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Purpose: We compared the management and outcome of supraglottic cancer in Ontario, Canada, with that in the Surveillance, Epidemiology, and End Results (SEER) Program areas in the United States. Methods: Electronic, clinical, and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Stage-stratified analyses compared initial treatment and survival in the SEER areas (n = 1,643) with a random sample from Ontario (n = 265). We also compared laryngectomy rates at 3 years in those patients 65 years and older at diagnosis. Results: Radical surgery was more commonly used in SEER, with absolute differences increasing with increasing stage: I/II, 17%; III, 36%; and IV, 45%. The 5-year survival rates were 74% in Ontario and 56% in SEER for stage I/II disease (P = .01), 55.7% in Ontario and 46.8% in SEER for stage III disease (P = .40), and 28.5% in Ontario and 29.1% in SEER for stage IV disease (P = .28). Cancer-specific survival results mirrored the overall survival results with the exception of stage IV disease, for which 34.6% of Ontario patients survived their cancer compared with 38.1% in SEER (P = .10). This stage IV difference was more pronounced when we further controlled for possible cause of death errors by restricting the comparison to patients with a single primary cancer (P = .01). Three-year actuarial laryngectomy rates differed. In stage I/II, these rates were 3% in Ontario compared with 35% in SEER (P < 10−3). In stage III disease, the rates were 30% and 54%, respectively (P = .03), and in stage IV disease they were 33% and 64% (P = .002). Conclusion: There are large differences in the management of supraglottic cancer between the SEER areas of the United States and Ontario. Long-term larynx retention was higher in Ontario, where radiotherapy is widely regarded as the treatment of choice and surgery is reserved for salvage. In stages I to III, survival was similar in the two regions despite the differences in treatment policy. In stage IV, there may be a small survival advantage in the U.S. SEER areas related to the higher use of primary surgery.

Complications arising from intubation and other airway management procedures can have significant morbidity and mortality risks. With the increasing interventional techniques employed by the anesthesiologist to acquire and maintain an airway, there is a potential for increasing airway injury. Awareness of the potential "difficult" airway and employing the appropriate techniques to maximize airway visualization can minimize the risk of these complications.

To examine the effects of an educational intervention, in the form of printed material, on patient knowledge and recall of possible risks from parotidectomy or thyroidectomy.Prospective, randomized, controlled study conducted during a 9-month period.Head and neck surgery clinic of an academic tertiary care hospital.One hundred twenty-five consecutive patients older than 16 years who were undergoing thyroidectomy or parotidectomy at the head and neck surgery clinic were recruited. Four patients were excluded from analysis because their follow-up interview was not within the required limits.At the preoperative visit during the routine consent process, both groups received a verbally delivered checklist of risks specific for the surgery to be performed. The intervention group was also given a pamphlet with written information accompanied by illustrations.The effectiveness of the educational intervention was determined by comparing the average rate of risk recall between the intervention and control groups. The effects of age, sex, level of education, and time between the consent and recall interviews on recall rate were also assessed.The overall risk recall rate for both procedures was 39.1%. The recall rate of the intervention group was 50.3% compared with 29.5% for the control group (P.001).The intervention consistently improved risk recall for all patients regardless of age, sex, and level of education. Patients' ability to recall potential risks was significantly increased by an educational intervention; all patients would benefit from this intervention.

Objectif: La muticentricite est citee pour justifier une thyroidectomie totale chez les patients avec carcinome papillaire de la thyroide (CPT) limite a un lobe. Le but de cette etude etait d'examiner l'incidence de multicentricite dans le CPT dans une cohorte de 165 patients avec une tumeur limitee a un seul lobe et d'examiner les facteurs cliniques et pathologiques qui pourraient aider a predire la presence de pathologie contralaterale. Methode: Etude retrospective de 165 patients avec CPT limite a un seul lobe et traites au Toronto General Hospital (un hopital de soins tertiaires) entre 1992 et 1997. Mesures: Nous avons analyse les facteurs predictifs de multicentricite. Resultats: L'incidence de CPT dans le lobe contralateral est de 56.3%. Nous n'avons pas ete capables de trouver de correlation avec l'âge, le sexe, le volume de la tumeur, la dissemination extrathyroidienne, la thyroidite, ou la variante a grandes cellules du CPT. Il y avait une tendance vers une plus grande incidence de pathologie contralaterale chez les patients avec une histoire anterieure de radiotherapie et ceux avec des metastases lymphatiques mais cette tendance n'atteint pas le seuil de significativite statistique. Conclusions: L'incidence de pathologie contralaterale dans le CPT traite au Toronto General Hospital etait de 56.3%. Il y avait une tendance vers une plus grande incidence de contralateralite chez les patients avec une histoire anterieure de radiotherapie et chez ceux avec des metastases lymphatiques bien que la significativite statistique ne soit pas atteinte.

Le lambeau du muscle sterno-cleido-mastoidien (SCM) pourrait jouer un role important dans la prevention du syndrome de Frey et dans l'amelioration de l'aspect esthetique apres une parotidectomie. Parmi les patients ayant subit une parotidectomie superficielle entre aout 1992 et mars 1999, 26 ont accepte de participer a notre etude. Ils ont ete divise en deux groupes, un ayant beneficie d'un lambeau du SCM, le groupe controle etant similaire pour le sexe, l'âge, la pathologie, la radiotherapie postoperatoire, la date de l'intervention, et l'etendue de la dissection. Nous avons utilise le test a l'iode et a la fecule de mais pour evaluer le syndrome de Frey et l'echelle Observer Rated Disfigurement Scale pour mesurer le deficit esthetique et le contour facial. Les resultats de notre etude suggerent que le lambeau du SCM apres la parotidectomie n'affecte pas l'incidence du syndrome de Frey et n'ameliore pas significativement le contour facial et l'apparence esthetique.

minutes after treatment. We identify a chromatin architecture that defines a durable response to BETi, specifically in the context of immunoglobulin heavy chain (IgH) re-arrangements, classifying patient populations suitable for BET treatment. Our results suggest that the molecular response to BETi is highly dynamic and adapts over time, while high-occupancy BRD4 loading is generally a poor predictor of BET transcriptional control.

The WHSC1L1 gene is amplified and overexpressed in ∼12% of breast cancers, and is thought to be a driving oncogene when amplified and overexpressed, however the mechanism of transformation is not known. SUM44 cells harbor an amplification of WHSC1L1 as part of the 8p11-p12 amplicon, and express high levels of both the long and short isoforms of the gene. The short isoform, containing only a PWWP domain and no catalytic SET domain, is the major species present in SUM44 cells. To create a model to study the effect of WHSC1L1 on gene regulation, SUM44 cells were lentivirally transduced with either a control shRNA for LacZ (shLacZ), an shRNA specific for both isoforms of WHSC1L1 (shWHtotal), or a short isoform-specific shRNA (shWHshort). Cell growth was significantly reduced in shWHtotal cells compared to shLacZ, however, the greatest decrease in growth was observed in cells transduced with the short isoform-specific shRNA. To identify genes transcriptionally regulated by WHSC1L1, we performed genome-wide expression profiling of SUM44 breast cancer cells transduced with either shWHtotal or shLacZ. A total of 5185 genes were found to be differentially expressed in shWHtotal SUM44 cells compared to shLacZ control. Among the 5185 differentially expressed genes, we found ESR1 to be significantly downregulated (-7.3-fold, p < 0.0001) in the shWHtotal cells compared to shLacZ controls. In addition MYCN, which is amplified in SUM-44 cells was reduced by 7.43-fold, (p < 0.004), ERBB3 was reduced by 2.5-fold, (p < 0.0009), and ERBB4, which is highly expressed in SUM-44 cells was reduced by 2.12-fold, (p < 0.00001). Immunoblotting confirmed downregulation of estrogen receptor alpha (ERα) in the shWHtotal compared to shLacZ control. Interestingly, knockdown of WHshort resulted in an even greater decrease of ERα than the shWHtotal knockdown. To determine whether downregulation of ERα affects sensitivity to Tamoxifen, we measured the Tamoxifen LD50 in SUM44 shLacZ and SUM44 shWHtotal cells, and found a 10-fold decrease in Tamoxifen LD50 compared to shLacZ control (3.8nM vs. 35nM). Tamoxifen affected SUM-44 cells in a dose-dependent manner, however 500nM Tamoxifen resulted in complete growth arrest in SUM44 shWHtotal cells, while the cells infected with the shLacZ virus cells grew at the same dose, albeit slowly. Our data indicate that WHSC1L1 regulates ERα expression in SUM44 cells, and WHSC1L1 knockdown increased the cells' sensitivity to Tamoxifen. The decrease in both cell growth and ERα expression in the SUM44 WHshort-specific knockdown cells suggests that the catalytically inactive short isoform of WHSC1L1 may be the isoform driving the oncogenic activity of WHSC1L1 amplification, perhaps through a dominant-negative interaction with the long isoform of WHSC1L1. Data showing increases in global H3K36 methylation levels following knock down of WHSC1L1 are consistent with this hypothesis. Citation Format: Jonathan Curtis Irish, Alexandria Rutkovsky, Stephen P. Ethier. Overexpression of histone methyltransferase WHSC1L1 regulates expression of ER-alpha in SUM44 breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5148. doi:10.1158/1538-7445.AM2014-5148

BACKGROUND: Over half of oropharyngeal carcinomas (OPCs) are linked to high-risk human papillomavirus (HPV) infection. As compared to their HPV-positive (HPV+) counterparts, HPV-negative (HPV-) OPCs are associated with significantly worse survival, inferior treatment response and a distinct molecular expression profile. There are currently considerable efforts underway to personalize treatment based on HPV status; however, this remains challenging as the current understanding of the different biological mechanisms in HPV+ vs. HPV- OPCs is limited. Hence, a comprehensive proteomic analysis was performed, utilizing archival OPC tissues, in order to acquire greater insights into the distinct biological pathways. METHODS: Global protein expression profiling was conducted on 26 HPV- and 27 HPV+ pre-treatment formalin-fixed paraffin-embedded (FFPE) OPCs using an automated 5-step Multidimensional Protein Identification Technology (MudPIT) procedure on a LTQ-Orbitrap XL. Protein quantification was achieved by adjusted spectral counting. Differentially expressed proteins (p RESULTS: Among the 2633 high confidence protein groups identified, 174 were significantly differentially expressed in HPV+ vs. HPV- OPCs. Functional enrichment analysis of these proteins demonstrated enrichment of cell cycle, DNA repair, cytokine signaling, apoptosis, DNA packaging, and metabolism proteins. These results were in concordance with a previous publication of pooled OPCs (Slebos et al, 2012). In addition, utilizing The Cancer Genome Atlas (TCGA) data, we determined that the relative expression levels of many of these proteins could be attributed to changes in copy number, methylation, mRNA, or mutation profiles. Next, the top 4 proteins were selected for verification based on concordance with these datasets and reported biological relevance. Selected proteins are involved in actin assembly, purine metabolism, differentiation, and cell migration and invasion. As a result, the differential expression of 2 proteins was successfully validated by IHC, while 2 additional proteins exhibited the same trend as in the discovery cohort. CONCLUSION: This study provides the most in-depth and integrated protein-centric view of HPV+ and HPV- OPC. As a key finding, we highlight the identification of an actin assembly oncoprotein reported to be involved in a targetable radioresistance pathway. We hypothesize that this pathway is preferentially activated in HPV- OPCs. Hence, future experiments will focus on validating the in vivo observed expression pattern of this protein in vitro, and manipulating its expression to overcome radioresistance in OPC models. Citation Format: Lusia Sepiashvili, Angela Hui, Wei Shi, Wei Xu, Daryl Waggot, Paul Boutros, Alex Ignatchenko, Vladimir Ignatchenko, Shao Hui (Sophie) Huang, John Waldron, Brian O'Sullivan, Jonathan C. Irish, Fei-Fei Liu, Thomas Kislinger. Integrative systems analysis of HPV+ and HPV- oropharyngeal carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2490. doi:10.1158/1538-7445.AM2014-2490

Background: The extent of treatment for differentiated thyroid cancer remains controversial. The objective of this study was to describe the variations in practice prior to diagnosis and for the first year after diagnosis, including the investigations, the extent of surgery and the use of RAI 131, for all patients with thyroid cancer (TC) treated Jan 1 2000 to Dec 2008 across Ontario Canada. Method: Population-based study of all patients who had a therapeutic surgical procedure for TC based on the data holdings of the Institute of Clinical Investigative Sciences (ICES) linking the Ontario Cancer Registry to the Ontario Health Insurance Plan and to the Canadian Institutes of Health Information. The analysis includes comparisons between health care utilization/geographic regions and between treating specialties. The study population was 12957 patients. Results: There was a 112% increase in case detection over 9 years. Overall the initial (index) surgery was less-than-total thyroidectomy (LTT) in 37.6% and 63.4% of the patients who had total thyroidectomy (TT) as an index surgery went on to adjuvant RAI, however there was wide variation in all aspects of patient care across the province, between Local Health Networks and between surgical specialties. Conclusion: In Ontario, there was wide variation for most aspects of the management of TC and, as the incidence of TC is increasing at least 7% per year in females, these data provide a foundation for future discussions, the provision of health care services and research.

Purpose: Ipsilateral techniques designed to restrict treatment to the primary tumor and neck on the same side have been used in selected cases of cases of carcinoma of the tonsillar region at our institution for many years. The primary purpose of this study is to evaluate the risk of failure in the opposite neck in cases selected for unilateral radiotherapy over a 21-year period. Methods and Materials: Ipsilateral radiotherapy techniques were used in 228 of 642 patients with carcinoma of the tonsillar region from 1970 to 1991. Local control, regional lymph-node control (including contralateral failure), and survival were calculated for different degrees of tumor extent treated with these techniques. Results: Mean follow-up was 7 years. Cases tended to be T1 and T2, with N0 disease. The 3-year actuarial local control rate was 77% and cause-specific survival was 76%. Opposite neck failure was seen in 8 patients (crude rate of 3.5%). In the earlier period of the study, primary coverage was problematic in a proportion of cases and resulted in higher rates of local failure. Conclusion: Appropriately selected cases of carcinoma of the tonsil show minimal risk of failure in the opposite neck with ipsilateral techniques. Patients should undergo computed tomography planning to ensure adequate target coverage.

Summary The purpose of this study was to evaluate the effects of bilateral botulinum toxin injection into the thyroarytenoid (TA) muscles of a patient with essential voice tremor. Acoustic and aerodynamic data were collected weekly over a 16-week period. Flexible nasolaryngoscopy was performed prior to injection and 2, 6, 10, and 16 weeks postinjection. Perceptual analyses of the acoustic and nasolaryngoscopic data were performed. A reduction in frequency tremor and, to a lesser extent, amplitude tremor was observed during the 1–10 week period. Estimated laryngeal resistance decreased after injection and was accompanied in perceptual measures by a reduction in vocal effort, laryngeal tremor, and supraglottic hyperfunction. Essential voice tremor can be successfully attenuated with bilateral percutaneous injection of botulinum toxin A into the vocalis muscle.

Objectives/Hypothesis To evaluate the relative efficacy of unilateral and bilateral injections of botulinum toxin injection (BOTOX) in the treatment of essential tremor of the voice (ETV). Study Design Prospective open-label crossover study. Methods Patients referred to the Neurolaryngology Clinic at Toronto General Hospital with a diagnosis of ETV were eligible for the study. Patients were sequentially assigned to receive BOTOX as either a bilateral 2.5-U or a unilateral 15-U electromyography-guided injection, followed by the alternative injection 16 to 18 weeks later. Acoustic, aerodynamic, and nasopharyngoscopic data were collected approximately 2, 6, 10, and 16 weeks after each injection. Patients were asked to provide a perceptual evaluation of BOTOX effects at the conclusion of the study. Results Three of 10 patients demonstrated an objective reduction in tremor severity with bilateral injection, and 2 of 9 with unilateral injection. However, 8 of 10 patients wished to be re-injected at the conclusion of the study. A reduction in vocal effort appeared to be coincident with reduction in laryngeal airway resistance after BOTOX injection. Conclusions Using objective acoustic measures, only a small proportion of patients achieved benefit from BOTOX injection for ETV. However, a majority of patients in our study benefited from a subjective reduction in vocal effort that may have been attributable to reduced laryngeal airway resistance.

To determine if there is a difference in overall survival, cause-specific survival, and relapse-free rate between young patients (40 years of age) with head and neck squamous cell carcinoma (HNSCC) and older patients (40 years of age).A matched control study describing the outcome of 185 previously untreated HNSCC patients less than 40 years of age treated at the Princess Margaret Hospital, Toronto, Ontario, Canada, between 1958 and 1992. The young patient group was compared with a control group of older patients (40 years of age) which was selected randomly from an entire cohort of patients (n = 10,072) and matched for site, sex, and date of presentation.The medical records were reviewed and data abstracted for demographic information, tobacco and alcohol use, family history, primary site, clinical stage, primary treatment, histology, the occurrence of residual or recurrent disease, salvage treatment, development of subsequent primaries, survival, and the eventual cause of death. The patient's TNM stage was reclassified according to American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) 1992 criteria on the basis of the initial clinical description and staging investigations. A multivariate regression analysis was performed. To assess the importance of age as a prognostic factor for survival, the Cox proportion hazard model was used. Smoking status was also tested in the stratified Cox proportional hazard model.Tumor stage and treatment modalities were comparable in both groups. The 5-year, cause-specific survival in both groups was not statistically different (72% vs. 68%, P = .91). The young patient group had a significantly better 5-year overall survival compared with the older patient group (68% vs. 49%, P = .0011). Older patients developed more subsequent primary neoplasms than the younger patient population (18% vs. 8%, P = .005). There were significantly more females, an increased incidence of oral or oropharyngeal cancer, and fewer smokers in the young patient group. Smoking, however, had an important impact on outcome with all but one patient who developed a second primary in the upper aerodigestive tract having smoked. Multivariate analysis showed that only disease stage and cancer site were significant prognostic factors for survival.Young patients with HNSCC do not have a worse prognosis than a matched older patient group in this case-controlled study (power0.75 for a minimal detectable difference of 10% disease-free survival between the two groups).

Oral squamous cell carcinoma (OSCC) is associated with heavy smoking and drinking, but the molecular pathway of tumorigenesis is not understood. Inactivation of the p53 tumor suppressor gene is likely to play an important role since p53 mutation is frequently found. The p14ARF tumor suppressor gene is functionally linked to p53, because it is activated by oncogenes and causes p53-dependent growth arrest and apoptosis. The relationship between p14ARF and p53 inactivation has not been described for OSCC. We studied 25 cases of OSCC to determine if there is an inverse correlation between p53 mutation and p14ARF inactivation by homozygous deletion or mutation. p53 mutation was found in 16 of 25 cases (64%), including nine missense and seven truncating mutations. While all cases with missense mutations showed abnormal accumulation of p53 protein, there were also five carcinomas which showed increased p53 staining in the absence of mutation. p14ARF deletion or mutation was found in eight cases (32%), six of which also demonstrated p53 mutation. Our findings indicate that OSCC often involves loss of both p14ARF and p53 function and suggest that inactivation of these two tumor suppressor genes are not functionally equivalent during tumorigenesis.

Purpose: Evaluate and compare the morbidity and costs of different reconstructive strategies in oral and oropharyngeal carcinoma. Study Design: Retrospective cross-sectional. Patients and Methods: One hundred twenty-seven consecutive patients treated surgically for oral and oropharyngeal carcinoma between 1990 and 1996 were evaluated. Sixty-three patients had segmental mandibulectomies with 30 plate–soft tissue reconstructions and 33 bone–soft tissue flaps. Sixty-four patients had soft-tissue-only reconstructions. The following outcome parameters were analyzed: operative time, intraoperative blood loss, postoperative admission length, ICU and coronary care unit admission length, surgical interventions for complications, re-admissions, and prolonged (> 6 mo) gastrostomy tube feeding, and all costs within the disease-free interval. Means and standard deviations were calculated for continuous parameters. Differences among the three groups were analyzed using one-way analysis of variance. For discontinuous parameters, the chi-square test was applied. Results: Longer operative time (1.8 h) and more blood loss (150 mL) for bone-soft tissue flaps were the only statistically significant findings (P < .05) between the three groups. Conclusion: There is no rationale for allowing presumed factors of morbidity or cost select for type of reconstruction in patients with oral and oropharyngeal carcinoma.

Purpose: A prototype mobile C‐arm capable of real‐time fluoroscopy,tomosynthesis, and cone‐beam CT(CBCT) has been developed for intraoperative guidance of minimally invasive procedures. This work investigates the imaging performance, radiation dose, and image acquisition / reconstruction time associated with a range of 3D imaging techniques. In addition, protocols for intraoperative use are developed for implementation in clinical research trials. Method and Materials:Imaging performance was assessed in terms of spatial resolution as well as soft‐tissue and bony detail visualization in phantoms and cadavers. Image reconstruction via 3D filtered backprojection was performed across a range of tomosynthesis angle (10°–178°) and number of projections (5–200). The corresponding radiation dose was evaluated analytically and experimentally (using a Farmer chamber in cylindrical head and body phantoms) to quantify peripheral, central, and organ dose (e.g., dose to the eyes). Acquisition / reconstruction times were benchmarked in relation to operational time constraints. Results:CBCTimages exhibited sub‐mm spatial resolution and soft‐tissue visibility (∼20 HU) sufficient for interventional guidance at a central dose of 10 mGy. Tomosynthesis offered a useful, high‐speed adjuvant to CBCT, providing visualization of high‐contrast features at a fairly limited arc — e.g., visualization of the clivus (skull base) achieved at angles down to ∼30° (central dose ∼1.6 mGy). Reconstruction times were ∼62 sec (full CBCT volume, 0.8 mm voxels) and ∼20 sec (tomosynthesis “slab,” 0.4 mm voxels), respectively.Conclusion:C‐arm tomosynthesis and CBCT provide a valuable addition to the image guidance arsenal. The former offers fast, low‐dose 3D images sufficient for guidance with respect to high‐contrast bony features. The latter offers sub‐mm spatial resolution and soft‐tissue visibility at the cost of time and dose. Deployment of the C‐arm prototype in clinical research trials promises increased surgical precision, with protocols for intraoperative imaging consistent with operational time and dose constraints.

Objective: To comment on the role of surgical salvage following failed initial treatment for paranasal sinus malignancy. Design: A retrospective analysis of one hundred eighty patients treated at The Princess Margaret Hospital, Toronto, from 1976 to 1993. Materials and Methods: Thirty-four of 95 patients (36%) who failed initial treatment underwent surgical salvage. Initial therapy in this group was radiation only (n = 27) and combined therapy (n = 7). Patient, tumor, and surgical data were recorded. There were 23 T4, three T3, six T2, and two T1 carcinomas. Survival, recurrence rates, and the influence of a variety of variables on outcome were analyzed. Results: Two- and 5-year overall actuarial survival calculated from the date of diagnosis was 54% and 35%, respectively. Two- and 5-year overall actuarial survival calculated from the date of salvage surgery was 44% and 22%, respectively. Advanced age (P

The human Epstein-Barr herpesvirus (EBV) has distinct oncogenic potential, but with over 90% of the adult world population infected, malignancy is a rare outcome of carrier status. However, EBV's association with over half of Hodgkin's and non-Hodgkin's lymphomas as well as several solid tumors, notably nasopharyngeal carcinoma, makes EBV-linked malignancies one of the largest single cancer entities. EBV is a B-lymphotropic virus, well controlled by surveillant T cells in immunocompetent hosts. To determine the presence and site of principal virus reservoirs is a likely prerequisite for understanding the etiology of EBV-associated tumors. Its near 100% association with nasopharyngeal carcinoma led to postulates that the upper aerodigestive tract tissue may be common sites of persistent latent or low-grade replicating infection. Using a protocol designed to avoid viral crosscontamination, the authors employed polymerase chain reaction to detect genomic EBV DNA sequences in 231 biopsies from different mucosal sites in the upper aerodigestive tract, as well as from salivary gland tissue and neck nodes in individuals not suspected to have EBV-related malignancy. Only two samples, one from oral cavity mucosa and one from parotid gland tissue, were positive for EBV. The observation that oropharyngeal tissue is not the principal EBV reservoir has mechanistic implications for the development of EBV-positive tumors in that locale.

Objective: To comment on the use of surgery after the failure of radiotherapy in patients with advanced laryngeal, oropharyngeal, and hypopharyngeal carcinomas. Design: Randomized, controlled, clinical trial, with a mean follow-up period of 3.1 years. Setting: The Princess Margaret Hospital, Toronto, Ontario. Patients: Patients with advanced laryngopharyngeal carcinoma (T3 or T4 or N+). Intervention: Three hundred thirty-six patients who met the eligibility criteria were enrolled in a randomized, controlled, clinical trial and treated with primary radiotherapy using either the standard fractionation regimen or the hyperfractionation regimen. One hundred eight patients with recurrent disease underwent salvage surgery and were observed prospectively, with careful documentation of surgical and tumor data, complications, recurrences, and survival. Main Outcome Measures: Surgical complication rate and survival. Results: Of the 108 patients who underwent surgery, 29 (27%) had complications. One third of these had multiple complications. There was no statistical difference between the surgical complication rates of the 2 radiotherapy groups (16 patients [28%] in the standard fractionation radiotherapy group and 13 [25%] in the hyperfractionation radiotherapy group). Survival after surgery was statistically correlated with the TNM system for the stage of the recurrent tumor, the pathologic nodal status, and the surgical margin status. The overall 3-year survival rate, which was calculated from the date of surgery, for the group of patients who underwent surgery was 22%. Conclusions: In this patient population, the hyperfractionation regimen was not associated with a higher surgical complication rate. Using the policy of primary radiotherapy and reserving surgery for the management of failures of radiotherapy, 140 patients (71%) at highest risk (laryngeal and hypopharyngeal primary tumor sites) retained an intact larynx until the end of the study or death. Since it is the stage of the recurrent tumor that correlates with survival rather than the stage of the tumor at initial presentation, we suggest that tumors be re-staged at the time of recurrence. Arch Otolaryngol Head Neck Surg. 1997;123:420-424

Importance After surgical resection for oral cavity squamous cell carcinoma, adjuvant radiotherapy may be recommended for patients at higher risk for locoregional recurrence, but it can be difficult to predict whether a particular patient will benefit. Objective To construct a model to predict which patients with oral cavity squamous cell carcinoma would benefit from adjuvant radiotherapy. Design and Setting We constructed several types of survival models using a set of 979 patients with oral cavity squamous cell carcinoma. Covariates were age, sex, tobacco use, stage, grade, margins, and subsite. The best performing model was externally validated on a set of 431 patients. Participants The model was based on a set of 979 patients with oral cavity squamous cell carcinoma, including 563 from Memorial Sloan Kettering Cancer Center, New York, New York, and 416 from the Hospital AC Camargo, Sao Paulo, Brazil. The validation set consisted of 431 patients from Princess Margaret Hospital, Toronto, Ontario, Canada. Main Outcome and Measure The primary outcome measure of interest was locoregional recurrence-free survival. Results The lognormal model showed the best performance per the Akaike information criterion. An online nomogram was built from this model that estimates locoregional failure-free survival with and without postoperative radiotherapy. Conclusions and Relevance A web-based nomogram can be used as a decision aid for adjuvant treatment decisions for patients with oral cavity squamous cell carcinoma.

An amplified region of chromosome 8, the 8p11-p12 amplicon, is observed in ∼15% of breast cancers. This region contains 55 genes, of which 22 have been identified as candidate oncogenes based on higher than normal copy number and associated elevated expression levels in breast tumor cells compared to normal breast epithelial cells. Our lab previously identified the short isoform of one amplicon gene, Wolf Hirschhorn Syndrome Candidate 1-Like 1 (WHSC1L1), to be a potent inducer of transformation when over expressed in MCF10A breast epithelial cells in vitro. WHSC1L1 is a member of the NSD family of methyltransferases, and has been shown to methylate lysines 4, 27, and 36 of the histone H3 subunit, however, the potently transforming short isoform (WHshort) lacks the catalytic SET domain. Our lab has shown that over expression of WHshort in the immortalized human breast epithelial cell line MCF10A causes a significant increase in proliferation in insulin-free culture conditions, and the ability to form colonies in soft agar. In SUM44 cells, an ER+ breast cancer cell line harboring the 8p11-p12 amplicon, shRNA knockdown of WHSC1L1 resulted in growth arrest. The WHSC1L1 family member NSD1 has been shown to act as an oncogene in acute myelogenous leukemia by blocking differentiation in developing lymphocytes through H3K36me3-mediated inhibition of the polycomb repressor complex, resulting in constitutive activation of the HOXA gene family. While WHSC1L1 may work by a similar mechanism, little is known about the specific substrates of WHSC1L1, or even whether its oncogenic activity is caused by histone methylation changes. Knockdown by shRNA of WHSC1L1 in SUM44 cells resulted in a significant reduction in transcript levels of several genes important in breast cancer cell proliferation, including ESR1, MYCN (amplified in SUM-44), ERBB3, and ERBB4. Interestingly, Carroll et al. recently reported that ER+ breast tumors can be stratified by gene expression signature into poor outcome and good outcome groups, and that ER-alpha binding site patterns on chromatin were altered in the two groups. In this study, WHSC1L1 was part of the ER-regulated gene signature of the poor outcome group. Therefore, we hypothesize that WHSC1L1 may influence histone H3K36me3 marks at specific gene loci, leading to altered ER-alpha binding that is associated with the expression signatures of poor-outcome ER+ breast cancers. To investigate chromatin changes as a result of changes in WHSC1L1 expression, we have accomplished shRNA knockdown of WHSC1L1 in SUM44 cells using GIPZ and TRIPZ lentiviral vectors. Using these cell lines, we are investigating changes in H3K36me3 marks and ER-alpha binding patterns by chromatin immunoprecipitation followed by sequencing (ChIP-seq). These experiments will help to elucidate the interaction of WHSC1L1 and ER in regulated gene expression in breast cancer cells with the 8p11 amplicon. Citation Format: Jonathan C. Irish, Gang Liu, Stephen P. Ethier. Epigenetic mechanisms of transformation by WHSC1L1 in breast cancer cells with the 8p11-p12 amplicon. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2964. doi:10.1158/1538-7445.AM2013-2964

Purpose : To evaluate the outcome of patients with verrucous carcinoma of the larynx treated at the Princess Margaret Hospital with respect to control rates with radiotherapy, the salvage of local failure, the risk of regional lymph node metastasis following radiation therapy, and the risk of anaplastic transformation following radiotherapy. Methods and Materials : Forty-eight patients underwent primary treatment for verrucous carcinoma of the larynx in the period between January 1961 and December 1990. This represented 1.1% of cases of laryngeal cancer seen in this time period. Forty-three received radiotherapy and 5 had surgery as the primary treatment. Several radiation dose-fractionation schedules were used, the most frequent being 50 Gy in 20 fractions in 4 weeks (31 cases), while eight patients were treated with 55 Gy over 5 weeks. Results : The 5-year rate of local control was 59% for the 43 patients treated with radiotherapy. Surgical salvage was universally successful in all cases where it was attempted. The five cases treated with surgery alone did not experience relapse. Only one patient died of verrucous carcinoma. He had been medically unfit for surgical intervention at the time of initial treatment and at the time of relapse. He underwent a truncated course of radiotherapy (24 Gy in 3 fractions over three weeks in 1975). There was no evidence of increased neck relapse compared to other forms of laryngeal carcinoma following radiation treatment. No evidence to support anaplastic transformation of tumors treated with radiotherapy was evident in this series. Conclusions : Local control using radiation treatment is less successful than with ordinary invasive and in situ squamous carcinomas of the larynx. Nevertheless, the treatment is effective and provides an appropriate option for laryngeal conservation, especially in advanced lesions where total laryngectomy may be the only treatment alternative. Surgical salvage of radiation failures contributes to very high rates of cure for verrucous carcinoma of the larynx. Anaplastic transformation of cases treated with radiotherapy was not observed in any case in this series.

We reviewed our experience with combined approaches to lesions that transcend the bones of the skull base. Seventy-seven skull base procedures were performed on 73 patients during a 10-year period from 1982 to 1992. There were 34 patients (44%) with region lesions (anterior), seven patients (9%) with region II lesions (anterior-lateral), 25 patients (32%) with region III lesions (lateral-posterior), and 11 patients (14%) with lesions that invaded more than one anatomic site. The histopathology in this series was quite variable, with 22 patients (29%) having squamous cell carcinoma and eight patients (10%) having basal cell carcinoma. Forty-one patients had surgery by an anterior approach and 38 patients had lateral approaches, with 18 undergoing an infratemporal approach and 29 undergoing temporal bone resections. Overall, 44% of the patients had a postoperative complication. Survival of this heterogeneous group of patients is 79% at 2 years and 71% at 4 years, with those patients with region II disease having a statistically significant poorer prognosis with no survivors at 4 years.

Background A recently developed probe-based technology, the NanoString nCounter™ gene expression system, has been shown to allow accurate mRNA transcript quantification using low amounts of total RNA. We assessed the ability of this technology for mRNA expression quantification in archived formalin-fixed, paraffin-embedded (FFPE) oral carcinoma samples. Results We measured the mRNA transcript abundance of 20 genes (COL3A1, COL4A1, COL5A1, COL5A2, CTHRC1, CXCL1, CXCL13, MMP1, P4HA2, PDPN, PLOD2, POSTN, SDHA, SERPINE1, SERPINE2, SERPINH1, THBS2, TNC, GAPDH, RPS18) in 38 samples (19 paired fresh-frozen and FFPE oral carcinoma tissues, archived from 1997-2008) by both NanoString and SYBR Green I fluorescent dye-based quantitative real-time PCR (RQ-PCR). We compared gene expression data obtained by NanoString vs. RQ-PCR in both fresh-frozen and FFPE samples. Fresh-frozen samples showed a good overall Pearson correlation of 0.78, and FFPE samples showed a lower overall correlation coefficient of 0.59, which is likely due to sample quality. We found a higher correlation coefficient between fresh-frozen and FFPE samples analyzed by NanoString (r = 0.90) compared to fresh-frozen and FFPE samples analyzed by RQ-PCR (r = 0.50). In addition, NanoString data showed a higher mean correlation (r = 0.94) between individual fresh-frozen and FFPE sample pairs compared to RQ-PCR (r = 0.53). Conclusions Based on our results, we conclude that both technologies are useful for gene expression quantification in fresh-frozen or FFPE tissues; however, the probe-based NanoString method achieved superior gene expression quantification results when compared to RQ-PCR in archived FFPE samples. We believe that this newly developed technique is optimal for large-scale validation studies using total RNA isolated from archived, FFPE samples.

• Although there is much literature devoted to the role that fine-needle biopsy plays in the management of the thyroid mass, only a handful of studies deal with the diagnostic accuracy of the frozen section and final paraffin section of thyroid lesions. Fine-needle biopsy results, frozen-section diagnoses, final paraffin-section diagnoses, and panel review diagnoses were recorded for 137 consecutive patients who underwent thyroidectomy procedures. The overall accuracy of fine-needle biopsy, frozen-section, and paraffinsection diagnoses was 81%, 87%, and 94%, respectively. The high positive predictive value and specificity of both the fine-needle and frozen-section modalities suggests that intraoperative pathology consultation, given that the preoperative needle aspirate is positive for malignant neoplasia, can offer little further in the treatment of the patient. Stastistical analysis of the accuracy of the three modalities suggests strategies for accurate treatment of the thyroid nodule. (Arch Otolaryngol Head Neck Surg. 1992;118:918-922)

Objectif: Comparer la morbidite et le cout entre les patients subissant une reconstruction par transplant et ceux reconstruits avec un lambeau myocutane du grand pectoral (LMGP)apres l'exerese d'un carcinome epidermoide de la cavite buccale ou de l'oropharynx. Methode: Sur une periode de 6 ans, 36 patients ont subit un LMGP et 127 une reconstruction par un quelconque transplant apres l'exerese d'un cancer buccal ou oropharynge. Nous avons corrige les facteurs confondants possibles en appariant pour les variables suivantes, les 36 patients du premier groupe avec des transplantes: l'âge, le sexe, le stade T (selon la classification de l'UICC-AJC. Le sous-site de la tumeur et un traitement par radiotherapie. Le resultat est deux groupes de 32 patients avec comme seule difference le type de reconstruction. Nous avons ensuite analyse les variables suivantes : la duree de l'intervention, les pertes sanguines, la duree de l'hospitalisation (qui incluait le temps passe aux soins intensifs), les complications, les interventions secondaires, les readmissions et le statut nutritionnel. Nous avons aussi calcule les couts totaux, incluant les soins infirmiers, l'equipement et les fournitures hospitalieres sans oublier les frais chirurgicaux et anesthesiques. L'analyse statistique inclut des tests de Student et de Chi carre. Resultats: De tous les facteurs analyses, seul le temps operatoire etait different, plus long dans le groupe des transplants (p 0.0001) Conclusions: Nous n'avons pas trouve de difference de moribidite et de couts entre la reconstruction par LMGP ou par transplant, si ce n'est le temps operatoire qui est plus long dans le dernier groupe.

OBJECTIVE To determine patients' smoking status after the diagnosis and treatment of squamous cell carcinoma of the head and neck (SCCHN) and to identify factors associated with smoking cessation. DESIGN Cross-sectional survey study conducted over a 2-year period. SETTING Head and neck surgery clinic of an academic tertiary care hospital. METHODS Two hundred thirteen consecutive patients diagnosed with SCCHN were interviewed to ascertain patients' smoking status and the incidence of smoking cessation. Information on demographics, tobacco and alcohol history, disease characteristics, and treatment modality was also collected. MAIN OUTCOME MEASURES The rate of smoking cessation was evaluated, in which smoking cessation is defined as the use of no cigarettes at least 1 month prior to the interview. Possible predictors of smoking cessation were evaluated. RESULTS One hundred twenty-five patients were found to be smoking at the time of diagnosis. Among these patients, 53.6% stopped smoking after diagnosis or during treatment. In the univariate analyses, tumour site (p = .01), concurrent alcohol use (p = .03), and number of attempts to quit pre- (p = .03) and postdiagnosis (p = .001) were found to be highly predictive of patient smoking cessation. Multivariable modelling showed that gender, tumour site, and number of attempts to quit smoking were significantly and independently related to smoking cessation. CONCLUSIONS Although smoking cessation would be presumed to be high after cancer diagnosis, this study has identified patient subgroups in which postdiagnosis smoking cessation intervention programs need to be made more effective.

Objective: Papillary microcarcinomas (PMCs) of the thyroid (measuring less than 1 cm in maximum dimension) are extremely common incidental histologic findings, and most of these tumors are not considered clinically significant. However, rare PMCs behave aggressively and metastasize early, giving rise to clinically significant metastatic disease. We hypothesized that p27 and MIB-1/Ki-67 immunoreactivity would allow us to identify this small subgroup of PMCs that have the potential to behave aggressively. Methods: We reviewed the histopathology reports of 2000 patients who underwent thyroid surgery at our institution between 1995 and 1999 and identified 22 patients who presented with gross regional metastases from a primary PMC. The primary and metastatic tumors were stained for ret, p53, p27, and MIB-1 using the avidinbiotin-peroxidase complex technique. A control group of 33 nonmetastasizing PMCs was also analyzed. Results: Immunoreactivity for ret, p53, and MIB-1 showed no difference between metastasizing and nonmetastasizing PMCs. In most tumors, ret was present, while p53 immunoreactivity was absent in all tumors. MIB-1 staining was present in a small number of cells in both groups of tumors. Immunoreactivity for p27 was quantitated by the intensity of expression as well as the distribution of positive cells within each tumor. All tumors showed lower p27 expression than normal thyroid tissue. However, metastasizing PMCs demonstrated a significantly lower expression of p27 than nonmetastasizing PMCs (P.001). Conclusion: Our results suggest that p27 immunohistochemical analysis may be a valuable diagnostic tool in predicting aggressive potential in PMCs. Arch Otolaryngol Head Neck Surg. 2002;128:253-257

Objectives To determine the prevalence of alternative medicine use in the population with head and neck cancer and correlate with demographics and tumor characteristics. Design Cross-sectional survey study. Setting Two tertiary cancer centers. Patients Two hundred consecutive outpatients with consecutive head and neck cancer. Interventions A 10- to 25-minute patient interview administered by primary investigator. Main Outcome Measures Demographic markers (sex, age, education, household income, marital status, ethnic background, and geographic location); tumor characteristics (tumor site, pathology, staging, time since diagnosis, and incidence of recurrence); conventional mode of treatment; attitudes regarding alternative medicine, source of exposure to alternative medicine, therapeutic rationale, treatment efficacy, sources of information, and discussions with physicians about alternative medicine. Results Seventy-seven (38.5%) of 200 patients had used alternative medicine for some purpose, and 45 (22.5%) of 200 did so for head and neck cancer. Increased use of alternative medicine occurred among patients of younger age, having a postsecondary education, higher personal income, and Indo-Asian extraction. Of those patients using alternative anticancer therapy, increased use was noted among patients with tumors of the nasopharynx, nonsquamous cell carcinoma pathology, and recurrent disease. Conventional mode of treatment had no association with alternative medicine use. Physicians were believed to be the most knowledgeable about alternative medicine, while the usual proponents of alternative medicine were identified least frequently. Conclusions Alternative cancer therapy use among patients with head and neck cancer was 22.5%, with increased use in younger, affluent, better educated patients, and those of Indo-Asian extraction. Patients view physicians as being knowledgeable about alternative medicine. Otolaryngologists should inform themselves about alternative medicine to counsel patients more effectively.

The riboprotein telomerase has been linked to cellular immortality and is believed to play a key role in tumorigenesis.To determine if telomerase is expressed in patients with oral squamous cell carcinoma.Twenty patient samples of oral squamous cell carcinoma and 20 adjacent histologically normal mucosal samples were assayed using the telomeric repeat amplification protocol (TRAP) method for detection of telomerase activity. The leukemic cell line, K562, was used as a positive control and the human fibroblast line, Hs21Fs, as a negative control.Consecutive series of patients with oral squamous cell carcinoma presenting to a tertiary referral center.A sample was classified as telomerase positive when an RNase-sensitive hexameric repeat ladder was observed. Absence of laddering was considered a negative result.Eighteen (90%) of 20 tumor samples and 7 (35%) of 20 adjacent histologically normal samples were telomerase positive. A statistically significant difference was observed in telomerase activity for T1 and T2 cancers compared with T4 cancers (P.05 by analysis of variance). No statistically significant difference was observed in activity for T1 and T2 cancers vs T3 cancers.The finding of telomerase activity in 90% of tumor samples is consistent with the concept of telomerase playing a key role in tumorigenesis. Further study is needed to determine the usefulness of this enzyme as a molecular marker.

ObjectiveThis study aimed to examine atypical and malignant papillary oral lesions for low- and high-risk human papillomavirus (HPV) infection and to correlate HPV infection with clinical and pathologic features.Study DesignSections of 28 atypical papillary lesions (APLs) and 14 malignant papillary lesions (MPLs) were examined for HPV by in situ hybridization and for p16 and MIB-1 by immunohistochemistry; 24 conventional papillomas were studied for comparison.ResultsLow-risk HPV was found in 10 of 66 cases, including 9 APLs and 1 papilloma. All low-risk HPV–positive cases showed suprabasilar MIB-1 staining, and the agreement was statistically significant (P < .0001). Diffuse p16 staining combined with high-risk HPV was not seen in any of the cases. A subset of HPV− APLs progressed to carcinoma.ConclusionsOral papillary lesions are a heterogeneous group. Low-risk HPV infection is associated with a subset of APLs with a benign clinical course. Potentially malignant APLs and MPLs are not associated with low- or high-risk HPV.

Background The primary objective of this study is to describe variations in incidence rates, resection rates, and types of surgical ablations performed on patients diagnosed with major salivary gland cancers in Ontario. Methods All major salivary gland cancer cases in Ontario (2003–2010) were identified from the Ontario Cancer Registry (n = 1,241). Variations in incidence rates, resection rates, and type of surgical therapy were compared by sex, age group, neighbourhood income, community population, health region, and physician specialty. Results Eight-year incidence rates per 100,000 vary significantly by sex (male: 15.5, female: 9.7), age (18–54 years: 6.7, 75+ years: 53.4), neighborhood income (lowest quintile: 11.8, highest quintile: 13.7), and community size (cities with a population greater than 1.5 million: 10.6, cities with a population of less than 100,000: 14.7). There was a significant correlation between the likelihood to receive a resection and age with the elderly (75+ years) being the least likely to receive resection (69%). Large differences in incidence and resection rates were observed by health region. Otolaryngology-Head & Neck surgeons provide the majority of total/radical resections (95%). Conclusions Major salivary gland cancer incidence rates vary by sex, age, neighborhood income, community size, and health region. Resection rates vary by age and health region. These disparities warrant further evaluation. Otolaryngology-Head & Neck Surgeons provide the majority of major salivary gland cancer surgical care.

Background To identify prognostic factors in patients with parotid gland carcinomas who were treated at the Princess Margaret Hospital. Methods Clinical outcome of two hundred fifteen patients with malignancies of the parotid gland was evaluated over a 16-year period. Results Two-hundred-fifteen patients with adenoid cystic carcinoma (n = 20), adenocarcinoma (n = 19), acinic cell carcinoma (n = 62), basal cell adenocarcinoma (n = 7), carcinoma-ex-pleomorphic adenoma (n = 18), mucoepidermoid carcinoma (n = 70) and salivary duct carcinoma (n = 19) have been included. The 5- and 10-year overall and disease-free survivals were 80.62 %/69.48 % and 74.37 %/62.42 %, respectively. Multivariable analysis showed that age greater than 60 years, advanced pN classification, histopathological grade and the presence of lymphovascular invasion significantly worsened overall and disease-free survival. Univariable analysis revealed periparotid lymph node involvement was associated with decreased overall (p

Background SNAI1 can initiate epithelial-mesenchymal transition (EMT), leading to loss of epithelial characteristics and, in cancer, to invasion and metastasis. We hypothesized that SNAI1 reactivation occurs in oral squamous cell carcinoma (OSCC) where it might also be associated with focal adhesion kinase (FAK) expression and p63 loss. Methods Immunohistochemistry was performed on 46 tumors and 26 corresponding lymph node metastases. Full tissue sections were examined to account for rare and focal expression. Clinical outcome data were collected and analyzed. Results SNAI1-positivity (nuclear, ≥ 5% tumor cells) was observed in 10 tumors and 5 metastases (n = 12 patients). Individual SNAI1(+) tumor cells were seen in primary tumors of 30 patients. High level SNAI1 expression (>10% tumor cells) was rare, but significantly associated with poor outcome. Two cases displayed a sarcomatoid component as part of the primary tumor with SNAI1(+)/FAK(+)/E-cadherin(-)/p63(-) phenotype, but disparate phenotypes in corresponding metastases. All cases had variable SNAI1(+) stroma. A mesenchymal-like immunoprofile in primary tumors characterized by E-cadherin loss (n = 29, 63%) or high cytoplasmic FAK expression (n = 10, 22%) was associated with N(+) status and tumor recurrence/new primary, respectively. Conclusions SNAI1 is expressed, although at low levels, in a substantial proportion of OSCC. High levels of SNAI1 may herald a poor prognosis and circumscribed SNAI1 expression can indicate the presence of a sarcomatoid component. Absence of p63 in this context does not exclude squamous tumor origin. Additional EMT inducers may contribute to a mesenchymal-like phenotype and OSCC progression.

Objectives The objective of this study was to determine the frequency of complications in median and paramedian mandibulotomies. In addition, the interdental space in the median and paramedian region was calculated. Study design Retrospective study. Setting Tertiary care center. Methods A retrospective chart review was performed for all cases where a mandibulotomy was performed from 2002 to 2010. 117 charts (61 paramedian and 56 median) were identified. We included data on complications, which fell in the following 2 categories: plate and dental complications. For our second objective, we evaluated 40 different patients with base of tongue or tonsillar cancer treated with intensity modulated radiation therapy (IMRT). The interdental space between the lateral incisors and the canines was electronically calculated on the digital Panorex images. Main outcome measures Dental and plate complications were evaluated. We also assessed interdental space. Results Patient characteristics were not significantly different. The median group had significantly more dental complications (p=0.0375, RD=0.19 and 95% CI (0.0139-0.3661)). The paramedian group had significantly more plate complications (p=0.0375, RD=0.082 and 95% CI (0.0131-0.1508). The distance between the central incisors was significantly less than the distance between the lateral incisors and canines both at the crestal and apical levels (p=0.0086 and p Conclusions There are significantly more dental complications in the median approach. There were significantly more plate complications in the paramedian group. In addition, there is significantly less space in the between the median region as compared to the paramedian region. This is the first study that documents the advantage of the paramedian approach for dental complications.