Treatment outcomes of standard (high dose) cisplatin and non-standard chemotherapy for locally advanced head and neck cancer.

INTRODUCTION: Concurrent chemoradiotherapy with high-dose (HD) cisplatin is the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Due to the higher treatment-related adverse effects with standard therapy, alternative regimens (non-standard therapy), namely, lower dose weekly cisplatin, carboplatin/paclitaxel, or cetuximab are considered. There is, however, no consensus on non-standard regimens. We aimed to investigate the efficacy and safety profile of these regimens. METHODS: This single centre retrospective cohort study included all consecutive adult patients with newly diagnosed LA-HNSCC treated with either standard or non-standard regimens between January 2016 and April 2021. The primary outcome was 2-year failure-free survival (FFS). The secondary outcomes included acute toxicities, hospitalisation rates, dose modifications, treatment failure rates (TFR), and overall survival. RESULTS: About 235 patients were included in the final analysis; median age was 61 years (IQR 55-67), and 87% were male. Most had oropharyngeal tumours (85.5%) and p16-positivity was frequent (80%). About 56% received non-standard regimens: weekly cisplatin = 79 and non-cisplatin = 48. These patients had higher Charlson Comorbidity Index (CCI; p < .001) and lower European Cooperative Oncology Group (ECOG)-0 (p = .003). There was no difference in 2-year FFS (hazard ratio [HR] = 1.16; 95% confidence interval - [CI] 0.65-2.05), hospitalisation and grade-3 toxicity rates between the two regimens. Nausea and vomiting were lower in the non-standard regimen (3.0% vs. 16%, p < .001). Dose reductions, adjusted for age, sex, and CCI, were less likely in the non-standard regimen (OR = 2.36; 95%-CI: 1.01-5.49, p = .007). CONCLUSIONS: We demonstrated similar efficacy of lower dose weekly cisplatin and carboplatin/paclitaxel regimens and better safety profile of weekly cisplatin compared to standard HD cisplatin regimens for LA-HNSCC. Multicenter randomised control trials are required in HD cisplatin-ineligible patients.

How 3D Printing Is Reshaping Translational Research.

"Translational Research" has traditionally been defined as taking basic scientific findings and developing new diagnostic tools, drugs, devices and treatment options for patients, that are translated into practice, reach the people and populations for whom they are intended and are implemented correctly. The implication is of a unidirectional flow from "the bench to bedside". The rapidly emergent field of additive manufacturing (3D printing) is contributing to a major shift in translational medical research. This includes the concept of bidirectional or reverse translation, early collaboration between clinicians, bio-engineers and basic scientists, and an increasingly entrepreneurial mindset. This coincides with, and is strongly complemented by, the rise of systems biology. The rapid pace at which this type of translational research can occur brings a variety of potential pitfalls and ethical concerns. Regulation surrounding implantable medical devices is struggling to keep up. 3D printing has opened the way for personalization which can make clinical outcomes hard to assess and risks putting the individual before the community. In some instances, novelty and hype has led to loss of transparency of outcomes with dire consequence. Collaboration with commercial partners has potential for conflict of interest. Nevertheless, 3D printing has dramatically changed the landscape of translational research. With early recognition and management of the potential risks, the benefits of reshaping the approach to translational research are enormous. This impact will extend into many other areas of biomedical research, re-establishing that science is more than a body of research. It is a way of thinking.

An Emergence Framework of Carcinogenesis.

Experimental paradigms provide the framework for the understanding of cancer, and drive research and treatment, but are rarely considered by clinicians. The somatic mutation theory (SMT), in which cancer is considered a genetic disease, has been the predominant traditional model of cancer for over 50 years. More recently, alternative theories have been proposed, such as tissue organization field theory (TOFT), evolutionary models, and inflammatory models. Key concepts within the various models have led to them being difficult to reconcile. Progressively, it has been recognized that biological systems cannot be fully explained by the physicochemical properties of their constituent parts. There is an increasing call for a 'systems' approach. Incorporating the concepts of 'emergence', 'systems', 'thermodynamics', and 'chaos', a single integrated framework for carcinogenesis has been developed, enabling existing theories to become compatible as alternative mechanisms, facilitating the integration of bioinformatics and providing a structure in which translational research can flow from both 'benchtop to bedside' and 'bedside to benchtop'. In this review, a basic understanding of the key concepts of 'emergence', 'systems', 'system levels', 'complexity', 'thermodynamics', 'entropy', 'chaos', and 'fractals' is provided. Non-linear mathematical equations are included where possible to demonstrate compatibility with bioinformatics. Twelve principles that define the 'emergence framework of carcinogenesis' are developed, with principles 1-10 encapsulating the key concepts upon which the framework is built and their application to carcinogenesis. Principle 11 relates the framework to cancer progression. Principle 12 relates to the application of the framework to translational research. The 'emergence framework of carcinogenesis' collates current paradigms, concepts, and evidence around carcinogenesis into a single framework that incorporates previously incompatible viewpoints and ideas. Any researcher, scientist, or clinician involved in research, treatment, or prevention of cancer can employ this framework.

Utility of SUVmax on 18 F-FDG PET in detecting cervical nodal metastases.

BACKGROUND: The presence of cervical lymph node metastasis is an important prognostic factor for patients with head and neck squamous cell carcinomas (HNSCC). Accurate assessment of lymph node metastasis in these patients is essential for appropriate prognostic and management purposes. Here, we evaluated the effectiveness of the maximum standardized uptake value (SUVmax) on positron emission tomography (PET) in assessing lymph node metastasis in HNSCC prior to surgery. METHODS: A retrospective review of 74 patients with HNSCC who underwent PET/CT prior to neck dissection were examined. Pre-operative PET/CT scans were reviewed by two experienced nuclear medicine physicians and SUVmax of the largest node in each nodal basin documented. These were compared with the histology results of the neck dissection. RESULTS: A total of 359 nodal basins including 86 basins with metastatic nodes were evaluated. A nodal SUVmax ≥3.16 yielded a sensitivity of 74.4 % and specificity of 84.9 % in detecting metastatic nodes. The nodal SUVmax/Liver SUVmax ratio was found on receiver operating characteristic (ROC) to be effective in detecting metastatic nodes with an area under ROC curve of 0.90. A nodal SUVmax/Liver SUVmax ratio ≥0.90 yielded a sensitivity of 74.1 % and specificity of 93.4 %. By comparison, visual inspection yielded sensitivities of 66.3 and 61.6 % in observers 1 and 2 respectively. The corresponding specificities were 77.7 and 86.5 %. CONCLUSIONS: Nodal SUVmax and nodal SUVmax/liver SUVmax are both useful in the pre-operative detection of metastatic nodes with the latter being superior to visual inspection. The ratio is likely to be more useful as it corrects for inter-scanner variability.

Surgical margins in head and neck squamous cell carcinoma: Effect of heat artifact on immunohistochemistry as a future tool for assessment.

BACKGROUND: Margins in head and neck squamous cell carcinoma (HNSCC) are determined by morphological changes assessed via hematoxylin-eosin staining. Physiological changes may not be detected by this technique. The purpose of this study was to determine if a protein biomarker, laminin-332γ2, overexpressed in cancer cells at the invasive front in HNSCC, remains unaffected by heat produced during resection, supporting a role for immunohistochemistry assessment of margins. METHODS: Archived tissue blocks from glottic squamous cell carcinomas (SCCs) resected by CO2 laser likely to contain both cancer cells and artifact were identified; 129-paired slides were obtained. One slide of each pair was stained with hematoxylin-eosin; the second stained for laminin-332γ2. The presence of cancer cells, artifact, and positive laminin-332γ2 staining was recorded. Twenty-seven pairs met the inclusion criteria. RESULTS: Immunohistochemistry staining of laminin-332γ is preserved in presence of heat artifact. CONCLUSION: This study supports use of immunohistochemistry to assess margins. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1401-1406, 2016.

Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.

Quantitative methodology is critical for assessing DNA methylation and impacts on correlation with patient outcome.

BACKGROUND: DNA hypermethylation is reported as a frequent event and prognostic marker in head and neck squamous cell carcinomas (HNSCC). Methylation has been commonly assessed with non-quantitative methodologies, such as methylation-specific PCR (MSP). We investigated previously reported hypermethylated genes with quantitative methodology in oral tongue squamous cell carcinomas (OTSCC). RESULTS: The methylation status of 12 genes in 115 OTSCC samples was assessed by one or more of three quantitative analyses: methylation sensitive high resolution melting (MS-HRM), sensitive-melting analysis after real time-methylation specific PCR (SMART-MSP), and bisulfite pyrosequencing. In contrast to much of the literature, either no or infrequent locus-specific methylation was identified by MS-HRM for DAPK1, RASSF1A, MGMT, MLH1, APC, CDH1, CDH13, BRCA1, ERCC1, and ATM. The most frequently methylated loci were RUNX3 (18/108 methylated) and ABO (22/107 methylated). Interrogation of the Cancer Genome Atlas (TCGA) HNSCC cohort confirmed the frequency of significant methylation for the loci investigated. Heterogeneous methylation of RUNX3 (18/108) and ABO (22/107) detected by MS-HRM, conferred significantly worse survival (P = 0.01, and P = 0.03). However, following quantification of methylation levels using pyrosequencing, only four tumors had significant quantities (>15%) of RUNX3 methylation which correlated with a worse patient outcome (P <0.001), while the prognostic significance of ABO hypermethylation was lost. RUNX3 methylation was not prognostic for the TCGA cohort (P = 0.76). CONCLUSIONS: We demonstrated the critical need for quantification of methylation levels and its impact on correlative analyses. In OTSCC, we found little evidence of significant or frequent hypermethylation of many loci reported to be commonly methylated. It is likely that previous reports have overestimated the frequency of significant methylation events as a consequence of the use of non-quantitative methodology.

Frequency of fibroblast growth factor receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome.

OBJECTIVES: Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) amplification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 amplification in OTSCC. MATERIALS AND METHODS: The frequency of FGFR1 amplification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 amplification with clinical characteristics and outcome were determined. RESULTS: FGFR1 gene amplification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 amplification was seen more commonly in males (9/10 amplified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 amplified and non-amplified patients. CONCLUSIONS: Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing amplification of the gene. FGFR1 amplification may represent a therapeutic target in OTSCC.

Factors leading to the use of alternate treatment modalities following transoral laser excision of T1 and T2 glottic squamous cell carcinoma.

BACKGROUND: CO(2) transoral laser surgery and radiotherapy are both recognized as acceptable treatments for early glottic squamous cell carcinoma (SCC) with similar rates of cure. The reasons why some of the patients in our series undergoing laser resection as their primary modality of treatment subsequently underwent radiotherapy or chemoradiotherapy will be discussed. METHODS: Retrospective study between January 2003 and August 2010 of all T1 and T2 glottic SCCs treated with laser resection at a major tertiary centre. Tis lesions were excluded. A review of the cases in which primary control with laser resection was not achieved was undertaken. Failure was defined as patients treated initially with laser resection who subsequently received radiotherapy, combined chemoradiotherapy or open surgery for the same tumour. Factors leading to failure were analysed, including tumour location, histology, stage and patient factors. RESULTS: Thirty-one patients were identified, with the majority (27) having T1 disease. Mean number of laser excisions per patient was 1.7. Local control rate was 71% with laser alone. One patient had nodal recurrence with no primary recurrence. Mean follow-up was 32 months. Of the nine patients in whom local control was not achieved with laser alone, all had tumour at or crossing the anterior commissure. Four patients were deemed potentially curable with further excision but chose radiotherapy. Two patients were deemed appropriate for radiotherapy and chemoradiotherapy. Three patients had loco-regional recurrence and underwent laryngectomy. All had anterior commissure involvement. CONCLUSION: Transoral laser excision is a safe, function-preserving treatment of early glottic SCC. Anterior commissure involvement was the major factor for potential failure with laser resection in T1 and T2 glottic tumours.

Malignant otitis externa: an Australian case series.

OBJECTIVES: To establish a clinicopathological profile of malignant otitis externa (MOE) in an Australian tertiary referral institution. STUDY DESIGN: Retrospective cohort outcomes study. METHODS: 24 patients were identified with MOE between January 1998 and July 2007. Patients were classified into Radiological Grades I-IV. Laboratory investigations Including C-reactive protein (CRP), white cell count (WCC), glycosylated haemoglobin (HBA1c) and average glucose level over admission were recorded. RESULTS: Radiological Grade was significantly associated with duration of therapy (rank correlation 0.57, p = 0.004). CRP was a useful indicator confirming disease resolution. Diabetics with MOE had elevated average blood sugar levels during their Hospital admission (p < 0.001) and had poor overall glycaemic control represented by Elevated HBA1c scores (p < 0.001). CONCLUSIONS: Malignant otitis externa is a rare disease, which is best managed in a multidisciplinary team setting. This practical grading system can be used to predict the duration of therapy at time of diagnosis, which enables the efficient utilisation of Hospital resources. Poorly controlled diabetics are more susceptible to developing. MOE than diabetics with satisfactory glycaemic control and may represent a subgroup of more brittle diabetics. CRP combined with appropriate clinical and radiological investigations is useful in assessing disease resolution.

Endoscopic stapling of pharyngeal pouch: a 10-year review of single versus multiple staple rows.

OBJECTIVE: To compare the outcomes obtained in patients undergoing endoscopic stapling of pharyngeal pouches with single versus multiple rows of staples. STUDY DESIGN: A retrospective, 10-year review. SUBJECTS AND METHODS: Review of medical records in 38 patients who underwent endoscopic pharyngeal pouch repair. RESULTS: Patients who underwent stapling with multiple rows had a higher postoperative leak rate than patients who were stapled with a single row (36% vs 0%, P < 0.05). Patients with multiple rows also had a more prolonged length of stay and a slower return to both clear fluids and solid diet (P < 0.05). There was no difference in recurrence rate or patient satisfaction between the two groups. CONCLUSION: The technique of endoscopic pharyngeal pouch stapling has the potential to achieve excellent results. The application of more than one row of staples may be necessary to divide the common wall. However, in our series this is associated with a significantly increased risk of esophageal or pouch perforation. Care should be taken during the placement of multiple rows of staples.

Frozen section for parotid surgery: should it become routine?

BACKGROUND: The role of fine-needle aspiration (FNA) in salivary gland lesions as a preoperative diagnosis has always been under scrutiny. Several studies have shown that frozen section (FS) is accurate for pathological diagnosis and decision-making during the surgery. This study has been carried out to assess the accuracy of FNA and FS in parotid surgeries. METHODS: All parotid lesions removed between July 1998 and June 2003 by the Department of Otolaryngology, Head and Neck unit at Monash Medical Centre were reviewed. FNA, FS and definitive pathology were collected and discrepancies were identified. RESULTS: Eighty-five parotid tumours had been removed. Thirty-three were malignant in which squamous cell carcinoma was the most common. FS was able to differentiate benign tumours from malignant with 100% accuracy (30 cases). FS was able to alter the surgical decisions in six cases. FNA had been carried out in 62 cases, with sensitivity and specificity of 77.2 and 90%, respectively. CONCLUSION: Frozen section in parotid surgery is accurate, inexpensive and may add important information that alters management and improves the outcome. The use of FS routinely in parotid surgery is recommended.

Early-stage glottic cancer: oncological results and margins in laser cordectomy.

OBJECTIVES: To assess local control of early-stage glottic cancer by laser cordectomy in comparison with previously published external partial laryngectomy series and to determine the relevance of histological margins in glottic cancers excised with laser cordectomy. DESIGN: Retrospective review of laser cordectomy for carcinoma in situ (Tis) and stage T1 glottic cancer from January 1991 to January 2004. SETTING: University hospital. PATIENTS: Fifty-two patients with Tis or T1 glottic cancer. INTERVENTION: Endoscopic laser cordectomy, classified using the system proposed by the European Laryngeal Society Working Committee. MAIN OUTCOME MEASURES: Local control after initial surgery and after salvage compared with a published historical control group, according to the type of cordectomy performed and the histological margins of the removed specimen. RESULTS: Sixteen patients with Tis, 30 with T1a tumors, and 6 with T1b tumors were followed up for an average of 38 months. Type I cordectomy was the most common procedure used to treat Tis, and type II and type III were the most common for treating T1a and T1b tumors. Of 6 recurrences, 4 were treated with laser cordectomy and 2 were treated with external partial laryngectomy. The rate of laryngeal preservation was 100%. There were 3 recurrences despite histologically clear margins. Three (17%) of 18 patients with suspicious margins developed recurrences. The rate of local control with single intervention (46 [89%] of 52) was lower than with partial external laryngectomy. However, 46 (89%) of 52 patients ultimately had less tissue removed by laser than would have been removed by external partial laryngectomy. CONCLUSIONS: Laser cordectomy provides excellent local control and laryngeal preservation. Close follow-up of patients with positive or suspicious margins is an alternative to further routine treatment.

Dilatation for assisted ventilation-induced laryngotracheal stenosis.

OBJECTIVE: To assess the long-term results of dilatation and our experience with dilatation for assisted ventilation-induced laryngotracheal stenosis. DESIGN: A retrospective study of 32 patients primarily treated with dilatation for assisted ventilation-induced laryngotracheal stenosis between 1977 and 2002. SETTING: A tertiary care center and university teaching hospital. PATIENTS: There were 19 men and 13 women aged 15 to 76 years. The stenosis was cicatricial with some inflammatory process in 27 patients and completely mature in 5 patients. The stenosis involved the cricoid and the trachea in four patients. In 28 patients, the stenosis involved only the trachea. METHODS: Dilatation was performed with serially sized rigid bronchoscopes. Endoscopic laser vaporization was never performed in this series. Six patients were treated with only one dilatation. The 26 remaining patients were treated with successively 2 to 10 dilatations (mean, 3.3 dilatations). The dilatation success rate was analyzed using the Kaplan-Meier method. RESULTS: Median duration of follow-up was 1.8 years. Mortality rate was 9.4%. The overall failure rate was 71.8%. Twenty patients presented with recurrent stenosis. The treatment of recurrent stenosis consisted of tracheal resection with end-to-end anastomosis (11 patients, 55%), cricotracheal anastomosis (5 patients, 25%), tracheal endoprosthesis (2 patients, 10%), and tracheotomy (1 patient, 5%). All patients who underwent tracheal or cricotracheal anastomosis were successfully treated. None of the variables under analysis (sex, age, medical history, cause for intubation, intubation type and duration, delay from initial injury, degree of stenosis, length of trachea involved, number of dilatations) were statistically related to the incidence of complications and the success rate of dilatations. CONCLUSIONS: We do not recommend dilatation technique as the sole treatment for assisted ventilation-induced laryngotracheal stenosis. This technique is helpful in case of emergency to restore an airway and useful for the assessment of stenosis.

Concha bullosa: reducing middle meatal adhesions by preserving the lateral mucosa as a posterior pedicle flap.

BACKGROUND: Concha bullosa, an extensively pneumatized middle turbinate, may obstruct the paranasal sinuses. Messerklinger's partial lateral turbinectomy is commonly used to debulk the concha bullosa, leaving a raw surface with the potential for adhesions. MATERIALS AND METHODS: A modified technique of partial lateral turbinectomy is described. A posterior pedicled mucosal flap covers the inferior raw surface of the medial lamella of the middle turbinate. Three-month follow up of a consecutive series is compared with concurrent controls. RESULTS: Two (7 per cent) of 28 posterior pedicled flap and four (21 per cent) of 19 traditional partial lateral turbinectomies developed mild middle meatal adhesions (p = 0.011). Posterior pedicled flap reduced the need for post-operative cleaning of the middle meatus. CONCLUSION: The posterior pedicled mucosal flap is a simple modification to partial lateral turbinectomy that covers the raw surface facing the lateral nasal wall, significantly reducing adhesions and speeding recovery.