IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

Association of AXIN2 with non-syndromic oral clefts in multiple populations.

We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.

Analysis of the performance characteristics of the University of Washington Quality of Life instrument and its modification (UW-QOL-R).

BACKGROUND: During a 5-year period, we analyzed 3 patient subsets from the University of Washington Quality of Life (UW-QOL) Registry and published the results. In each instance, editorial review has raised legitimate concerns regarding the UW-QOL instrument that deserve public comment. We present our response to these criticisms. Since our original publication (1993), we have added domains to the original UW-QOL instrument. These additions reflected our concern that we might be missing important elements in the spectrum of disease-specific response to treatment. Using the data we have accumulated in the last 5 years, we present an analysis of the internal consistency of the UW-QOL. We have identified those domains that are responsive (or not responsive) to treatment effect and have revised the UW-QOL accordingly to create the UW-QOL-R, which is recommended for future use. DESIGN: The project began January 1, 1993, after approval by the UW Human Subjects Committee. Critical comments offered by external review were collated and responded to. Internal consistency was evaluated by interitem correlation matrix (Cronbach alpha) testing. SUBJECTS: All new patients presenting to the UW Medical Center (Seattle) with a diagnosis of head and neck cancer were asked to participate in a prospective analysis of QOL changes during and after treatment. INTERVENTION: Patients completed the pretreatment QOL questionnaire on the day of their initial workup. The format for the pretreatment test was an interviewer-supervised self-administered test; the subsequent tests were self-administered and were completed at 3, 6, 12, 24, and 36 months. Other data entered for each patient included site, stage, treatment, histologic classification, reconstruction, and current status. A QOL registrar was responsible for patient follow-up, data collection, and collation. All data were entered into the departmental relational database. RESULTS: Criticisms by external review included the following: "it is improper to call it [UW-QOL] a measure of quality of life"; "the summary scale is problematic because it implies that each of the subscales are weighted or 'valued' equally"; "some domain questions relate to surgery specific issues. while others are specific to radiation"; "we were confused by the scoring"; and "the UW-QOL index does not specifically address the psychological impact of the disease and its treatment." After evaluation of internal consistency, the UW-QOL was modified by removing 2 domains that correlated poorly with the others. This resulted in a 10-item instrument (UW-QOL-R) with an overall internal consistency score of 0.85. CONCLUSIONS: The UW-QOL can be effectively and accurately used to compare treatment effects in the management of head and neck cancer. With this revised instrument, the 10 items appear to measure the domains of overall QOL in a highly consistent and reliable fashion over time.

Quality of life in head and neck cancer.

Because treatments for patients with cancer of the head and neck can have major impact on physical, social, and psychological function, the collection of quality of life (QOL) data in this group of patients is critical for our specialty. The University of Washington Quality of Life data have been collected and analyzed on three subsets of cancer patients. Information learned from these patients is summarized and strategies for future projects are outlined.

Quality of life in patients with head and neck cancer: lessons learned from 549 prospectively evaluated patients.

OBJECTIVES: To summarize our quality-of-life (QOL) research findings for patients with head and neck cancer, to suggest areas for future productive QOL research, and to discuss how to undertake QOL studies in a cost-effective manner. DESIGN: Review of previously published analyses of advanced larynx cancer, advanced oropharynx cancer, and neck-dissection cases and current data from the complete set of patients. PATIENTS: From January 1, 1993, through December 31, 1998, data on 549 patients were entered in our head and neck database. Of these patients, 364 met additional criteria for histologic findings (squamous cell carcinoma) and the restriction of their cancer to 4 major anatomical sites (oral, oropharynx, hypopharynx, or larynx). Of these, 339 patients were more than 1 year beyond initial treatment. Complete baseline TNM staging and QOL data were obtained for 260 of these patients, of whom 210 presented with an untreated first primary tumor (index cases) to the University of Washington, Seattle. INTERVENTION: Pretreatment QOL was assessed with an interviewer-supervised self-administered questionnaire. Subsequent self-administered tests were completed at 3, 6, 12, 24, and 36 months. Other data collected on each patient included cancer site, stage, treatment, histologic findings, type of surgical reconstruction, and current disease and vital status. RESULTS/CONCLUSIONS: It is difficult to achieve "statistically significant" results in a single-institution setting. The "composite" QOL score may not be a sufficiently sensitive tool. Analysis of separate domains may be more effective.

Quality of life after laryngectomy: are functional disabilities important?

BACKGROUND: The purpose of this study was to determine the functional disabilities and overall quality of life (QOL) of patients successfully treated (ie, without evidence of disease at two years) for laryngeal or hypopharyngeal cancer by a total laryngectomy. METHODS: The University of Washington QOL questionnaire was administered to 10 patients prior to laryngectomy, at one year postlaryngectomy, and at two years postlaryngectomy. RESULTS: Postlaryngectomy QOL scores were not significantly different from prelaryngectomy scores. In all QOL domains the severity of functional disability was not significantly correlated with its importance. Ninety percent of patients (9/10) reported that compared with one year prior to the diagnosis of cancer their general health was the same or better at two years postlaryngectomy. Seventy percent of patients (7/10) reported having a good to excellent overall QOL. CONCLUSIONS: Though the loss of voice is disabling, the functional limitations caused by a laryngectomy do not necessarily translate into a worse overall QOL. Future research is needed to determine whether the importance of individual QOL domains changes as patients adjust to the experience of having and surviving cancer.

Results with sphincter pharyngoplasty and pharyngeal flap.

OBJECTIVE: To evaluate speech outcomes and complications of sphincter pharyngoplasty and pharyngeal flap performed for management of velopharyngeal insufficiency (VPI). DESIGN: Case series. SETTING: Tertiary care children's hospital. PATIENTS: All patients who underwent pharyngeal flap or sphincter pharyngoplasty from 1990 to 1995. METHODS: Perceptual speech analysis was used to assess severity of VPI, presence of nasal air emissions and quality of nasal resonance (hyper, hypo, or normal). Pre-operative measures of velopharyngeal function were based upon nasendoscopy and videofluoroscopic speech assessment. Recommendations for management were made by the attending surgeon. Complications of hyponasality and obstructive sleep symptoms (OSS) were noted. Patient characteristics were compared using univariate analysis. RESULTS: Sixteen patients underwent sphincter pharyngoplasty and 18 patients underwent superiorly based pharyngeal flap. Patients were similar in terms of lateral pharyngeal wall medial motion and palatal elevation. The groups were also similar with regard to VPI severity, though there was a trend for more severe VPI in patients undergoing sphincter pharyngoplasty than pharyngeal flap (50 vs. 33.3%, respectively). Patients with pharyngoplasty had a higher rate of resolution of VPI than those who had pharyngeal flap (50 vs. 22.2%, respectively), although this was not statistically significant. Post-operative hyponasality and obstructive sleep symptoms were present in both groups. However, only patients who underwent PF and had postoperative OSS had obstructive sleep apnea (OSA). CONCLUSIONS: There were no detectable anatomic differences between treatment groups implying that treatment selection during the study period was not guided by strict anatomic criteria. Sphincter pharyngoplasty may have a higher success rate with a lower risk of OSS.

Laryngeal long latency response conditioning in abductor spasmodic dysphonia.

Previously, we demonstrated that patients with adductor spasmodic dysphonia (ADSD) have a disinhibition of laryngeal responses to sensory input. In this study, sensorimotor responses to stimulation of the superior laryngeal nerve were compared between 10 subjects with abductor spasmodic dysphonia (ABSD) and 15 normal volunteers. The groups had similar latency and frequency characteristics of their unconditioned adductor responses (p>.05). The conditioned R1 (early) responses of the subjects with ABSD were greater and more variable in amplitude than those of the normal volunteers (p< or =.008). Similar R2 (late) conditioning effects were found in both groups, with a nonsignificant trend toward reduced inhibition of contralateral R2 responses at lower interstimulus intervals (p = .01) in the patient group. Thus, inhibitory mechanisms that modulate the R1 laryngeal sensorimotor pathway in the brain stem may be abnormal in subjects with ABSD. Abnormal modulation of laryngeal sensorimotor responses seems present in both types of spasmodic dysphonia.

Geographic variation in the utilization of esophagoscopy and bronchoscopy in head and neck cancer.

OBJECTIVE: To determine the extent to which esophagoscopy and bronchoscopy are being used in various regions of the United States in the initial examination of patients with head and neck cancer. DESIGN: Population-based study derived from Medicare claims data and information from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. SETTING: Five SEER areas (San Francisco, Calif; Connecticut; Seattle, Wash; Iowa; and Detroit, Mich). PARTICIPANTS: The cohort included 1410 Medicare patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx diagnosed between March 1, 1991, and December 31, 1993, in the 5 SEER areas. MAIN OUTCOME MEASURE: Rates of esophagoscopy and bronchoscopy according to SEER area. RESULTS: The proportion of patients who underwent esophagoscopy ranged from 12.9% (San Francisco) to 39.8% (Detroit) for patients with local cancer and from 22.2% (San Francisco) to 59.7% (Detroit) for patients with regional cancer. The proportion of patients who underwent bronchoscopy ranged from 6.9% (San Francisco) to 32.6% (Detroit) for patients with local cancer and from 12.8% (San Francisco) to 50.7% (Detroit) for patients with regional cancer. After controlling for differences in age, sex, race, tumor site, tumor grade, comorbidity, and socioeconomic status, SEER area remained independently associated with esophagoscopy and bronchoscopy (both P < .001). CONCLUSIONS: There is substantial geographic variation in the use of esophagoscopy and bronchoscopy as part of the initial examination of patients diagnosed as having head and neck cancer that cannot be explained by differences in patient or tumor characteristics. This variation likely underscores uncertainty and disagreement about the value of endoscopic screening for synchronous tumors. Additional research is required to determine whether routine endoscopic screening increases survival rates or improves quality of life.

Quality of life of disease-free survivors of advanced (stage III or IV) oropharyngeal cancer.

BACKGROUND: This study assessed the quality of life (QOL) of patients with advanced oropharyngeal cancer (stage III or IV) who were disease-free at 1 year posttreatment. METHODS: Between 1993 and 1994, 13 consecutive cases were identified from the University of Washington QOL registry. Patients were divided into two groups, depending on treatment: surgical group, 6 patients treated with surgical resection and postoperative radiotherapy; and nonsurgical group, 7 patients treated with definitive radiotherapy. RESULTS: Composite pretreatment and posttreatment QOL scores were similar for the two treatment groups. Subset analysis of QOL domains revealed that both treatment groups generally reported a worsening of chewing and swallowing. A worsening of appearance and of speech was more frequently reported by the surgical group. Sixty-seven percent of the surgically treated patients reported pain relief, as opposed to only 29% of the nonsurgical group. CONCLUSION: Composite QOL-score sensitivity may be compromised by inverse changes in individual QOL domains. Treatment-specific QOL domains may be more sensitive measures of outcome.

Comparison of cost and function in reconstruction of the posterior oral cavity and oropharynx. Free vs pedicled soft tissue transfer.

OBJECTIVE: To compare the cost and functional results of free and pedicled soft tissue reconstruction after posterior oral cavity and oropharyngeal extirpation. DESIGN: Retrospective study of 53 consecutive patients undergoing extirpation with primary soft tissue reconstruction from January 1, 1991, to December 31, 1995. Median follow-up was 298 days. SETTING: Academic tertiary care medical center. INTERVENTION: Twenty-four patients underwent reconstruction with a pedicled pectoralis major myocutaneous flap (PMMF); 29 patients, with a fasciocutaneous free flap (FF) (27 radial forearm, 1 lateral arm, and 1 scapular). MAIN OUTCOME MEASURES: Direct (inpatient hospital resources used and monetary costs) and intangible (post-operative complications and function) costs. RESULTS: Operative time was longer for FF reconstructions (P = .003), but both patient groups had similar intensive care unit and hospital stays. Treatment cost for FF reconstructions was $41,122, compared with $37,160 for PMMF reconstructions (P = .003). This difference was due to increased professional fees for FF reconstruction (P < .001) which was offset by intangible cost differences. The PMMF group tended toward an increased rate of flap-related complications, compared with the FF group. At last follow-up, 4 patients in the FF group (15%) and 3 in the PMMF group (15%) had their tracheotomy. In contrast, 17 (85%) patients in the PMMF group and 11 (39%) patients in the FF group required enteral tube feedings (P = .002). Also, 18 (64%) patients in the FF group were eating at least a soft diet compared with 6 (30%) patients in the PMMF group (P = .02). CONCLUSIONS: Comparison of direct costs reveals only a modest difference in reconstruction costs that is outweighed by the intangible costs of PMMF reconstruction. The functional benefits of FF reconstruction appear to justify its slight increased expense and its use rather than PMMF reconstruction after extirpation in the posterior oral cavity and oropharynx.

Risk of lung cancer among patients with head and neck cancer.

A cohort of 5180 patients with head and neck cancer, who were part of the tumor registry of the Surveillance, Epidemiology, and End Results area of western Washington State, was followed up for as many as 15 years to determine the risk of lung cancer. A sample of 522 patients from this cohort was interviewed to determine smoking history. Lung cancer developed in 356 (6.9%) of the 5180 patients. The overall annual incidence of lung cancer remained relatively constant between approximately 1.0% and 2.0% during the 15 years of follow-up. Men had an increased risk of lung cancer compared with women (relative risk (RR) = 1.56; 95% confidence interval (CI) = 1.18 to 2.03). Compared with patients with oral cavity cancer (RR = 1.00), the relative risk of lung cancer developing by the site of the index tumor was 0.63 (95% CI = 0.40 to 0.98) for lip, 1.12 (95% CI = 0.81 to 1.56) for intrinsic larynx, 1.73 (95% CI = 1.21 to 2.47) for oropharynx, 1.84 (95% CI = 1.16 to 2.92) for hypopharynx, and 2.28 (95% CI = 1.60 to 3.24) for extrinsic larynx. Among the 522 patients who were interviewed, men smoked more than women (p < 0.0001), and patients with laryngeal or pharyngeal cancer smoked more than patients with cancer of the lip or the oral cavity (p < 0.05). Among patients with head and neck cancer, the risk of lung cancer is highest for men and for patients with cancer of the pharynx or extrinsic larynx. These findings may be explained by differences in smoking consumption.

Exostoses of the external auditory canal in Oregon surfers.

PURPOSE: The objectives of this study were to determine the cold water exposure necessary to produce exostoses of the external auditory canal in individuals who predominantly surf along the Oregon and/or the northern California coastline and to ascertain from surfers' otologic histories symptoms attributable to exostoses. MATERIALS AND METHODS: Free ear examinations were provided at two surf shops in northern Oregon. The ear canals were examined with an otoscope, and each surfer was given a summary score indicating the percentage of both canals that was obstructed by exostoses. Surfers were then categorized according to the number of years surfing and the number of sessions surfing per year. RESULTS: Twenty-one surfers met our criteria for analysis. The degree of ear canal obstruction significantly increased with increasing number of years surfing (P < .001) and with increasing number of sessions surfing per year (P < .01). The median summary scores were 7.5, 63.0, and 93.0 for individuals who respectively surfed between 1 and 5 years, between 6 and 15 years, and greater than 15 years. The median summary scores were 10.0 for individuals who surfed 50 sessions or less per year versus 87.5 for individuals who surfed greater than 50 sessions per year. Most surfers with exostoses had minimal complaints. Only one patient had a history of surgical treatment. CONCLUSION: Individuals who surf 5 years or less are unlikely to develop exostoses unless they are surfing greater than 50 sessions per year. Exostoses are typically a benign malady that do not require surgical therapy.

Alcoholism: independent predictor of survival in patients with head and neck cancer.

BACKGROUND: Despite recognition of the high prevalence of alcoholism among patients with head and neck cancer, the prognostic importance of alcoholism has not been evaluated adequately. Previous investigators have speculated that alcoholic patients may have a poorer prognosis than nonalcoholic patients because of more advanced stage of cancer, the immunosuppressive effects of alcohol, and an increased rate of death due to other alcohol-related diseases. PURPOSE: The goal of this population-based study was to identify the features of alcoholism that are associated with survival for patients with head and neck cancer and to develop an alcoholic severity staging system from a composite of the independent features of alcoholism. METHODS: This prospective study included 649 patients who were diagnosed with cancer of the oral cavity, oropharynx, hypopharynx, or larynx during the period from September 1, 1983, through February 28, 1987, in a three-county area of western Washington state that participates in the Surveillance, Epidemiology, and End Results Program of the U.S. National Cancer Institute. Details on lifetime alcohol consumption, treatment for alcoholism, abstinence from alcohol prior to the diagnosis of cancer, and alcohol-related health problems were ascertained through in-person interviews near the time of diagnosis. Patients were classified as either nonalcoholics or alcoholics according to their responses to questions from the Michigan Alcoholism Screening Test. The measures of alcohol consumption and abuse that were found to be independently associated with 5-year survival by logistic regression analysis were combined using conjunctive consolidation to create a final composite variable, called an alcoholic severity stage. Cox proportional hazards regression analysis was done to estimate the relative risk (R) of death within 5 years due to specific causes of death for each of the alcoholic severity stages. RESULTS: Alcoholism (RR = 2.06; 95% confidence interval [CI] = 1.43-2.98) and a history of alcohol-related systemic health problems (i.e., liver disease, pancreatitis, delirium tremens, or seizures) (RR = 2.76; 95% CI = 1.69-4.49) were associated with an increased risk of death, whereas abstinence (i.e., the consumption of fewer than one drink per week at 1 year prior to the diagnosis of cancer) (RR = 0.62; 95% CI = 0.39-0.97) was associated with a decreased risk of death. These associations were independent of age, site of cancer, anatomical stage, histopathologic grade, smoking, and type of antineoplastic treatment. Patients in the two worst alcoholic severity stages had an increased risk of dying not only of head and neck cancer but also of cardiovascular disease, pulmonary disease, and other alcohol-related causes. CONCLUSIONS: Alcohol abuse, measured by alcohol consumption, functional impairment, a history of alcohol-related health problems, or abstinence, can provide important prognostic information for patients with head and neck cancer. Our results suggest that sobriety among alcoholic patients can lead to prolonged survival.

Relative prognostic importance of histologic invasion of the laryngeal framework by hypopharyngeal cancer.

This study assessed the relative prognostic importance of histologic invasion of the laryngeal framework by hypopharyngeal cancer. The laryngeal specimens and medical records of 55 patients found to have primary hypopharyngeal cancer between 1962 and 1988 were reviewed. Full 3-year follow-up information was obtained for 51 patients. The overall 3-year survival rate was 43% A(22/51). The 3-year survival rate was 55% (17/31) without histologic invasion versus 25% (5/20) with invasion (p < .05). To assess how invasion affected survival rates in conjunction with clinical predictors, we divided the cohort into two groups (mild versus severe illness) based on the presence or absence of anemia and comorbidity. Only in the group with mild illness did histologic invasion provide additional prognostic information. These results demonstrate that the inclusion of clinical variables in predictions of prognosis can strikingly alter the prognostic importance of invasion of the laryngeal framework.

Abnormalities in long latency responses to superior laryngeal nerve stimulation in adductor spasmodic dysphonia.

Sensorimotor responses to repeated electrical stimulation of the superior laryngeal nerve were compared in 8 patients with adductor spasmodic dysphonia (ADSD) and 11 normal controls to determine if adductor response disinhibition occurred in ADSD. Pairs of electrical pulses were presented at interstimulus intervals varying from 100 to 5,000 milliseconds (ms). Three responses were measured in thyroarytenoid muscles: ipsilateral R1 responses at 17 ms and ipsilateral and contralateral R2 responses between 60 and 75 ms. Conditioned response characteristics, the percent occurrence and percentage amplitude of initial responses, were measures of response inhibition. As a group, the patients had reduced response inhibition: their conditioned ipsilateral R1 response amplitudes were increased, as was the frequency of their conditioned contralateral muscle responses (p < or = .002) compared to normal. However, the patients' initial responses were normal in latency and frequency characteristics, demonstrating that the brain stem mechanisms for these responses were intact. These results suggest a central disinhibition of laryngeal responses to sensory input in ADSD.

The re-emergence of scrofula with HIV infection: a review of epidemiology, pathogenesis, diagnosis and treatment.

Scrofula has been called "The Dangerous Masquerader" because of its propensity to mimic other diseases. Scrofula has been mistaken for metastatic carcinoma, regional neoplasms, thyroglossal duct cysts, fungal disease, toxoplasmosis, lymphoma, osteosarcoma, chondrosarcoma, bacterial adenitis, and collagen vascular disease. Because of the enormous number of infectious and neoplastic diseases acquired by the HIV positive population, the diagnosis of scrofula may be further delayed in some patients. In these patients the early diagnosis of scrofula might allow the early identification of HIV infection and the early institution of anti-retroviral therapy. The recommended duration of anti-tuberculosis therapy is also different in HIV positive patients. Therefore, to ensure the patient of the most beneficial therapy, the physician must always consider scrofula in the differential diagnosis of a neck mass, and particularly because of the increases incidence of intrapulmonary tuberculosis in AIDS patients, he must consider the possibility of HIV infection.