Anti-PD-1 mAb pre-radiotherapy (RT) loading dose and fractionated RT induce better tumor-specific immunity and tumor shrinkage than sequential administration in an HPV+ head and neck cancer model

Radiotherapy (RT) is a standard therapeutic strategy in the treatment in head and neck cancer (HNC), but many patients still experience recurrence and metastasis. Interestingly, radiotherapy (RT) may also induce immunomodulatory effects. Given the recent, exciting responses seen using anti-PD-1 (programmed death-1) checkpoint blockade immunotherapy in recurrent/metastatic disease, including HNC, we evaluated the combination of RT with anti-PD-1 therapy in a pre-clinical mouse model of locally advanced, untreated HPV-positive HNC. We compared utilizing PD-1 blockade before, during or after RT, as well as whether a single large faction (12Gy) or multiple smaller RT doses (2 Gy X 10 fractions) confers optimal antitumor immune responses and tumor shrinkage. We observed that fractionated doses of RT induced the highest PD-L1 (programmed death-ligand 1) expression on HNC cells in vitro and in treated mice. A loading dose of anti-PD-1 mAb therapy prior to RT appeared to be important for best therapeutic outcome, with greatest tumor response and tumor-specific immunity using PD-1 Ab loading dose than sequential administration of anti-PD-1 mAb after fractionated RT (p < 0.0001). Expression and intensity of PD-1 receptor expression on circulating T cells differentially impacted the T cell phenotype and anti-tumor outcome, with loss of PD-1(high) exhausted T cells during the best tumor response (p < 0.05). The combination of fractionated RT + anti-PD-1 Ab optimally upregulated the frequency of HPV E7 tumor antigen-specific T cells (p < 0.05). This study may facilitate strategies required for the combination of RT and immune checkpoint inhibitor in clinical trials, enabling more effective clinical activity and biomarker evaluation

A Polymorphic Variant of AFAP-110 Enhances cSrc Activity12

Enhanced expression and activity of cSrc are associated with ovarian cancer progression. Generally, cSrc does not contain acti- vating mutations; rather, its activity is increased in response to signals that affect a conformational change that releases its auto- inhibition. In this report, we analyzed ovarian cancer tissues for the expression of a cSrc-activating protein, AFAP-110. AFAP-110 activates cSrc through a direct interaction that releases it from its autoinhibited conformation. Immunohistochemical analysis re- vealed a concomitant increase of AFAP-110 and cSrc in ovarian cancer tissues. An analysis of the AFAP-110 coding sequence revealed the presence of a nonsynonymous, single-nucleotide polymorphism that resulted in a change of Ser403 to Cys403. In cells that express enhanced levels of cSrc, AFAP-110403C directed the activation of cSrc and the formation of podosomes indepen- dently of input signals, in contrast to wild-type AFAP-110. We therefore propose that, under conditions of cSrc overexpression, the polymorphic variant of AFAP-110 promotes cSrc activation. Further, these data indicate a mechanism by which an inherited genetic variation could influence ovarian cancer progression and could be used to predict the response to targeted therapy

A genetic variant of the adaptor protein, AFAP -110, efficiently activates c-Src resulting in podosome formation.

The actin filament associated protein of 110 kDA (AFAP-110) is a well-characterized protein composed of amino-terminal binding motifs that function upstream of a carboxy-terminal actin binding domain. In vitro studies demonstrate that the amino-terminal pleckstrin homology 1 (PH1) domain interacts with activated PKCα, relaying signals that activate Src family kinases via SH3 and SH2 binding. Serving as an adaptor protein, AFAP-110 relays signals that result in the assembly of motility structures. These findings could be of physiological as well pathological significance as AFAP-110 colocalizes with SFKs in the developing brain as well as in the glial-derived tumor, glioblastoma multiforme. More recently, AFAP-110 and c-Src expression were analyzed in ovarian cancer. While c-Src exhibits a diffuse expression pattern, AFAP-110 localized focally. Interestingly, colocalization between AFAP-110 and c-Src always occurs in desmoplastic regions of the tumor. In order to determine if a genetic variant of AFAP-110 exists, a PCR analysis of AFAP cDNA derived from ovarian cancer cell lines, ovarian tumor sections, as well as normal myometrium revealed a nucleotide change of G1426C resulting in an amino-acid change of serine (S) to cysteine (C) at position 403 of AFAP-110 (AFAP-110403S/C). This SNP was found to exist in approximately 25% of the samples. Molecular modeling predicts that the tertiary structure of AFAP-110403S/C could be contorted in a manner that facilitates altered protein binding. This is supported by GST-absorption studies that suggest that AFAP-110403S/C may differ from AFAP WT in its ability to self-associate. Altered self-association could present AFAP in a conformation that facilitates c-Src activation. In a model system that mimics the level of c-Src over-expression in ovarian cancer, transient transfection of AFAP-110403S/C results in the activation of c-Src and the formation of podosomes. This could be of clinical significance as the generation of invasive motility structures could facilitate tumor progression. In addition, the efficient activation of c-Src by AFAP-110403S/C could contribute to rapid development of paclitaxel resistance. Therefore, the genetic variant of AFAP-110 could be used in a gene assay to predict those most likely to exhibit rapid tumor progression as well as those most likely to develop chemotherapy-resistance

Salvage stereotactic body radiotherapy for locally recurrent non-small cell lung cancer after sublobar resection and I125 vicryl mesh brachytherapy

Purpose: Locally-recurrent non-small cell lung cancer (LR-NSCLC) remains challenging treat, particularly in patients having received prior radiotherapy. Heterogeneous populations and varied treatment intent in existing literature result in significant limitations in evaluating efficacy of lung re-irradiation. In order to better establish the impact of re-irradiation in patients with LR-NSCLC following high-dose radiotherapy, we report outcomes for patients treated with prior sublobar resection and brachytherapy that subsequently underwent stereotactic body radiotherapy (SBRT).Methods: A retrospective review of patients initially treated with sublobar resection and I125 vicryl mesh brachytherapy, who later developed LR-NSCLC along the suture line, was performed. Patients received salvage SBRT with curative intent. Dose and fractionation was based on tumor location and size, with a median prescription dose of 48 Gy in 4 fractions (range 20-60 Gy in 1-4 fractions).Results: Thirteen consecutive patients were identified with median follow-up of 2.1 years (range 0.7-5.6 years). Two in-field local failures occurred at 7.5 and 11.1 months, resulting in 2-year local control of 83.9% (95% CI 63.5-100.0%). Two-year disease-free survival and overall survival estimates were 38.5% (95% CI 0.0-65.0%) and 65.8% (95% CI, 38.2-93.4%). Four patients (31%) remained disease-free at last follow-up. All but one patient who experienced disease recurrence developed isolated or synchronous distant metastases. Only one patient (7.7%) developed grade ≥3 toxicity, consisting of grade 3 esophageal stricture following a centrally located recurrence previously treated with radiofrequency ablation.Conclusion: Despite high local radiation doses delivered to lung parenchyma previously with I125 brachytherapy, re-irradiation with SBRT for LR-NSCLC results in excellent local control with limited morbidity, allowing for potential disease cure in a subset of patients

Fractionated stereotactic radiosurgery for the treatment of meningiomas

Background: Although the vast majority of meningiomas are not malignant, their location within the cranial vault often leads to the development of symptoms. Traditional therapy has included observation, surgical resection, radiation therapy or a multimodality approach. The objective of this study is to review the outcomes in patients with meningioma treated at our institution using stereotactic radiosurgery. Materials and Methods: A total of 73 patients (median age of 59, 15 male and 58 female) with meningioma (median volume of 5.54 cc) underwent Cyber Knife TM stereotactic radiosurgery at our institution. Sixty patients had WHO grade 1 meningioma, eleven patients had WHO grade 2 meningioma, and two patients had WHO grade 3 meningioma. Treatment consisted of a median dose of 17.5 Gy (range, 6 - 27 Gy) delivered over a median of three fractions (range: 1 - 5). The patients were followed by clinical examination as well as serial imaging with magnetic resonance imaging (MRI). Results: The median follow-up was 16.1 months (range, 1.5 - 98.0). Follow-up MRI was available in all 73 patients. Local failure was documented in 11 cases. Actuarial local control at one year was 95, 71, and 0% for WHO grade 1, WHO grade 2, and WHO grade 3, respectively. There was no acute grade 3 or greater toxicity and only one episode of late grade 3 toxicity. A subjective improvement in the existing, tumor-related symptoms was noted in 60% of the patients. Conclusion: Stereotactic radiosurgery is a safe and effective treatment for meningioma. Tumor-related symptoms often improve after treatment

Prescription dose and fractionation predict improved survival after stereotactic radiotherapy for brainstem metastases

<p>Abstract</p> <p>Background</p> <p>Brainstem metastases represent an uncommon clinical presentation that is associated with a poor prognosis. Treatment options are limited given the unacceptable risks associated with surgical resection in this location. However, without local control, symptoms including progressive cranial nerve dysfunction are frequently observed. The objective of this study was to determine the outcomes associated with linear accelerator-based stereotactic radiotherapy or radiosurgery (SRT/SRS) of brainstem metastases.</p> <p>Methods</p> <p>We retrospectively reviewed 38 tumors in 36 patients treated with SRT/SRS between February 2003 and December 2011. Treatment was delivered with the Cyberknife™ or Trilogy™ radiosurgical systems. The median age of patients was 62 (range: 28–89). Primary pathologies included 14 lung, 7 breast, 4 colon and 11 others. Sixteen patients (44%) had received whole brain radiation therapy (WBRT) prior to SRT/SRS; ten had received prior SRT/SRS at a different site (28%). The median tumor volume was 0.94 cm³ (range: 0.01-4.2) with a median prescription dose of 17 Gy (range: 12–24) delivered in 1–5 fractions.</p> <p>Results</p> <p>Median follow-up for the cohort was 3.2 months (range: 0.4-20.6). Nineteen patients (52%) had an MRI follow-up available for review. Of these, one patient experienced local failure corresponding to an actuarial 6-month local control of 93%. Fifteen of the patients with available follow-up imaging (79%) experienced intracranial failure outside of the treatment volume. The median time to distant intracranial failure was 2.1 months. Six of the 15 patients with distant intracranial failure (40%) had received previous WBRT. The actuarial overall survival rates at 6- and 12-months were 27% and 8%, respectively. Predictors of survival included Graded Prognostic Assessment (GPA) score, greater number of treatment fractions, and higher prescription dose. Three patients experienced acute treatment-related toxicity consisting of nausea (n = 1) and headaches (n = 2) that resolved with a short-course of dexamethasone.</p> <p>Conclusion</p> <p>SRT/SRS for brainstem metastases is safe and achieves a high rate of local control. We found higher GPA as well as greater number of treatment fractions and higher prescription dose to be correlated with improved overall survival. Despite this approach, prognosis remains poor and distant intracranial control remains an issue, even in patients previously treated with WBRT.</p

Tumor bed radiosurgery following resection and prior stereotactic radiosurgery for locally-persistent brain metastasis

Purpose: Despite advances in multimodality management of brain metastases, local progression following stereotactic radiosurgery (SRS) can occur. Often, surgical resection is favored, as it frequently provides immediate symptom relief as well as pathologic characterization of any residual tumor. Should the pathological specimen contain viable tumor cells, further radiation therapy is an option to sterilize the tumor bed. We evaluated the use of repeat SRS (rSRS) in lieu of whole brain radiation therapy (WBRT) as a means of improving local control (LC) while minimizing potential toxicity and dose to the normal brain. Material/Methods: A retrospective review was performed to identify patients with brain metastases who underwent SRS and then surgical resection for locally recurrent or persistent disease. From 2004 to 2014, thirteen consecutive patients or 15 lesions were treated with rSRS after resection, either post-operatively to the tumor bed (n=10, 66.6%) or after a second local recurrence (n=5, 33.3%). LC, distant brain failure (DBF), and radiation toxicity were determined using patient records, RECIST criteria v1.1, and CTCAE v4.03. Results: At a median follow-up interval of 9.0 months (range 1.8-54.9 months) from time of rSRS, 5 patients remain alive. Following rSRS, 13 of the 15 (86.6%) lesions were locally controlled with an estimated 100% LC at 6-months and 75% LC at 1- year. However, 11 of the 15 (73.3%) treated lesions developed DBF after rSRS with 3 of 13 patients proceeding to WBRT. Two of 15 (13.3%) resulted in either grade 2 radionecrosis with grade 3 seizures or grade 3 radionecrosis.Conclusion: Repeat SRS represents a potential salvage therapy for patients with locally-recurrent brain metastases, providing additional tumor control with acceptable toxicity, even in the setting of prior SRS and surgical resection. Repeat SRS may be reasonable to use as an alternative to WBRT in this setting