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Objectives: This study aims to investigate the utility of adjuvant radiation in patients who undergo surgical resection for the management of node-negative sinonasal adenocarcinoma (SNAC)., Study Design: Retrospective database review., Methods: The 2004-2016 National Cancer Data Base (NCDB) was used to extract patients with surgically resected node-negative SNAC. Kaplan-Meier survival analysis and Cox-Proportional Hazards Modelling were used to analyze the impact of adjuvant radiation on overall survival (OS) following surgery., Results: 349 patients with SNAC underwent surgical resection. Of these patients, 154 (44.1%) received adjuvant radiotherapy (RT). Although there was no significant difference in race, age, or sex of those receiving RT, those receiving RT have more advanced diseases and are more likely to have positive margins. Kaplan Meier analysis showed no significant difference in 5-year OS in patient who received adjuvant RT in comparison to those who underwent surgical resection alone (65.7% vs. 72.6%, respectively; p = 0.378). In addition, when looking at only patients with positive margins, 5-year OS still did not have a significant difference (73.8% vs. 61.6%, respectively; p = 0.101). Only patients with clinical AJCC T4 showed a statistically significant survival benefit with adjuvant RT (56.9% vs. 29.9%, respectively; p = 0.009)., Conclusions: Adjuvant RT does not appear to provide a significant survival benefit in patients with resected SNAC, with the exception of those with clinically AJCC T4 disease., Level of Evidence: 4 Laryngoscope, 133:2603-2612, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In 2015, Oregon's Medicaid program implemented a performance improvement project to reduce high-dose opioid prescribing across its 16 coordinated care organizations (CCOs). The objective of this study was to evaluate the effect of that program on prescription opioid use and outcomes., Methods: Using Medicaid claims data from 2014 to 2017, we conducted interrupted time-series analyses to examine changes in the prescription opioid use and overdose rates before (July 2014 to June 2015) and after (January 2016 to December 2017) implementation of Oregon's high-dose policy initiative (July 2015 to December 2015). Prescribing outcomes were: 1) total opioid prescriptions 2) high-dose [> 90 morphine milligram equivalents per day] opioid prescriptions, and 3) proportion of opioid prescriptions that were high-dose. Opioid overdose outcomes included emergency department visits or hospitalizations that involved an opioid-related poisoning (total, heroin-involved, non-heroin involved). Analyses were performed at the state and CCO level., Results: There was an immediate reduction in high dose opioid prescriptions after the program was implemented (- 1.55 prescription per 1000 enrollee; 95% CI - 2.26 to - 0.84; p < 0.01). Program implementation was also associated with an immediate drop (- 1.29 percentage points; 95% CI - 1.94 to - 0.64 percentage points; p < 0.01) and trend reduction (- 0.23 percentage point per month; 95% CI - 0.33 to - 0.14 percentage points; p < 0.01) in the monthly proportion of high-dose opioid prescriptions. The trend in total, heroin-involved, and non-heroin overdose rates increased significantly following implementation of the program., Conclusions: Although Oregon's high-dose opioid performance improvement project was associated with declines in high-dose opioid prescriptions, rates of opioid overdose did not decrease. Policy efforts to reduce opioid prescribing risks may not be sufficient to address the growing opioid crisis., (© 2022. The Author(s).)

Background: The impact of radiotherapy (RT) modality and dose on survival in hypopharyngeal cancer managed with definitive RT is unclear., Methods: The National Cancer Database was queried for patients with hypopharyngeal squamous cell carcinoma (HPSCC) treated with definitive RT. Intensity-modulated radiotherapy (IMRT) was compared with other RT techniques. Clinicopathologic variables, RT modality, and dose impact on overall survival (OS) were assessed using log-rank test and Cox proportional hazard models., Results: A total of 3928 patients with HPSCC were identified. Patients receiving IMRT (2098 patients) were more likely to be white, have higher income, have advanced classification, receive ≥66 Gy, and receive chemoradiotherapy compared with those receiving non-IMRT techniques (1830 patients). The 5-year OS was 41.9% (95% CI = 39.4%-44.4%) for the IMRT group and 36.8% for the non-IMRT group (95% CI = 34.3%-39.2%). After propensity score matching, IMRT had significantly better OS (P = .013)., Conclusion: In HPSCC treated with definitive RT, IMRT may provide a significant survival benefit over non-IMRT modalities., (© 2018 Wiley Periodicals, Inc.)

Objectives/hypothesis: Laryngeal chondrosarcomas are rare entities that arise from the cartilaginous structures of the larynx, including the cricoid, thyroid cartilage, epiglottis, and arytenoid cartilages. These tumors represent a minority of malignancies involving the larynx and can be mistaken for benign pathologies. The treatment has historically been surgical excision, often by total laryngectomy. This review investigates treatment modalities and patient outcomes., Study Design: Systematic review using PubMed/MEDLINE and EMBASE database., Methods: The databases were used to identify articles reporting cases of chondrosarcomas occurring exclusively in the larynx. Variables analyzed included patient demographics, presenting symptoms, grade, therapeutic approach, patient outcomes, and follow-up., Results: Five hundred and ninety-two cases were identified. The average age reported was 62.5 years. There was a 3:1 male to female ratio. The most common surgical approach was local excision in 178 cases, followed by total laryngectomy in 174 cases. Nonsurgical treatment such as radiotherapy and chemotherapy was only used in 0.8% and 0.2%, respectively. Disease-specific survival rates for 1, 5, 10, and 20 years were 97.7%, 91.4%, 81.8%, and 68.0%, respectively, with no differences when comparing 5-year survival rates for location, grade, and therapy., Conclusion: Laryngeal chondrosarcomas are rare with a good prognosis. Various surgical approaches exist, with no difference noted in 5-year survival outcomes. Nonsurgical approaches were rarely used for these lesions., Level of Evidence: N/A. Laryngoscope, 2016 127:430-439, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Although chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients undergoing laryngeal cancer surgery, the impact of this comorbidity in this setting is not well established. In this analysis, we used the Nationwide Inpatient Sample (NIS) to elucidate the impact of COPD on outcomes after laryngectomy for laryngeal cancer., Methods: The NIS was queried for patients admitted from 1998 to 2010 with laryngeal cancer who underwent total or partial laryngectomy. Patient demographics, type of admission, length of stay, hospital charges, and concomitant diagnoses were analyzed., Results: Our inclusion criteria yielded a cohort of 40,441 patients: 3,051 with COPD and 37,390 without. On average, COPD was associated with an additional $12,500 (P < 0.001) in hospital charges and an additional 1.4 days (P < 0.001) of hospital stay. There was no significant difference in incidence of in-hospital mortality between the COPD and non-COPD groups after total laryngectomy (1.1% in COPD vs. 1.0% in non-COPD; P = 0.776); however, there was an increased incidence of in-hospital mortality in the COPD group compared to the non-COPD group after partial laryngectomy (3.4% in COPD vs. 0.4% in non-COPD; P < 0.001). Multivariate adjusted logistic regression revealed that COPD was associated with greater odds of pulmonary complications after both partial laryngectomy (odds ratio [OR] = 3.198; P < 0.001) and total laryngectomy (OR = 1.575; P < 0.001)., Conclusion: Chronic obstructive pulmonary disease appears to be associated with greater hospital charges, length of stay, and postoperative pulmonary complications in patients undergoing laryngectomy for laryngeal cancer. Chronic obstructive pulmonary disease after partial, but not total, laryngectomy appears to be associated with increased risk of in-hospital mortality., Level of Evidence: 2C. Laryngoscope, 2016 127:417-423, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Laryngeal adenocarcinoma not otherwise specified (LAdC NOS) is a category to which variants of minor salivary gland tumors of the larynx that do not fit other well-characterized histological subtypes are assigned. Its rare nature and inconsistency in available reports has hindered the investigation and further understanding of this malignancy. In this study, a national population-based resource was used to evaluate the epidemiology and survival of this rare entity., Study Design: Retrospective population-based analysis., Methods: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with LAdC NOS between 1973 and 2012. Patient demographics, tumor location, TNM stage, grade, incidence, and survival trends were collected and analyzed., Results: One hundred eleven patients met criteria for diagnosis of LAdC NOS, of which the majority were male (80.2%), white (84.7%), with a mean age of 65 years. The supraglottis was the most common site at presentation (38.7%). The majority presented with grade II tumor (45.7%). TNM staging revealed T2 (36.8%), N0 (72.2%), and M0 (88.9%) to be the most common classification. The overall incidence between the years of 2000 and 2012 was 0.008/100,000 individuals. The overall 5-year disease-specific survival (DSS) was 60.1%, compared to 85.7% in patients treated with combination surgery and radiotherapy., Conclusions: LAdC NOS is an uncommon malignancy. It most commonly affects men in their mid-60s, indiscriminate of race. Lesions most commonly present in the supraglottis and are more often low grade histologically. DSS is highest in patient treated with combination surgery and radiotherapy., Level of Evidence: 4 Laryngoscope, 2016 127:424-429, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Unplanned readmissions within 30 days of surgery represent a significant marker for healthcare quality. Small institutional studies have described rates of readmission for patients undergoing head and neck free flap reconstruction. However, large, multi-institutional analyses have not previously been described., Study Design: Retrospective study of cases from the American College of Surgeons National Surgical Quality Improvement Program database., Methods: Patients who underwent free flap reconstruction of the head and neck from 2011 to 2013 were identified. Univariate and multivariate analyses of unplanned readmission based on patient, laboratory, and hospital course characteristics were conducted., Results: In total, 1,238 patients who underwent head and neck microvascular free flap reconstruction were included within the database, of which 1,204 patients had information pertaining to readmission. Overall 30-day readmission rate was 9.6%. A multivariate analysis of preoperative variables demonstrated that leukocytosis, diabetes mellitus, and hyponatremia were all associated with increased rates of readmission (odds ratio 2.224, 1.843, and 1.7423, respectively). A similar analysis of postoperative variables demonstrated that wound-related complications (surgical site infections and wound disruption), perioperative blood transfusion, and sepsis were associated with an increased rate of readmission., Conclusion: In patients with microvascular free flap reconstruction of the head and neck, the 30-day readmission rate was 9.6%. Preoperative diabetes mellitus, hyponatremia, and leukocytosis were associated with an increased rate of 30-day readmissions. Postoperative complications, particularly wound infections, perioperative blood transfusions, and sepsis, were found to be significant contributors to readmission., Level of Evidence: 4. Laryngoscope, 2016 127:325-330, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective/hypothesis: The aim of this population-based study is to analyze the survival benefits of elective neck dissection (END) over neck observation in T1/T2N0M0 oral tongue squamous cell carcinoma (OT-SCC) cases., Study Design: Retrospective administrative database analysis., Subjects and Methods: The SEER database (Surveillance, Epidemiology, and End Results) was queried for patients diagnosed with T1/T2N0M0 OT-SCC from 1998 to 2011. Data included patient demographics, initial treatment, and survival outcomes. The Kaplan-Meier model and the Cox proportional hazards model were utilized for survival analysis., Results: Out of 7010 T1/T2N0M0 cases, END was performed in 1770 T1 and 950 T2 cases, and the neck was observed in 3278 T1 and 1001 T2 cases. Significantly poorer 5-year disease-specific survival (DSS) rates were noted for the neck observation group when compared with the END group for tumors with moderately differentiated (72.1% vs 86%, P < .0001) and poorly differentiated or undifferentiated (55.6% vs 71.5%, P = .0001) histologic grades. No significant survival benefit was seen between the END group and the neck observation group when tumor size was <1 cm, regardless of histology grade. However, those with tumors >1 cm had a significantly better 5-year DSS with END, except for the well-differentiated tumor cohort, which showed improved survival only when the tumors were >2 cm (5-year DSS: END vs neck observation, 83.5% vs 65.7%, P = .0002)., Conclusion: END improves DSS versus neck observation in T1/T2N0M0 OT-SCC patients with moderately differentiated, poorly differentiated, or undifferentiated histologic grade tumors >1 cm. Those with well-differentiated tumors benefited from END only when tumor size was >2 cm., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Objective: Retrosternal goiters pose a significant challenge in determining the indications and appropriate approach for surgical removal while limiting postoperative morbidity and mortality. The objective of this study is to use the National Surgical Quality Improvement Program (NSQIP) database to compare outcomes of transcervical and transthoracic approaches for retrosternal goiter removal and to review the literature regarding the varying indications for the 2 surgical approaches., Study Design: Administrative database analysis., Setting: NSQIP database., Subjects and Methods: The NSQIP database was queried for all cases of retrosternal thyroid: 2716 patients were included, which represents one of the largest data reviews of patients with retrosternal thyroid pathology who underwent surgery. Data were analyzed to examine morbidity and mortality of the cervical and transthoracic approaches., Results: Patient demographics and preoperative comorbidities were similar between groups. Patients undergoing a transthoracic approach experienced increased rates of unplanned intubations and need for transfusion and length of stay postoperatively., Conclusions: A transthoracic approach is associated with increased rates of several critical postoperative morbidities, and the data indicate the potential of increased overall mortality. Given equivalent retrosternal extension, a transcervical approach should be attempted whenever anatomically possible, regardless of pathology., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm of secretory glands of the upper aerodigestive tract. It accounts for 3-5% of head and neck malignancies and most commonly arises from the minor salivary glands of the oral cavity. The clinical behavior of ACC from specific anatomic subsites, including the oral cavity, is not well described in the literature. We aim to elucidate patient demographics, clinicopathologic features, incidence, and survival trends for oral cavity ACC (OCACC)., Methods: Retrospective population-based analysis of OCACC in the SEER database between 1973 and 2012., Results: 1066 OCACC patients were identified, of which 57.7% were female (P<0.0001). Incidence was 0.049 per 100,000. Whites were most commonly affected (81.1%). The hard palate was the most commonly involved subsite (44.1%). Nodal involvement was seen in 8.4% of cases and distant metastasis was present in 6.2% of cases at the time of presentation. Disease-specific survival (DSS) rates at 1, 5, 10, 15, and 20years were 97.4%, 83.9%, 69.9%, 57.6%, and 46.2%, respectively. Females had a higher 5-year DSS (87.8%) than males (78.4%, P=0.0004). Cases treated with surgery had a favorable prognosis regardless of whether they received radiotherapy (P<0.0001). Nodal involvement reduced 5-year DSS by 51.6% (P<0.0001), while distant metastasis reduced 5-year DSS by 46.4% (P<0.0001)., Conclusions: OCACC is a rare malignancy with females and whites being more commonly affected. At presentation, regional and distant metastases are uncommon. Poor prognostic indicators include male gender, nonsurgical therapy, nodal involvement, and distant metastasis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Laryngeal cancer most commonly arises from the glottis. Comparable outcomes in survival have been shown in patients with early glottic squamous cell carcinoma treated with either surgery or radiotherapy., Study Design and Setting: Administrative database study., Subjects and Methods: The US National Cancer Institute's SEER database (Surveillance, Epidemiology, and End Results) was queried for cases of early glottic cancer (T1-T2N0M0, 1988-2012). We identified 13,312 qualifying cases. Patient demographics, therapeutic measures, and survival outcomes were examined with appropriate univariate and multivariate analyses., Results: Early glottic cancer has a mean age at diagnosis of 64.8 ± 11.6 years and a male:female ratio of 6.9:1. The most common treatment modality was radiotherapy alone (51.6%), followed by combination therapy with surgery first (31.5%). Overall, the 5-year disease-specific survival (DSS) rate was 88.4%. When stratified by treatment modality and stage, 5-year DSS for T1 tumors was 93.2% with surgery alone and 89.0% with radiation alone (P < .0001). With combination therapy, the 5-year DSS was 91.3% for surgery first and 84.9% for radiation first (P = .0239). In T2 tumors, 5-year DSS was improved with single-modality therapy versus multimodality therapy (81.1% vs 76.4; P = .0255)., Conclusion: In T1 disease, surgery alone shows improved 5-year DSS versus radiation alone, but this difference was not observed in T2 tumors. Additionally, surgery, rather than radiation, shows improved 5-year DSS when implemented as a first-line therapy. Combination therapy does not show improved 5-year DSS for early glottic cancer., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Objective: Regional lymph node metastasis is an important prognostic factor in squamous cell carcinoma of the head and neck, decreasing survival by up to 50%. Oral cavity squamous cell carcinoma (OC-SCCa) most commonly spreads to levels I, II, and III., Study Design: Retrospective analysis of a population-based tumor registry., Setting: Academic medical center., Subjects and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of OC-SCCa from 2004 to 2011 (22,973 cases). Resulting data including patient demographics, clinicopathological features, topographical distribution of nodal metastasis, and survival based on lymph node level involvement were analyzed., Results: In total, 8281 patients were identified with OC-SCCa who underwent neck dissection. Level I, closely followed by levels II and III, represented the most commonly involved nodal basins. The 5-year disease-specific survival (DSS) for patients with only level I, II, or III was 42.0% compared with 30.6% for the level IV group (P < .0001) and 26.4% for the level V group (P < .0001). Surgery with adjuvant radiotherapy improved 5-year DSS for patients with level I to III, level IV, and level V neck disease compared with surgery alone (50.7% vs 48.6%, P = .0109; 39.9% vs 23.2%, P < .0001; and 33.3% vs 9.1%, P = .0005, for levels I-III, IV, and V, respectively)., Conclusion: Oral cavity squamous cell carcinoma most commonly involves nodal levels I, II, and III. Involvement of nodal level IV or V portends a worse prognosis than patients with only level I to III disease, and multimodality therapy should be considered for these patients., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Objectives: The aim of this study is to analyze the survival benefits of surgery and/or radiation therapy over no therapy in patients with metastatic (M1) squamous cell carcinoma of the head and neck region (HN-SCC)., Study Design: Retrospective administrative database analysis., Subjects and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for M1 HN-SCC cases from 1988 to 2012 (6663 patients). Patient demographics, initial treatment, and survival outcomes were analyzed. Survival was analyzed with the Kaplan-Meier model., Results: Of the 6663 patients identified with M1 HN-SCC in the SEER database, 1669 patients received no therapy; 2459 patients, radiotherapy; 570 patients, surgery; and 1100 patients, surgery with adjuvant radiotherapy. The mean survival was 8.44 months for patients who did not undergo any therapy. In comparison, patients who underwent radiotherapy alone, surgery alone, or surgery with radiotherapy had mean survivals of 18.03 (P < .0001), 31.07 (P < .0001), and 39.93 (P < .0001) months, respectively. The 5-year disease-specific survival rates were 6.35% for no therapy, 17.51% for radiotherapy alone, 30.50% for surgery alone, and 33.75% for surgery with radiotherapy (P < .0001). Site-specific analysis revealed that surgery and/or radiation provides disease-specific survival benefit as compared with no therapy at all subsites within the head and neck region., Conclusions: Surgery and/or radiation-which has been shown to improve quality of life in patients with advanced cancer-is associated with an increased survival when utilized in patients with distant metastatic disease., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Objectives/hypothesis: Hemangiopericytomas (HPC) are tumors that arise from pericytes. Hemangiopericytomas of the head and neck are rare and occur both extracranially and intracranially. This study analyzes the demographic, clinicopathologic, treatment modalities, and survival characteristics of extracranial head and neck hemangiopericytomas (HN-HPC) and compares them to HPCs at other body sites (Other-HPC)., Methods: The Surveillance, Epidemiology, and End Results (SEER) database (1973-2012) was queried for HN-HPC (121 cases) and Other-HPC (510 cases). Data were analyzed comparatively with respect to various demographic and clinicopathologic factors. Disease-specific survival (DSS) was analyzed using the Kaplan-Meier model., Results: There was no significant difference in age at time of diagnosis between HN-HPC and Other-HPC. Head and neck HPC was most commonly located in the connective and soft tissue (18.4%), followed by the nasal cavity and paranasal sinuses (8.5%). Head and neck HPCs were smaller than Other-HPC (P < 0.0001) and more likely to be a lower histologic grade (P < 0.0097). The primary treatment modality for HN-HPC was surgery alone, used in 55.8% of cases. The 5-, 10-, and 20-year DSS for HN-HPC were 84.0%, 79.4%, and 69.4%, respectfully. Higher histologic grade and the presence of distant metastases were poor prognostic factors for HN-HPC., Conclusion: Head and neck HPCs are rare tumors. This study represents the largest series of HN-HPCs to date. Surgery alone is the primary treatment modality for HN-HPC, with a favorable prognosis. Adjuvant radiotherapy does not appear to confer a survival benefit for any body site., Level of Evidence: 4. Laryngoscope, 126:643-650, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Adenoid cystic carcinoma is a malignant minor salivary gland tumor that represents <1% of all laryngeal tumors. The submucosal location of laryngeal adenoid cystic carcinoma (LACC) results in delayed presentation. Here, we present the first systematic review of reported cases of LACC to determine trends in presentation, diagnostic and treatment modalities, and patient outcome., Data Sources: PubMed, Web of Science, MEDLINE, and EMBASE databases., Methods: A search of the above databases was done to identify articles reporting cases of LACC. The variables included in the analysis were patient demographics, presenting symptoms, tumor location, imaging, treatment, follow-up time, recurrence, and outcome., Results: A total of 50 articles and 120 cases were included in the review. The most common presenting symptom was dyspnea (48.8%), followed by hoarseness (43.9%). LACC arose most frequently from the subglottis (56.7%). At presentation, 14.6% (13 of 89) of patients had regional disease. The average follow-up time was 54.0 months. At follow-up, distant metastasis was reported in 30 cases (33.3%). Surgery alone (43.3%) and surgery with radiotherapy (43.3%) were used most frequently and resulted in 57.1% and 55.3% of patients alive with no evidence disease at follow-up, respectively., Conclusion: LACC was most often located in the subglottis. Patients commonly presented with dyspnea and hoarseness. In this systematic review, surgery with radiotherapy and surgery alone were the most commonly employed treatment modalities, and both resulted in slightly more than 50% of patients alive with no evidence of disease at follow-up., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Objective: The impact of diabetes mellitus (DM) on surgical outcomes and cost of care for patients undergoing surgery for head and neck cancer (HNCA) is not well established. We used the Nationwide Inpatient Sample to analyze the postoperative impact of DM on HNCA patients., Study Design: Population-based inpatient registry analysis., Setting: Academic medical center., Subjects and Methods: Discharge data from the Nationwide Inpatient Sample were analyzed for patients undergoing HNCA surgery from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between HNCA patients with and without DM., Results: Of 31,075 patients, 4029 patients (13.0%) had a DM diagnosis. DM patients were older (65.7 ± 10.8 vs 61.1 ± 14.1 years old; P < .001), had more preexisting comorbidities, had longer hospitalizations, and incurred greater hospital charges. Compared with the non-DM cohort, DM patients experienced significantly higher rates of postoperative infections (2.6% vs 2.1%, P = .025), cardiac events (9.0% vs 4.3%, P < .001), pulmonary edema/failure (6.6% vs 5.7%, P = .023), acute renal failure (3.3% vs 1.5%, P < .001), and urinary tract infections (2.8 % vs 2.1%, P = .005). No differences in surgical wound healing rates were observed (0.1 vs 0.1, P = .794). On multivariate logistic regression corrected for age and race, DM patients had greater odds of postoperative infections (1.382, P = .007), cardiac events (1.893, P < .001), and acute renal failure (2.023, P < .001)., Conclusions: DM is associated with greater length of stay and hospital charges among HNCA patients. DM patients have significantly greater rates of postoperative complications, including postoperative infections, cardiac events, and acute renal failure., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Objective: Subglottic squamous cell carcinoma (SCCa) is a rare malignancy representing <5% of all laryngeal cancers. Patients often present with late-stage disease, and survival outcomes are reportedly worse than those for SCCa in other regions of the larynx., Study Design: Analysis of a population-based tumor registry., Setting: Academic medical center., Subjects and Methods: The US National Cancer Institute's Surveillance, Epidemiology, and End Results database was queried for cases of subglottic SCCa from 1973 to 2011 (889 cases). Resulting data were analyzed, including patient demographics, therapeutic measures, and survival outcomes., Results: Subglottic SCCa most frequently occurred in the fifth to seventh decade of life, with a mean age at diagnosis of 65.7 ± 11.3 years. There was a strong male predilection, with a male:female ratio of 3.83:1. Most patients were stage III and IV (64.4%) per the American Joint Committee on Cancer. The most common treatment modality was a combination of radiotherapy and surgery (38.8%), followed by radiotherapy alone (33.9%), and surgery alone (17.0%). Overall 5-year disease-specific survival rate was 53.7%. When stratified by treatment modality, 5-year disease-specific survival was 62.4% for surgery alone, 56.7% for radiotherapy alone, and 55.1% for surgery with adjuvant radiotherapy (P = .3892)., Conclusion: This study represents the largest cohort of subglottic SCCa. It shows a strong predilection for men in the US population. Surgery with adjuvant radiotherapy was the most commonly employed treatment modality. No statistically significant differences were observed in 5-year DSS by treatment modality., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Objectives: Malignant peripheral nerve sheath tumors (MPNSTs) are a group of tumors that arise from peripheral nerves or from the various elements of the nerve sheath, including Schwann cells and perineural fibroblasts. Head and neck MPNSTs (HN-MPNSTs) are rare, accounting for 8% to 16% of all soft tissue sarcomas. This study analyzes the demographic, clinicopathologic, and survival characteristics of HN-MPNSTs and establishes comparisons with MPNSTs at other body sites (other-MPNSTs)., Study Design: Analysis of population-based tumor registry., Setting: Academic medical center., Subjects and Methods: The SEER database (Surveillance, Epidemiology, and End Results; 1973-2012) was queried for HN-MPNSTs (324 cases) and other-MPNSTs (1680 cases). Data were analyzed comparatively with respect to various demographic and clinicopathologic factors. Disease-specific survival was analyzed with the Kaplan-Meier model., Results: Mean age at diagnosis for HN-MPNST was 49.1 years, compared with 46.1 years for other-MPNSTs (P = .0169). There was a sex predilection for males in HN-MPNSTs (60.2%) versus a female predilection for other-MPNSTs (54.2%; P < .0001). Average tumor size for HN-MPNSTs was 4.9 cm, compared with 8.7 cm for other-MPNSTs (P < .0001). HN-MPNSTs were more commonly of low histologic grade types, whereas other-MPNSTs were mostly of high histologic grade (P = .0073). HN-MPNSTs had a higher 5-year disease-specific survival than other-MPNSTs (65.1% vs 57.4%; P = .0209)., Conclusions: HN-MPNSTs are rare entities. This study represents the largest series of HN-MPNSTs to date. Although HN-MPNSTs and other-MPNSTs share a common histology, there are important clinical differences between the 2 groups., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Pain is among the most common reasons for patient visits to healthcare providers, especially to dental practitioners. This case illustrates the obligation of the general dentist and specialist to recognize facial pain disorders of nonodontogenic origin, and outlines a paradigm for treatment of this unusual case. A 59-year-old man presented with chronic, progressive right periorbital pain since 2006, of 7 years duration. The initial diagnosis was a fracture of the right outer rim of the orbit secondary to trauma. The patient had undergone a variety of clinical and radiographic evaluations, pharmacologic therapies, and limited surgical procedures with no benefit. The description of his pain varied. Initially complaints were consistent with musculoskeletal pain, ie chronic, localized, aching, and evoked by pressure. It evolved into a neuropathic quality with increasing and spontaneous pain associated with sensory changes. Pain levels, which were initially mild, became moderate to severe. After a detailed review of the patient's history, radiographic records, and a comprehensive clinical evaluation, a CBCT of the maxilla was performed. While not considered a routine radiographic study, CBCT is readily available to the general dentist and specialist. CBCT was indicated in this case and revealed a rare interosseous hemangioma of the maxilla. The portion of the maxilla containing the lesion was surgically removed and a prosthetic replacement was placed. At 12 months after the procedure the patient remains pain free.

Objective: Laryngeal neuroendocrine carcinoma (LNEC) is a rare malignancy with various subtypes, each with different characteristics. Classification of these subtypes is used to delineate treatment and management, as most are clinically aggressive with poor prognosis. This study analyzes the characteristics and survival outcomes of LNEC using population-based data., Study Design: Analysis of a population-based tumor registry., Setting: Academic medical center., Subjects and Methods: The Surveillance, Epidemiology, and End Results (SEER) database (1973-2011) was queried for LNEC cases. Data analyzed included patient demographics, incidence, treatment modality, and survival., Results: In total, 257 LNEC cases were extracted from the SEER database. Sixty-three percent were male, and the mean age of diagnosis was 61.9 years. Most cases were located in the supraglottis (62.6%), were of the small cell carcinoma (52.9%) histologic subtype, and were grade IV (40.9%) and American Joint Committee on Cancer (AJCC) stage IV (59.4%). Surgery and radiotherapy were used as treatment modalities in 38.3% and 59.8% of patients, respectively. Overall 5-year disease-specific survival (DSS) for all LNEC was 30.2%, with lower grade, lower AJCC stage, and treatment with surgery having higher 5-year DSS., Conclusions: LNEC often presents as an aggressive tumor at an advanced stage and has poor survival outcomes. Poor prognostic factors include high histologic grade, advanced stage disease, and not undergoing surgical resection. LNEC may be best treated depending on its histologic differentiation, with surgery being beneficial for early grade tumors while radiotherapy is inconclusive in its benefit for late-stage disease., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Importance: Suicide rates among patients with cancer in the US are significantly higher than those of the general population. To our knowledge, large cohort studies examining suicide rates among patients with head and neck cancer have not been performed., Objective: To identify incidence rate, trends, and risk factors of suicide in patients with cancer of the head and neck., Design, Setting, and Participants: This was a retrospective cohort study of geographic areas served by the Surveillance, Epidemiology, and End Results (SEER) program. In total, 350,413 cases of patients with head and neck cancer were recorded within the SEER registry between 1973 and 2011. Data analyses were performed in 2014. Incidence data were calculated from the subset of that population that had the cause of death category coded as "suicide and self-inflicted injury.", Exposures: Patients diagnosed as having a primary cancer of the head and neck region., Main Outcomes and Measures: Influence of demographic factors, anatomic site of tumor, disease stage, and time since diagnosis on risk for suicide., Results: Among 350,413 SEER registry patients with head and neck cancer, observed for 2,263,376 person-years, 857 suicides were identified with an age-, sex-, and race-adjusted suicide rate of 37.9/100,000 person-years. In contrast, the US general population suicide rate was 11.8 per 100,000 person-years. Suicide rates were higher in those treated with radiation alone (standardized mortality ratio [SMR], 5.12; 95% CI, 3.83-6.41) compared with those treated with surgery alone (SMR, 2.57; 95% CI, 1.66-3.49). The highest suicide risk was seen in patients with cancers of the hypopharynx (SMR, 13.91; 95% CI, 11.78-16.03) and larynx (SMR, 5.48; 95% CI, 4.14-6.81)., Conclusions and Relevance: Patients with head and neck cancer have more than 3 times the incidence of suicide compared with the general US population. Furthermore, suicide rates were highest among those with cancers of the larynx and hypopharynx.

Objectives/hypothesis: Adenoid cystic carcinoma (ACC) occurs infrequently in the larynx. Consequently, no large samples describing its clinical behavior are available in the literature. Our objective was to use a nationally representative population-based resource to evaluate clinical behavior, patient demographics, and outcomes among patients diagnosed with laryngeal ACC (LACC)., Study Design: Retrospective database analysis., Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was analyzed for patients diagnosed with LACC between 1973 and 2011. Patient demographics, incidence, treatment, and survival between LACC and other laryngeal malignancies were compared., Results: Of 69 LACC patients, 63.8% were female, 78.2% Caucasian, and the median age was 54 years. LACC patients were much more likely to have subglottic lesions (44.9%) than individuals with other malignancies (1.6%). The incidence of LACC was 0.005/100,000 individuals. The majority of patients with LACC harbored T4 lesions at initial diagnosis, although 87.9% had N0 disease, and only 6.1% had distant metastasis at diagnosis. Disease-specific survival (DSS) was greater at 1 year for LACC compared to other laryngeal malignancies, but not at 5 or 10 years. Five-year DSS was greater for LACC patients who underwent surgery versus those who did not undergo surgery., Conclusions: This analysis notes that LACC has a low incidence with no significant change in incidence over the study period. Compared to other laryngeal malignancies, LACC has a female preponderance, is much more common in the subglottis, presents at a younger age, and more often presents with T4 disease. Surgery was noted to confer a survival advantage in LACC., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Epithelial-myoepithelial carcinoma (EMC) is a rare neoplasm of the salivary glands. In this study, we aim to examine the demographic, clinicopathologic, and survival features of EMC using a population-based approach., Study Design and Setting: Retrospective cohort study., Subjects and Methods: The Surveillance, Epidemiology, and End Result (SEER) database (1973-2010) was queried for EMC of the major salivary glands. Data were analyzed with respect to various demographic and clinicopathologic factors. Survival was analyzed using the Kaplan-Meier and Cox proportional hazards models., Results: In total, 246 cases were available for frequency analysis and 207 for survival analysis. Mean ± SD age at diagnosis was 63.8 ± 15.4 years. EMC affected females more frequently (57.3%). Distant metastases were present at diagnosis in only 4.5% of cases. Overall disease-specific survival (DSS) at 60, 120, and 180 months was 91.3%, 90.2%, and 80.7%, respectively. Patients with low-grade histology had significantly better survival at 180 months relative to those with high-grade tumors (90.6% vs 0.0%, P = .0246). When stratified by tumor size, patients with lesions >4 cm had the worst survival at 180 months (58.8%, P = .0003). All but 9 of the 207 cases available for survival analysis underwent surgery. A total of 85 patients (41.1%) received radiotherapy in addition to surgery. No survival benefit was noted for patients who received radiotherapy compared with those who did not (P = .4832)., Conclusion: This report represents the largest series of EMC to date. Despite being regarded as a low-grade, indolent tumor, a significant fraction of our cohort underwent radiotherapy in addition to surgery, with no apparent added survival benefit., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Objectives/hypothesis: Polymorphous low-grade adenocarcinoma (PLGA) is a rare malignant neoplasm of the minor salivary glands. This study analyzes the demographic, clinicopathologic, incidence, and survival characteristics of head and neck PLGA (HN-PLGA)., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for HN-PLGA cases from 2001 to 2011 (460 cases). Data analyzed included patient demographics, incidence trends, and survival outcomes., Results: Head and neck PLGA occurred most frequently in the sixth and seventh decades of life. Mean age at diagnosis was 61.3 (± 15.0) years. There was a female predilection with a female-to-male ratio of 2.15:1. There was a predilection toward blacks among the US population, with black-to-white incidence rate ratio of 2.33:1. The most common site of HN-PLGA was the palate (57.2%), followed by the lip (7.0%). Average tumor size was 2.1 (± 1.3) cm at presentation. The majority of cases were localized at the time of presentation (70.5%), with rare distant metastasis (4.3%). The most common treatment modality was surgery alone (77.9%), followed by surgery with radiotherapy (19.5%). Elective neck dissection was performed in 5.3% of the cases. Survival analysis showed excellent 10-year disease-specific (96.4%) and relative (94.7%) survival rates. Ten-year disease-specific survival was better among those treated with surgery alone (98.0%) or surgery with adjuvant radiotherapy (90.9%) than those treated with radiotherapy alone (75.0%) (P < 0.0001)., Conclusion: This study represents the largest cohort of HN-PLGA cases. Head and neck PLGA shows a predilection for women and blacks in the US population. It has an excellent survival outcome with surgery being the treatment of choice., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Transoral techniques for oropharyngeal tumors, such as transoral robotic surgery (TORS) and transoral laser microsurgery, require new reconstructive considerations., Methods: Defects from 92 patients undergoing TORS were classified into 4 classes. A reconstruction algorithm was followed. Perioperative outcomes and complications were assessed. Forty-seven patients completed the MD Anderson Dysphagia Inventory (MDADI) swallowing questionnaire and a modified Velopharyngeal Insufficiency Quality of Life (VPIQL) questionnaire postoperatively., Results: The most common reconstructions involved velopharyngoplasties with local flaps (39%), local flaps alone (25%), or secondary healing (20%). More advanced defects (class III and IV defects) required regional and free flaps more often. No significant differences were found in MDADI scores or VPIQL scores among the 4 defect classes. Only adjuvant radiotherapy was a predictor of poor swallowing (p = .02)., Conclusion: The classification system for transoral oropharyngeal defects maps defects into 4 classes and guides the reconstructive thought process., (Copyright © 2014 Wiley Periodicals, Inc.)

Early functional and oncological outcome studies suggest that transoral robotic surgery (TORS) may have a role for early stage cancers of the oropharynx. Unlike with traditional mandibular swing or pharyngotomy approaches, access to the oropharynx for reconstruction in TORS cases is limited. Maintaining a good functional result necessitates preserving physiological function where possible. The principles that should guide reconstructive surgeons include maintaining a velopharyngeal sphincter to prevent velopharyngeal insufficiency, maintaining sensate mucosa and restoring bulk in the tongue base to prevent aspiration, maintaining separation between the cervical and pharyngeal components, and covering exposed vessels in the pharynx. We present here principles and surgical techniques of TORS to reconstruct oropharyngeal defects using a subsite-based approach using secondary healing, local musculomucosal flaps, and free tissue transfer guided by the above principles., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models., Methods: The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days -7, -4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used., Results: DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03)., Conclusions: The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.

Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-beta stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10,000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-beta stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of well-differentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.

More effective immunosuppressants are needed to improve lung-transplantation survival. PX3.102 is a novel immunosuppressant isolated from a mixture of traditional Chinese herbs. We tested its protective role on chronic lung rejection in the heterotopic tracheal transplant model. C57BL/6 mice received BALB/c tracheal grafts and were treated with PX3.102, cyclosporine A, or vehicle. PX3.102 improved tracheal allograft lumen patency (*P<0.01 vs. vehicle and P=0.14 vs. cyclosporine A) but not epithelialization (P>0.2 vs. vehicle). Subsequent in vitro studies demonstrated that PX3.10 was toxic to fully differentiated human tracheal epithelial cells in a dose-dependent manner. PX3.102 markedly suppressed antigen-specific lymphocyte proliferation in vitro at a concentration 10 times lower than cyclosporine A. In conclusion, PX3.102, a promising and potent immunosuppressant, although exhibiting toxicity to airway epithelial cells at high doses, is effective in inhibiting chronic airway allograft rejection.

This essay responds to D. Davis and W. C. Follette (2002), who question the value of motive evidence in murder cases. They argue that the evidence that a husband had extramarital affairs, that he heavily insured his wife's life, or that he battered his wife is ordinarily of infinitesimal probative value. We disagree. To be sure, it would be foolish to predict solely on the basis of such evidence that a husband will murder his wife. However, when this kind of evidence is combined with other evidence in a realistic murder case, the evidence can be quite probative. We analyze cases in which it is virtually certain that the victim was murdered but unclear who murdered her, and in which it is uncertain whether the husband murdered the wife or she died by accident. We show that in each case motive evidence, such as a history of battering or of infidelity, can substantially increase the odds of the husband's guilt. We also consider the actual case on which Davis and Follette base their paper. We argue that testimony of Davis on the basis of the analysis presented in their paper was properly excluded, for it would have been misleading and unhelpful.

Objective: The purpose of this paper was to evaluate the age-specific survival for women diagnosed with endometrioid adenocarcinoma of the uterus., Methods: A retrospective analysis was conducted of 328 patients diagnosed with endometrioid adenocarcinoma of the uterus between January 1990 and December 1997. Patients were followed for 3 to 96 months with a mean of 43 months. The impact of age on survival was assessed using Cox proportional hazard regression and multivariate analysis for age, stage, and grade. Stage and grade were analyzed using log-rank tests, and survival curves were generated by the Kaplan-Meier method., Results: A total of 328 patients were evaluated. Multivariate analysis revealed age, stage, and grade were all significant independent predictors of survival (P < 0.0001). Age-specific survival varied from a high of 90% at age 40 to a low of 55% at age 80. Interval age-specific survival decreased below 86% at age 50. Subset analysis of patients younger than 50 compared with older patients revealed no difference in surgical stage or grade of tumors among these patients. Patients older than 50, however, were 41% more likely to receive adjuvant radiation therapy., Conclusion: Age is a specific, significant predictor of outcome in endometrioid adenocarcinoma of the uterus. Survival decreases significantly in patients older than 50. This decreased survival associated with age is unrelated to surgical stage or grade of adenocarcinoma. Decreased survival could involve molecular differences in the developing endometrial cancer or an increased risk of death from other non-cancer-related factors., (Copyright 2000 Academic Press.)

Objective: To determine the impact of pelvic lymph node sampling on survival in women with FIGO stage I and II endometrial adenocarcinoma., Methods: We reviewed data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program on 9185 women with stage I endometrial cancer and 881 women with stage II endometrial cancer. Life table analysis was used to compare survival rates., Results: Overall, lymph node sampling did not appear to convey survival benefit. The 5-year relative survival for 6363 women with stage I endometrial cancer who did not undergo lymph node sampling was 0.98, compared to 0.96 for 2831 women who did undergo lymph node sampling at the time of hysterectomy, a nonsignificant difference. Lymph node sampling (LNS) was associated with increased survival among those with stage I, grade 3 disease, but not grade 1 or grade 2. Women with stage I, grade 3 disease who underwent LNS had a relative 5-year survival of 0.89, compared to 0.81 for those who did not undergo LNS (P = 0.0110). Nonsignificantly improved survival associated with LNS for women with grade 3 disease was observed in International Federation of Gynecology and Obstetrics stages Ib, Ic, and II., Conclusions: The observed survival benefit associated with lymph node sampling may be due to identification of women with more advanced endometrial cancer. Accurate determination of grade and extent of tumor is necessary to delineate which patients may benefit from lymph node sampling at hysterectomy. Effective cooperation between surgical pathology and gynecology services may be required to ensure adequate examination of the hysterectomy specimen. A surgeon with expertise in performing lymph node sampling should be available if operative findings render lymph node sampling appropriate., (Copyright 1998 Academic Press.)

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.

Uterine sarcomas are unusual neoplasms of the female genital tract whose molecular etiology is largely unknown. We examined 20 leiomyomas as well as 23 uterine leiomyosarcomas for the presence of mutations in the Ki-ras and p53 genes, and overexpression of the MDM2 gene. Codons 12, 13, and 61 from the Ki-ras gene were characterized for the presence of mutations by restriction enzyme polymorphisms using mismatched primers and nucleic acid sequencing as appropriate. Activated Ki-ras genes were identified in 3/20 leiomyomas and 0/23 leiomyosarcomas. The p53 gene was analyzed by SSCP, nucleic acid sequencing, and immunohistochemical staining. None of 20 leiomyomas and 6/23 leiomyosarcomas exhibited p53 abnormalities. The SSCP/sequencing results did not consistently correlate with the IHC staining. MDM2 overexpression occurred in 0/20 leiomyomas and 3/23 sarcomas. Clinical correlation suggested that tumors with p53 mutations have a higher histologic grade or stage at presentation. We conclude that leiomyomas and leiomyosarcomas have different patterns of molecular alterations and are separate biologic entities. In addition, p53 and MDM2 overexpression may play a role in the development of a subset of leiomyosarcomas.

In an attempt to characterize the molecular alterations of cervical adenocarcinoma, we analyzed 32 paraffin-embedded specimens for the presence of K-ras mutations, p53 overexpression, p16 and Rb protein expression, and the presence of HPV 16 and 18 DNA. Overall 25/32 (78%) of the tumors displayed an abnormality in at least one of these analyses. K-ras mutations were detected by PCR amplification and RFLP analysis in 3 tumors, including 2 at codon 12 and 1 at codon 61. p53 overexpression determined by immunohistochemistry was demonstrated with > 80% of tumor nuclei staining in 4 cases, 10-15% of nuclei staining in 3 cases, and < 1% of nuclei staining in 5 cases. The pattern of staining was diffuse in 6 cases, focal in 1 case, and scattered in 5 cases. Analysis of p16 protein expression in 23 specimens revealed 1 tumor with abnormal staining, while Rb protein expression was determined to be normal in all 25 tumors tested. HPV DNA, detected by PCR with type-specific primers, was found in 16 tumors (50%), including 7 (22%) with HPV 16 and 9 (28%) with HPV 18. There was no correlation among these abnormalities except that the presence of HPV and strong p53 overexpression (> 80% tumor nuclei staining) were mutually exclusive events. Clinical correlation demonstrated that p53 overexpression involving the majority of tumor cell nuclei is characteristic of advanced stage disease, while HPV positivity and activated ras genes are associated with early stage disease.

We analyzed the expression of the retinoblastoma (Rb) gene in a group of ovarian neoplasms previously characterized for mutations in the p53 suppressor gene and the Ki-ras oncogene. Using immunohistochemical techniques, a total of 59 ovarian neoplasms spanning the histiologic spectrum from benign to malignant were examined for the expression of the Rb protein. All benign cystic adenomas and low malignant potential tumors exhibited normal expression of the Rb protein. Abnormalities in Rb protein staining were noted in 3 of 22 (14%) ovarian carcinomas. The staining patterns included tumors that were totally or focally negative for Rb protein. One tumor focally expressed Rb. This tumor demonstrated a direct juxtaposition of sections of Rb expressing and nonexpressing malignant epithelial cells. Two of the three tumors with abnormal Rb expression also had p53 mutations and staining on serial sections demonstrated that selected ovarian cancer cells possessed mutations in both oncogenes. These data suggest that the loss of Rb gene expression may play a role in the pathogenesis of a small number of invasive ovarian malignancies, but not in noninvasive ovarian neoplasms.

Ovarian cancer meets the criteria of a disease for which screening can be justified. The disease is most often diagnosed in advanced stages, when chances for long-term survival are poor. Yet effective treatment exists for early-stage disease, such that early detection can increase long-term survival. However, screening for early-stage ovarian cancer with the high specificity necessary for this low-prevalence disease has proven to be a challenge. This article reviews the issues of early detection of ovarian cancer, including pathology, statistical considerations, diagnostic modalities, and results of the major clinical studies undertaken.

The Gynecologic Oncology Group (GOG), a program of ACOG, is one of 12 cooperative groups conducting clinical trials supported by the National Cancer Institute. Recently, an occurrence of research fraud was found in one of the other cooperative groups. The GOG maintains a quality assessment and assurance program that includes three primary functions: Original source documentation is examined to verify accuracy of treatment modalities, all protocols are regularly scrutinized for consistency and validity, and regular on-site audits are conducted at all institutions. The group endeavors to reassure physicians and their patients that research fraud is not rampant in the cooperative group system and that data published by the cooperative groups are reliable.

Gynecologic malignancies, representing 13% of all cancers affecting women, have a major impact on women's health. Cervical, endometrial, and ovarian cancers comprise the majority of these tumors and contribute significant morbidity and mortality to the female population. While cervical and endometrial cancers can be detected early in their development, sadly, many patients present with advanced disease, as do the majority of patients with ovarian cancer. Unfortunately, advanced cases of these malignancies are usually lethal despite modern therapeutic modalities. In order to impact upon these grim statistics, gynecologic researchers have turned to molecular biology in an attempt to elucidate the etiology of these cancers. Recent research describing dominant oncogene and tumor suppressor gene mutations common to these malignancies is providing a basis for the molecular genesis of these cancers. This information should offer new avenues for the development of early detection and chemoprevention, as well as novel treatment strategies.

In an effort to define the pathogenic relationship between ovarian neoplasms spanning the clinicopathological spectrum from benign to malignant, the incidence of Ki-ras and p53 mutations was determined in 20 ovarian cystadenomas, 20 low malignant potential (LMP) tumors of the ovary, and 23 ovarian carcinomas. Using DNA extracted from paraffin embedded tissue, polymerase chain reaction amplification, designed restriction fragment length polymorphism analysis, and DNA sequencing, 1 cystadenoma (5%), 6 LMP tumors (30%), and 1 ovarian carcinoma (4%) demonstrated an activated Ki-ras gene. All of the Ki-ras mutations identified except one were GGT to GAT transversions at codon 12. One LMP tumor demonstrated a CAA to CAC transversion at codon 61. Using polymerase chain reaction/single strand conformational polymorphism, DNA sequencing, and immunohistochemistry, 11 ovarian carcinomas (48%) demonstrated a p53 mutation. These mutations included 5 missense, 2 nonsense, and 1 frameshift mutation located within exons 6-8 and 3 mutations that were identified only by immunohistochemical staining. No p53 mutations could be identified in cystadenomas or LMP tumors. Clinically, the presence of either a Ki-ras or p53 mutation was associated with advanced stage disease. The pattern of Ki-ras and p53 mutations appears to distinguish LMP tumors from invasive carcinomas and suggests that they may be separate biological entities.

Background: Despite the success of cytologic techniques in the diagnosis of neoplastic changes in the epithelium of the uterine cervix and the resultant decrease in the incidence of cervical invasive malignancies, 4440 women in this country will die of cervical cancer in 1992. Although radiation therapy and surgery form the basis for treatment of disease limited to the pelvis, those who have advanced disease or recurrences after locoregional therapy depend on systemic treatment for any hope of disease control., Method: Patients with advanced disease (not curable by surgery and/or irradiation) and recurrent cervical cancer have received single and combination cytotoxic chemotherapeutic regimens., Results: Thirty-eight cytotoxic agents alone and in combination have been reported. Although none have produced a significant number of cures, several have shown moderate activity. Of particular interest, because of the relatively high response rates and carefully done trials, are cisplatin, ifosfamide, and dibromodulcitol with partial and complete response rates of 23%, 22%, and 22%, respectively. Currently, no combinations have been shown to be better than single agents., Conclusions: No chemotherapy for advanced or recurrent carcinoma of the cervix is more effective than single-agent cisplatin. The major thrust of current and future investigation seeks to identify additional active agents and to develop combinations that offer greater patient benefit.

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.

One hundred forty-four patients with clinical stage I endometrial adenocarcinoma were treated over an 11-year period at Madigan Army Medical Center and Brooke Army Medical Center. Following surgical staging, 44 selected patients were placed on oral estrogen replacement for a median duration of 64 months. In the estrogen user group, there were no recurrent endometrial cancer and no intercurrent death. Of the 99 nonestrogen users, there were 8 recurrences (8%) and 8 intercurrent deaths. Patients placed on estrogen replacement had low-risk factors for recurrence, namely, low tumor grade (grades 1 and 2), less than 1/2 myometrial invasion, and no metastases to lymph nodes or other organs. Postoperative estrogen replacement appears to be safe in selected low-risk patients.

Endometrial carcinoma has been regarded as one of the more curable gynecologic malignancies. Clinical stage, grade, and depth of myometrial invasion are well-established prognostic variables. We examined the clinical course of 520 patients with endometrial carcinoma treated at Walter Reed Army Medical Center and the Naval Hospital, Bethesda, Maryland, between January 1, 1960 and December 31, 1982. Life table 5-year survivals for stages Ia, Ib, II, III, and IV were 89, 92, 77, 27, and 0%, respectively. Compared with patients with grade 1 endometrial adenocarcinomas, significant decreases in survival were noted for patients with grade 2 or 3 endometrial, papillary endometrioid, serous papillary, and clear-cell tumors. There were six treatment-related deaths (1.2%). Thirty-eight patients (7.3%) developed recurrent disease, with a median time to recurrence of 15 months and a median survival of 21 months. Two of 11 patients with pelvic recurrence were salvaged by radiotherapy, whereas none of 27 patients with distant failure survived. Sixteen advanced-stage patients (3.1%) with persistent disease had a median survival of 4.5 months. Patients with advanced disease or unfavorable histologic subtypes responded poorly to conventional therapy. Current salvage treatments are largely ineffective. Combined-modality therapy and systemic adjuvant therapy should be prospectively evaluated in high-risk patient subgroups.

A 5-month-old Hispanic female, diagnosed as having endodermal sinus tumor of the vagina, was treated with combination chemotherapy in an attempt to preserve pelvic function. An incisional biopsy was performed before starting chemotherapy. After completion of chemotherapy, no residual disease was found at exploratory laparotomy. The patient received no further therapy and is disease-free 45 months later. This case represents successful treatment of a vaginal endodermal sinus tumor without any operative excision.