Joseph Scharpf

Reconstruction with radial forearm flaps after ablative surgery for hypopharyngeal cancer

Patients afflicted with advanced hypopharyngeal cancer must contend with both potentially poor survival prognosis and a compromised quality of remaining life. After extensive ablative surgery, it is imperative to use a reliable, low morbidity reconstructive strategy that will allow for an expedient reconstitution of speech and swallowing.

Multi-agent concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer in the elderly

The reported decreasing benefit with increasing age from concurrent chemoradiotherapy in head and neck cancer patients prompted this retrospective review.

HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with more than half a million people being diagnosed with the disease annually. Within the last 2 decades, the human papillomavirus (HPV) has been found to be associated with this malignancy. More recently, HPV‐infected HNSCC has been found to exhibit higher levels of global DNA methylation. In a recent study, we identified five tumor suppressive genes (IRX1, EBF3, SLC5A8, SEPT9, and FUSSEL18) as frequently methylated in HNSCC biopsies using a global methylation analysis via restriction landmark genomic scanning. In this study, we verify these genes as valid methylation markers in two separate sets of HNSCC specimens. By using the available clinical information linked to the patient specimens, we found a strong association between promoter methylation of FUSSEL18, IRX1, and EBF3 and prior radiation therapy (P < 0.0001) irrespective of HPV status. Also, promoter methylation of FUSSEL18 and SEPTIN9 was found to correlate significantly with exposure to alcohol and tobacco (P = 0.021). Importantly, in this study, we preliminarily show a trend between HPV16 positivity and specific target gene hypermethylation of IRX1, EBF3, SLC5A8, and SEPT9. If replicated in a larger study, the HPV status may be a patient selection biomarker when determining the most efficacious treatment modality for these different subsets of patients (e.g., inclusion or exclusion of epigenetic therapies). Equally notable and independent of HPV status, hypermethylation of the promoters of a subset of these genes in recurrences especially in the setting of prior radiation or in the setting of alcohol and tobacco use might help guide adjunctive inclusion or exclusion or epigenetic therapy.

The Role of Pain in Head and Neck Cancer Recurrence and Survivorship

OBJECTIVE To examine pain, a common symptom in patients with head and neck cancer, and its relationship to recurrence and survivorship. DESIGN Prospective, observational study. SETTING Tertiary care institution. PATIENTS A total of 339 patients with head and neck carcinomas who participated in the Department of Otolaryngologys Outcomes Assessment Project between February 28, 1998, and November 30, 2001. Of 355 patients enrolled during this period, 7 were omitted from the study because they presented with persistent disease and 9 were omitted owing to a lack of valid pain data. Data on health-related quality of life were collected from the remaining patients at diagnosis and then at 3, 6, 9, and 12 months after diagnosis. INTERVENTION Administration of surveys and questionnaires. MAIN OUTCOME MEASURES The relationship of self-reported pain level with health-related quality of life during the first year, recurrence status, and 5-year disease-specific survivorship was determined through univariate and multivariate analyses. RESULTS Pain was associated with age, general physical and mental health conditions, depressive symptoms, survival rate, and recurrence within the first year. The 5-year survival rate was 81.8% for patients with low posttreatment pain and 65.1% for those with high pain. Posttreatment pain and tumor site were independent predictors of recurrence. Pain level, age, and treatment modality were independent predictors of 5-year survival. CONCLUSION Because of its association with recurrence and survival, pain within the first year of treatment for head and neck cancer is an important symptom that should be appropriately monitored and managed during routine follow-up.

Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma

Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Here we begin to explore the pilot hypothesis that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Microbiomic profiling by 16S rRNA sequencing of matched tumor and adjacent normal tissue specimens in 42 individuals with HNSCC demonstrate a significant association of specific bacterial subpopulations with HNSCC over normal tissue (P < 0.01). Furthermore, microbial populations can separate tumors by tobacco status (P < 0.008), but not by alcohol status (P = 0.41). If our subhypothesis regarding a mechanistic link from microorganism to carcinogenesis via inflammation and consequent aberrant DNA methylation is correct, then we should see hypermethylation of relevant genes associate with specific microbiomic profiles. Methylation analysis in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation shows significantly increased methylation in tumor samples compared with normal oral mucosa. Of these, MDR1 promoter methylation associates with specific microbiomic profiles in tumor over normal mucosa. Additionally, we report that MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial subpopulations, Enterobacteriaceae and Tenericutes (P < 0.001 for each). These associations may lead to a different, and potentially more comprehensive, perspective on the pathogenesis of HNSCC, and support further exploration of mechanistic linkage and, if so, novel therapeutic strategies such as demethylating agents and probiotic adjuncts, particularly for patients with advanced or refractory disease.

Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy.

IMPORTANCE Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

Use of In Situ Hybridization to Detect Human Papillomavirus in Head and Neck Squamous Cell Carcinoma Patients Without a History of Alcohol or Tobacco Use

CONTEXT Head and neck squamous cell carcinoma is commonly associated with tobacco and alcohol use. There are, however, a group of patients without a significant history of tobacco or alcohol use, and the etiology of these tumors is incompletely understood. OBJECTIVE To examine tumors in this subpopulation for association with human papillomavirus (HPV) using newly available in situ hybridization probes. DESIGN Between October 2004 and October 2005, 22 patients who did not use alcohol or tobacco were included. Formalin-fixed, paraffin-embedded tissue sections were used to perform in situ hybridization using newly available probe sets (Ventana Medical Systems, Tucson, Ariz). The slides were examined for the presence of integrated HPV using light microscopy. Positive and negative xenograft controls were run with the assay. Results.-The mean age of the patients was 64 years. There were 14 men and 8 women. The most common anatomic sites included tongue (n = 8), tonsil (n = 7), and larynx (n = 7). All cases and controls were successfully stained. Only 2 cases were positive for high-risk HPV, and both demonstrated an integrated pattern. Both cases were tumors of the tonsil. No cases were positive for low-risk HPV. CONCLUSIONS These results demonstrate that the new probe sets for HPV can be used very efficiently in clinical pathology material of head and neck squamous cell carcinoma. Our data show that high-risk HPV is an uncommon finding in head and neck squamous cell carcinoma from patients who do not have a history of tobacco or alcohol use; low-risk HPV was not seen in any case.

Salvage Laryngectomy in Patients with Recurrent Laryngeal Cancer in the Setting of Nonoperative Treatment Failure

Objective To investigate the effectiveness of salvage partial and total laryngectomy in the treatment of recurrent laryngeal cancer in the setting of initial nonoperative treatment failure and to identify factors influencing long-term survival. Study Design Case series with planned chart review. Setting Tertiary medical center. Subjects and Methods Patients with recurrent squamous cell carcinoma of the larynx initially treated with either radiation or chemoradiation, who underwent salvage laryngectomy at the Cleveland Clinic Foundation from 1997 to 2011, were identified. The cohort was divided into an early-stage group and an advanced-stage group based on initial tumor staging. Survival outcome was evaluated separately in each group against tumor staging, methods of treatment, and nodal status. Secondary endpoints of speech and swallowing were also evaluated. Results A total of 100 patients were identified, with 72 patients in the early-stage group and 28 patients in the advanced-stage group. The overall postsalvage locoregional control rate was 70%, and the 5-year disease-specific survival was 70% and 55.2% in the early and advanced group, respectively (P = .39). The 5-year disease-specific survival was not significant in either group when compared with recurrent staging, initial treatment, salvage treatment, or nodal disease (P = ns). Using voice prostheses, good to excellent speech function was achieved postoperatively in most patients. Conclusion Tumor staging, methods of initial and salvage treatment, and nodal disease were not significant predictors of survival. Both salvage partial and total laryngectomy were effective methods in the treatment of recurrent laryngeal cancer in carefully selected patients.

Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma

The management of initially bulky nodal disease after primary nonsurgical treatment for stage IV head and neck squamous cell carcinoma (HNSCC) continues to be a subject of debate.

A novel technique for peripheral nerve repair

Objective To evaluate a novel technique for the repair of neural deficits using a single fascicle to bridge an injury in the rat sciatic nerve.