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.

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 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.

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate.

An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in "intrinsic heart rate" (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that age-dependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L- and T-type Ca(2+) currents and the "funny current" (If), and a hyperpolarizing shift in the voltage dependence of If. The age-dependent reduction in sinoatrial node function was not associated with changes in ß-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L- and T-type Ca(2+) currents, and If. Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging.

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.

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.

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.

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.

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.