A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity.

The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.

The impact of distance to facility on treatment modality, short-term outcomes, and survival of patients with HPV-positive oropharyngeal squamous cell carcinoma.

PURPOSE: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility. MATERIALS AND METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions. RESULTS: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions. CONCLUSIONS: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC.

Metastatic merkel cell carcinoma to the thyroid gland: Case report and review of the literature.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive and rare neuroendocrine tumor, accounting for less than 1% of skin cancers. Metastasis primarily manifests in the cervical lymph nodes but rarely affect the thyroid. METHODS: We report a case of primary head and neck cutaneous MCC with metastasis to the thyroid gland. A review of the literature of MCC with thyroid metastasis was conducted. RESULTS: We identified five cases of MCC with thyroid metastasis. Primary sites included the distal upper and lower extremities, axilla, buttock, and groin. Treatment courses varied including thyroidectomy, immunotherapy, and expectant palliative measures. Time from initial diagnosis to thyroid metastasis ranged from four months to four years. Tissue diagnosis was achieved in 5 of 6 cases. CONCLUSIONS: MCC with thyroid metastasis is rare and likely represents aggressive disease. Despite advances in treatment and surveillance, outcomes for MCC remain poor. Ongoing research may establish predictors for treatment response.

An Update on Protein Kinases as Therapeutic Targets-Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein-Protein Interactions.

Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor-kinase interactions that can facilitate the development of next-generation PKC modulators.

An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases.

Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).

Novel Circulating and Tissue Monocytes as Well as Macrophages in Pancreatitis and Recovery.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS: We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS: Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-ß, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

Limited English proficiency and head and neck cancer outcomes.

PURPOSE: Limited English proficiency (LEP) is common among hospitalized patients and may impact clinical care and outcomes. This study aimed to examine the relationship between LEP and clinical oncological outcomes for patients with head and neck cancer (HNC). MATERIALS AND METHODS: A single center retrospective review was conducted including adult patients with squamous cell carcinoma of the head and neck who received treatment with curative intent between January 1, 2014 and July 1, 2019. Clinical data collected included patient demographics and clinical variables. Univariate and multivariate analysis was performed to determine whether there was an association between LEP and demographic and clinical factors. RESULTS: There were 477 patients included in the study; 426 (81%) were English proficient (EP) while 51 (10.7%) were LEP. The LEP patients were diagnosed with cancer at a later overall stage (p = 0.03) and less frequently treated with surgery alone compared to English speaking patients (p < 0.001). After adjusting for overall stage and primary site, LEP patients were significantly more likely to receive primary surgical management compared to primary non-surgical management [OR = 2.29 95% CI (0.93, 5.58), p = 0.008]. There was also a significant association between LEP and primary site of tumor (p < 0.01). Kaplan-Meyer curves for overall survival and disease specific survival showed no significant differences between the two cohorts (p = 0.8063 and p = 0.4986, respectively). CONCLUSIONS: LEP may impact access to care resulting in more advanced overall tumor stage at presentation and treatment with primary surgery compared to non-surgical management after adjusting for tumor stage and primary site. Interventions to provide better access to care, awareness of HNC in the LEP populations, and earlier detection may improve outcomes for LEP patients.

The effect of a statewide prescription drug monitoring program on opioid prescribing patterns.

PURPOSE: Determine whether opioid prescribing patterns have changed as a result of implementation of a prescription drug monitoring program (PDMP) in the state of Massachusetts. MATERIALS AND METHODS: A multicentered retrospective study was performed including patients who received tonsillectomy, parotidectomy, thyroidectomy or direct laryngoscopy and biopsy with or without rigid esophagoscopy and/or rigid bronchoscopy at Lahey Hospital and Medical Center (Burlington, MA) or Boston Medical Center (Boston, MA). Opioid prescribing patterns were compared for the 12 months prior to implementation of the Massachusetts Prescription Awareness Tool (MassPAT) to 36 months of prescribing patterns post implementation. Quantity of opioids prescribed was based on morphine milligram equivalents (MME). Continuous variables were compared using analysis of variance (ANOVA) while categorical variables were compared using chi-squared test or Fisher's exact test. Multivariate analysis was performed using linear regression. RESULTS: A total of 2281 patients were included in the study. There was a significant association in mean overall MME prescribed comparing pre-MassPAT and post-MassPAT data [tonsillectomy: 635.9 ± 175.6 vs 463.3 ± 177.7 (p < 0.0001), parotidectomy: 250.4 ± 71.33 vs 169.8 ± 79.26 (p < 0.0001), thyroidectomy: 186.2 ± 81.14 vs 118.3 ± 88.79 (p < 0.0001), direct laryngoscopy with biopsy: 308.3 ± 246.9 vs 308.3 ± 246.9 (p = 0.0201)]. There was also a significant association between length of opioid prescription (days) and implementation of MassPAT, but there was no significant difference in the percent of patients requiring refills pre- MassPAT and post-MassPAT. CONCLUSION: This study demonstrates that prescribers have been able to significantly decrease the amount of opioids prescribed for tonsillectomy, parotidectomy, thyroidectomy, and direct laryngoscopy and biopsy and patients have not required additional opioid refills.

Oral cancer patients achieve comparable survival at high safety-net burden hospitals.

PURPOSE: To evaluate the impact of hospital safety-net burden and social demographics on the overall survival of patients with oral cavity squamous cell carcinoma. MATERIALS AND METHODS: We identified 48,176 oral cancer patients diagnosed between the years 2004 to 2015 from the National Cancer Database and categorized treatment facilities as no, low, or high safety-net burden hospitals based on the percentage of uninsured or Medicaid patients treated. Using the Kaplan Meier method and multivariate analysis, we examined the effect of hospital safety-net burden, sociodemographic variables, and clinical factors on overall survival. RESULTS: Of the 1269 treatment facilities assessed, the median percentage of uninsured/Medicaid patients treated was 0% at no, 11.6% at low, and 23.5% at high safety-net burden hospitals and median survival was 68.6, 74.8, and 55.0 months, respectively (p < 0.0001). High safety-net burden hospitals treated more non-white populations (15.4%), lower median household income (<$30,000) (23.2%), and advanced stage cancers (AJCC III/IV) (54.6%). Patients treated at low (aHR = 0.97; 95% CI = 0.91-1.04, p = 0.405) and high (aHR = 1.05; 95% CI = 0.98-1.13, p = 0.175) safety-net burden hospitals did not experience worse survival outcomes compared to patients treated at no safety-net burden hospitals. CONCLUSION: High safety-net burden hospitals treated more oral cancer patients of lower socioeconomic status and advanced disease. Multivariate analysis showed high safety-net burden hospitals achieved comparable patient survival to lower burden hospitals.

Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRα+ Cells Is a New Marker for Inflammatory Bowel Disease.

Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRα+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRα+ cells. ADAMDEC1 protein was mainly released from PDGFRα+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRα+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRα+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRα+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRα+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

The use of vitamin D in preventing post-thyroidectomy hypocalcemia: An endocrinologist survey study.

OBJECTIVE: To evaluate the use of preoperative vitamin D levels and postoperative vitamin D supplementation among endocrinologists for the prevention of post-thyroidectomy hypocalcaemia. METHODS: Endocrinologist members of the American Thyroid Association (ATA) were contacted via email to complete a 21-question survey, which included both questions about demographic information, and preventing and managing postoperative hypocalcaemia after thyroidectomy. Univariate and multivariate analysis was performed to determine the respondents' use of preoperative vitamin D levels, dose and duration of preoperative vitamin D repletion, decision to delay surgery for low vitamin D levels in the case of a benign or malignant disease, and routine prescription of postoperative calcium or vitamin D supplementation. RESULTS: 225 endocrinologists who were ATA members responded to the questionnaire. When compared to endocrinologists practicing in other countries, those that practice in the United States were 2.5 times more likely to check preoperative vitamin D levels (95% CI[1.404, 4.535], P = .002), significantly more likely to replete vitamin D deficient patients with high-dose vitamin D (ie ≥50K IU/week), 4.458 times more likely to prescribe prophylactic supplemental calcium (95% CI[2.446, 8.126]; P < .0001) and 3.48 more likely to prescribe supplemental vitamin D (95% CI [1.906, 6.355]; P < .0001). Endocrinologists who have been in practice for >10 years were also 1.915 times more likely to prescribe supplemental vitamin D (95% CI (1.080, 3.395); P = .0263). Physicians that treat >50 thyroidectomy cases/year were 2.083 more likely to recommend a vitamin D repletion duration of >1 month than those that treat ≤50 cases/year ([1.036, 4.190], P = .0395). Lastly, if the patient has low preoperative vitamin D levels, 47.05% of respondents chose to delay surgery in a benign disease, while only 11.61% of respondents would do so in a case of malignant disease. CONCLUSIONS: Approximately one-half of surveyed endocrinologists reported using preoperative vitamin D levels to assess a patient's risk for post-thyroidectomy hypocalcaemia. Endocrinologists practicing in the United States, compared to those practicing in other countries, were more likely to both test for preoperative vitamin D levels and to recommend prophylactic post-thyroidectomy calcium and vitamin D supplementation.

Preventative and management strategies of hypocalcemia after thyroidectomy among surgeons: An international survey study.

OBJECTIVE: To determine international surgeon practice patterns for transient postoperative hypocalcemia in patients undergoing total thyroidectomy. METHODS: All member surgeons of the American Thyroid Association and the International Association of Thyroid Surgeons were contacted via email to complete a 20-question survey which included both questions about demographic information and preventing and managing postoperative hypocalcemia after thyroidectomy. Univariate analysis was performed to determine whether providers check preoperative vitamin D levels, postoperative calcium trends and/or PTH to assess for postoperative hypocalcemia. RESULTS: A total of 332 surgeons responded to the survey with 72.26% in practice for >10 years and 82.18% performing >50 total thyroidectomies per year. 13.29% of surgeon's surveyed reported that they routinely check preoperative vitamin D levels. Surgeon case volume, type of practice (academic vs non-academic practice), and geographic location in the US were significant predictors of whether surgeons check preoperative Vitamin D levels. International surgeons were significantly more likely to check both postoperative serum Ca and PTH compared to US based surgeons (p < .01). There was no significance difference in practice patterns based on whether the surgeon was a General Surgeon or an Otolaryngologist. CONCLUSIONS: Using a questionnaire distributed to both General Surgeons and Otolaryngologists, we demonstrated that there is significant variation in practice patterns between surgeons practicing in the United States and surgeons practicing in other countries, and practice often differs from recommended guidelines.

Determining the optimal osteotomy distance with the fibula free flap in mandibular reconstruction.

OBJECTIVE: Fibula free tissue transfer is a common and reliable method for mandibular reconstruction. Functional outcomes from this procedure are dependent on the successful union of the osseous segments postoperatively. This study was conducted to define the maximum gap-size criteria for osseous union to occur at osteotomy sites in fibula free flap reconstruction of the mandible. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care academic center. SUBJECTS AND METHODS: A retrospective chart review of computed tomography and medical records was conducted on patients who underwent fibula free flap surgery and had imaging of the mandible at <3 months and >6 months after surgery. Distances between osteotomies were measured and evaluated for interval healing. Secondary data included subject age, sex, smoking status, diabetes, number of osteotomies, complications, and adjuvant therapy. RESULTS: Thirty-eight osteotomy sites were analyzed from thirteen subjects and a total of 190 measurements were made. The mean gap size at the first scan that demonstrated union by the second scan interval was 1.31 mm and mean gap size demonstrating non-union was 2.55 mm (p < 0.01). Complication rate, number of osetotomies, adjuvant therapy, or medical co-morbidities did not significantly affect rates of union. CONCLUSIONS: In this study, osseous union was achieved with a mean osteotomy gap size of 1.31 mm. The data suggests that distances between ossesous segments >2 .55mm have a higher risk of non-union. We believe the information from this study will help augment current and future techniques in the field of mandible reconstruction.

Quality improvement in tracheostomy care: A multidisciplinary approach to standardizing tracheostomy care to reduce complications.

PURPOSE: Develop a model for quality improvement in tracheostomy care and decrease tracheostomy-related complications. METHODS: This study was a prospective quality improvement project at an academic tertiary care hospital. A multidisciplinary team was assembled to create institutional guidelines for clinical care during the pre-operative, intra-operative, and post-operative periods. Baseline data was compiled by retrospective chart review of 160 patients, and prospective tracking of select points over 8 months in 73 patients allowed for analysis of complications and clinical parameters. RESULTS: Implementation of a quality improvement team was successful in creating guidelines, setting baseline parameters, and tracking data with run charts. Comparison of pre- and post-guideline data showed a trend toward decreased rate of major complications from 4.38% to 2.74% (p = 0.096). Variables including time to tracheotomy for prolonged intubation, surgical technique, day of first tracheostomy tube change, and specialty performing surgery did not show increased risk of complications. There were increased tracheostomy-related complications in cold months (p = 0.04). CONCLUSIONS: An interdisciplinary quality improvement team can improve tracheostomy care by identifying system factors, standardizing care among specialties, and providing continuous monitoring of select data points.

Immunomodulatory receptors are differentially expressed in B and T cell subsets relevant to autoimmune disease.

Inhibitory cell-surface receptors on lymphocytes, often called immune checkpoints, are powerful targets for cancer therapy. Despite their direct involvement in autoimmune pathology, they are currently not exploited therapeutically for autoimmune diseases. Understanding the expression pattern of these receptors in health and disease is essential for targeted drug design. Here, we designed three 23-colour flow cytometry panels for peripheral-blood T cells, including 15 lineage-defining markers and 21 immunomodulatory cell-surface receptors, and a 22-marker panel for B cells. Blood samples from healthy individuals, multiple sclerosis (MS), and lupus (SLE) patients were included in the study. Several receptors show differential expression on regulatory T cells (Treg) compared to T helper (Th) 1 and Th17 cells, and functional relevance of this difference could be shown for BTLA and CD5. Unbiased multiparametric analysis revealed a subset of activated CD8+ T cells and a subset of unswitched memory B cells that are diminished in MS and SLE, respectively.

Randomized double blind trial of amitriptyline versus placebo in treatment of chronic laryngopharyngeal neuropathy.

OBJECTIVE: A neuropathic etiology has been suggested for patients with chronic laryngopharyngitis symptoms without visible structural pathology. Prior studies have shown that treatment with neuro-modulating medications is beneficial, but it is unknown if this was due to placebo effect. Our objective was to compare the efficacy of amitriptyline versus placebo in treating chronic laryngopharyngeal neuropathy. STUDY DESIGN: Prospective, randomized placebo-controlled trial. METHODS: Patients were randomized to receive placebo or amitriptyline for 8weeks. Primary outcome was change in modified Reflux Symptom Index (mRSI) score. Secondary outcomes were change in Voice Handicap Index-10 (VHI) scores, rates of adverse effects, and overall symptom severity. RESULTS: Eighteen patients completed the study. The average difference in mRSI and VHI-10 scores after treatment were not significantly different between study arms. However, more subjects taking amitriptyline felt their symptoms had subjectively improved (6 out of 9, 67%), while the remainder noted no change. In the placebo group, only 4 out of 9 subjects (44%) felt their symptoms were better and 2 felt worse. Subjects took an average of 25mg of amitriptyline or placebo daily by the end of the 8-week treatment period. No serious adverse effects were noted. CONCLUSION: Although there was a trend toward greater subjective improvement in overall symptoms with amitriptyline, interpretation is limited due to the small sample size. Larger randomized controlled trials to determine the efficacy of neuro-modulating agents in the treatment of chronic laryngopharyngeal neuropathy, as well as better metrics to characterize this disorder, are warranted.

Adenoid cystic carcinoma of the base of tongue: A population-based study.

BACKGROUND: The objective was to assess demographic and survival patterns in patients with adenoid cystic carcinoma of the base of tongue. METHODS: Patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database from 1973 through 2012 and were categorized by age, gender, race, historical stage A, and treatment. Incidence and survival were compared with Kaplan Meier curves and mortality hazard ratios. RESULTS: A total of 216 patients were included. After adjusting for age, gender, race and tumor-directed treatment, patients over the age of 70years had a significantly increased mortality [HR=2.847, 95% CI (1.499, 5.404) p=0.0014]. Furthermore mortality among patients with distant disease was significantly increased [HR=2.474 95% CI (1.459, 4.195) p=0.00008]. CONCLUSION: By examining the largest collection of patients we have demonstrated that there is a significant difference in mortality based on both the age at diagnosis and in the setting of distant disease.