lower socioeconomic status (SES) have been shown to have worse outcomes, but the influence of neighborhood-level SES has not been well-established. One widely used geographic measure of SES is via a publicly available, U.S. Census-based neighborhood disadvantage metric called the Area Deprivation Index (ADI). We hypothesized that residence in a lower SES neighborhood, as indicated by higher ADI, would be associated with worse progression-free (PFS) and overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR). Materials/Methods A retrospective review was conducted using an institutional database containing patient and disease characteristics including race, smoking status, and Charlson Comorbidity Index (CCI) scores. Neighborhood-level factors, such as ADI and rural-urban codes, were incorporated by applying clinical informatics to manage large-scale data. Loss to follow-up was defined as being alive but with no follow-up > 6 months after completing SABR. Kaplan-Meier with log-rank analysis and Cox regression were conducted for PFS and OS, and logistic regression was performed to evaluate for predictors of loss to follow-up. Statistical significance was set at P Results There were 513 patients treated from 2004-2018 with a median follow-up of 25 months (range: 0-190). Median PFS was 20 months, and median OS was 36 months. The median age was 73 years; 45% were male, 14% were Black, 30% were actively smoking, 74% were from an urban neighborhood. Median SABR dose was 54 Gray in 3 fractions. ADI scores ranged from 21.68 to 156.85 and were normally distributed; the first quintile mean ADI was 71.49 (least disadvantaged) and the fifth quintile mean ADI was 124.97 (most disadvantaged). On Kaplan-Meier (log-rank) analysis, loss to follow-up was associated with worse PFS and OS (P Conclusion Loss to follow-up, urban home location, and lower socioeconomic status, as represented by higher ADI values, were found to be independently associated with worse OS, suggesting the importance of considering SES and potential barriers to follow-up in patient care.

Purpose/Objective(s) Polyethylene glycol (PEG) hydrogel perirectal spacers can reduce prostate cancer (PCa) radiotherapy (RT)-related gastrointestinal (GI) toxicity. Accurate hydrogel contouring requires T2 MRI simulation (sim), as hydrogels have Hounsfield units (HU) comparable to soft tissue on computerized tomography (CT). A PEG hydrogel containing covalently bound iodine was recently developed and approved for clinical use. However, its characteristics in routine clinical practice have yet to be reported. Here we evaluated iodinated hydrogel volume, perirectal spacing, and HU from treatment images for PCa patients receiving RT at our institution. Materials/Methods Patients with biopsy-proven, clinically localized PCa (cT1c-cT2N0M0) who had same-day CT/MRI sim after fiducial markers and iodinated hydrogel placement were identified. Hydrogel was contoured on CT sim, MRI, and cone beam CT (CBCT) at treatment start (CBCT#1) and completion (CBCT#2). Prostate and hydrogel volumes and anterior-posterior mid-gland perirectal spacing at midline were measured on CT/MRI and CBCTs, and HU was measured on CT sim and CBCTs using treatment planning software. Patient differences were evaluated using paired, two-tailed Student's t-tests, with significance at P Results Twenty-three patients were identified (mean age 71.1 ± 7.8 years; mean prostate volume 61.9 ± 29.2 cm3; mean initial PSA 7.36 ± 1.9), treated with IMRT: 79.2 Gy/44 fx (n = 3), 70 Gy/28 fx (n = 15), or 36.25 Gy/5 fx (n = 5). Hydrogel was identified on all sim scans and was larger on T2 MRI vs CT (MRI mean volume 9.9 ± 1.7 cm3 vs CT 9.3 ± 1.6 cm3 vs; P = 0.03), and comparable mean perirectal distance at mid-gland/midline (MRI 1.02 ± 0.55 cm vs CT 1.03 ± 0.53 cm; P = 0.65). Perirectal spacing was maintained between CT sim and CBCT#1 (1.03 ± 0.51 cm; P = 0.97) done an average of 16.7 ± 7.1 days post sim and CT sim and CBCT#2 (1.03 ± 0.53 cm vs 1.02 ± 0.54; P = 0.74) done an average of 53.8 ± 19 days post sim. No significant change in hydrogel volume between CBCT#1 and CBCT#2 for 44 fx (10.9 ± 1.7 cm vs 10.4 ± 1.3 cm; P = 0.17), 28 fx (10.2 ± 1.4 vs 9.83 ± 1.7 cm; P = 0.11), or 5 fx (9.9 ± 2.1 vs 9.54 ± 1.9; P = 0.45) patients was observed. Hydrogel mean HU on CT sim was not significantly changed at CBCT#1 (CT sim 152.1 ± 30.5 vs CBCT#1 129.1 ± 51.6; P = 0.08), but mean HU at CBCT#2 (109.3 ± 47.9 cm) was lower vs CT sim (P = 0.001). For 44 fx treatments hydrogel HU significantly decreased between CBCT#1 and CBCT#2 (140.7 ± 10.0 vs 94.2 ± 80.4; P = 0.01), but not for 28 fx (123.5 ± 54.4 vs 103.4 ± 44.0; P = 0.13) or 5 fx (138.4 ± 38.5 vs 136 ± 37.2; P = 0.60) regimens. Conclusion PEG-based iodinated hydrogel can be delineated on CT sim comparable to MRI sim, and maintains visibility and perirectal spacing through 5, 28, and 44 fx RT courses as assessed by CBCT. Hydrogel HU decreased over 44 fx relative to CT sim, with no significant difference in HU seen for 28 fx and 5 fx courses. Use of perirectal hydrogel containing covalently bound iodine may obviate reliance on T2 MRI for accurate hydrogel contouring during RT treatment planning.

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310–21. ©2017 AACR.

Background: Retroperitoneal sarcomas (RPS) are rare and primarily managed with surgery, which improves local recurrence-free and overall survival. Radiation can improve local control or provide palliation for inoperable or metastatic RPS by eliciting tumor cell death via irreparable DNA damage. In extraordinary circumstances radiation-induced cell death promotes immune-mediated regression of non-irradiated lesions in a process termed the abscopal effect. Abscopal effects are rare and incompletely understood, involving a balance of radiation's immunogenic and immunosuppressive effects. There are currently no methods to predict abscopal responses following radiotherapy. Case reports documenting post-radiotherapy abscopal effects provide additional information to better characterize these responses and to inform ongoing and future clinical trials attempting to harness radiation-induced immune responses to improve outcomes with systemic therapy, such as SARC-032, a cooperative group trial of pre-operative radiation ± pembrolizumab. We present a case of inoperable metastatic RPS treated with proton radiotherapy with complete responses of un-irradiated metastases.Case Presentation: A 67 year-old female with inoperable metastatic unclassified round cell RPS was treated with palliative proton radiotherapy only to the primary tumor. Following completion of radiotherapy, the patient demonstrated complete regression of all un-irradiated metastases, and near complete response of the primary lesion without additional therapy.Conclusions: Metastatic RPS is typically managed with first-line chemotherapy, with objective response rates

e17054 Background: Conventionally fractionated radiotherapy (CFRT) or moderately hypofractionated radiotherapy (MFRT) ± short-course androgen deprivation therapy (ADT) is commonly employed for unfavorable intermediate-risk (UIR) prostate cancer. Stereotactic body radiation therapy (SBRT) has not been widely adopted, but may have radiobiologic advantages over more conventionally fractionated treatments. We hypothesized that radiotherapy dose-escalation with SBRT (35-40Gy in ≤5 fractions) is associated with improved overall survival (OS) relative to biologically equivalent doses of CFRT (72-86.4Gy in 1.8-2.0Gy/fraction) or MFRT (≥60Gy in 2.4-3.2Gy/fraction) ± ADT. Methods: The National Cancer Database (NCDB) was used to identify 28,028 men with UIR prostate cancer who received CFRT with (n = 12,872) or without ADT (n = 12,984), MFRT with (n = 251) or without ADT (n = 281), and SBRT with (n = 212) or without ADT (n = 1,428). SBRT+ADT patients were excluded due to low patient numbers. Inverse probability of treatment weighting was used to balance measured confounders. Unweighted- and weighted- multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios. Results: Relative to CFRT without ADT, CFRT+ADT (Hazard Ratio (HR): 0.92, [95% Confidence Interval: 0.87-0.97], P = .002) and SBRT without ADT (HR: 0.74 [0.61-0.89], P = .002) were both associated with improved OS on MVA. Relative to CFRT+ADT, SBRT without ADT correlated with improved OS on MVA (HR: 0.81 [0.67-0.99], P = .04). Weight-adjusted MVA demonstrated that SBRT (HR: 0.80 [0.65-0.98], P = .036) and ADT (HR: 0.91 [0.86-0.97], P = .002) correlated with improved OS. SBRT was not associated with improved OS relative to MFRT. Conclusions: Using inverse propensity treatment weighting, we adjusted for age, comorbidity score, and tumor factors, and observed a significant overall survival benefit in favor of administering dose-escalated SBRT over CFRT+ADT. To our knowledge, this is the first study to show that SBRT is associated with improved OS relative to CFRT for men with UIR prostate cancer. Together, this suggests that SBRT offers a cheaper and shorter course of therapy that mitigates COVID-19 exposure, which also is associated with improved OS relative to CFRT for UIR prostate cancer and may obviate the need for ADT in this population. While we await results from several ongoing clinical trials, we believe this study lends support to the use of SBRT in men with UIR prostate cancer.