Price, Daniel L

Background Neoadjuvant treatment has become standard for patients with high-risk operable stage III melanoma, but the optimal regimen is unknown. Targeted therapy approaches yield high pathological response rates, while immunotherapy regimens show favorable recurrence-free survival (RFS). NeoACTIVATE was designed to address whether a neoadjuvant combination of both targeted therapy and immunotherapy might leverage the benefits of each. Methods We tested neoadjuvant treatment with 12 weeks of vemurafenib, cobimetinib, and atezolizumab for patients with BRAF-mutated (BRAFm) melanoma (cohort A) and cobimetinib and atezolizumab for patients with BRAF-wild-type (BRAFwt) melanoma (cohort B), regimens which we have shown generate a substantial major pathological response. After therapeutic lymph node dissection, patients received 24 weeks of adjuvant atezolizumab. Here, we report survival outcomes and their association with biomarkers assayed among the gut microbiome and peripheral blood immune subsets. Results With 49 months median follow-up, the median RFS was not reached for cohort A and was 40.8 months for cohort B. At 24 months after operation, 2 of 14 cohort A patients and 4 of 13 cohort B patients had experienced distant relapse. Key findings from correlative analyses included diversity, taxonomic and functional metagenomic gut microbiome signals associated with distant metastasis-free survival at 2 years. Notably, we observed a strong correlation between low microbial arginine biosynthesis (required for T-cell activation and effector function) and early distant recurrence (p=0.0005), which correlated with taxonomic differential abundance findings. Peripheral blood immune monitoring revealed increased double-positive (CD4+CD8+) T cells in patients with early recurrence. Conclusions Neoadjuvant treatment with cobimetinib and atezolizumab±vemurafenib was associated with a low rate of distant metastasis in patients with high-risk stage III melanoma. Freedom from early distant metastasis was highly associated with taxonomic differences in gut microbiome structure and with functional pathway alterations known to modulate T cell immunity. Identification of predictive biomarkers will permit optimization of neoadjuvant therapy regimens for individual patients. Trial registration number NCT03554083.

AbstractObjective The objective of this study is to describe the clinical presentation, tumor characteristics, natural history, and treatment patterns of sinonasal osteosarcoma.Methods Fourteen patients who had been treated for osteosarcoma of the nasal cavity and paranasal sinuses at a tertiary care center were reviewed. In addition, a systematic review of the literature for osteosarcoma of the sinonasal cavity was performed.Results In a systematic review, including 14 patients from the authors' institution, 53 total studies including 88 patients were assessed. Median follow-up was 18 months (interquartile range: 8–39 months). The most common presenting symptoms were facial mass or swelling (34%), and nasal obstruction (30%). The most common paranasal sinus involved by tumor was the maxillary sinus (64%), followed by the ethmoid sinuses (52%). The orbit (33%), dura (13%) and infratemporal fossa (10%) were the most common sites of local invasion. The majority of patients underwent surgery followed by adjuvant therapy (52.4%). Increasing age was associated with decreased overall survival rate (unit risk ratio [95% confidence interval (CI)] = 1.02 [1.003–1.043]; p = 0.0216) and T4 disease was associated with decreased disease-specific survival rate (hazard ratio [HR] = 2.87; p = 0.0495). The 2- and 5-year overall survival rates were 68 and 40%, respectively, while 2- and 5-year disease-specific survival rates were 71% and 44%, respectively.Conclusion Sinonasal osteosarcomas are uncommon tumors and can pose a significant therapeutic challenge. Increasing age and T4 disease are associated with worse prognosis. This disease usually warrants consultation by a multidisciplinary team and consideration of multimodality therapy.

Background. Although alcohol and tobacco use are known risk factors for development of squamous cell carcinoma in the head and neck, human papillomavirus (HPV) has been increasingly associated with this group of cancers. We describe the case of a married couple who presented with HPV-positive oropharynx squamous cell carcinoma within two months of each other.Methods. Tumor biopsies were positive for p16 and high-risk HPV in both patients. Sanger sequencing showed a nearly identical HPV16 strain in both patients. Both patients received chemoradiation, and one patient also underwent transoral robotic tongue base resection with bilateral neck dissection.Results. Both patients showed no evidence of recurrent disease on follow-up PET imaging.Conclusions. New head and neck symptoms should be promptly evaluated in the partner of a patient with known HPV-positive oropharynx cancer. This case expands the limited current literature on concurrent presentation of HPV-positive oropharynx squamous cell carcinoma in couples.

ObjectiveReview Mayo Clinic experience of localized tongue amyloidosis.Study DesignCase series with retrospective chart review.SettingAcademic medical center.Subjects and MethodsCases of localized tongue amyloidosis were identified from the dysproteinemia database at the Mayo Clinic in Rochester, Minnesota. Electronic records were reviewed with focus on presenting symptoms, laboratory results (ie, serum or urine immunoelectrophoresis, bone marrow biopsy, and fat aspirate analysis), treatment modality, and status of disease at follow‐up.ResultsSix cases of localized tongue amyloidosis presented to the Mayo Clinic between 1969 and 2011. Mean patient age was 69 years (range, 43‐90). Patients presented with asymptomatic tongue mass(es). Biopsy of the tongue mass in all patients showed amyloid on Congo red stains. Work‐up for systemic amyloidosis, including bone marrow biopsy, fat aspiration, and serum and urine protein immunoelectrophoresis, was negative for all 6 patients, nor was there other organ involvement. Two patients underwent resection of the lesions, and the remaining patients elected for observation. Recurrence requiring repeat excision occurred in 1 of the patients that underwent resection. Repeat evaluation for systemic involvement was performed in 3 patients 1 to 3 years after the initial diagnosis. None of these patients went on to develop systemic involvement.ConclusionsLocalized tongue amyloidosis remains a rare diagnosis and requires exclusion of systemic involvement. Localized lesions may be observed or resected; however, recurrence may occur with resection. Patients with localized tongue amyloidosis do not appear to be at increased risk of developing systemic involvement.

Objectives/HypothesisTo determine the incidence of level IIB lymph node metastasis in patients with laryngeal or hypopharyngeal squamous cell carcinoma and to evaluate the need for elective and therapeutic neck dissection of level IIB.Study DesignRetrospective cohort study and review of the literature.MethodsPatients with laryngeal or hypopharyngeal squamous cell carcinoma (N = 65) were primarily treated with surgery at Mayo Clinic (Rochester, Minnesota) from 2004 through 2010. Neck dissection specimens were analyzed by a pathologist, and metastases to level IIB were reported. In addition, 18 previously published studies, totaling 1,114 neck dissections, were reviewed.ResultsLevel IIB lymph node metastases were present in 4% and 17% of elective and therapeutic neck dissections, respectively. Ipsilateral IIB metastasis was more common than contralateral IIB metastasis in elective and therapeutic neck dissection specimens. Level IIB lymph node metastasis was not significantly associated with level IIA nodal metastasis, level III nodal metastasis, clinical primary tumor stage, clinical nodal stage, or pathologic confirmation of extracapsular spread in either laryngeal or hypopharyngeal squamous cell carcinoma.ConclusionsThe rate of occult IIB metastasis in laryngeal and hypopharyngeal squamous cell carcinoma is exceedingly low. In a clinically node‐negative case, the ipsilateral and contralateral level IIB nodal packet should not be dissected. For clinically node‐positive cases, ipsilateral level IIB dissection should be performed; contralateral IIB dissection should be performed only when indicated.Level of Evidence4. Laryngoscope, 123:3032–3036, 2013

Objectives/HypothesisTo determine the incidence of level IIB lymph node metastasis in patients with oropharyngeal squamous cell carcinoma (OPSCC) and to evaluate the necessity of level IIB dissection for elective and therapeutic neck dissections.Study DesignRetrospective cohort study.MethodsPatients with OPSCC (N = 348) were surgically managed at our institution from 2004 through 2010. Neck dissection specimens were reviewed by a pathologist, and level IIB metastases were analyzed with respect to clinical and pathologic data.ResultsLevel IIB lymph node metastases were present in 2.5% and 25% of elective and therapeutic neck dissections, respectively. Level IIA metastasis, clinical tumor stage, clinical nodal stage, extracapsular spread, and primary tumor location in the tonsil were significantly associated with level IIB metastasis.ConclusionsThis study uniquely demonstrated a statistically significant association between clinical tumor stage and tonsil subsite with level IIB metastasis in OPSCC. Considering the predicted incidence of nodal metastasis, we conclude that level IIB neck dissection can be omitted in early stage (T1 or T2) clinically node negative (cN0) OPSCC. In patients with a cN0 neck and advanced OPSCC (T3 or T4), primary tumor in the tonsil, or ipsilateral clinically node positive (cN+) and contralateral cN0 neck, level IIB dissection should be considered. Level IIB dissection should be performed routinely in patients with cN+ OPSCC.Level of Evidence4. Laryngoscope, 123:2700–2705, 2013

Objectives/HypothesisAssess the role of retropharyngeal lymph node dissection in oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS).Study DesignProspective case series.MethodsRetrospective analysis of 72 patients with oropharyngeal squamous carcinoma treated with transoral oropharyngectomy, neck dissection, and retropharyngeal node dissection.ResultsEight of 55 (14.5%) patients with tonsil primaries had retropharyngeal metastases in contrast to none with tongue base primaries. The presence of pathologically positive retropharyngeal nodes was associated with clinical tumor (T) (P=.002) and node (N) stage (P=.007), preoperative computed tomography (CT) (P<.001), and positron emission tomography (PET)‐CT scan (P<.001). The negative predictive value of early T (Tx,1‐2) and N stage (N0‐N2a) was 91.7% and 100%, respectively. Preoperative CT and PET‐CT both yielded a positive predictive value of 100%, while the negative predictive value of imaging was optimized to 95.3% when these modalities were combined.ConclusionsIn patients with tonsil cancer the risk of retropharyngeal metastases is negligible in the presence of clinically T1‐2, N0‐N2a disease and negative CT and PET‐CT. We estimate that 40% of patients meet these criteria and may safely forego treatment of the retropharyngeal nodes. Approximately 10% of patients will have positive imaging and we recommend retropharyngeal node dissection at the time of surgery to treat macroscopic disease. In the remaining patients at risk for retropharyngeal node involvement, adjuvant radiotherapy is generally indicated based on other adverse features, and these nodes may be incorporated into the treatment field.Level of Evidence4. Laryngoscope, 2013

ObjectivesTo determine the cost of treatment of oropharyngeal squamous cell carcinoma (OP SCCA) with transoral surgery with concomitant neck dissection (TOS), TOS with adjuvant radiation therapy (TOS + RT), TOS with adjuvant chemoradiation therapy (TOS + CRT), and primary chemoradiation therapy (CRT).Study DesignCase series.SettingTwo tertiary care teaching hospitals.Subjects and MethodsUsing the databases of 2 teaching hospitals, patients were identified who had OP SCCA treated with TOS, TOS + RT, TOS + CRT, and primary CRT in 2009 to 2010. Costs were analyzed from an institutional perspective looking at reimbursement. Patients with government payers and patients with private payers in each group were identified, and net revenue data obtained for the 3‐month period from diagnosis were calculated and averaged for each group. Cost was defined as the reimbursement for all charges surrounding the 3‐month episode of treatment. All revenue associated with inpatient and outpatient care, including pharmacy charges, was included.ResultsThe mean cost of TOS (private payers/government payers) was $37,435/$15,664 (range, $22,486‐$48,746/$13,325‐$16,885). The mean cost of TOS + RT (private payers/government payers) was $74,484/$34,343 (range, $72,400‐$84,825/$31,565‐$40,810). The mean cost of TOS + CRT (private payers/government payers) was $191,780/$53,245 (range, $145,450‐$217,220/$49,400‐$58,325). The mean cost of CRT (private payers/government payers) was $198,285/$57,429 (range, $168,216‐$298,945/$52,900‐$59,545).ConclusionAn algorithm of transoral surgical treatment of OP SCCA with adjuvant treatment as indicated by pathology is more cost conscious than an algorithm of treatment of all OP SCCA with CRT.