Adaptive replanning using cone beam CT for deformation of original CT simulation.

BACKGROUND: During a course of radiation therapy, anatomical changes such as a decrease in tumour size or weight loss can trigger the need for repeating a computed tomography (CT) simulation scan in order to generate a new treatment plan. This adaptive approach requires a separate appointment for an additional CT scan which generates additional burden, cost, and radiation exposure for patients. CASE PRESENTATION: Here, we present a case of a head and neck cancer patient who required palliative radiation for a large neck mass. During treatment, he had a remarkable response which required a replan due to rapid tumour downsizing. In this case, we used a novel technique to avoid repeating the planning CT simulation by using a mid-treatment high-quality cone beam CT (CBCT) to deform the secondary image (plan CT) of the original planning CT and generate a new adapted treatment plan. CONCLUSION: This is the first report to our knowledge using a Halcyon CBCT to deform the original planning CT in order to generate a new radiation treatment plan, and this novel technique represents a new potential method of adaptive replanning for select patients.

Activated B Cells and Plasma Cells Are Resistant to Radiation Therapy.

PURPOSE: B cells play a key role in outcomes of cancer patients and responses to checkpoint blockade immunotherapies. However, the effect of radiation therapy on B cell populations is poorly understood. Here we characterize the effects of radiation on the development, survival, and phenotype of physiological B-cell subsets. METHODS AND MATERIALS: Naïve and immunized tumor bearing and nontumor bearing mice were treated with large-field or focal stereotactic radiation and distinct B-cell subsets of varying developmental stages were analyzed by flow cytometry and real-time reverse transcription polymerase chain reaction. RESULTS: We first report that focal stereotactic radiation is highly superior to large-field radiation at inducing tumor infiltration of B cells, CD8+ T cells, and macrophages. We observed that radiation affects B cell development in the bone marrow, increasing frequencies of early pro-B cells and late pro-B cells while inducing upregulation of programmed cell death protein 1. We then demonstrate that class switched B cells and plasma cells are highly resistant to radiation therapy compared with naïve B cells and upregulate activation markers programmed cell death 1 ligand 2 and major histocompatibility complex class II) after radiation. Mechanistically, radiation upregulates Xbp1 and Bcl6 in plasma cells, conferring radioresistance. Furthermore, using an immunization approach, we demonstrate that radiation enhances activation-induced cytidine deaminase mediated class switching and somatic hypermutation in primed B cells. CONCLUSIONS: These data demonstrate that stereotactic radiation is superior to large-field radiation at inducing infiltration of immune cells into tumors and that plasma cells and class switched B cells are highly resistant to radiation therapy. These results represent the most comprehensive analysis of the effects of radiation on B cells to date and identify novel mechanisms by which radiation modulates immune cells within the tumor microenvironment.

Defining the Role of Immunotherapy in the Curative Treatment of Locoregionally Advanced Head and Neck Cancer: Promises, Challenges, and Opportunities.

Recent advancements in the development of immunotherapies have raised the hope for patients with locally-advanced HNSCC (LA-HNSCC) to achieve improved oncologic outcomes without the heavy burden of treatment-related morbidity. While there are several ongoing late phase clinical trials that seek to determine whether immunotherapy can be effectively employed in the definitive setting, initial results from concurrent immuno-radiotherapy therapy trials have not shown strong evidence of benefit. Encouragingly, evidence from preclinical studies and early-phase neoadjuvant studies have begun to show potential pathways forward, with therapeutic combinations and sequences that intentionally spare tumor draining lymphatics in order to maximize the synergy between definitive local therapy and immunotherapy. The intent of this review is to summarize the scientific rationale and current clinical evidence for employing immunotherapy for LA-HNSCC as well as the ongoing efforts and challenges to determine how to optimally deliver and sequence immunotherapy alongside traditional therapeutics. In both the preclinical and clinical settings, we will discuss the application of immunotherapies to both surgical and radiotherapeutic management of HNSCC.

Quality improvement intervention to reduce time to postoperative radiation in head and neck free flap patients.

BACKGROUND: Best-practice guidelines for head and neck cancer patients advise postoperative radiation therapy (PORT) initiation within 6 weeks of surgery. We report our institutional experience improving timeliness of adjuvant radiation in free-flap patients. METHODS: Thirty-nine patients met inclusion criteria in the 2017-2019 study period. We divided into "Early" (n = 19) and "Late" (n = 20) time-period groups to compare performance over time. The primary endpoint was time to PORT initiation, with success defined as <6 weeks. RESULTS: The number of patients achieving timely PORT improved from 10.5% in the Early group to 50.0% in the Late group (p = 0.014). Patients undergoing concurrent adjuvant chemoradiation were more likely to meet the PORT target in the Late group (p = 0.012). CONCLUSIONS: We ascribe this quality improvement in free-flap patients to increased communication among multidisciplinary care teams, proactive consultation referrals, and a targeted patient-navigator intervention. Though work is needed to further improve performance, insight gained from our experience may benefit other teams.

Evaluating predictive factors for toxicities experienced by head & neck cancer patients undergoing radiotherapy.

PURPOSE: The purpose of this study was to evaluate if HPV status serves as an independent predictor of early and late dysphagia outcomes when considered alongside standard patient characteristics and dose metrics for head and neck cancer patients treated with radiotherapy. METHODS AND MATERIALS: The age, sex, smoking history, cancer type (oropharyngeal vs non-oropharyngeal), HPV status, and early and late dysphagia outcomes were obtained for 99 retrospective head and neck cancer patients treated at our clinic with radiotherapy. Additionally for each patient, the mean radiation dose to the pharynx, superior/middle/inferior pharyngeal constrictor muscles, and cricopharyngeus was calculated. The predictive power of these clinical characteristics and radiation metrics was evaluated using chi-square tests for categorical variables and t-tests for continuous variables. Then multi-variate logistic models were built for each outcome using a single dose metric at a time, and either HPV status, cancer type, or both. Multi-variate models were built using both top-down and bottom-up technique to establish the most predictive independent covariates. RESULTS: In the univariate analysis for early dysphagia, cancer type (p = 0.04) and four dose metrics (p ≤ 0.02) were significantly associated with outcome, while for late dysphagia, only cancer type (p = 0.04) was associated with outcome. In the multivariate analysis for early dysphagia, cancer type, smoking history, and mean dose to the five structures were consistently selected as covariates. For late dysphagia, either HPV status or cancer type was selected in each model and the mean dose to the cricopharyngeus was selected in one model. CONCLUSION: While HPV is a known contributing factor for tumor prognosis in oropharyngeal cancers, its role in normal tissue toxicities for head and neck cancers has not previously been evaluated. Our results indicate having an oropharyngeal cancer may increase a patient's risk of high-grade early and late dysphagia while HPV status was seldom selected.

End of treatment cone-beam computed tomography (CBCT) is predictive of radiation response and overall survival in oropharyngeal squamous cell carcinoma.

BACKGROUND: Image guidance in radiation oncology has resulted in significant improvements in the accuracy and precision of radiation therapy (RT). Recently, the resolution and quality of cone beam computed tomography (CBCT) for image guidance has increased so that tumor masses and lymph nodes are readily detectable and measurable. During treatment of head and neck squamous cell carcinoma (HNSCC), on-board CBCT setup imaging is routinely obtained; however, this CBCT imaging data is not utilized to predict patient outcomes. Here, we analyzed whether changes in CBCT measurements obtained during a course of radiation therapy correlate with responses on routine 3-month follow-up diagnostic imaging and overall survival (OS). MATERIALS/METHODS: Patients with oropharyngeal primary tumors who received radiation therapy between 2015 and 2018 were included. Anatomical measurements were collected of largest nodal conglomerate (LNC) at CT simulation, end of radiation treatment (EOT CBCT), and routine 3-month post-RT imaging. At each timepoint anteroposterior (AP), mediolateral (ML) and craniocaudal (CC) measurements were obtained and used to create a 2-dimensional (2D) maximum. RESULTS: CBCT data from 64 node positive patients were analyzed. The largest nodal 2D maximum and CC measurements on EOT CBCT showed a statistically significant correlation with complete response on 3-month post-RT imaging (r = 0.313, p = 0.02 and r = 0.318, p = 0.02, respectively). Furthermore, patients who experienced a 30% or greater reduction in the CC dimension had improved OS (Binary Chi-Square HR 4.85, p = 0.028). CONCLUSION: Decreased size of pathologic lymph nodes measured using CBCT setup imaging during a radiation course correlates with long term therapeutic response and overall survival of HNSCC patients. These results indicate that CBCT setup imaging may have utility as an early predictor of treatment response in oropharyngeal HNSCC.

Role of B Cells in Responses to Checkpoint Blockade Immunotherapy and Overall Survival of Cancer Patients.

The role of B cells in the tumor microenvironment and B-cell-mediated antitumor immune responses remains relatively understudied. Recent seminal studies have discovered that B cells and associated tertiary lymphoid structures correlate with responses to checkpoint blockade immunotherapy and are prognostic for overall survival of cancer patients. B-cell subsets have remarkable functional diversity and include professional antigen-presenting cells, regulatory cells, memory populations, and antibody-producing plasma cells. Importantly, secreted antibodies can independently activate innate immune responses and induce the cancer immunity cycle. Thus, B cells and B-cell-mediated antibody responses comprise the largely underappreciated second arm of the adaptive immune system and certainly deserve further attention in the field of oncology. Here, we review the known functions of B cells in the tumor microenvironment, the contribution of B cells to the antitumor activity of immunotherapies, and the role of B cells in the overall survival of cancer patients.

Gene alterations as predictors of radiation-induced toxicity in head and neck squamous cell carcinoma.

BACKGROUND: Optimizing the therapeutic ratio for radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC) is uniquely challenging owing to high rates of early and late toxicity involving nearby organs at risk. These toxicities have a profound impact on treatment compliance and quality of life. Emerging evidence suggests that RT dose alone cannot fully account for the variable severity of RT-related adverse events (rtAEs) observed in HNSCC patients. Next-generation sequencing has become an increasingly valuable tool with widespread use in the oncology field and is being robustly explored for predicting rtAEs beyond dosimetric data. METHODS: Patients who had Foundation Medicine sequencing data and received RT for primary or locally recurrent HNSCC were selected for this study. Early and late toxicity data were collected and reported based on Common Terminology Criteria for Adverse Events version 5.0. Dosimetric parameters were collected for pertinent structures. RESULTS: A total of HNSCC 37 patients were analyzed in this study. Genetic alterations in BRCA2, ERBB3, NOTCH1 and CCND1 were all associated with higher mean grade of toxicity with BRCA2 alteration implicated in all toxicity parameters evaluated including mucositis, early dysphagia, xerostomia and to a lesser extent, late dysphagia. Interestingly, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a twofold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Furthermore, several gene alterations were associated with improved toxicity outcomes. Within an RT supersensitive patient subset, alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8. All of these alterations were not found in the RT insensitive patient subset. We found 17 gene alterations in the RT insensitive patient subset that were not found in the RT supersensitive patient subset. CONCLUSION: Despite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying factors associated with toxicity outcomes offers a new avenue for personalized precision RT therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations with severity of rtAEs. Further analysis is urgently needed to identify genetic patterns associated with rtAEs in order to reduce harmful outcomes in this challenging population.

Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.

BACKGROUND: Radiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP. CASE PRESENTATION: Our first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy. CONCLUSIONS: Immunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.

Racial, Ethnic, and Socioeconomic Discrepancies in Opioid Prescriptions Among Older Patients With Cancer.

PURPOSE: Minority race and lower socioeconomic status are associated with lower rates of opioid prescription and undertreatment of pain in multiple noncancer healthcare settings. It is not known whether these differences in opioid prescribing exist among patients undergoing cancer treatment. METHODS AND MATERIALS: This observational cohort study involved 33,872 opioid-naive patients of age > 65 years undergoing definitive cancer treatment. We compared rates of new opioid prescriptions by race or ethnicity and socioeconomic status controlling for differences in baseline patient, cancer, and treatment factors. To evaluate downstream impacts of opioid prescribing and pain management, we also compared rates of persistent opioid use and pain-related emergency department (ED) visits. RESULTS: Compared with non-Hispanic White patients, the covariate-adjusted odds of receiving an opioid prescription were 24.9% (95% CI, 16.0 to 33.9, P < .001) lower for non-Hispanic Blacks, 115.0% (84.7 to 150.3, P < .001) higher for Asian-Pacific Islanders, and not statistically different for Hispanics (-1.0 to 14.0, P = .06). There was no significant association between race or ethnicity and persistent opioid use or pain-related ED visits. Patients living in a high-poverty area had higher odds (53.9% [25.4 to 88.8, P < .001]) of developing persistent use and having a pain-related ED visit (39.4% [16.4 to 66.9, P < .001]). CONCLUSION: For older patients with cancer, rates of opioid prescriptions and pain-related outcomes significantly differed by race and area-level poverty. Non-Hispanic Black patients were associated with a significantly decreased likelihood of receiving an opioid prescription. Patients from high-poverty areas were more likely to develop persistent opioid use and have a pain-related ED visit.

Association Between Lymph Node Ratio and Recurrence and Survival Outcomes in Patients With Oral Cavity Cancer.

Importance: Oral cavity squamous cell carcinoma (OCSCC) is associated with often-delayed clinical diagnosis, poor prognosis, and expensive therapeutic approaches. Prognostic accuracy is important in improving treatment outcomes of patients with this disease. Objectives: To assess lymph node ratio (LNR) and other factors in estimating response to treatment and provide prognostic information helpful for clinical decision making. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 2000, to December 31, 2015, at an academic hospital in Denver, Colorado. Participants included 149 patients with primary OCSCC who received curative-intent surgery and/or postoperative adjuvant therapies. Analysis was performed from December 8, 2017, to August 15, 2018. Main Outcomes and Measures: Overall survival (OS), disease-free survival (DFS), locoregional disease-free survival (LRDFS), and distant metastasis-free survival (DMDFS) adjusted for known prognostic risk factors, as well as correlation of LNR with other histopathologic prognostic factors. Results: Of the 149 patients included in analysis, 105 were men (70.5%); the median age at diagnosis was 59 years (range, 28-88 years). Using the Kaplan-Meier method, the 5-year survival estimates for OS rate was 40.4% (95% CI, 31.3%-49.3%); DFS, 48.6% (95% CI, 38.6%-58.0%); LRDFS, 57.7% (95% CI, 46.6%-67.2%); and DMDFS, 74.7% (95% CI, 65.1%-82.0%). The median follow-up was 20 months for all patients and 34.5 months (range, 0-137 months) for surviving patients. Nonwhite race (hazard ratio [HR], 2.15; 95% CI, 1.22-3.81), T3-T4 category (HR, 1.99; 95% CI, 1.18-3.35), and LNR greater than 10% (HR, 2.71; 95% CI, 1.39-5.27) were associated with poorer OS. Nonwhite patients also had higher risk of locoregional failures (HR, 2.47; 95% CI, 1.28-4.79), whereas women were more likely to have distant metastasis (HR, 2.55; 95% CI, 1.14-5.71). Floor-of-mouth subsite had fewer locoregional recurrences than did other subsites (HR, 0.45, 95% CI, 0.21-0.99). An LNR greater than 10% independently was associated with worse OS (HR, 2.71; 95% CI, 1.39-5.27), DFS (HR, 2.48; 95% CI, 1.18-5.22), and DMDFS (HR, 6.05; 95% CI, 1.54-23.71). The LNR was associated with N-stage (Cramer V, 0.69; 95% CI, 0.58-0.78), extracapsular extension (Cramer V, 0.55; 95% CI, 0.44-0.66), lymphovascular invasion (Cramer V, 0.46; 95% CI, 0.27-0.61); number of excised lymph nodes (Cramer V, 0.24; 95% CI, 0.06-0.37), margin (Cramer V, 0.22; 95% CI, 0.05-0.38), and tumor thickness combined with depth of invasion (Cramer V, 0.25; 95% CI, 0.05-0.38). Conclusions and Relevance: Locoregional treatment failure remained the predominant pattern of failure. An advanced pathologic stage and nonwhite race were found to be associated with worse outcomes. The findings from this study suggest that LNR is the most robust prognostic factor and appears to have implications for risk stratification in this disease.

The Bcl-2 Homology-3 Domain (BH3)-Only Proteins, Bid, DP5/Hrk, and BNip3L, Are Upregulated in Reactive Astrocytes of End-Stage Mutant SOD1 Mouse Spinal Cord.

The molecular mechanisms leading to motor neuron death in amyotrophic lateral sclerosis (ALS) are unknown; however, several studies have provided evidence of a central role for intrinsic apoptosis. Bcl-2 homology-3 domain (BH3)-only proteins are pro-apoptotic members of the Bcl-2 family whose enhanced expression acts as a trigger for the intrinsic apoptotic cascade. Here, we compared the relative expression of BH3-only proteins in the spinal cord of end-stage G93A mutant SOD1 mice to age-matched wild-type (WT) mice. Large alpha motor neurons in lumbar spinal cord sections of both WT and end-stage mutant SOD1 mice stained positively for a number of BH3-only proteins; however, no discernible differences were observed in either the relative intensity of staining or number of BH3-immunoreactive motor neurons between WT and mutant SOD1 mice. On the other hand, we observed significantly enhanced staining for Bid, DP5/Hrk, and BNip3L in GFAP-positive astrocytes only in end-stage G93A mutant SOD1 spinal cord. Staining of additional end-stage G93A mutant SOD1 tissues showed specific upregulation of DP5/Hrk in lumbar spinal cord sections, but not in cerebellum or cortex. Finally, examination of protein expression using western blotting also revealed marked increases in DP5/Hrk and BNip3L in G93A mutant SOD1 lumbar spinal cord lysates compared to WT controls. The upregulation of a specific subset of BH3-only proteins, including Bid, DP5/Hrk, and BNip3L, in reactive astrocytes suggests that these proteins may execute a novel non-apoptotic function within astrocytes to promote ALS disease progression, thus providing a new potential target for therapeutic intervention.

Survival benefit of postoperative radiation in papillary meningioma: Analysis of the National Cancer Data Base.

AIM/BACKGROUND: Papillary meningioma represents a rare subset of World Health Organization (WHO) Grade III meningioma that portends an overall poor prognosis. There is relatively limited data regarding the benefit of postoperative radiation therapy (PORT). We used the National Cancer Data Base (NCDB) to compare overall survival (OS) outcomes of surgically resected papillary meningioma cases undergoing PORT compared to post-operative observation. MATERIALS AND METHODS: The NCDB was queried for patients with papillary meningioma, diagnosed between 2004 and 2013, who underwent upfront surgery with or without PORT. Overall survival (OS) was determined using the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) analyses were performed. RESULTS: In total, 190 patients were identified; 89 patients underwent PORT, 101 patients were observed. Eleven patients received chemotherapy (6 with PORT, 5 without). 2-Year OS was significantly improved with PORT vs. no PORT (93.0% vs. 74.4%), as was 5-year OS (78.5% vs. 62.5%) (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27-0.85; p = 0.01). On MVA, patients receiving PORT had improved OS compared to observation (HR, 0.41; 95% CI, 0.22-0.76; p = 0.005). On subset analysis by age group, the benefit of PORT vs. no PORT was significant in patients ≤18 years (n = 13), with 2-year OS of 85.7% vs. 50.0% (HR, 0.08; 95% CI, 0.01-0.80; p = 0.032) and for patients >18 years (n = 184), with 2-year OS of 94.7% vs. 76.1% (HR, 0.55; 95% CI, 0.31-1.00; p = 0.049), respectively. CONCLUSIONS: In this large contemporary analysis, PORT was associated with improved survival for both adult and pediatric patients with papillary meningioma. PORT should be considered in those who present with this rare, aggressive tumor.

A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione.

Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing ß-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases.

Survival impact of pre-treatment neutrophils on oropharyngeal and laryngeal cancer patients undergoing definitive radiotherapy.

BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) represents an array of disease processes with a generally unfavorable prognosis. Inflammation plays an important role in tumor development and response to therapy. We performed a retrospective analysis of HNSCC patients to explore the relationship of the lymphocyte and neutrophil counts, the neutrophil-to-lymphocyte ratio (NLR) overall survival (OS), cancer-specific survival (CSS), local control (LC) and distant control (DC). MATERIALS/METHODS: All patients received definitive treatment for cancers of the oropharynx or larynx between 2006-2015. Neutrophil and lymphocyte counts were collected pre-, during-, and post-treatment. The correlations of patient, tumor, and biological factors to OS, CSS, LC and DC were assessed. RESULTS: 196 patients met our inclusion criteria; 171 patients were Stage III or IV. Median follow-up was 2.7 years. A higher neutrophil count at all treatment time points was predictive of poor OS with the pre-treatment neutrophil count and overall neutrophil nadir additionally predictive of DC. Higher pre-treatment and overall NLR correlated to worse OS and DC, respectively. CONCLUSION: A higher pre-treatment neutrophil count correlates to poor OS, CSS and DC. Lymphocyte counts were not found to impact survival or tumor control. Higher pre-treatment NLR is prognostic of poor OS.

A comparison of concurrent cisplatin versus cetuximab with radiotherapy in locally-advanced head and neck cancer: A bi-institutional analysis.

AIM: To present our experience comparing cisplatin- and cetuximab-based radiotherapy for locally-advanced head and neck squamous cell carcinoma. BACKGROUND: The comparative effectiveness of cisplatin-based chemoradiotherapy (CRT) versus cetuximab-based bioradiotherapy (BRT) for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) continues to be explored. MATERIALS AND METHODS: Outcomes of LAHNSCC patients treated with CRT (125) or BRT (34) at two institutions were compared retrospectively, with attention to overall survival (OS), cancer-specific survival (CSS), locoregional control (LRC), and distant control (DC). Univariate analysis (UVA) using Cox regression was performed to explore the association of intervention with survival and disease control, and multivariate (MVA) Cox regression was then performed to assess the association of intervention with survival. RESULTS: There were significant baseline differences between the CRT and BRT groups with respect to age, race, performance status, N-classification, tobacco history, and human papillomavirus status. UVA demonstrated inferiority of BRT versus CRT with respect to both OS (hazard ratio [HR] 2.19, 95% confidence interval [95%CI] 1.03-4.63, p = 0.04) and CSS (HR 3.33, 95%CI 1.42-7.78, p < 0.01), but non-significantly different outcomes in LRC (HR 0.99, 95%CI 0.37-2.61, p = 0.98) and DC (HR 2.01, 95%CI 0.78-5.37, p = 0.14). On MVA, there was no significant OS difference between interventions (HR 1.19, 95%CI 0.42-3.35, p = 0.74); there were too few events for the other outcomes to draw meaningful conclusions with MVA. CONCLUSIONS: In our retrospective analysis, patients undergoing CRT experienced improved OS and CSS over those receiving BRT; however, disease control did not significantly differ. These findings may inform management of LAHNSCC patients.

Durable Control and Overall Survival Benefit with Focal Reirradiation in Cervical Cancer.

Local recurrence following definitive chemoradiation in cervical cancer ranges from 5-18%. Currently, there are limited options available for patients recurring in para-aortic or iliac lymph nodes. We present two cases of reirradiation for non-central recurrences with intensity-modulated radiotherapy (IMRT). Both patients achieved a complete response with manageable short-term toxicities and no late adverse effects with a follow-up of over one year and three years after reirradiation. While further follow-up is needed, IMRT is a feasible and safe option in cervical cancer patients with recurrent in-field failures involving the lymph nodes.

Stereotactic body radiotherapy as primary therapy for head and neck cancer in the elderly or patients with poor performance.

OBJECTIVE: Stereotactic body radiotherapy (SBRT) is increasingly used to treat a variety of tumors, including head and neck squamous cell carcinoma (HNSCC) in the recurrent setting. While there are published data for re-irradiation using SBRT for HNSCC, there are limited data supporting its use as upfront treatment for locally advanced disease. STUDY DESIGN/METHODS: Here, we describe three patients who received SBRT as the primary treatment for their HNSCC along with a review of the current literature and discussion of future pathways. RESULTS: The three cases discussed tolerated treatment well with manageable acute toxicities and had either a clinical or radiographic complete response to therapy. CONCLUSION: Head and neck squamous cell carcinoma presents a unique challenge in the elderly, where medical comorbidities make it difficult to tolerate conventional radiation, often given with a systemic sensitizer. For these individuals, providing a shortened course using SBRT may offer an effective alternative.

A Cystine-Rich Whey Supplement (Immunocal(®)) Delays Disease Onset and Prevents Spinal Cord Glutathione Depletion in the hSOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.

Depletion of the endogenous antioxidant, glutathione (GSH), underlies progression of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. Here, we investigated the effects of a unique non-denatured whey protein supplement, Immunocal(®), in the transgenic Gly position 93 to Ala (G93A) mutant hSOD1 (hSOD1(G93A)) mouse model of ALS. Immunocal(®) is rich in the GSH precursor, cystine, and is therefore capable of bolstering GSH content. Transgenic hSOD1(G93A) mice receiving Immunocal(®) displayed a significant delay in disease onset compared to untreated hSOD1(G93A) controls. Additionally, Immunocal(®) treatment significantly decreased the rate of decline in grip strength and prevented disease-associated reductions in whole blood and spinal cord tissue GSH levels in end-stage hSOD1(G93A) mice. However, Immunocal(®) did not extend survival, likely due to its inability to preserve the mitochondrial GSH pool in spinal cord. Combination treatment with Immunocal(®) and the anti-glutamatergic compound, riluzole, delayed disease onset and extended survival in hSOD1(G93A) mice. These findings demonstrate that sustaining tissue GSH with Immunocal(®) only modestly delays disease onset and slows the loss of skeletal muscle strength in hSOD1(G93A) mice. Moreover, the inability of Immunocal(®) to rescue mitochondrial GSH in spinal cord provides a possible mechanism for its lack of effect on survival and is a limiting factor in the potential utility of this supplement as a therapeutic for ALS.