Nasal turbinate mucosal graft for management of contracted anophthalmic socket.

A 67-year-old Caucasian male presented with severe contraction of socket lining 8 years after enucleation, dermis fat graft and successful ocular prosthesis fitting. Following two failed attempts at using amniotic membrane grafts to reform the socket lining, a total socket reconstruction was attempted using a novel nasal turbinate mucosal graft technique. This was performed in a staged fashion with lower fornix reconstruction followed by upper fornix reconstruction 3 months later. The patient was stable at 12 months review, with a satisfactory cosmetic outcome. Nasal turbinate mucosa was used as it was surgically accessible, provided natural socket lubrication due to its mucosal surface, and avoided oral mucosa and its associated morbidity. This case report suggests that nasal turbinate mucosa is a suitable autologous grafting material for total socket reconstruction in contracted anophthalmic sockets.

Validation of the 8th edition UICC/AJCC TNM staging system for HPV associated oropharyngeal cancer patients managed with contemporary chemo-radiotherapy.

BACKGROUND: To compare outcomes of high-risk human papilloma virus-related oropharyngeal squamous cell carcinoma (HPV OPSCC) treated with modern radiation treatment (RT) and daily image-guidance, staged with the 7th versus the 8th Edition (Ed) Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) TNM staging systems. METHODS: All eligible patients with HPV OPSCC treated definitively over a 10-year period (2007-2016) at a single institution were included. Protocols consisting of either RT or chemo-radiation (CRT) (weekly cisplatin or cetuximab) +/- neoadjuvant chemotherapy for those with bulky disease were used. All patients were Fluorine-18-deoxyglucose positron emission tomography (FDG-PET) staged at baseline and at intervals for up to 2 years post-treatment. Patients received parotid-sparing intensity modulated or volumetric modulated arc therapy with simultaneous integrated boost to either 70Gy in 35 fractions or 66Gy in 30 fractions. The overall survival (OS) was determined for each stage using the 7th Ed and subsequently with the updated 8th Ed staging system. RESULTS: One hundred fifty-three patients were analysed. Patient stage groupings varied between the 7th and 8th Eds respectively; Stage I (0.7% vs 64.7%), Stage II (8.5% vs 22.2%), stage III (21.6% vs 12.4%) and stage IV (69.3% vs 0.7%). In the 7th Ed, the 5 year probability of OS for stages I to III was 90%, versus stage IV 85.5%. There was no statistically significant difference between the staging groups (p = 0.85). In the 8th Ed there was a statistically significant difference in 5 year OS for stage I and stage II disease (96.9% vs 77.1% respectively; p < 0.0001), but not between stage II and III disease (p = 0.98). CONCLUSIONS: The new 8th Ed UICC/AJCC TNM staging system better discriminates between stage I and Stage II HPV OPSCC with respect to OS compared with the 7th Ed staging system. Further investigation is required for stage III or IV patients.

Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.

Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn(2+)]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn(2+) was blocked by ATP13A2 overexpression, Zn(2+) chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.

Systemic inflammation is an independent predictive marker of clinical outcomes in mucosal squamous cell carcinoma of the head and neck in oropharyngeal and non-oropharyngeal patients.

BACKGROUND: Currently there are very few biomarkers to identify head and neck squamous cell carcinoma (HNSCC) cancer patients at a greater risk of recurrence and shortened survival. This study aimed to investigate whether a marker of systemic inflammation, the neutrophil-to-lymphocyte ratio (NLR), was predictive of clinical outcomes in a heterogeneous cohort of HNSCC cancer patients. METHODS: We performed a retrospective analysis to identify associations between NLR and clinicopathological features to recurrence free survival (RFS) and overall survival (OS). Univariate analysis was used to identify associations and selected variables were included in multivariable Cox regression analysis to determine predictive value. RESULTS: A total of 145 patients with stage I-IV HNSCC that had undergone radiotherapy were analysed. Seventy-six of these patients had oropharyngeal cancer and 69 had non-oropharyngeal HNSCC and these populations were analysed separately. NLR was not associated to any clinicopathological variable. On univariate analysis, NLR showed associations with RFS and OS in both sub-populations. Multivariable analysis showed patients with NLR > 5 had shortened OS in both sub-populations but NLR > 5 only predicted RFS in oropharyngeal patients. Poor performance status predicted OS in both sub-populations and current smokers had shortened OS and RFS in non-oropharyngeal patients. CONCLUSIONS: The results show patients with NLR > 5 predict for shorter overall survival. Further prospective validation studies in larger cohorts are required to determine the clinical applicability of NLR for prognostication in HNSCC patients.

Functional swallowing outcomes in nasopharyngeal cancer treated with IMRT at 6 to 42 months post-radiotherapy.

We sought to evaluate the swallowing function of 18 patients surviving nasopharyngeal cancer, who had been treated using an intensity-modulated radiotherapy (IMRT) protocol designed to minimise functional impairment. We compared the outcomes of a patient-reported oral function score with fiberoptic endoscopic examination of swallow (FEES), Australian Therapy Outcome Measures (AusTOMs) and a measure of trismus. While all patients returned to a fully oral diet, there was ongoing swallow dysfunction characterised by bolus residue and delay, but no aspiration. Dysphagia was of mild or moderate severity on all measures, generally because of the need for texture modification, impaired bolus transit or dysgeusia. There was xerostomia on self-reported measurement combined with reports of behaviours adaptive to xerostomia on AusTOMs; however, salivary functioning was less impaired on FEES. There was no trismus in this cohort. Our cohort lacked the morbidity experienced by cohorts reported in earlier studies, potentially due to the use of IMRT.

Transoral robotic-assisted free flap reconstruction after radiation therapy in hypopharyngeal carcinoma: report of two cases.

The objective was to assess the feasibility and safety of transoral robotic surgery (TORS)-assisted free flap reconstruction for hypopharyngeal carcinoma after radiation therapy. The study evaluated the feasibility, surgical margins, the need for a tracheotomy, a nasogastric tube as well as surgery-related complications. Two patients underwent TORS-assisted free flap reconstruction after radiation therapy. The resection margins were free of tumor in both patients. A tracheotomy was performed in one patient who had been decannulated on the sixth postoperative day. One patient resumed satisfactory oral feeding in the fourth postoperative month and the second patient on postoperative day 7. No intraoperative complication and one postoperative complication (neck hematoma) were reported. After a follow-up period of 24 and 30 months, no local recurrence was observed. TORS is feasible for hypopharyngeal resection and assisted free flap reconstruction after radiation therapy. It represents a further step in the development of minimally invasive surgery for the treatment of head and neck cancers with laryngeal preservation.

SDH deficiency is very common in carotid body paragangliomas: Genetic counseling and testing should be offered to all patients.

BACKGROUND: Collectively, germline pathogenic variants in succinate dehydrogenase (SDH) genes are the most common cause of hereditary paragangliomas. Loss of immunohistochemical expression of SDHB protein (termed SDH deficiency) occurs whenever there is biallelic inactivation of any SDH gene. We sought to estimate the prevalence of SDH deficiency in patients with carotid body paragangliomas. METHODS: We identified all carotid body paragangliomas that had undergone surgical excision at our institution over the last 30 years. If SDHB immunohistochemistry was not performed at the time of excision, it was performed on archived material. RESULTS: There were 64 carotid body paragangliomas identified in the 62 patients. Two-thirds of the patients were female, and 43 (67%) were SDH-deficient. CONCLUSION: Up to two-thirds of all carotid body paragangliomas are associated with SDH deficiency. Therefore, genetic testing and counseling should be offered to all patients with carotid body paragangliomas, regardless of age or family history.

Reference rate for post-tonsillectomy haemorrhage in Australia-A 2000-2020 national hospital morbidity database analysis.

This study aims to provide a national benchmark rate of post-tonsillectomy haemorrhage (PTH) in Australia. Using data from Australia's National Hospital Morbidity Database (NHMD) from 1 July 2000 to 30 June 2020, we have conducted a nation-wide population-based study to estimate a reference rate of PTH. Outcomes of interest included the overall rate and time-trend of PTH, the relationship between PTH rates with age and gender as well as the epidemiology of tonsillectomy procedures. A total of 941,557 tonsillectomy procedures and 15,391 PTH episodes were recorded for the study period. Whilst the incidence of tonsillectomy procedures and the number of day-stay tonsillectomy procedures have increased substantially over time, the overall rate of PTH for all ages has remained relatively constant (1.6% [95% CI: 1.61 to 1.66]) with no significant association observed between the annual rates of PTH and time (year) (Spearman correlation coefficient, Rs = 0.24 (95% CI: -0.22 to 0.61), P = 0.3). However, the rate of PTH in adults (aged 15 years and over) experienced a statistically significant mild to moderate upward association with time (year) Rs = 0.64 (95% CI: 0.28 to 0.84), P = 0.003. Analysis of the odds of PTH using the risk factors of increasing age and male gender showed a unique age and gender risk pattern for PTH where males aged 20 to 24 years had the highest risk of PTH odds ratio 7.3 (95% CI: 6.7 to 7.8) compared to patients aged 1 to 4 years. Clinicians should be mindful of the greater risk of PTH in male adolescents and young adults. The NHMD datasets can be continually used to evaluate the benchmark PTH rate in Australia and to facilitate tonsillectomy surgical audit activities and quality improvement programs on a national basis.

The Indoor Environment and Otitis Media among Australian Children: A National Cross-Sectional Study.

The association between the indoor environment and lifetime prevalence of otitis media (OM) in Australian children was assessed. We analysed data from a cross-sectional study of children, aged 7-11 years, performed in twelve Australian cities during 2007-2008. The main outcome was a parental report of their child's diagnosis with OM by a doctor. Information on the indoor environment (energy sources used for heating, cooling, and cooking, pets, and second-hand smoke exposure), in the first year of life and at present, was collected from parents by a questionnaire. Multi-level logistic regression models were used to adjust for individual- and area-level confounders. Our analysis comprised 2872 children (51% female, mean age: 10.0 (SD 1.2)). Of those, 1097 (39%) were reported to have OM. Exposure to gas heating in the first year of life was significantly associated with higher odds of OM in adjusted models (OR:1.22; 95% CI: 1.00,1.47), as was current exposure to reverse-cycle air conditioning (OR: 1.52, 95% CI: 1.27,1.82). Ownership of a cat or dog at any time was also associated with high odds of OM (OR: 1.50; 95% CI: 1.17,1.92). No other significant associations were observed. In this national study of Australian children, indoor environmental exposures associated with the lifetime prevalence of OM were gas heating, reverse-cycle air conditioning and pet ownership. Exposures in both early life and later childhood may both play a role in OM.

Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism.

Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS.

Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.

Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, an important regulator of peroxisome biogenesis. Using whole genome sequencing, we detected previously unreported, biallelic variants in PEX16 [NM_004813.2:c.658G>A, p.(Ala220Thr) and NM_004813.2:c.830G>A, p.(Arg277Gln)] in an individual with leukodystrophy, spastic paraplegia, cerebellar ataxia, and craniocervical dystonia with normal plasma very long chain fatty acids. Using olfactory-neurosphere derived cells, a population of neural stem cells, we showed patient cells had reduced peroxisome density and increased peroxisome size, replicating previously reported findings in PEX16 cell lines. Along with alterations in peroxisome morphology, patient cells also had impaired peroxisome function with reduced catalase activity. Furthermore, patient cells had reduced oxidative stress levels after exposure to hydrogen-peroxide (H2O2), which may be a result of compensation by H2O2 metabolising enzymes other than catalase to preserve peroxisome-related cell functions. Our findings of impaired catalase activity and altered oxidative stress response are novel. Our study expands the phenotype of PEX16 mutations by including dystonia and provides further insights into the pathological mechanisms underlying PEX16-associated disorders. Additional studies of the full spectrum of peroxisomal dysfunction could improve our understanding of the mechanism underlying PEX16-associated disorders.

Tumour thickness as a determinant of nodal metastasis in oral tongue carcinoma.

BACKGROUND: Tumour thickness is a strong predictor for cervical node involvement in oral cavity squamous cell carcinomas (SCCs), with a recent meta-analysis concluding a 4-mm optimal prognostic cut-off point. No consensus has been reached for the tumour thickness cut-off for oral tongue SCCs. METHODS: A retrospective review of prospectively collected data from 112 patients by the Northern Sydney Cancer Centre (Australia) with primary oral tongue SCC was conducted. Tumour thickness was measured by standard histopathological techniques and cervical node involvement was determined either from neck dissection histopathology or by clinical and radiological follow-up. RESULTS: Neck dissection was performed in 78 patients (70%). Tumour thickness was a significant predictor of cervical node disease (P < 0.01), with a median tumour thickness of 5.5 mm. Cervical node metastasis rates for tumours <2, 2-3.9 and ≥4 mm thick were 10%, 42.1% and 46.5%, respectively. The rate of cervical node metastasis was significantly higher for patients with tumours thicker than a cut-off of 2 mm (odds ratio: 7.53, P < 0.01). A 4-mm thickness cut-off was also statistically significant (P < 0.05); however, the odds ratio was smaller at 2.52. CONCLUSION: Despite some previous evidence for a 4-mm tumour thickness cut-off in oral tongue SCCs, thinner tumours (2-3.9 mm) can also have a propensity for cervical node metastasis. Patients in this category require close monitoring for regional recurrence if they do not have a neck dissection.

Atypical Pharyngeal Pouch Arising Bilaterally between the Hyoid Bone and Thyroid Cartilage.

Introduction. Pharyngoesophageal diverticuli are a common cause of dysphagia; they are associated with various morbidities and a decreased quality of life. There are several different types of the diverticuli, and they are divided based on the anatomical location of origin relative to the cricopharyngeal muscle; these include Zenker's, Killian-Jamieson's, and Laimer's diverticula. The authors present a unique case of pharyngoesophageal diverticulum that has not been previously described. Case Presentation. A 65-year-old male presented with a 12-month history of dysphagia and odynophagia for solids. Barium swallow revealed bilateral moderately sized diverticuli that altered in size during the different phases of swallow. CT scan of the neck with oral contrast further identified the anatomy of the diverticuli, arising between the hyoid bone and thyroid cartilage. Discussion. An external transcervical approach was utilised to successfully repair the diverticuli. Subsequent cricopharyngeal spasm was treated with botulinum toxin, and the patient recovered with no ongoing symptoms. The barium swallow study is a commonly utilised initial investigation as it is easy to perform and safe and has good diagnostic value. Definitive management usually involves either endoscopic or open surgery. This case depicts a unique case of a pharyngeal diverticulum arising between the hyoid bone and thyroid cartilage.

Simultaneous branchial cleft and thyroid disorders may present a management challenge.

BACKGROUND: Cysts, sinuses or abscesses arising from second, third or fourth branchial cleft remnants may lie either within the body of, or in close proximity to the thyroid gland. Given their infrequent nature they may pose both diagnostic and management challenges for the treating surgeon when they occur in association with thyroid disorders. METHODS: This is a case series. All patients with concomitant thyroid disorders and a branchial cleft anomaly treated in the University of Sydney Endocrine Surgical Unit in the 10-year period 1994-2003 comprised the study group. Patient demographics, clinical presentation, imaging, surgical management, definitive histology and outcomes were documented. RESULTS: Six patients were identified with an age range of 3-76 years and a male : female ratio of 1:5. Five branchial cleft anomalies were left sided, one was right sided. Two patients had second cleft anomalies, both of which were initially thought to represent metastatic lymph nodes in association with thyroid cancer. A further two patients had third cleft abnormalities presenting as suppurative thyroiditis. The final two patients had fourth cleft abnormalities causing intraoperative management problems. CONCLUSIONS: Branchial cleft remnants and anomalies are rare but may occur in association with thyroid disease. They may pose a diagnostic and management dilemma either preoperatively, when mistaken for metastatic thyroid cancer, or intraoperatively when mistaken for a thyroid nodule.

Analysis of local recurrence in patients with selected T1-3N0M0 squamous cell carcinoma of the true vocal cord managed with a platinum-based chemotherapy-alone regimen for cure.

Based on an inception cohort of 35 patients with T1-3N0M0 squamous cell carcinoma of the true vocal cord who had a complete clinical response after a platinum-based induction chemotherapy regimen and a minimum of 3 years of follow-up, the current retrospective study documented the long-term results and consequences of local recurrence following the use of a platinum-based chemotherapy-alone regimen for cure. During the years 1985 to 1996, 231 patients with invasive squamous cell carcinoma of the true vocal cord classified as T1-3N0M0 were managed at our department with a platinum-based induction chemotherapy regimen. A complete clinical response was achieved in 77 patients. Thirty-five of the 77 patients with complete clinical response were managed at our institution with a platinum-based chemotherapy-alone regimen. The statistical analysis of data on survival, local control, nodal control, distant metastasis, and metachronous second primary tumor incidence was based on the Kaplan-Meier product limit method. Univariate analysis was performed for potential statistical relation between local recurrence and various variables. The 3- and 5-year actuarial survival estimates were 91.4% and 88.6%, respectively. Overall, the causes of death were intercurrent disease in 6 patients and metachronous second primary tumor in 4 patients. The 3- and 5-year actuarial local control estimate was 64.8%. No significant statistical relation could be demonstrated between the incidence for local recurrence and the variables under analysis. Salvage treatment in patients with local recurrence yielded a 100% local control rate and laryngeal preservation rate. The 3- and 5-year actuarial lymph node control estimate was 97.1%. The 3- and 5-year actuarial estimate for patients with distant metastasis was 0%. The 5- and 10-year actuarial estimates for patients with metachronous second primary tumor were 9.7% and 28.1%, respectively. Although local recurrence was noted in almost a third of patients with complete clinical response who were managed with a platinum-based chemotherapy-alone regimen, it did not appear to be detrimental, as none of the patients who had local recurrence ultimately died from their disease or lost their larynx.

Fine-needle aspiration cytology in the management of salivary gland tumors: an Australian experience.

We conducted a retrospective study of 104 cases of salivary gland tumors that were initially assessed by fine-needle aspiration biopsy (FNAB). Based on subsequent histopathologic analysis of excised specimens, we found that preoperative FNAB was highly sensitive and specific for both benign and malignant tumors-including the most common, pleomorphic adenomas and squamous cell carcinomas, respectively. Despite its possible drawbacks, we conclude that preoperative FNAB is a useful tool in the management of salivary gland tumors.

[Supracricoid laryngectomy with cricohyoidoepiglotopexy (CHEP). Preliminary report of the National Institute of Cancer]. / Laringectomía supracricoidea con cricohioidoepiglotopexia (CHEP). Reporte preliminar del Instituto Nacional de Cancerología.

OBJECTIVE: To present the preliminary results in our institute with supracricoid laryngectomy with cricohyoidoepiglotopexy (CHEP), as well as to evaluate possible short-term complications. METHODS: This study included eight patients with diagnosis of squamous cell carcinoma of the larynx glottic region (three patients were in stage I, two in II and three in III). Histologic grade was well differentiated in three patients, moderately differentiated in four and poorly differentiated in one. RESULTS: Supracricoid laryngectomy with cricohyoidoepiglotopexy were performed in all cases, and bilateral elective functional neck dissection was done in 6 patients. Both cricoarytenoid units were preserved in 6 patients and only one in the other two cases. Mean time of hospitalization was 11 days. Mean time of decanulation was 12 days for the whole group; however, in those patients that preserved both cricoarytenoid units, the mean time of decanulation was 6 days, and in those that preserved one cricoarytenoid unit it was 31 days. Physiologic phonation was achieved in all patients at the moment of decanulation. Mean time for remotion of nasogastric sonde was 25 days, and it was 17 days for those who preserved both cricoarytenoid units and for patients with one cricoarytenoid unit it was 46 days. CONCLUSIONS: Supracricoid laryngectomy with cricohyoidoepiglotopexy allows to preserve the basic functions of the larynx (respiration, degluttion and phonation), as well as the reintegration of affected patients to social life. All patients must be evaluated carefully in order avoid changing the stage or the surgical plan due to substadification of the tumor.

Intracranial and internal jugular vein thrombosis secondary to ENT infections: a report of 3 cases.

We report 3 cases of rare, life-threatening intracranial and internal jugular vein (IJV) thrombosis that were caused by common ENT infections. These infections included otitis media in a 6-year-old girl, tonsillitis in a 21-year-old woman, and odontogenic sepsis in a 56-year-old woman. All 3 patients were treated with culture-directed systemic antibiotics; 2 of them also required surgical drainage (the child and the older adult). The 2 adults also received therapeutic anticoagulation, which was continued until venous recanalization was documented; the duration of combined antibiotic and anticoagulation treatment was 6 weeks. All 3 patients made uneventful recoveries. Significant morbidities associated with intracranial and IJV thrombosis were avoided as a result of prompt diagnosis and judicious treatment.

Intensity-modulated radiotherapy using simultaneous-integrated boost for definitive treatment of locally advanced mucosal head and neck cancer: outcomes from a single-institution series.

INTRODUCTION: The study aims to report outcomes for patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous-integrated boost and weekly cisplatin for American Joint Committee on Cancer stage III/IV mucosal head and neck squamous cell carcinomas (HNSCCs). METHODS: Records for 67 patients treated definitively with IMRT for HNSCC were reviewed. By including only those treated with weekly cisplatin, 45 patients were eligible for analysis. Treatment outcomes, effect of patient, tumour and treatment characteristics on disease recurrence were analysed. RESULTS: All patients completed IMRT to 7000 cGy in 35 fractions, with concurrent weekly cisplatin 40 mg/m(2) (median 6 cycles). Median follow-up was 28 months for living patients. Two-year loco-regional recurrence-free, metastasis-free and overall survival were 85.4, 81.0 and 87.4%, respectively. Local recurrence occurred in three patients, and distant recurrence in eight patients. CONCLUSIONS: Our results show efficacy of IMRT and weekly cisplatin in the treatment of stage III/IV HNSCC at our institution with respect to loco-regional control.

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations.

Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.