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Purpose: In glioma surgery, it is critical to maximize tumor resection without compromising adjacent noncancerous brain tissue. Optical coherence tomography (OCT) is a noninvasive, label-free, real-time, high-resolution imaging modality that has been explored for glioma infiltration detection. Here, we report a novel artificial intelligence (AI)-assisted method for automated, real-time, in situ detection of glioma infiltration at high spatial resolution. Experimental Design: Volumetric OCT datasets were intraoperatively obtained from resected brain tissue specimens of 21 patients with glioma tumors of different stages and labeled as either noncancerous or glioma-infiltrated on the basis of histopathology evaluation of the tissue specimens (gold standard). Labeled OCT images from 12 patients were used as the training dataset to develop the AI-assisted OCT-based method for automated detection of glioma-infiltrated brain tissue. Unlabeled OCT images from the other 9 patients were used as the validation dataset to quantify the method detection performance. Results: Our method achieved excellent levels of sensitivity (∼100%) and specificity (∼85%) for detecting glioma-infiltrated tissue with high spatial resolution (16 μm laterally) and processing speed (∼100,020 OCT A-lines/second). Conclusions: Previous methods for OCT-based detection of glioma-infiltrated brain tissue rely on estimating the tissue optical attenuation coefficient from the OCT signal, which requires sacrificing spatial resolution to increase signal quality, and performing systematic calibration procedures using tissue phantoms. By overcoming these major challenges, our AI-assisted method will enable implementing practical OCT-guided surgical tools for continuous, real-time, and accurate intraoperative detection of glioma-infiltrated brain tissue, facilitating maximal glioma resection and superior surgical outcomes for patients with glioma.

Lymphopenia is associated with decreased survival outcomes in head and neck squamous cell carcinoma (HNSCC). This is a significant concern especially for frail individuals who are more vulnerable to immunological dysregulations. A robust analysis is needed to understand whether we should expend efforts to limit treatment-related hematological toxicities in HNSCC. First, we would like to understand the prognostic significance for baseline (BL) vs. treatment-related lymphopenia (TRL). We want to know if lymphopenia is merely a reflection of the patient’s frailty at baseline, or if this is iatrogenic and therefore can be a target for treatment modifications in a bid to improve survival. Here, we identified 222 newly diagnosed M0 HNSCC patients treated with radiation ± systemic therapy in 2015-2018 at our institution. Clinical frailty is defined by age ≥ 65 or KPS ≤ 70. Using Kaplan Meier estimates and Cox regression with dichotomous variables, we performed multivariate analysis for both overall survival (OS) and progression-free survival (PFS). Important predictors included frailty (p ≤ 0.002) and ≥ 2K/mm3 decrease in absolute lymphocyte counts (ALC) (p ≤ 0.006). BL did not significantly impact OS or PFS (p ≤ 0.37). For TRL, ALC decrease had greater prognostic significance compared with ALC nadirs (p ≤ 0.45). Next, we simplified our survival model to include only frailty and TRL. Overall, fit patients with modest ALC decline (< 2K/mm3) achieved excellent survival outcomes while frail patients with severe ALC decline (≥ 2K/mm3) had inferior outcomes (3-year OS 95% vs. 56%, p < 0.0001; 3-year PFS 84% vs. 42%, p = 0.002). On subgroup analyses, similar outcomes were also identified for HPV+ HNSCC (n = 172, 3-year OS 96% vs. 71%, p = 0.002; 3-year PFS 89% vs. 54% p = 0.03). Finally, we want to know if ALC decline is determined primarily by treatment intensity, or if frail patients are naturally predisposed to greater ALC decline during treatment. In our data, frail patients had more modest ALC decline when compared to fit patients (1.26 ± 0.57 vs. 1.54 ± 0.58 K/mm3 p = 0.0006). In our survival model, we did not observe any first-order interactions between frailty and ALC decline (p = 0.54). The extent of ALC decline was also higher for patients with concurrent administrations of cisplatin (as opposed to radiation alone, p < 0.0001). Thus, we postulate that the extent of ALC decline is determined primarily by treatment intensity. It is possible that frail patients with severe ALC decline have inferior survival outcomes because they cannot maintain immunological balance and respond poorly when there is significant TRL. This opens opportunities to re-evaluate if the risk of TRL is modifiable by limiting the number of concurrent cycles of chemotherapy administered, and by considering radiation dose de-intensification especially for HPV-associated HNSCC. Lastly, TRL becomes an important consideration when immunotherapeutics are grafted onto existing CRT treatment paradigms. Citation Format: Carmen Kut, Todd McNutt, Carole Fakhry, Theodore DeWeese, Harry Quon. Lymphocyte kinetics, frailty and survival outcomes in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1971.

PURPOSE/OBJECTIVE(S) Severe lymphopenia during chemoradiation is often associated with higher risk of death, disease progression and distant metastases. Recent data has shown that head and neck cancer (HNC) patients with lymphopenia has a decreased 5-year overall survival of 70 vs 90%. While both radiation and chemotherapy have been associated with lymphopenia, the mechanism of action remains unclear. Here, we propose a spatially-defined model that evaluates the combined effects of lymphotoxic radiation doses to head and neck organs-at-risk (HN-OARs) which include the cervical bone marrow and the circulating blood pool. Our objective is to investigate the spatial dose relationships related to treatment-related lymphopenia (TRL) in HNC patients. MATERIALS/METHODS We have identified a prospectively acquired dataset of 40 HNC patients treated at our institution with 31 oropharynx, 3 oral cavity, 4 nasopharynx and 2 larynx cases. Weekly lymphocyte counts were extracted at baseline and for 8 weeks since initiation of radiotherapy. Chemotherapy timing, dosage and regimens were documented. HN-OARs were manually contoured on CT simulation scans. To generate the spatially-defined linear regression model, we included these inputs (x): internal jugular veins (IJVs), carotid arteries (CAs), capillary bed (CB) and vertebral bodies (VBs). The output (y) is defined by % decrease between baseline and nadir lymphocyte counts. Then, we segmented VBs by vertebral levels, and other HN-OARs by disease laterality (ipsilateral vs contralateral). IJVs and CAs are further segmented by anatomic zones (zone 1: C1 to hyoid, zone 2: hyoid to cricoid, and zone 3: cricoid to C7). Stepwise selection was used to identify influential HN-OARs. Finally, we proposed spatial dose parameters associated with high risk lymphopenia (defined as ≥70% decrease) and performed sensitivity/specificity (Se/Sp) analyses. RESULTS Using stepwise (forward) selection, we identified IJVs as potential targets to spare low dose bath parameters Dmin and D90 (P-values 0.028 to 0.056), and VBs as potential targets to spare point max doses Dmax and D10 (P-values < 0.001 to 0.020). To avoid overfitting, we also performed backward selection with a more liberal P-value criterion of 0.50 which showed similar results. Key anatomic zones for potential dose sparing include C1-3 VBs and contralateral zone 1 IJVs. Overall, we proposed these dose parameters to limit TRL risks: Dmax ≤ 60 Gy for VBs (Se/Sp: 76%/86%, AUC 0.84) and D90 ≤ 13 Gy for contralateral IJVs (Se/Sp: 72%/86%, AUC 0.79). CONCLUSION The risk of treatment-related lymphopenia (TRL) appears to be spatially related to radiation doses to the VBs and IJVs. Better understanding of the spatial dose relationship with HN-OARs may lead to insights in reducing TRL risks and improving oncologic outcomes, especially as we consider the benefits of recent dose de-escalation studies (to reduce point max doses) and proton treatment techniques (to reduce low dose baths) in the management of head and neck cancers.

Gliomas are CNS neoplasms that infiltrate the surrounding brain parenchyma, complicating their treatment. Tools that increase extent of resection while preventing neurological deficit are essential to improve prognosis of patients diagnosed with gliomas. Tools such as intraoperative MRI, ultrasound and fluorescence-guided microsurgery have been used in the surgical resection of CNS gliomas with the goal of maximizing extent of resection to improve patient outcomes. In addition, emerging experimental techniques, for example, optical coherence tomography and Raman spectroscopy are promising techniques which could 1 day add to the increasing armamentarium used in the surgical resection of CNS gliomas. Here, we present the potential advantages and limitations of these imaging techniques for the purposes of identifying gliomas in the operating room.

The purpose of this critical review is to explore the controversy regarding the relationship between radiation dose to the neural progenitor cell (NPC) niches and patient outcomes, in terms of both toxicity and tumor control. NPCs in the subventricular zone (SVZ) and hippocampus are paradoxically associated with long-term neurocognitive sequelae of brain irradiation, as well as resistance to therapy and tumor recurrence. The reconciliation of these somewhat opposing functions is challenging. Current literature suggests that radiation and other treatments against the NPC in the hippocampus and the SVZ may influence patient outcome. As a result, both the SVZ and the hippocampus could have important implications on radiation treatment planning strategies, and future laboratory and clinical evaluations will be critical in designing studies to optimize treatment outcome, effectiveness, and safety.

Purpose To determine whether frameless thermoplastic mask-based immobilization is adequate for image-guided cranial radiosurgery. Methods and Materials Cone-beam CT localization data from patients with intracranial tumors were studied using daily pre- and posttreatment scans. The systems studied were ( 1 ) Type-S IMRT (head only) mask (Civco) with head cushion; ( 2 ) Uni-Frame mask (Civco) with head cushion, coupled with a BlueBag body immobilizer (Medical Intelligence); ( 3 ) Type-S head and shoulder mask with head and shoulder cushion (Civco); ( 4 ) same as previous, coupled with a mouthpiece. The comparative metrics were translational shift magnitude and average rotation angle; systematic inter-, random inter-, and random intrafraction positioning error was computed. For strategies 1–4, respectively, the analysis for interfraction variability included data from 20, 9, 81, and 11 patients, whereas that for intrafraction variability included a subset of 7, 9, 16, and 8 patients. The results were compared for statistical significance using an analysis of variance test. Results Immobilization system 4 provided the best overall accuracy and stability. The mean interfraction translational shifts (± SD) were 2.3 (± 1.4), 2.2 (± 1.1), 2.7 (± 1.5), and 2.1 (± 1.0) mm whereas intrafraction motion was 1.1 (± 1.2), 1.1 (± 1.1), 0.7 (± 0.9), and 0.7 (± 0.8) mm for devices 1–4, respectively. No significant correlation between intrafraction motion and treatment time was evident, although intrafraction motion was not purely random. Conclusions We find that all frameless thermoplastic mask systems studied are viable solutions for image-guided intracranial radiosurgery. With daily pretreatment corrections, symmetric PTV margins of 1 mm would likely be adequate if ideal radiation planning and targeting systems were available.

Figure 1 in the above-referenced article was publishedwithout an acknowledgment in error. The figure should have been credited as follows:© 2006MediVisuals Inc. Reprintedwith permission fromBarani IJ, Benedict SH, Lin PS, “Neural stem cells: implications for the conventional radiotherapy of central nervous systemmalignancies,” Int J RadiatOncol Biol Phys 68(2):324-333, 2007.We regret the omission.

INTRODUCTION: Tumor cells are passively carried by extracellular fluid flow to regional lymph nodes in most systemic cancers including breast cancer, melanoma and colorectal cancer. Although the brain does not contain lymphatics, cancer spread within the brain may be a function of extracellular fluid velocity. As malignant brain tumors are characterized by a disrupted blood-brain-barrier that leaks albumin from blood vessels into brain parenchyma, we hypothesize that this albumin influx will pull water in osmotically and increase flow rates and glioma cell dissemination down adjacent white matter tracts. High flow rates may increase tumor dissemination via the WMT. This study sought to determine if increasing intracranial albumin concentrations affect WMT flow rates. If true, restricting albumin extravasation (through steroids or VEGF inhibitors) has the potential to reduce glioma dissemination and may have implications for future radiation planning and steroid/VEGF inhibitor dosing. METHODS: Our study examines flow rates in white matter tracts after intracranial administration of albumin. 0.12-6 mg bovine albumin were mixed with 20 μL of 2% Evans Blue and injected stereotactically into the right frontal lobe at the gray-white matter junction over 80 minutes in 15 anesthetized Sprague-Dawley female rats. Seven hours later, the rats were sacrificed and the brains sectioned into 0.5mm coronal slices, and imaged to determine interstitial flow rates. RESULTS: Average anterior-posterior (AP) velocity for rats receiving 0.12 mg and 6.0 mg of albumin were 0.43 and 1.02 mm/hour respectively (p = 0.029). Correlation was observed between administered albumin dose and interstitial fluid velocity (R = 0.57). In vivo MRI results were consistent with ex vivo Evans blue results and demonstrate markedly increased edema (T2) in the hemisphere where albumin was injected. CONCLUSIONS: This study demonstrates higher interstitial fluid flow rates in adjacent white matter tracts in response to albumin-induced-edema. These observations provide insight into expected pathways for glioma dissemination which could be used to tailor radiation plans for individual patients. Furthermore, these findings provide a rationale for interventions to reduce glioma dissemination by limiting the extravasation of albumin through the blood-brain-barrier while local radiation is being administered. Citation Format: Carmen Kut, Vadappuram Chacko, Betty Tyler, Arvind P. Pathak, Zaver Bhujwalla, Elliot R. McVeigh, Xingde Li, Daniel A. Herzka, Stuart A. Grossman. Determining extracellular fluid velocity along white matter tracts with injections of increasing concentrations of intracranial albumin using both histological and radiological techniques. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3931. doi:10.1158/1538-7445.AM2013-3931