Demonstration of real-time positron emission tomography biology-guided radiotherapy delivery to targets.

BACKGROUND: Biology-guided radiotherapy (BgRT) is a novel technology that uses positron emission tomography (PET) data to direct radiotherapy delivery in real-time. BgRT enables the precise delivery of radiation doses based on the PET signals emanating from PET-avid tumors on the fly. In this way, BgRT uniquely utilizes radiotracer uptake as a biological beacon for controlling and adjusting dose delivery in real-time to account for target motion. PURPOSE: To demonstrate using real-time PET for BgRT delivery on the RefleXion X1 radiotherapy machine. The X1 radiotherapy machine is a rotating ring-gantry radiotherapy system that generates a nominal 6MV photon beam, PET, and computed tomography (CT) components. The system utilizes emitted photons from PET-avid targets to deliver effective radiation beamlets or pulses to the tumor in real-time. METHODS: This study demonstrated a real-time PET BgRT delivery experiment under three scenarios. These scenarios included BgRT delivering to (S1 ) a static target in a homogeneous and heterogeneous environment, (S2 ) a static target with a hot avoidance structure and partial PET-avid target, and (S3 ) a moving target. The first step was to create stereotactic body radiotherapy (SBRT) and BgRT plans (offline PET data supported) using RefleXion's custom-built treatment planning system (TPS). Additionally, to create a BgRT plan using PET-guided delivery, the targets were filled with 18F-Fluorodeoxyglucose (FDG), which represents a tumor/target, that is, PET-avid. The background materials were created in the insert with homogeneous water medium (for S1 ) and heterogeneous water with styrofoam mesh medium. A heterogeneous background medium simulated soft tissue surrounding the tumor. The treatment plan was then delivered to the experimental setups using a pre-commercial version of the X1 machine. As a final step, the dosimetric accuracy for S1 and S2 was assessed using the ArcCheck analysis tool-the gamma criteria of 3%/3 mm. For S3 , the delivery dose was quantified using EBT-XD radiochromic film. The accuracy criteria were based on coverage, where 100% of the clinical target volume (CTV) receives at least 97% of the prescription dose, and the maximum dose in the CTV was ≤130% of the maximum planned dose (97 % ≤ CTV ≤ 130%). RESULTS: For the S1, both SBRT and BgRT deliveries had gamma pass rates greater than 95% (SBRT range: 96.9%-100%, BgRT range: 95.2%-98.9%), while in S2 , the gamma pass rate was 98% for SBRT and between 95.2% and 98.9% for BgRT plan delivering. For S3 , both SBRT and BgRT motion deliveries met CTV dose coverage requirements, with BgRT plans delivering a very high dose to the target. The CTV dose ranges were (a) SBRT:100.4%-120.4%, and (b) BgRT: 121.3%-139.9%. CONCLUSIONS: This phantom-based study demonstrated that PET signals from PET-avid tumors can be utilized to direct real-time dose delivery to the tumor accurately, which is comparable to the dosimetric accuracy of SBRT. Furthermore, BgRT delivered a PET-signal controlled dose to the moving target, equivalent to the dose distribution to the static target. A future study will compare the performance of BgRT with conventional image-guided radiotherapy.

BIOGUIDE-X: A First-in-Human Study of the Performance of Positron Emission Tomography-Guided Radiation Therapy.

PURPOSE: Positron emission tomography (PET)-guided radiation therapy is a novel tracked dose delivery modality that uses real-time PET to guide radiation therapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for PET-guided therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiation therapy plan. METHODS AND MATERIALS: This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (2-5 cm) in the lung or bone. For cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for PET-guided therapy. For cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiation therapy. PET-guided therapy dose distributions were modeled on the patient's computed tomography anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared with the physician-approved plan. RESULTS: Cohort I demonstrated adequate FDG activity in 6 of 6 evaluable participants (100.0%) with the first injected dose level of 15 mCi FDG. In cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in dose distributions that were accurate with respect to the approved PET-guided therapy plan. The 17th data point was just below the 95% threshold for accuracy (dose-volume histogram score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations. CONCLUSIONS: PET-guided therapy is a novel radiation therapy modality in which a radiolabeled tumor can act as its own fiducial for radiation therapy targeting. Emulated therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2 to 5 cm in size with adequate FDG signal characteristics.

Advances in PET/CT Imaging for Breast Cancer.

One out of eight women will be affected by breast cancer during her lifetime. Imaging plays a key role in breast cancer detection and management, providing physicians with information about tumor location, heterogeneity, and dissemination. In this review, we describe the latest advances in PET/CT imaging of breast cancer, including novel applications of 18F-FDG PET/CT and the development and testing of new agents for primary and metastatic breast tumor imaging and therapy. Ultimately, these radiopharmaceuticals may guide personalized approaches to optimize treatment based on the patient's specific tumor profile, and may become a new standard of care. In addition, they may enhance the assessment of treatment efficacy and lead to improved outcomes for patients with a breast cancer diagnosis.

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

BACKGROUND: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO). METHODS: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression. RESULTS: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. CONCLUSIONS: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

The Effect of Slice Thickness on Contours of Brain Metastases for Stereotactic Radiosurgery.

OBJECTIVES: Stereotactic radiosurgery is a common treatment for brain metastases and is typically planned on magnetic resonance imaging (MRI). However, the MR acquisition parameters used for patient selection and treatment planning for stereotactic radiosurgery can vary within and across institutions. In this work, we investigate the effect of MRI slice thickness on the detection and contoured volume of metastatic lesions in the brain. METHODS AND MATERIALS: A retrospective cohort of 28 images acquired with a slice thickness of 1 mm were resampled to simulate acquisitions at 2- and 3-mm slice thickness. A total of 102 metastases ranging from 0.0030 cc to 5.08 cc (75-percentile 0.36 cc) were contoured on the original images. All 3 sets of images were recontoured by experienced physicians. RESULTS: Of all the images detected and contoured on the 1 mm images, 3% of lesions were missed on the 2 mm images, and 13% were missed on the 3 mm images. One lesion that was identified on both the 2 mm and 3 mm images was determined to be a blood vessel on the 1 mm images. Additionally, the lesions were contoured 11% larger on the 2 mm and 43% larger on the 3 mm images. CONCLUSIONS: Using images with a slice thickness >1 mm effects detection and segmentation of brain lesions, which can have an important effect on patient management and treatment outcomes.

Prognostic value of disease distribution in secondary central nervous system diffuse large B cell lymphoma treated with radiation therapy.

This study aimed to assess the prognostic value of baseline disease distribution for patients with the secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy and radiation (RT). 44 patients with secondary CNS DLBCL were reviewed. Twenty patients had leptomeningeal disease (LMD), and 24 had localized/targetable disease (LTD). Of 8 patients who received stem cell transplantation (SCT) after RT, 6 had LTD with a complete or partial response after RT. Median time to CNS relapse after RT was 10.1 months; 3/24 patients with LTD and 5/15 with LMD had CNS relapse. The median overall survival (OS) was 8 and 20 months for patients with LMD and LTD, respectively (p = 0.20). On multivariable analysis, LTD, receipt of SCT, and response after RT were associated with better OS and CNS-disease-free survival. Patients with localized secondary CNS DLBCL may benefit from RT serving as a bridge to SCT.

Real-world evaluation of the impact of radiotherapy and chemotherapy in elderly patients with glioblastoma based on age and performance status.

BACKGROUND: This retrospective study investigated the impact of, in addition to age, the management and outcomes of elderly patients with glioblastoma (GBM). METHODS: The National Cancer Database was queried between 2004 and 2015 for GBM patients age 60 years and older. Three age groups were created: 60 to 69, 70 to 79, and 80 years and older, and 4 age/KPS groups: "age ≥ 60/ KPS < 70" (group 1), "age 60 to 69/KPS ≥ 70" (group 2), "age 70 to 79/KPS ≥ 70" (group 3), and "age ≥ 80/KPS ≥ 70" (group 4). Multivariable (MVA) modeling with Cox regression determined predictors of survival (OS), and estimated average treatment effects analysis was performed. RESULTS: A total of 48 540 patients with a median age of 70 years (range, 60-90 years) at diagnosis, and a median follow-up of 6.8 months (range, 0-151 months) were included. Median survival was 5.0, 15.2, 9.6, and 6.8 months in groups 1, 2, 3, and 4, respectively (P < .001). On treatment effects analysis, all groups survived longer with combined chemotherapy (ChT) and radiation therapy (RT), except group 1, which survived longer with ChT alone (P < .001). RT alone was associated with the worst OS in all groups (P < .01). Across all groups, predictors of worse OS on MVA were older age, lower KPS, White, higher comorbidity score, worse socioeconomic status, community treatment, tumor multifocality, subtotal resection, and no adjuvant treatment (all P < .01). CONCLUSIONS: In elderly patients with newly diagnosed GBM, those with good KPS fared best with combined ChT and RT across all age groups. Performance status is a key prognostic factor that should be considered for management decisions in these patients.

Computed Tomography Radiomics Kinetics as Early Imaging Correlates of Osteoradionecrosis in Oropharyngeal Cancer Patients.

Osteoradionecrosis (ORN) is a major side-effect of radiation therapy in oropharyngeal cancer (OPC) patients. In this study, we demonstrate that early prediction of ORN is possible by analyzing the temporal evolution of mandibular subvolumes receiving radiation. For our analysis, we use computed tomography (CT) scans from 21 OPC patients treated with Intensity Modulated Radiation Therapy (IMRT) with subsequent radiographically-proven ≥ grade II ORN, at three different time points: pre-IMRT, 2-months, and 6-months post-IMRT. For each patient, radiomic features were extracted from a mandibular subvolume that developed ORN and a control subvolume that received the same dose but did not develop ORN. We used a Multivariate Functional Principal Component Analysis (MFPCA) approach to characterize the temporal trajectories of these features. The proposed MFPCA model performs the best at classifying ORN vs. Control subvolumes with an area under curve (AUC) = 0.74 [95% confidence interval (C.I.): 0.61-0.90], significantly outperforming existing approaches such as a pre-IMRT features model or a delta model based on changes at intermediate time points, i.e., at 2- and 6-month follow-up. This suggests that temporal trajectories of radiomics features derived from sequential pre- and post-RT CT scans can provide markers that are correlates of RT-induced mandibular injury, and consequently aid in earlier management of ORN.

Image-based personalization of computational models for predicting response of high-grade glioma to chemoradiation.

High-grade gliomas are an aggressive and invasive malignancy which are susceptible to treatment resistance due to heterogeneity in intratumoral properties such as cell proliferation and density and perfusion. Non-invasive imaging approaches can measure these properties, which can then be used to calibrate patient-specific mathematical models of tumor growth and response. We employed multiparametric magnetic resonance imaging (MRI) to identify tumor extent (via contrast-enhanced T1-weighted, and T2-FLAIR) and capture intratumoral heterogeneity in cell density (via diffusion-weighted imaging) to calibrate a family of mathematical models of chemoradiation response in nine patients with unresected or partially resected disease. The calibrated model parameters were used to forecast spatially-mapped individual tumor response at future imaging visits. We then employed the Akaike information criteria to select the most parsimonious member from the family, a novel two-species model describing the enhancing and non-enhancing components of the tumor. Using this model, we achieved low error in predictions of the enhancing volume (median: - 2.5%, interquartile range: 10.0%) and a strong correlation in total cell count (Kendall correlation coefficient 0.79) at 3-months post-treatment. These preliminary results demonstrate the plausibility of using multiparametric MRI data to inform spatially-informative, biologically-based predictive models of tumor response in the setting of clinical high-grade gliomas.

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). METHODS: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). RESULTS: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). CONCLUSIONS: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

A mathematical model for the quantification of a patient's sensitivity to checkpoint inhibitors and long-term tumour burden.

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.

Outcomes after radiation therapy for T2N0/stage II glottic squamous cell carcinoma.

BACKGROUND: We report outcomes for patients with T2N0M0 glottic squamous cell carcinoma (SCC) treated with radiation therapy (RT). METHODS: Patients who received definitive RT for T2 glottic SCC from 2000 through 2013 were retrospectively reviewed. RESULTS: One hundred and thirteen patients were analyzed (median follow-up time 91 months; 85 patients received three-dimensional conformal radiotherapy [3D-CRT] and 28 received intensity-modulated radiation therapy [IMRT]). Fractionation was conventional (58%) or altered (42%); 20 patients (18%) received concurrent chemotherapy. Five-year local control was 83% for the 3D-CRT vs 81% for the IMRT group (P = .76). The ultimate locoregional control at 5 years was 100% for IMRT vs 91% for 3D-CRT (P = .1). The 5-year overall survival (OS) was 78% for 3D-CRT vs 81% for IMRT (P = .83). On multivariate analysis, younger age was the only independent predictor of improved OS (P = .0002). CONCLUSIONS: Oncologic and survival outcomes were excellent for patients with T2N0 glottic cancer. Patients treated with IMRT and 3D-CRT had no statistically significant differences in all investigated endpoints.

Optimal Timing of Radiotherapy Following Gross Total or Subtotal Resection of Glioblastoma: A Real-World Assessment using the National Cancer Database.

Treatment for glioblastoma (GBM) includes surgical resection and adjuvant radiotherapy (RT) and chemotherapy. The optimal time interval between surgery and RT remains unclear. The National Cancer Database (NCDB) was queried for patients with GBM. Overall survival (OS) was estimated using Kaplan-Meier and log-rank tests. Univariate (UVA) and multivariable Cox regression (MVA) modeling was used to determine predictors of OS. A total of 45,942 patients were included. On MVA: younger age, female gender, black ethnicity, higher KPS, obtaining a gross total resection (GTR), MGMT promoter-methylated gene status, unifocal disease, higher RT dose, and RT delay of 4-8 weeks had improved OS. Patients who underwent a subtotal resection (STR) had worsened survival with RT delay ≤4 weeks and patients with GTR had worsened survival when RT was delayed >8 weeks. This analysis suggests that an interval of 4-8 weeks between resection and RT results in better survival. Delays >8 weeks in patients with a GTR and delays <4 weeks in patients with a STR/biopsy resulted in worse survival. This impact of time delay from surgery to RT, in conjunction with extent of resection, should be considered in the clinical management of patients and future designs of clinical trials.

Detection of Glioblastoma Subclinical Recurrence Using Serial Diffusion Tensor Imaging.

Glioblastoma is an aggressive brain tumor with a propensity for intracranial recurrence. We hypothesized that tumors can be visualized with diffusion tensor imaging (DTI) before they are detected on anatomical magnetic resonance (MR) images. We retrospectively analyzed serial MR images from 30 patients, including the DTI and T1-weighted images at recurrence, at 2 months and 4 months before recurrence, and at 1 month after radiation therapy. The diffusion maps and T1 images were deformably registered longitudinally. The recurrent tumor was manually segmented on the T1-weighted image and then applied to the diffusion maps at each time point to collect mean FA, diffusivities, and neurite density index (NDI) values, respectively. Group analysis of variance showed significant changes in FA (p = 0.01) and NDI (p = 0.0015) over time. Pairwise t tests also revealed that FA and NDI at 2 months before recurrence were 11.2% and 6.4% lower than those at 1 month after radiation therapy (p < 0.05), respectively. Changes in FA and NDI were observed 2 months before recurrence, suggesting that progressive microstructural changes and neurite density loss may be detectable before tumor detection in anatomical MR images. FA and NDI may serve as non-contrast MR-based biomarkers for detecting subclinical tumors.

Correlation of normal lung density changes with dose after stereotactic body radiotherapy (SBRT) for early stage lung cancer.

BACKGROUND AND PURPOSE: To investigate the correlation between normal lung CT density changes with dose accuracy and outcome after stereotactic body radiation therapy (SBRT) for patients with early stage non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Thirty-one patients (with a total of 33 lesions) with non-small cell lung cancer were selected out of 270 patients treated with SBRT at a single institution between 2003 and 2009. Out of these 31 patients, 10 patients had developed radiation pneumonitis (RP). Dose distributions originally planned using a 1-D pencil beam-based dose algorithm were retrospectively recomputed using different algorithms. Prescription dose was 48 Gy in 4 fractions in most patients. Planning CT images were rigidly registered to follow-up CT datasets at 3-9 months after treatment. Corresponding dose distributions were mapped from planning to follow-up CT images. Hounsfield Unit (HU) changes in lung density in individual, 5 Gy, dose bins from 5 to 45 Gy were assessed in the peri-tumoral region. Correlations between HU changes in various normal lung regions, dose indices (V20, MLD, generalized equivalent uniform dose (gEUD)), and RP grade were investigated. RESULTS: Strong positive correlation was found between HU changes in the peri-tumoral region and RP grade (Spearman's r = 0.760; p < 0.001). Positive correlation was also observed between RP and HU changes in the region covered by V20 for all algorithms (Spearman's r ≥ 0.738; p < 0.001). Additionally, V20, MLD, and gEUD were significantly correlated with RP grade (p < 0.01). MLD in the peri-tumoral region computed with model-based algorithms was 5-7% lower than the PB-based methods. CONCLUSION: Changes of lung density in the peri-tumoral lung and in the region covered by V20 were strongly associated with RP grade. Relative to model-based methods, PB algorithms over-estimated mean peri-tumoral dose and showed displacement of the high-dose region, which correlated with HU changes on follow-up CT scans.

HPV-related oropharyngeal cancer prevalence in a middle eastern population using E6/E7 PCR.

BACKGROUND: Given the paucity of data and widely variable rates that have been reported, the main objective of this study was to examine the prevalence of HPV-positivity in oropharyngeal squamous cell carcinoma (OPSCC) in Middle Eastern patients presenting to one of the region's largest tertiary care centers using polymerase chain reaction (PCR) amplification of the HPV E6/E7 oncogenes, a highly sensitive and specific method of detection. METHODS: Medical charts and archived pathological specimens were obtained for patients diagnosed with biopsy proven oropharyngeal cancer who presented to the American University of Beirut Medical Center between 1972 and 2017. DNA was extracted from paraffin-embedded specimens and tested for 30 high-risk and low-risk papilloma viruses using the PCR-based EUROarray HPV kit (EuroImmun). RESULTS: A total of 57 patients with oropharyngeal cancer were initially identified; only 34 met inclusion/exclusion criteria and were included in the present study. Most patients were males (73.5%) from Lebanon (79.4%). The most common primary tumor site was in the base of tongue (50%), followed by the tonsil (41.2%). The majority of patients (85.3%) tested positive for HPV DNA. CONCLUSION: The prevalence of HPV-positivity amongst Middle Eastern OPSCC patients, specifically those from Lebanon, may be far greater than previously thought. The Lebanese population and other neighboring Middle Eastern countries may require a more vigilant approach towards HPV detection and awareness. On an international level, further research is required to better elucidate non-classical mechanisms of HPV exposure and transmission.

Impact of smoking on pathological features in oral cavity squamous cell carcinoma.

OBJECTIVES: We sought to determine whether smokers with oral cavity squamous cell carcinoma (OCSCC) have tumors with more adverse pathological features than in nonsmokers and whether or not these are predictive of outcomes. MATERIALS AND METHODS: We retrospectively identified 163 patients with American Joint Committee on Cancer stages I-IVa OCSCC diagnosed between 2005 and 2015 and treated with curative intent. A pathological risk score (PRS) was calculated using the National Comprehensive Cancer Network adverse risk factors: positive margin, extracapsular extension of lymph node metastases, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion, and lymphovascular space invasion. Multivariable models were constructed to determine the independent predictors of overall survival (OS), recurrence-free survival (RFS), and PRS. RESULTS: A total of 108 (66.26%) were smokers and 55 nonsmokers. Three-year actuarial OS and RFS were 62% and 68% in smokers and 81% and 69% in nonsmokers, respectively (P = 0.06 and P = 0.63). Smokers were more likely to have advanced disease stage and tumors with aggressive pathological features than nonsmokers. Smokers had significantly worse PRS (mean ± standard deviation; 2.38 ± 2.19, median; 2.00) than nonsmokers (0.89 ± 1.21, 0.00) (P < 0.001). Older age, higher PRS, and smoking status were independent predictors of OS. Smoking or PRS did not predict for worse RFS. On multivariate analysis, independent predictors of PRS were smoking status and grade (P < 0.001). CONCLUSION: In patients with OCSCC, smokers have more aggressive disease as evidenced by more adverse pathological features than nonsmokers. Moreover, smoking is an independent predictor of OS but not RFS. The PRS is a significant predictor of OS and needs validation in the future studies.

A Novel Mechanism of High Dose Radiation Sensitization by Metformin.

Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation. Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment. Results: In vivo, metformin provided equally effective tumor growth delay when given 24 h after radiation as when given 1 h or 4 h before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs. 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen. Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen.

The Use of 68Ga-DOTATATE PET/CT in the Non-invasive Diagnosis of Optic Nerve Sheath Meningioma: A Case Report.

We hereby report the case of a patient with optic nerve sheath meningioma (ONSM), whose diagnosis and multidisciplinary management was guided by the use of Gallium-68 (68Ga)-labeled dodecanetetraacetic acid-tyrosine-3-octreotate (DOTATATE) positron emission tomography (PET)/computed tomography (CT) scan. We briefly review the diagnosis and management of ONSM, and review the literature on the role and current status of nuclear imaging with somatostatin receptor ligands in the non-invasive diagnosis and management of meningiomas.

Trastuzumab Emtansine for the Treatment of HER-2 Positive Carcinoma Ex-pleomorphic Adenoma Metastatic to the Brain: A Case Report.

Background: Carcinoma Ex-pleomorphic adenoma is a malignant transformation of the common benign neoplasm of the salivary glands, "pleomorphic adenoma." Only two cases were ever reported with brain metastases, with absence of good evidence guiding management of such cases. Case Presentation: A 61-year-old woman presenting with facial paralysis was found to have carcinoma ex-pleomorphic adenoma of the parotid gland. Twenty months after local treatment, she developed brain metastases, treated with whole brain radiation therapy. The patient then had progressive intracranial disease after the end of radiation therapy in addition to the appearance of liver metastases. Pathology showed overexpression of HER2, so she was treated with Trastuzumab Emtansine (TDM1). Follow-up imaging revealed significant decrease in the number and size of the metastatic brain lesions in keeping with a good response to TDM1 treatment. Conclusion: Prognosis of metastatic carcinoma ex-pleomorphic adenoma is very poor, and there is no clear management for such cases. We present a case of carcinoma ex-pleomorphic adenoma with brain and liver metastases with a very good response to TDM1 treatment.