The role of non-oropharyngeal biopsies in head and neck squamous cell carcinoma of unknown primary: A systematic review.

INTRODUCTION: This systematic review aims to evaluate the role of biopsies in non-oropharyngeal subsites in patients with cervical metastasis from head and neck squamous cell carcinoma of unknown primary (HNSCCUP). METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Articles that encompassed non-oropharyngeal biopsies in HNSCCUP as part of the diagnostic work-up were selected and analysed. RESULTS: A comprehensive search strategy was used to search relevant literature in PubMed from inception to October 2021. Eleven articles out of 860 were included, comprising 990 patients. There are no randomised control trials comparing the outcomes of survival and or locoregional control between patients who have or have not undergone non-targeted biopsies of non-oropharyngeal sub-sites for HNSCCUP. Several retrospective studies which showed an extremely low yield from random biopsies (range of yield, 0%-9%) of non-oropharyngeal subsites. Even targeted biopsies showed a low yield (range of yield, 0.6%-16.6%) from non-oropharyngeal subsites. The primary site identified for Epstein-Barr virus (EBV) positive cervical lymph nodes with an unknown primary is mainly the nasopharynx (51.7%). Narrow band imaging (NBI) (sensitivity range, 64%-91%) helps in the detection of primaries to target biopsies in non-oropharyngeal subsites. CONCLUSIONS: On the basis of this systematic review, it is not appropriate to offer biopsies of clinically and radiologically normal upper aerodigestive tract mucosa at non-oropharyngeal sites. Offer nasopharyngeal biopsies when the cervical node sampling reveals EBV-positive metastasis. Where available, NBI should be used to help detect and target biopsies in non-oropharyngeal subsites.

Outcomes of anastomotic venous flow couplers in head and neck free flap reconstruction - five-year experience in a single centre.

Flow couplers for venous anastomosis, which enable the invasive monitoring of free flaps during the postoperative period with a continuous venous signal audible immediately after completion of the anastomosis, have been reported to be reliable, sensitive, and specific as anastomotic flap monitoring adjuncts. The purpose of this study was to evaluate the reliability, sensitivity, specificity, and outcomes of surgical exploration, and the impact on free-flap survival of the venous anastomotic flow coupler for microvascular head and neck reconstruction in a consecutive series of patients. This is a retrospective review of consecutive patients treated in the department of oral and maxillofacial surgery who underwent reconstruction of a head and neck defect using venous anastomosis with a flow coupler-vascularised free flap between October 2015 and December 2020. A total of 189 patients had free-flap reconstruction of head and neck defects. We compared the venous flow coupler group (n = 72) with patients who had free flaps with hand-sewn anastomoses over the same period (n = 117). There were no false positive/negatives associated with the flow coupler as an implantable flap monitor. The flow coupler cohort had a significantly higher flap salvage rate compared with free flaps that were monitored clinically (p = 0.04). The venous flow coupler has been shown to be a reliable microvascular anastomotic and invasive flap monitor that enables accurate and timely detection of flap compromise and prompt, successful free-flap salvage.

Football-related maxillofacial injuries.

Maxillofacial injuries sustained playing sports are becoming increasingly common, and in the UK where football is the most popular team sport, associated maxillofacial injuries are a regular occurrence. This study retrospectively examined data on patients who were referred with facial injuries sustained playing football between 2007 and 2019 (n = 265). Demographics, mechanism of injury, diagnosis, and treatment received were analysed. The mean (SD) age was 25 (11.0) years (range 3-85) and there was a strong male predominance (n = 256, 97% male). Facial fractures were diagnosed in 143 (54%) patients. The most common injury was a midface fracture and the most common mechanism of injury was a clash of heads. Patients with a facial fracture were significantly more likely to have sustained a concurrent head injury (p = 0.006). Those who were elbowed or punched were significantly more likely to have a facial fracture than a soft tissue or dentoalveolar injury (p ≤ 0.05). Players who clashed heads were significantly more likely to have a midface fracture (p ≤ 0.001). In conclusion, football-related maxillofacial injuries predominantly affect young adult males following a clash of heads. An elbow or punch to the face carries a significant risk of facial fracture and concurrent head injury. Therefore, to reduce the percentage of maxillofacial injuries seen in this sport, observed intentional contact between players, using an elbow or fist to the face in particular, must continue to carry the highest sanction.

Merkel cell carcinoma of the head and neck in the south-east of England.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy of the skin. Its incidence is increasing with half of cases involving the head and neck. To the best of our knowledge, few large studies have been published in the UK, and to date this is the largest reported series of head and neck MCC. We retrospectively reviewed the outcomes of patients with MCC in three hospitals in the south-east of England over a 12-year period (2008-2019). Diagnosis was based on histological data following biopsy. Overall survival and disease-specific survival were calculated using Kaplan-Meier and log-rank tests. Fifty-eight patients met the inclusion criteria (24 stage I, 22 stage II, 9 stage III, and 3 unclassified). Median disease-free survival was 36 months (95% CI 0 to 77.2) and median overall survival 50 months (95% CI 29.9 to 70). Overall five-year survival was 34.4% (95% CI 17% to 52%) with two-year survival at 62% (95% CI 48% to 76%). Five-year disease-free survival was 26.7% (95% CI 17 to 52%) with two-year disease-free survival at 54% (95% CI 40% to 68%). To date, this is the largest UK based study reporting overall and disease-free survival associated with MCC of the head and neck. Half the patients presented late, and surgery was the mainstay of treatment, augmented by adjuvant radiotherapy. There is a need to better stratify patients at risk of developing metastatic disease, with the use of sentinel lymph node biopsy and positron-emission tomography-computed tomography (PET-CT), as immunotherapy and targeted agents are now available to treat advanced disease.

Operative time, length of stay and reoperation rates for orthognathic surgery.

Orthognathic surgery improves quality of life in terms of oral function and facial aesthetics. Our aim was to establish and compare operative time and length of inpatient stay for orthognathic procedures, and to assess the reoperation rate. Departmental electronic data base was used to identify all patients undergoing orthognathic surgery in a single unit between the 01/01/2016 and the 01/08/2018. 251 patients were identified who underwent 409 orthognathic surgery procedures. The mean operating time for a bimaxillary osteotomy (n=107) was 139.3 min. For single jaw procedures, the mean operating time for a Le Fort I osteotomy (n= 42) was 82.2 min and for a bilateral sagittal split osteotomy (BSSO) (n= 102) was 80.3min. Bimaxillary osteotomy combined with genioplasty (n=17) this increased the operating time on average by 31 min. and of a BSSO combined with a genioplasty (n=14) by 27 mins. The mean postoperative hospital stay was 1.2 ± 0.2 days. 96.4% patients spent only one postoperative night in hospital. 6/251 (2.4%) patients required re-operation. In regression analysis, age was the only significant factor in increasing length of stay (p<0.008), 95% CI 0.03-0.2). Our review shows short operating times and postoperative inpatient stays in a large cohort of patients undergoing orthognathic surgery. This is combined with a low reoperation rate. This may point to a patient benefit from high volume orthognathic centres.

Pleomorphic dermal sarcoma: a clinical and histological review of 49 cases.

Pleomorphic dermal sarcoma (PDS) is a rare mesenchymal neoplasm that shares histopathological features with atypical fibroxanthoma (AFX), but has additional features of deep invasion of the superficial subcutis, tumour necrosis, and vascular and perineural invasion, which confers a risk of local recurrence and metastases. To study the clinical and pathological spectrum more comprehensively, we retrieved 49 cases of pleomorphic dermal sarcoma from our departmental files. There was a strong male predominance (n=45). The mean (range) age at presentation was 80 (47-97) years. The tumours had a median (range) maximum dimension of 23.5 (5-75) mm. There was a strong predilection for the head and face (n=47), with the scalp (n=32) being the most common site. Ulceration was observed in 21 patients, tumour necrosis in seven, perineural infiltration in six, and lymphovascular invasion in two. CD10 was expressed in all cases. Smooth muscle actin was expressed in 15 and CD68 in 14. Follow up was available in 41 cases (mean (range) 22.4 (2-90) months). Six patients had local recurrences, despite all having originally undergone primary surgical resections and having reports of clear margins. Progressive metastatic disease was observed in one patient who died from their disease. Based on the Kaplan Meier method, median overall survival was 70.8 (8.4-133.1) months. Although AFX and PDS may be part of a spectrum, distinction is important to emphasise the potential for malignant behaviour in PDS.

Process mapping and Lean principles applied to orthognathic surgery.

Process mapping in industry is a well-established tool to improve efficiency. It is defined as a quality improvement technique that breaks down a process, or task, into its individual components, or steps, then analyses it. Lean principles are used to reduce waste and produce consistently good outcomes. Improving the operative efficiency of orthognathic surgery has many benefits. There is increasing demand for this complex surgery, and patients have appropriately high expectations with relation to their outcome. There are also increasing pressures for hospitals to reduce costs. In a recent paper by our group (Bowe et al, in press), we have published operating times for orthognathic procedures that are significantly shorter than in previously available series, with an average time for a bimaxillary osteotomy of 2 hours and 19 mins. Through observation of the senior authors' uniform technique, refined from experience of over 2,000 cases, a bimaxillary osteotomy was broken down into individual steps, all arranged in a process-mapped template with which to increase efficiency and results. We show here the multiple small operative efficiencies we have developed, and the Lean surgical principles which we use. This has enabled us to reduce the operative time of these common procedures, without compromising outcomes. This study presents an approach to process map bimaxillary orthognathic operations and shows how the application of Lean principles improves operative efficiency, and produces consistent results.

Neutrophil to lymphocyte ratio as a prognostic marker of deep neck space infections secondary to odontogenic infection.

Neutrophil to lymphocyte ratio (NLR) is a marker of infection and is used as a prognostic marker for cancer and cardiovascular disease. There is little application of NLR as a biomarker for odontogenic infection. C-reactive protein (CRP) is a commonly used marker for odontogenic infection that correlates with length of stay (LOS). The aim of this study was to assess the clinical utility of NLR as a prognostic marker of deep neck space infections secondary to odontogenic infection and to analyse its correlation with admission CRP and LOS. Data from January 2019 to December 2019 were retrospectively examined for patients admitted with a deep neck space infection of odontogenic cause. Data on admission CRP, NLR, sex, age, site of infection, LOS, treatment, ICU admission, and presence of comorbidities were analysed. A total of 161 patients were included, 89 (52.7%) of whom were male, and 72 (42.6%) female. Mean (SD) age was 38.4 (16.8) years (range: 5-86 years). Mean (SD) admission CRP and NLR were 105.9 (93.1) mg/L and 7.5 (7.7). Mean (SD) LOS was 2.9 (3.2) days (range: 0.5-35 days). Both admission CRP (p≤0.01) and admission NLR (p≤0.01). were significantly associated with LOS. Receiver operating characteristics analysis for LOS≥2 days produced an area under the curve for CRP and NLR of 0.666 and 0.639. The optimum cut-off value of NLR for LOS≥2 days was 4.65. In conclusion, NLR can be used as a prognostic marker for patients admitted with deep neck space infection secondary to odontogenic infection. Patients with NLR≥4.65 are likely to require LOS≥2 days.

Challenges and outcomes in establishing a sentinel lymph node biopsy service for oral squamous cell carcinoma in a regional district specialist hospital.

UK national guidelines in 2016 recommended that sentinel lymph node biopsy (SLNB) should be offered to patients with early oral squamous cell carcinoma (OSCC). We review the establishment of an OSCC SLNB service with specific consideration to resources, service implications and patient outcomes. A review of processes was performed to identify key stages in establishing the service, and subsequently a retrospective cohort study consisting of 46 consecutive patients with T1/T2 N0 OSCC was undertaken. The key stages identified were: coordinating a nuclear medicine pathway and reliable cost-appropriate pathology service, constructing a Trust business case, and gaining approval of a new interventional service policy. A median (range) of 3.3 (1-8) sentinel nodes (SLN) were removed, with 17 patients having a positive SLN. The negative predictive value of SLNB was 100%, with 12 having a SLN outside the field if elective neck dissection (END) was planned. There was a significantly increased risk of a positive SLN with increasing depth of invasion (DOI) (p=0.007) and increased diameter (p=0.036). We also identified a longer-than-ideal time to completion neck dissection and inadequate ultrasound follow up of negative SLNB patients. Establishment of a service requires careful planning. Our results were in keeping with those reported in the literature, and showed that SLNB for OSCC has a high negative predictive value and can identify at-risk SLN outside the traditional END levels, even in well-lateralised tumours. Our findings show that DOI and size of SLN were significantly associated with a positive SLN, and also identified areas requiring improvement.

Comparison of the eighth edition of the TNM and Brigham Women's Hospital staging systems for cutaneous squamous cell carcinoma of the head and neck: a six-year review.

This study was undertaken with the aim to compare the T stages in a series of cutaneous squamous cell carcinoma (cSCC) patients using both the eighth edition of the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours (TNM8) and Brigham and Women's Hospital (BWH) staging systems. This would allow comparison of the two to determine suitability with regards to T stage and the effect on local recurrence and nodal disease. This was a six-year retrospective cohort study of patients with primary invasive cSCC of the head and neck who were diagnosed and treated at Western Sussex Hospitals Trust in the United Kingdom between 2007 and 2012. The TNM8 and BWH staging systems were applied to these primary cSCCs. A total of 695 invasive cSCCs treated in 604 patients over six years were identified. Most patients were male (76%), with a mean (range) age of 81 (50-103) years. The most common location for local recurrence was the scalp (n=26, 58%). Regional metastasis occurred most commonly in the parotid gland (n=20, 63%). All tumours were classified using both staging systems. Specifically, 432 tumours remained in the same T stage (61%), and 192 were downstaged (27%) and 71 upstaged using the BWH (10%). The median (SD) follow-up time was 23 (28) months (range 1-123). The BWH alternative staging system overlapped with the TNM8 in high-stage and low-stage tumour assignment. The highest percentage of local recurrence and regional metastasis occurred in T2b tumours.

Management of regional metastatic disease in cutaneous malignancy of the head and neck. 3. Merkel cell carcinoma.

This is the third of three articles that give an overview of the current evidence for management of the neck and parotid in patients with cutaneous cancers of the head and neck. In this paper we discuss Merkel cell carcinoma (MCC) and review the latest evidence for management of the regional nodes.

Presynaptic congenital myasthenic syndrome due to quantal release deficiency.

OBJECTIVE: To provide clinical, electrophysiologic, and ultrastructural findings in three patients with a presynaptic congenital myasthenic syndrome (CMS). BACKGROUND: Familial infantile myasthenia and paucity of synaptic vesicles are the only two fully characterized CMS. We are describing here three patients with another form of presynaptic CMS characterized by deficiency of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter from the nerve terminal. METHODS: The authors performed electromyography and anconeus muscle biopsies that included intracellular recordings and electron microscopy of the neuromuscular junction in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium alpha(1)-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. RESULTS: In these patients there were additional neurologic findings including nystagmus and ataxia. In all three patients the end-plate potential quantal content (m) was markedly reduced but neither the amplitudes nor the frequencies of miniature end-plate potentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-membrane-bound sacs containing synaptic vesicles were present in the nerve terminal of all three patients. The screening of reported pathogenic mutations in the CACNA1A and a mutational analysis of AChR subunit genes were negative. CONCLUSION: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal calcium mechanism or impaired endocytosis and recycling of synaptic vesicles.

D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?

D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.

Functional properties and nodal spacing of myelinated fibers in developing rat mental and sural nerves.

While the postnatal length growth of the largest internodes in the rat sural nerve (SN) is proportional to nerve elongation, in the developing inferior alveolar nerve (IAN), early postnatal myelin sheath remodelling allows internodal lengthening to exceed the growth rate of the whole nerve. To assess the functional consequences of ongoing myelin sheath remodelling in a developing nerve, we examined the physiological properties of the mental nerve (MN), a cutaneous IAN branch and the SN during maturation. In addition, the nodal spacing and the microscopic anatomy of the nodes in the two nerves were studied. The youngest MNs and SNs (2 weeks) exhibited comparable sensitivities to K(+)-channel blockade with 4-aminopyridine (4-AP), although myelin sheath remodelling was more frequent in the MNs. Subsequently, myelin sheath remodelling ceased in both nerves but the MNs exhibited a greater sensitivity to 4-AP. Large fibers in adult MNs and SNs had a similar nodal anatomy but the former had shorter internodes. Thus, myelin sheath remodeling, per se, does not appear to be a determinant of 4-AP sensitivity in mammalian myelinated fibers. Rather, sensitivity to potassium channel blockade is more likely mediated at the internodal or molecular level.

Delayed depolarization and slow sodium currents in cutaneous afferents.

1. Intraaxonal recordings were obtained in vitro from the sural nerve (SN), the muscle branch of the anterior tibial nerve (ATN), or the deafferented ATN (dATN) in 5- to 7-wk-old rats. Whole-nerve sucrose gap recordings were obtained from the SN and the ATN. This allowed study of cutaneous (SN), mixed motor and muscle afferent (ATN), and isolated muscle afferent (dATN) axons. 2. Application of the potassium channel blocking agent 4-aminopyridine (4-AP) to ATN or dATN resulted in a slight prolongation of the action potential. In contrast, a distinct delayed depolarization followed the axonal action potential in cutaneous afferents (SN) exposed to 4-AP. The delayed depolarization could be induced by a single whole-nerve stimulus or by injection of constant-current depolarizing pulses into individual axons. The delayed depolarization often gave rise to bursts of action potentials and was followed by a prominent afterhyperpolarization (AHP). 3. In paired-pulse experiments on single SN axons, the recovery time (half-amplitude of the action potential) was 3.06 +/- 1.82 (SE) ms (n = 12). After exposure to 4-AP the recovery time of the delayed depolarization was considerably longer (half-recovery time: 99.0 +/- 28.3 ms; n = 15) than that of the action potential (18.8 +/- 9.1 ms; n = 16). 4. Application of tetraethylammonium (TEA) to cutaneous or muscle afferents alone had little effect on single action potential waveform. However, TEA reduced the amplitude of the AHP elicited by a single stimulus in cutaneous afferent axons after exposure to 4-AP and resulted in repetitive spike discharge. 5. The delayed depolarization and spike burst activity induced by 4-AP in SN was present in Ca(2+)-free solutions containing 1 mM ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and was not blocked by Cd2+ (1.0 mM). 6. We obtained whole-cell patch-clamp recordings to study Na+ currents from either randomly selected dorsal root ganglion neurons or cutaneous afferent neurons identified by retrograde labeling with Fluoro-Gold. The majority of the randomly selected neurons had a singular kinetically fast Na+ current. In contrast, no identified cutaneous afferent neurons had a singular fast Na+ current. Rather, they had a combination of kinetically separable fast and slow currents or a singular relatively slow Na+ current.(ABSTRACT TRUNCATED AT 400 WORDS)

Different effects of 4-aminopyridine on regenerated cutaneous and muscular rat sciatic nerve branches.

Developing and regenerated myelinated rat dorsal and ventral root fibers respond differently to the fast potassium channel blocking agent 4-aminopyridine (4-AP). To pursue this issue further, we made unilateral sciatic nerve crushes in adult rats. Sural (SN) and lateral gastrocnemius (LGN) nerve branches were collected 4-6 months later, for physiological and morphological examination. Regenerated and control nerves in Ringers solution showed generally similar compound action potential (CAP) waveforms, but CAPs of regenerated SNs and LGNs in 4-AP were markedly different. While regenerated SNs showed a prominent late CAP negativity with a "rippled" appearance and markedly compromised recovery properties, the CAP and recovery properties of regenerated LGNs were minimally changed. Light and electron microscopic examination of SN and LGN fibers failed to reveal any features obviously related to the observed physiological differences. We conclude, that the effect of 4-AP on regenerated cutaneous afferents differs from its action on regenerated muscular afferents and efferents. This physiological diversity lacks obvious structural correlates.

Gastrointestinal hemorrhage associated with gastric polyps in Menkes disease.

We describe two infants with Menkes disease who had serious gastrointestinal bleeding from solitary gastric polyps. Hemorrhage in one patient was acute and proved fatal. Histopathologic examinations showed submucosal vascular ectasia with mucosal hyperplasia, edema, and ulceration. Gastric polyps may represent an underappreciated clinical abnormality in Menkes disease.