Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.

Conscious Perception of Facial Asymmetry in a Unilateral Cleft Lip Model.

OBJECTIVE: Lip asymmetry after a unilateral cleft lip repair can be perceived as an unsatisfactory result. The objective of this study is to determine the degree of upper lip asymmetry and/or nasal alar hooding required for recognition of asymmetry in a simulated model of unilateral cleft lip. DESIGN: A model of unilateral cleft lip was created using digital morphing software to simulate asymmetries in vermilion height and nasal hooding in photographs of children. Volunteers were shown photographs for different time intervals and with varying degrees of asymmetry. Ability to detect facial asymmetry was recorded and analyzed. SETTING: This study was conducted by surveying layperson volunteers in public community settings. PARTICIPANTS: 108 layperson volunteers were randomly surveyed. MAIN OUTCOME MEASURES: The primary outcome measure was a reported lip or nose asymmetry by the volunteers. Proportions and corresponding 95% confidence intervals were obtained to estimate the probability of reporting an asymmetry at 3- and 10-second intervals. RESULTS: After 3- and 10-second exposure, labial asymmetry was perceived by ≥50% of subjects at 2 mm (62%, P = .001) and 1 mm (89%, P < .0001), respectively. Nasal asymmetry was detected by <50% of subjects at 3 seconds, but ≥50% perceived a 3-mm alteration at 10 seconds (64%, P < .0001). Photographs with combined nasal and labial modification did not lower the threshold for asymmetry perception compared to either deformity alone. CONCLUSIONS: This study is the first to determine a predictable millimeter threshold for perceived asymmetry in cleft lip deformity using a digital model.

Head and neck soft tissue sarcomas: unique lack of significance of synchronous node metastases.

BACKGROUND: Regional lymph node metastasis (RLNM) has been identified as a poor prognostic indicator for patients with soft tissue sarcomas (STS) of the extremities and trunk. However, the effect of RLNM on survival in patients with STS of the head and neck (HN) has not previously been explored. Our objective was to analyze RLNM as a prognostic indicator in HN-STS, and to compare this cohort to patients with STS of non-head and neck regions (NHN-STS). METHODS: STS patients were identified using the Surveillance, Epidemiology, and End Results database. Only patients without concurrent distant metastasis who underwent surgery and pathologic node staging were included. Patients were categorized based on tumor location: (1) HN-STS and (2) NHN-STS. Clinicopathologic data and disease-specific survival (DSS) were compared between node-negative and node-positive patients in each group. RESULTS: We identified 183 cases of node-positive STS (25 HN-STS, 158 NHN-STS). In the HN-STS group, pN1 status was not associated with any of the clinicopathologic factors that we analyzed. DSS was similar among pN0 and pN1 patients with HN-STS (P = 0.59); however, in the NHN-STS group, node-positivity was significantly associated with disease-specific mortality (P < 0.001). CONCLUSIONS: Synchronous RLNM may not affect DSS in patients HN-STS. Node-positive patients with HN-STS appear to be unique from those with NHN-STS.

Sex-based outcomes in type I thyroplasty for nonparalytic glottic incompetence.

OBJECTIVE: Clinical outcomes for type I Gore-Tex thyroplasty (GMT) for nonparalytic glottic incompetence (GI) have been reported in the literature. Given differences in male and female laryngeal anatomy, sex-based outcomes should also be evaluated. We endeavored to evaluate sex-specific post-GMT voice outcomes. METHODS: We performed a retrospective review of patients undergoing GMT for nonparalytic GI. Multidimensional voice outcome measures including voice-related quality of life (VRQOL), Glottal Function Index (GFI), and grade/roughness/breathiness/asthenia/strain (GRBAS) were analyzed at postoperative time frames: 0 to 3 months, 3 to 9 months, and 9 to 18 months. RESULTS: Eighty-five subjects (43 females, 42 males) with mean age 53.5 undergoing GMT for nonparalytic GI from 2005 to 2017 met inclusion criteria. Etiologies included vocal fold hypomobility (N = 36, 42%), paresis (N = 18, 21%), vocal fold atrophy (N = 17, 20%), and scarring (N = 14, 17%). Females had significantly greater improvement on VRQOL at 0 to 3 months and 9 to 18 months timeframes compared to males, with mean change in VRQOL: 41.3 versus 22.4 (P = 0.0002) and 42.5 versus 20.8 (P = 0.002), respectively. Similarly, women had significantly greater improvement in GFI at 0 to 3 months follow-up (mean difference - 10.8 vs. -4.9, respectively, P = 0.0002). There was no statistically significant sex difference in GRBAS at any follow-up interval. CONCLUSION: Following GMT, females had greater improvement in patient-reported voice outcomes in the early postoperative period. No significant difference between sexes was noted in perceptual measures (GRBAS). Sex-specific outcomes should be evaluated for clinical interventions to improve specificity of preoperative counseling. LEVEL OF EVIDENCE: 4. Laryngoscope, 129:2543-2548, 2019.

Analysis of anterior and posterior maneuvers to enhance intraconal exposure.

BACKGROUND: The medial and inferior recti encompass the ideal surgical corridor to approach the intraconal space endonasally. Here, we describe 3 different maneuvers to achieve greater access to orbital contents through an expanded endonasal approach (EEA). METHODS: Four human cadaver heads were dissected bilaterally (n = 8). EEA to the medial intraconal orbit was executed. The following 3 maneuvers were performed: (1) anterior: extraocular muscles control (EOM); (2) posterior: annulus of Zinn (AZ) release; and (3) anterior/posterior combined. Measurements of the inferior and medial rectus corridor at the level of anterior ethmoidal artery (AEA) and posterior ethmoidal artery (PEA) and extent of optic nerve and medial rectus visualization was performed before and after each maneuver. RESULTS: Medial rectus length (MRL) and optic nerve length (ONL) achieved were 1.72 ± 0.28 cm and 0.85 ± 0.2 cm, respectively. Mean caudal-rostral distances between the rectus muscles at the level of the AEA and PEA were 3.45 ± 0.7 mm and 1.30 ± 0.3 mm, respectively. After EOM control, mean caudal-rostral distances at the same level were as follows: AEA 4.90 ± 1.15 mm (p = 0.009) and PEA 1.70 ± 0.20 mm (p = 0.016). With AZ release, MRL was 2.20 ± 0.7 cm (p = 0.002) and ONL was 1.30 ± 0.2 cm (p = 0.003), with mean rostral-caudal distance at the level of AEA at 4.03 ± 0.8 mm (p = 0.16) and PEA at 1.71 ± 0.36 mm (p = 0.039). Mean caudal-rostral distances achieved with AZ release and EOM control were as follows: AEA 5.6 ± 1.2 mm (p = 0.001) and PEA 2.15 ± 0.4 mm (p = 0.001). CONCLUSION: Progressive access to the orbital contents is afforded with the 3 delineated maneuvers. The magnitude of access is optimized with the combined maneuver. The actual anterior/posterior location of the target will determine which maneuvers are required.

Hypovolemic shock after labial and lingual frenulectomy: A report of two cases.

Lingual and labial frenulectomy are commonly performed as an outpatient procedure, either in an office setting or under general anesthesia. Frenulectomy is generally regarded by both otolaryngologists and dentists as a straightforward and low-risk procedure with limited evidence-based indications and similarly few contraindications. We describe two cases of hypovolemic shock occurring after outpatient frenulectomy requiring emergent interventions of cardiopulmonary resuscitation and blood transfusion. These rare, but life-threatening outcomes warrant recognition as potential complications for the presumed benign labial and lingual frenulectomy. We additionally briefly review indications for upper labial and lingual frenulectomy.

Trial Vocal Fold Injection Predicts Thyroplasty Outcomes in Nonparalytic Glottic Incompetence.

OBJECTIVES: Trial vocal fold injection (TVFI) may be used prior to permanent medialization when voice outcome is uncertain. We aimed to determine whether voice outcomes of TVFI are predictive of, or correlate with outcomes after type I Gore-Tex medialization thyroplasty (GMT) in patients with nonparalytic glottic incompetence (GI). METHODS: Thirty-five patients with nonparalytic GI who underwent TVFI followed by GMT were retrospectively reviewed. Change in voice-related quality of life (VRQOL) after TVFI was compared to change in VRQOL 3 to 9 months after GMT. Similar comparisons were made for change in glottal function index (GFI) and change in grade, roughness, breathiness, asthenia, and strain (GRBAS). Sample correlation coefficients were calculated. RESULTS: Change in VRQOL after TVFI showed good correlation with change in VRQOL after GMT, r = 0.55. Change in GFI after TVFI showed strong correlation with change in GFI after GMT, r = 0.74. Change in GRBAS after TVFI showed excellent correlation with change in GRBAS after GMT, r = 0.90. CONCLUSION: The TVFI is a useful tool in nonparalytic GI when outcomes from glottic closure procedures are not clear. Voice outcome measures after TVFI strongly correlate with outcomes from GMT. These data may be used to more confidently counsel patients regarding their predicted outcomes of permanent medialization.

Longitudinal Voice Outcomes After Type I Gore-tex Thyroplasty for Nonparalytic Glottic Incompetence.

OBJECTIVE: Type I Gore-tex thyroplasty (GTP) for nonparalytic glottic incompetence (GI) results in significantly improved subjective and perceptual voice outcomes. We endeavored to investigate the longitudinal course of voice outcomes measuring the same patients across time points stratified by diagnostic subgroup. METHODS: Seventy-five patients with nonparalytic GI treated with GTP in the past 9 years were retrospectively reviewed and grouped according to their primary diagnoses (atrophy, scar, hypomobility, and paresis). Voice outcome measures, Voice-Related Quality of Life (VRQOL), Glottal Function Index (GFI), and GRBAS (grade, roughness, breathiness, asthenia, and strain) for each individual patient and diagnostic subgroup were grouped by time interval following surgery: 0 to 90 days, 3 to 9 months, 9 to 18 months, 18 to 36 months, 3 to 5 years, and 5 to 10 years. RESULTS: Across all diagnoses, statistically significant improvement in VRQOL was maintained at 3 to 5 years (P = .03) and GFI at 5 to 10 years (P = .02). The GRBAS showed statistically significant improvements out to 18 to 36 months (P = .02). In the subgroup analysis, hypomobility/paresis patients maintained significant improvement voice measures longer than patients with other diagnoses. As a group, scar patients did not show statistically significant postoperative improvement in VRQOL or GFI at any of the tested time points. CONCLUSIONS: Gore-tex thyroplasty provides durable improvement in subjective and perceptual voice outcomes for patients with nonparalytic GI. Patients treated for hypomobility/paresis have the most durable vocal outcomes followed by atrophy and lastly, scar.

Carotid artery and lower cranial nerve exposure with increasing surgical complexity to the parapharyngeal space.

OBJECTIVES/HYPOTHESIS: To investigate the extent of carotid artery exposure attained, including the identification of the external carotid branches and lower cranial nerves in five sequential external approaches to the parapharyngeal space, and to provide an anatomical algorithm. STUDY DESIGN: Anatomical study. METHODS: Six latex-injected adult cadaver heads were dissected in five consecutive approaches: transcervical approach with submandibular gland removal, posterior extension of the transcervical approach, transcervical approach with parotidectomy, parotidectomy with lateral mandibulotomy, and parotidectomy with mandibulectomy. The degree of carotid artery exposure attained, external carotid branches, and lower cranial nerves visualized was documented. RESULTS: The transcervical approach exposed 1.5 cm (Standard Deviation (SD) 0.5) of internal carotid artery (ICA) and 1.25 cm (SD 0.25) of external carotid artery (ECA). The superior thyroid and facial arteries and cranial nerve XII and XI were identified. The posterior extension exposed 2.9 cm (SD 0.7) of ICA and 2.7 cm (SD 1.0) of ECA. Occipital and ascending pharyngeal arteries were visualized. The transparotid approach exposed 4.0 cm (SD 1.1) of ICA and 3.98 cm (SD 1.8) of ECA. Lateral mandibulotomy exposed the internal maxillary artery, cranial nerve X, the sympathetic trunk, and 4.6 cm (SD 2.4) of ICA. Mandibulectomy allowed for complete ECA exposure, cranial nerve IX, lingual nerve, and 6.9 cm (SD 1.3) of ICA. CONCLUSION: Approaches for the parapharyngeal space must be based on anatomic and biological patient factors. This study provides a guide for the skull base surgeon for an extended approach based on the desired anatomic exposure. LEVEL OF EVIDENCE: N/A. Laryngoscope, 127:585-591, 2017.

Trends in chronic rhinosinusitis research in the past three decades.

BACKGROUND: The objective of this work was to identify trends in chronic rhinosinusitis (CRS)-related publications for the past 3 decades. METHODS: Literature review was conducted using multiple terms, including sinusitis, chronic rhinosinusitis, chronic sinus disease, nasal polyposis, ethmoid sinusitis, frontal sinusitis, and maxillary sinusitis. Abstracts were divided into 3 decades: 1983 through 1992, 1993 through 2002, and 2003 through 2012. For each decade, we compared the total number of publications and journals, study design, use of validated outcome measures, quality of evidence, number of authors, country of origin, and clinical vs basic science. RESULTS: A total of 3406 abstracts were identified. There was a statistically significant increase in the number of publications with a 637% increase from 1983 through 1992 to 2003 through 2012 (p < 0.05). Likewise, the number of journals with CRS-related publications significantly increased during the study period (117 to 350; p < 0.05). Prospective studies increased (15.30% to 28.90%, p < 0.05) and retrospective studies decreased (33.00% to 17.36%, p < 0.05). Cohort studies were the most common type of design study (18.70% to 32.46%). In studies reporting outcome measures, the use of validated measures significantly increased over time (2.56% to 49.70%, p < 0.05). Although, the quality of evidence for most clinical publications for all 3 decades were grade C, the number and percentage of grade A and grade B publications increased significantly over time (0.99% to 7.23%, p < 0.05; 6.9% to 10.44%, p < 0.05; respectively). CONCLUSION: CRS-related publication quantity and quality have increased over the last 3 decades.

Active screening and surveillance in the United Kingdom for Middle East respiratory syndrome coronavirus in returning travellers and pilgrims from the Middle East: a prospective descriptive study for the period 2013-2015.

BACKGROUND: Over 25000 pilgrims from the UK visit Saudi Arabia every year for the Umrah and Hajj pilgrimages. The recent outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) in South Korea and the continuing reports of MERS-CoV cases from Saudi Arabia highlight the need for active surveillance for MERS-CoV in returning pilgrims or travellers from the Middle East. Public Health England Birmingham Laboratory (PHEBL) is one of a few selected UK public health laboratories responsible for MERS-CoV screening in travellers returning to the UK from the Middle East who present to hospital with severe respiratory symptoms. The results of the PHEBL MERS-CoV screening and surveillance over the past 3 years is presented. METHODS: UK travellers/pilgrims who returned from the Middle East and presented to a hospital with respiratory symptoms were studied over the period February 1, 2013 to December 31, 2015. Patients with respiratory symptoms, who satisfied the Public Health England MERS-CoV case algorithm, were tested for MERS-CoV and other respiratory tract viruses on admission to hospital. RESULTS: Two hundred and two patients suspected of having MERS-CoV were tested. None of them had a laboratory-confirmed MERS-CoV infection. A viral aetiology was detected in half (50.3%) of the cases, with rhinoviruses, influenza A (H1N1 and H3N2), and influenza B being most frequent. Peak testing occurred following the annual Hajj season and in other periods of raised national awareness. CONCLUSIONS: Respiratory tract infections in travellers/pilgrims returning to the UK from the Middle East are mainly due to rhinoviruses, influenza A, and influenza B. Whilst MERS-CoV was not detected in the 202 patients studied, heightened awareness of the possibility of MERS-CoV and continuous proactive surveillance are essential to rapidly identify cases of MERS-CoV and other seasonal respiratory tract viruses such as avian influenza, in patients presenting to hospital. Early identification and isolation may prevent outbreaks in nosocomial settings.

The Reverse-Flow Facial Artery Buccinator Flap for Skull Base Reconstruction: Key Anatomical and Technical Considerations.

Objective To highlight key anatomical and technical considerations for facial artery identification, and harvest and transposition of the facial artery buccinator (FAB) flap to facilitate its future use in anterior skull base reconstruction. Only a few studies have evaluated the reverse-flow FAB flap for skull base defects. Design Eight FAB flaps were raised in four cadaveric heads and divided into thirds; the facial artery's course at the superior and inferior borders of the flap was measured noting in which incisional third of the flap it laid. The flap's reach to the anterior cranial fossa, sella turcica, clival recess, and contralateral cribriform plate were studied. A clinical case and operative video are also presented. Results The facial artery had a near vertical course and stayed with the middle (⅝) or posterior third (⅜) of the flap in the inferior and superior incisions. Seven of eight flaps covered the sellar/planar regions. Only four of eight flaps covered the contralateral cribriform region. Lastly, none reached the middle third of the clivus. Conclusions The FAB flap requires an understanding of the facial artery's course, generally seen in the middle third of the flap, and is an appropriate alternative for sellar/planar and ipsilateral cribriform defects.

Sources and structures of mitotic crossovers that arise when BLM helicase is absent in Drosophila.

The Bloom syndrome helicase, BLM, has numerous functions that prevent mitotic crossovers. We used unique features of Drosophila melanogaster to investigate origins and properties of mitotic crossovers that occur when BLM is absent. Induction of lesions that block replication forks increased crossover frequencies, consistent with functions for BLM in responding to fork blockage. In contrast, treatment with hydroxyurea, which stalls forks, did not elevate crossovers, even though mutants lacking BLM are sensitive to killing by this agent. To learn about sources of spontaneous recombination, we mapped mitotic crossovers in mutants lacking BLM. In the male germline, irradiation-induced crossovers were distributed randomly across the euchromatin, but spontaneous crossovers were nonrandom. We suggest that regions of the genome with a high frequency of mitotic crossovers may be analogous to common fragile sites in the human genome. Interestingly, in the male germline there is a paucity of crossovers in the interval that spans the pericentric heterochromatin, but in the female germline this interval is more prone to crossing over. Finally, our system allowed us to recover pairs of reciprocal crossover chromosomes. Sequencing of these revealed the existence of gene conversion tracts and did not provide any evidence for mutations associated with crossovers. These findings provide important new insights into sources and structures of mitotic crossovers and functions of BLM helicase.

Differences in skull base thickness in patients with spontaneous cerebrospinal fluid leaks.

BACKGROUND: This study was designed to determine if differences in overall skull base thickness exist in patients with spontaneous cerebrospinal fluid (SCSF) leaks and to compare our institution's 10-year experience with the endoscopic repair of these leaks to the existing literature. A retrospective cohort study was performed in a tertiary rhinologic practice. METHODS: A retrospective study by two blinded independent reviewers compared the skull base thickness on computerized tomography (CT) imaging in our SCSF leak patients to nonleaking controls and patients with traumatic CSF leaks. Surgical outcomes were compared with a pooled analysis of the published literature. RESULTS: SCSF leaks were seen most commonly in obese, middle-aged women of African American descent. SCSF leak patients were shown to have thinner skull bases in the region of the ethmoid roof, lateral lamella, and anterior face of the sella (p < 0.05) compared with patients with traumatic leaks and nonleaking controls. No racial difference in skull base thickness was observed when patients were matched according to leak type. The success rate of primary endoscopic intervention in our patients was high at 94% and comparable with the published literature. CONCLUSION: Differences in skull base thickness exist in SCSF patients, but whether this predisposes to such leaks or is a consequence of the underlying pathophysiology remains unknown. The endoscopic endonasal approach provides a highly effective means of repairing such leaks with success rates comparable with the endoscopic repair of other leak types. Adjuvant measures including weight reduction, lumbar drain, and acetazolamide use may increase success rates and should be considered in their management.

Squamous cell carcinoma of the uvula: an analysis of factors affecting survival.

OBJECTIVES/HYPOTHESIS: Uvular squamous cell carcinoma (SCC) is usually considered with soft palate tumors as an oropharyngeal cancer subsite. This investigation aims to determine whether the uvula itself is a high-risk subsite in the oropharynx for primary squamous cell carcinomas. STUDY DESIGN: Retrospective analysis of a large population database. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified patients with T1 and T2 SCC of the oropharynx. Patients were categorized into two groups based on primary site: 1) uvula; and 2) oropharynx not otherwise specified. Clinicopathologic characteristics and disease-specific survival (DSS) were compared between the two groups. RESULTS: Of the 9,833 patients we identified, 129 (1.3%) had primary uvular tumors. Primary tumors of the uvula were more likely to be smaller lesions at diagnosis (P < .001) and to present at a lower anatomical stage (P < .001). They also presented with less concurrent nodal metastasis (P < .001) and lower histological grade (P < .001). There was no evidence that size of uvular SCC lesion had any effect on nodal disease (P = .54), and survival was the same for T1 and T2 uvular SCC patients (P = .14). DSS was similar between the two groups as well (P = .7629). CONCLUSIONS: Our data indicate that primary SCC of the uvula does not have a worse prognosis, and tends to be recognized earlier and treated more definitively than SCC found in other oropharyngeal regions. However, survival being equivalent between two distinctive groups is perplexing, and may indicate an underlying aggressiveness to uvular cancers.

Salivary morbidity and quality of life following radioactive iodine for well-differentiated thyroid cancer.

OBJECTIVE: Determine the prevalence of sialadenitis in a group of patients treated with radioactive iodine (RAI) for well-differentiated thyroid cancer and assess whether RAI treatment is associated with a reduction in swallowing-related or global head and neck quality of life. STUDY DESIGN: Retrospective self-administered questionnaire study. SETTING: Academic, tertiary care, National Cancer Institute-designated cancer center. SUBJECTS AND METHODS: Surviving patients seen for well-differentiated thyroid cancer were identified by review of the cancer center registry. Patients were mailed a baseline questionnaire, the M. D. Anderson Dysphagia Inventory (MDADI), the University of Washington Quality of Life Questionnaire (UW-QOL), and the Xerostomia-Related Quality of Life Scale (XeQOLS). RESULTS: The study included 121 women and 24 men, with a mean age of 52 years. Radioactive iodine exposure was correlated with an increase in sialadenitis and was dose dependent (R (2) = 0.335, P < .001). Sialadenitis was 2.47 times more likely to occur in patients who received greater than 150 mCi when compared with those who received less than 150 mCi (P = .04). Radioactive iodine exposure of over 150 mCi was also associated with a reduction in the recreation domain of the UW-QOL (P = .04), the daily swallowing domain of the MDADI (P = .02), and the psychological/personal, pain, and social domains of the XeQOLS (P = .03, .03, and .04, respectively). CONCLUSION: Patients treated with RAI exhibited an increased risk for sialadenitis as well as a reduction in swallowing-related and global head and neck quality of life. Our findings suggest these patients should be screened for salivary morbidity and may benefit from both pre-RAI prophylaxis and post-RAI intervention.