Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Surgical management of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder in which the inappropriate elevation in serum parathyroid hormone level results in hypercalcemia. Most cases are caused by a single adenomatous parathyroid gland and less than 15% are caused by multiglandular disease. The incidence of PHPT appears to be increasing. More patients are being identified earlier and often before symptoms develop. Parathyroidectomy is the only definitive management; with it, the patient can achieve biochemical homeostasis and symptom relief, and sequelae are prevented. Even for asymptomatic patients with PHPT, there is a growing trend to recommend early surgical intervention. Controversy continues regarding the role of and reliance on various technologies, such as preoperative localization imaging, intraoperative parathyroid hormone level measurements, and minimally invasive surgery. Although both traditional bilateral 4-gland exploration and targeted approaches are accepted surgical techniques, there is a growing trend in unilateral targeted operations often using these technologies. Regardless of surgical approach, the expected success rate is greater than 95%. This article provides an overview of the contemporary surgical management of PHPT.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Metastatic pilomatrix carcinoma: Not so rare after all? A case report and review of the literature.

Pilomatrixoma is a slowly growing benign tumor of the dermal hair cells. Metastatic disease is exceptionally rare. Pilomatrixoma can occur at any age, but most patients are older than 40 years at presentation. Approximately 60% of these lesions occur in the head and neck region. Their size is usually about 4 cm at the time of presentation. Surgical excision with adequate margins is still the preferred treatment. We report a case of an aggressive malignant metastatic pilomatrixoma in a 43-year-old woman who underwent multiple extensive local resections. However, she died within 4 months of presentation.

Massive temporal lobe cholesteatoma.

Introduction. Intracranial extension of cholesteatoma is rare. This may occur de novo or recur some time later either contiguous with or separate to the site of the original cholesteatoma. Presentation of Case. A 63-year-old female presented to a tertiary referral hospital with a fluctuating level of consciousness, fever, headache, and right-sided otorrhoea, progressing over several days. Her past medical history included surgery for right ear cholesteatoma and drainage of intracranial abscess 23 years priorly. There had been no relevant symptoms in the interim until 6 weeks prior to this presentation. Imaging demonstrated a large right temporal lobe mass contiguous with the middle ear and mastoid cavity with features consistent with cholesteatoma. The patient underwent a combined transmastoid/middle fossa approach for removal of the cholesteatoma and repair of the tegmen dehiscence. The patient made an uneventful recovery and remains well over 12 months later. Conclusion. This case presentation details a large intracranial cholesteatoma which had extended through a tegmen tympani dehiscence from recurrent right ear cholesteatoma treated by modified radical mastoidectomy over two decades priorly. There was a completely asymptomatic progression of disease until several weeks prior to this presentation.

A new angle to mandibular reconstruction: the scapular tip free flap.

BACKGROUND: The purpose of this study was to review our experience with the scapular tip free flap for mandibular reconstruction, describe the surgical approach, and highlight specific clinical applications. METHODS: A retrospective review of all patients undergoing oromandibular reconstruction using a scapular tip free flap at the London Health Sciences Centre was undertaken. Patient demographics, surgical data, and early outcomes were collated. RESULTS: Twenty patients were identified. The majority involved mandibular angle and short segment defects (16 of 20). Average length of the segmental defect was 6.2 cm with the longest measuring 8 cm. A single patient required an osteotomy. Six were revision cases. No vein grafts were required. One complete flap failure occurred. CONCLUSIONS: The natural scapular angle makes the scapular tip flap ideal for mandibular angle reconstruction. Short bone segments can be harvested with little donor-site morbidity. The long pedicle length may obviate vein grafts.

Comparison of fibular and scapular osseous free flaps for oromandibular reconstruction: a patient-centered approach to flap selection.

IMPORTANCE: Provides an approach to osseous free flap selection for reconstruction of segmental mandible defects that takes into consideration general medical status of the patient and reconstruction requirements; demonstrates the complementary qualities of fibular and subscapular system free flaps; and describes the different surgical indications for lateral border scapular and scapular tip free flaps. OBJECTIVES: To review our experience with osseous mandible reconstruction comparing the fibular and subscapular system free flaps, determine reconstruction-specific and general health variables that may differ between these patient groups, and present our approach to oromandibular reconstruction. DESIGN: Retrospective study. SETTING: Academic tertiary care medical center. PARTICIPANTS: A total of 110 patients (68 male, 42 female) undergoing single-stage oromandibular reconstructions with free-tissue transfers between May 1, 2006, and May 30, 2012. INTERVENTION: Single-stage oromandibular reconstruction with free-tissue transfer. MAIN OUTCOME MEASURES: Differences in patient demographics, bone and soft-tissue aspects of the reconstruction, operative time, flap outcomes, and major postoperative complications between fibular, lateral scapular border, and scapular tip free flaps. RESULTS: A total of 110 patients underwent 113 reconstructions, including 58 fibular free flaps (FFFs) (51.3%) and 55 subscapular system flaps (48.7%). Of the subscapular system free flaps, 27 flaps (49%) were scapular tip free flaps (STFFs) based on the angular artery branch of the thoracodorsal pedicle; the remaining 28 cases were lateral scapular border flaps (LSBFs). Patients undergoing reconstruction with FFFs were significantly younger than their subscapular system flap counterparts (56 vs 70 years, P < .001). Mean mandible defect lengths were similar for patients undergoing FFF and LSBF reconstruction (7.8 and 7.7 cm, respectively); STFFs were used to reconstruct significantly shorter defects (mean, 6.0 cm, P < .001). The FFFs were more commonly used for anterior mandible defects in which multiple osteotomies and limited soft tissue were required, while subscapular flaps were more commonly used for linear mandible defects with complex soft-tissue requirements. A single complete flap loss occurred in a patient who underwent reconstruction with an STFF; other complication rates were similar between groups. CONCLUSIONS AND RELEVANCE: The FFFs and subscapular flaps are complementary options for oromandibular reconstruction. The FFF is ideal for younger patients, extended defects, multiple osteotomies, and limited soft-tissue requirements. The subscapular system free flaps (LSBF and STFF) are excellent options for (1) elderly patients; (2) those with significant comorbidities, such as peripheral vascular disease; and (3) mandible defects associated with complex soft-tissue requirements. Furthermore, the STFF offers a reliable option to reconstruct short-segment defects, in particular, defects involving the angle of the mandible.

Transoral robotic total laryngectomy: report of 3 cases.

BACKGROUND: Because of the significant toxicity of chemoradiation regimens, there has been a resurgence of interest in the primary surgical management of head and neck cancer and, in particular, the use of minimally invasive surgery. One such technique is transoral robotic surgery (TORS). We aim to discuss the potential role of TORS in patients requiring total laryngectomy (TL). METHODS AND RESULTS: Three patients underwent TORS-assisted narrow-field TL. Relative data on preoperative, intraoperative, and postoperative management were collated including postoperative complications. CONCLUSIONS: We present 3 cases of transoral robotic surgery (TORS)-assisted TL in patients requiring narrow field laryngectomy without requirement for neck dissection. In reviewing these cases we provide a discussion of pertinent preoperative and intraoperative considerations that can assist in facilitating successful completion of the procedure. In particular, appropriate assessment at the pinsertlinePOLA_Del_Blank_PgPOLA_Shift_FramePORT_rem_fpg_underremovelinetabminilanning endoscopy in addition to a methodical surgical approach are vital to the successful use of the robot in TORS-assisted TL.

Development of a transoral robotic surgery program in Canada.

Due to significant differences in healthcare structure between the United States and Canada, there are unique barriers to adopting new medical technology in Canada. In this article, we describe our experience developing a transoral robotic surgery (TORS) program at Western University. Specifically, we outline the steps that were necessary to obtain institutional and multidisciplinary team approval, financial support, as well as surgeon and allied healthcare personnel training. This experience can potentially be used as a roadmap for other Canadian institutions pursuing a TORS program.

Does HPV type affect outcome in oropharyngeal cancer?

BACKGROUND: An epidemic of human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC) has been reported worldwide largely due to oral infection with HPV type-16, which is responsible for approximately 90% of HPV-positive cases. The purpose of this study was to determine the rate of HPV-positive oropharyngeal cancer in Southwestern Ontario, Canada. METHODS: A retrospective search identified ninety-five patients diagnosed with OPSCC. Pre-treatment biopsy specimens were tested for p16 expression using immunohistochemistry and for HPV-16, HPV-18 and other high-risk subtypes, including 31,33,35,39,45,51,52,56,58,59,67,68, by real-time qPCR. RESULTS: Fifty-nine tumours (62%) were positive for p16 expression and fifty (53%) were positive for known high-risk HPV types. Of the latter, 45 tumors (90%) were identified as HPV-16 positive, and five tumors (10%) were positive for other high-risk HPV types (HPV-18 (2), HPV-67 (2), HPV-33 (1)). HPV status by qPCR and p16 expression were extremely tightly correlated (p < 0.001, Fishers exact test). Patients with HPV-positive tumors had improved 3-year overall (OS) and disease-free survival (DFS) compared to patients with HPV-negative tumors (90% vs 65%, p = 0.001; and 85% vs 49%, p = 0.005; respectively). HPV-16 related OPSCC presented with cervical metastases more frequently than other high-risk HPV types (p = 0.005) and poorer disease-free survival was observed, although this was not statistically significant. CONCLUSION: HPV-16 infection is responsible for a significant proportion of OPSCC in Southwestern Ontario. Other high-risk subtypes are responsible for a smaller subset of OPSCC that present less frequently with cervical metastases and may have a different prognosis.

A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure.

The role of transoral robotic surgery in the management of oropharyngeal cancer: a review of the literature.

Background. Transoral robotic surgery (TORS) is an emerging treatment option for the treatment of head and neck malignancies, particularly for oropharyngeal squamous cell carcinoma (OPSCC). Preliminary studies have demonstrated excellent oncologic and functional outcomes that have led to a resurgence of interest in the primary surgical management of OPSCC. The aim of the present study was to review the evidence base supporting the use of TORS in OPSCC. Methods. Studies evaluating the application of TORS in the treatment of head and neck squamous cell carcinoma (HNSCC), and more specifically OPSCC, were identified for review. Further searches were made of reference lists for complete evaluation of minimally invasive surgery (MIS) in treating OPSCC. Results. Seventeen results relating to the application of TORS in treatment of OPSCC were identified. Further results relating to the role of transoral laser microsurgery (TLM) in OPSCC were included for review. Feasibility, oncologic, and functional data is summarized and discussed. Discussion. Management strategies for patients with OPSCC continue to evolve. Minimally invasive surgical techniques including TORS and TLM offer impressive functional and oncologic outcomes particularly for patients with early T-classification and low-volume regional metastatic disease. Potential exists for treatment deintensification, particularly in patients who are HPV positive.

Postlaryngectomy pharyngocutaneous fistula: determining the risk of preoperative tracheostomy and primary tracheoesophageal puncture.

BACKGROUND: This article considers whether preoperative tracheostomy and primary tracheoesophageal puncture (TEP) contribute as independent risk factors to the development of pharyngocutaneous fistula (PCF), as well as discusses the significant factors related to the perioperative management of these patients. METHODS: Retrospective data were collected on 145 patients treated with total laryngectomy/pharyngolaryngectomy between January 2003 and July 2010 at the Victoria Hospital in London, Ontario, including whether preoperative tracheostomy or primary TEP was performed. RESULTS: One in four (25%) patients developed a postoperative PCF. No increase in PCF rates was observed with either preoperative tracheostomy or primary TEP. Salvage surgery PCFs achieved lower rates of spontaneous closure compared to those undergoing primary surgery (p  =  .002). CONCLUSIONS: Neither preoperative tracheostomy nor primary TEP was associated with the development of PCF. Surgical closure of PCF is more likely to be required in the setting of salvage surgery.

A Pilot Study Comparing HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas by Whole Exome Sequencing.

Background. Next-generation sequencing of cancers has identified important therapeutic targets and biomarkers. The goal of this pilot study was to compare the genetic changes in a human papillomavirus- (HPV-)positive and an HPV-negative head and neck tumor. Methods. DNA was extracted from the blood and primary tumor of a patient with an HPV-positive tonsillar cancer and those of a patient with an HPV-negative oral tongue tumor. Exome enrichment was performed using the Agilent SureSelect All Exon Kit, followed by sequencing on the ABI SOLiD platform. Results. Exome sequencing revealed slightly more mutations in the HPV-negative tumor (73) in contrast to the HPV-positive tumor (58). Multiple mutations were noted in zinc finger genes (ZNF3, 10, 229, 470, 543, 616, 664, 638, 716, and 799) and mucin genes (MUC4, 6, 12, and 16). Mutations were noted in MUC12 in both tumors. Conclusions. HPV-positive HNSCC is distinct from HPV-negative disease in terms of evidence of viral infection, p16 status, and frequency of mutations. Next-generation sequencing has the potential to identify novel therapeutic targets and biomarkers in HNSCC.

Ki-67 expression predicts radiotherapy failure in early glottic cancer.

BACKGROUND: Early-stage laryngeal squamous cell carcinoma is managed with radiotherapy or endoscopic surgery. Although cure rates are high, radiation failures often require total laryngectomy for salvage. Biomarkers that can predict tumour radioresistance may be useful in modifying the treatment approach for individual patients. METHODS: Retrospective patient chart review yielded 75 patients with T1-T2 glottic squamous cell carcinoma treated with radiation therapy at the London Health Sciences Centre. Pretreatment tumour biopsies were immunostained for B-cell lymphoma 2 (Bcl-2), Ki-67, and epidermal growth factor receptor (EGFR) to correlate biomarker expression with disease-free survival (DFS). RESULTS: Ki-67 expression was strongly associated with recurrence following radiation and independently predicted poor DFS (hazard ratio 4.86, 95% CI 1.58-15.00; p  =  .006). EGFR and Bcl-2 were not associated with a risk of recurrence. CONCLUSIONS: Ki-67 expression identified a subset of patients with increased risk of local recurrence after radiation therapy. Ki-67 expression can potentially guide improved personalized treatments for patients with early-stage glottic squamous cell carcinomas.

Concordance between real-time telemedicine assessments and face-to-face consultations in paediatric otolaryngology.

OBJECTIVE: To determine agreement between diagnoses and management plans made during an initial videoconference appointment and subsequent face-to-face consultations in paediatric ear, nose and throat (ENT) surgery. DESIGN AND SETTING AND PARTICIPANTS: A paediatric ENT clinic servicing patients from Bundaberg, Queensland, was conducted through the Centre for Online Health at the Royal Children's Hospital (RCH) in Brisbane. Between January 2004 and February 2006, 152 consultations with 97 patients were carried out. We retrospectively audited patients' charts to compare the diagnosis and management plan formulated at the initial videoconference and the eventual diagnosis and surgical management after face-to-face consultation. The clinical outcomes for children who were not recommended for surgery at the RCH were ascertained by telephone survey. MAIN OUTCOME MEASURES: Agreement between videoconference and face-to-face consultation findings. RESULTS: Of the 97 patients, 75 were recommended for surgical management at the RCH. The remaining patients were either referred back to their general practitioner (9), followed up by the regional paediatrician (10) or lost to follow-up (3). At the conclusion of the study, seven patients were still awaiting surgery and were excluded. Among the 68 patients seen via videoconference and in person, the recorded diagnosis was the same in 99% of cases (67). Surgical management decisions were the same in 93% of cases (63). Telephone follow-up with paediatricians and GPs confirmed that there were no missed diagnoses or ongoing ENT-related problems in the 19 patients referred back to their care. CONCLUSIONS: Decisions about ENT surgical interventions for children assessed during videoconference clinics are in close agreement with decisions made by the same surgeon at face-to-face consultation. The way is open to employ telemedicine more widely for pre-admission ENT assessment. However, as in any telemedicine work, widespread application requires care.