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Intraoral radiation stents (IRS) are prosthetic devices that assist in the effective delivery of radiation to tumor tissues and aim to avoid unnecessary radiation to adjacent healthy tissues, thus limiting postradiotherapy toxicities. They are used to protect or displace vital structures, assist in positioning of the treatment beam for effective administration of radiotherapy, carry a radioactive material, shield healthy tissues of the oral cavity, and/or maintain the desired mouth opening during radiotherapy. With close collaboration between radiation oncologist and oral health care provider, several IRS can be fabricated by the latter for appropriate targeting and delivery of planned radiation dose and optimized treatment results. Modification of these IRS based on individual patient need is recommended to maximize prosthesis utility. The purpose of this review is to discuss the various types of IRS and highlight their clinical utility and benefits in patients receiving radiation therapy in the head and neck cancers.

Background A case-control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates. Methods Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status. Results The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio = 0.18, 95% Confidence interval: 0.03-0.97, p = .047) and more likely to have been exposed to bevacizumab (OR = 5.15, 95% CI: 1.67-15.95, p = .005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003. Conclusions We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.

PURPOSE: Dental evaluation and management prior to hematopoietic stem cell transplant (HSCT) plays a vital role in identifying and treating infections that may be life-threatening. The purpose of this study is to describe the dental management of patients undergoing pre-HSCT examination with the Dental Service at Memorial Sloan-Kettering Cancer Center (MSKCC) and to report on odontogenic complications. METHODS: Patients referred for evaluation as part of the standard preparation for HSCT were included. Following clinical and radiological examination, patients were assigned to one of three groups based on risk of odontogenic infection and treatment was provided as indicated. Patients were followed, and their medical records were reviewed for odontogenic complications during the transplant admission. RESULTS: Of the 375 patients evaluated, 350 patients underwent HSCT: Allogeneic 143 (40.9%), Autologous 207 (59.1%). The distribution of primary cancer diagnosis was as follows: multiple myeloma 104 (29.7%), leukemias 95 (27.1%), Hodgkin’s lymphoma 28 (8.0%), Non-Hodgkin’s Lymphoma 99 (28.3%), and other conditions 24 (6.9%). The median time from dental evaluation to transplant was 29 days. The median Decayed, Missing, Filled Teeth Index was 17. The median Community Periodontal Index was 1. Based on dental status, 145 patients (41.4%) were classified as low-risk, 133 (38%) as moderate-risk and 72 (20.6%) as high-risk of odontogenic infection. 114 patients (32.6%) required dental treatment prior to HSCT and 100 of these (28.6%) completed treatment. 2 (0.57%) patients had odontogenic complications. CONCLUSIONS: With conservative pre-HSCT dental treatment based on an infection risk classification system, a low odontogenic complication rate was observed.

Background Radiotherapy (RT), the main treatment for patients with head and neck cancer, can lead to dental complications. Methods We identified 244 patients with squamous cell carcinoma of the tonsil treated with RT from 2004 to 2013. For each patient, we contoured the 10 tooth-bearing regions and calculated the radiation dose (gray, Gy) to each region. From this data set, we built two predictive models to determine the expected maximum radiation dose, one for the non-molar regions and another for the molar regions. Results For the non-molars, the final model included location, T-classification, and overall stage, with a median absolute prediction error of 7.0 Gy. For the molars, the final model included location, T-classification, overall stage, and treatment year, with a median absolute error of 6.0 Gy. Conclusions Our current model offers a good estimation of the maximum radiation dose delivered to different regions of the jaw; future work will independently validate these models.

Background Although metastatic involvement of bony sites including cranial bones is common in neuroblastoma (NB), mandibular metastases (MM) are uncommon, and specific outcomes have not been reported upon in the modern therapeutic era. Methods In this retrospective study, medical records on patients with MM from NB were reviewed. Statistical analysis was performed using the Kaplan-Meier method. Results Of 29 patients, nine (31%) had MM at diagnosis, whereas in 20 (69%) MM were first detected at NB relapse at a median time of 26 (6-89) months from diagnosis. Median maximal diameter of lesions was 3 (range 0.8-4.9) cm. MM were unilateral in 83% of patients, with ascending ramus (55%) and mandibular body (38%) being the two most common sites. All patients received systemic chemotherapy, and 26 (93%) patients received radiotherapy to MM. At a median follow-up of 37.3 (24.2-219.5) months, eight of nine patients with MM at diagnosis did not experience mandibular progressive disease. Eighteen of 20 patients with MM at relapse received therapeutic radiotherapy; objective responses were noted in 78%. Seventy-two percent (5/18) had not experienced relapse within the radiation field at a median of 12 (2-276) months postradiotherapy. Dental findings at follow-up after completion of NB therapy included hypodontia, hypocalcification of enamel, and trismus. Median 3-year overall survival in patients with relapsed MM was 51 ± 12% months from relapse. Conclusion MM when detected at diagnosis is associated with a prognosis similar to that for other skeletal metastases of NB. Radiotherapy is effective for control of MM detected both at diagnosis and relapse. Significant dental abnormalities posttherapy warrant regular dental evaluations and appropriate intervention.

Purpose: This study investigated whether Magnetic Resonance image biomarkers (MR-IBMs) were associated with xerostomia 12 months after radiotherapy (Xer(12m)) and to test the hypothesis that the ratio of fat-to-functional parotid tissue is related to Xer(12m). Additionally, improvement of the reference Xer(12m) model based on parotid gland dose and baseline xerostomia, with MR-IBMs was explored.Methods: Parotid gland MR-IBMs of 68 head and neck cancer patients were extracted from pre-treatment T1-weighted MR images, which were normalized to fat tissue, quantifying 21 intensity and 43 texture image characteristics. The performance of the resulting multivariable logistic regression models after bootstrapped forward selection was compared with that of the logistic regression reference model. Validity was tested in a small external cohort of 25 head and neck cancer patients.Results: High intensity MR-IBM P90 (the 90th intensity percentile) values were significantly associated with a higher risk of Xer(12m). High P90 values were related to high fat concentration in the parotid glands. The MR-IBM P90 significantly improved model performance in predicting Xer(12m) (likelihood-ratio-test; p = 0.002), with an increase in internally validated AUC from 0.78 (reference model) to 0.83 (P90). The MR-IBM P90 model also outperformed the reference model (AUC = 0.65) on the external validation cohort (AUC = 0.83).Conclusion: Pre-treatment MR-IBMs were associated to radiation-induced xerostomia, which supported the hypothesis that the amount of predisposed fat within the parotid glands is associated with Xer(12m). In addition, xerostomia prediction was improved with MR-IBMs compared to the reference model. (C) 2018 The Authors. Published by Elsevier B.V.

Modern radiotherapy delivery systems and treatment strategies are aimed at limiting the irradiation of healthy structures in the head and neck. This seeks to mitigate post-treatment toxicities and complications such as osteoradionecrosis of the jaw. Given the changes to radiotherapy, conventional workflows for the management of patients requiring dentoalveolar surgery may no longer be suitable. It may therefore be appropriate to revisit current treatment algorithms for the management of patients with radiotherapy to the jaws who require dentoalveolar surgery. At present, there are poor data on this. Development of a randomised trial may be warranted to establish the true relative risk for extraction of teeth in the setting of modern radiation therapy delivery systems.

Objective The purpose of this study was to compare the dosimetric distribution of ipsilateral proton beam radiation therapy (PBRT) with intensity-modulated radiation therapy (IMRT) in the tooth-bearing region of the mandible in patients with head and neck cancer (HNC). Study Design The mandibular dosimetric distribution in patients with head and neck cancer treated with ≥60 Gy relative biologic equivalent PBRT was evaluated. The mean radiation doses were calculated in 5 regions: ipsilateral molar, ipsilateral premolar, anterior, contralateral premolar, and contralateral molar (CM) regions. CM was used as the reference region for comparative analysis. The mandibular dosimetric distribution in patients treated with PBRT was compared with that in IMRT patients with similar tumor sites and planning target volumes. Results The mean radiation dose to the contralateral regions was lower in patients treated with PBRT compared with those treated with IMRT. The average mean radiation doses to the reference region (CM) in patients treated with PBRT (relative biologic equivalent) versus IMRT were oropharynx (2.2 Gy vs 23.2 Gy; P P = .01), and oral cavity (0.4 Gy vs 15.6 Gy; P = .006). Conclusions This study revealed the effective tissue-sparing capability of PBRT compared with IMRT. Utilization of PBRT could translate to less radiation-related toxicity.

Based on their distinctive histologic and genetic features, the latest WHO classification of soft tissue tumors includes four pathologic variants of rhabdomyosarcoma (RMS): embryonal (ERMS), alveolar (ARMS), spindle cell-sclerosing (SRMS-ScRMS) and pleomorphic RMS. The aim of this study focused on a detailed clinicopathologic and survival analysis of head and neck RMS (HNRMS) using the latest pathologic and molecular criteria reflecting this new subclassification in a large cohort.Patients managed for HNRMS in our institution (1996-2015) were analyzed. The presence of a FOXO1 fusion was required for the classification of ARMS. MYOD1 mutations in SRMS-ScRMS were tested when material available. Univariate and multivariate analyses were performed to evaluate variables related to overall survival (OS).Ninety-nine HNRMS patients (52 males and 47 females, mean of 16years) were included in the study after pathologic re-review. The most common location was parameningeal (PM) (n=64), followed by non-orbital/non-PM (n=25) and orbital (n=10). There were 53 ERMS, 33 fusion-positive ARMS and 13 SRMS-ScRMS [SRMS (8); ScRMS (5)]. The 5-year OS rate for ERMS patients was significantly higher (82%) compared to ARMS (53%) and SRMS-ScRMS (50%) [SRMS (75%); ScRMS (30%)]. Univariate analysis showed that survival was dependent on histology (P=0.012), tumor size5cm (P0.001), regional lymph node involvement (P=0.002), metastasis at initial presentation (P0.001), stage (P0.001), and recurrence (P=0.002). Multivariate analysis confirmed histologic subtype to be significant (P=0.043).Our findings reinforce that HNRMS is a heterogenous disease with ARMS and SRMS-ScRMS having an equally unfavorable outcome.

Purpose: To identify imaged regions in which dose is associated with radiation-induced trismus after head and neck cancer radiation therapy (HNRT) using a novel image-based data mining (IBDM) framework. Methods and Materials: A cohort of 86 HNRT patients were analyzed for region identification. Trismus was characterized as a continuous variable by the maximum incisor-to-incisor opening distance (MID) at 6 months after radiation therapy. Patient anatomies and dose distributions were spatially normalized to a common frame of reference using deformable image registration. IBDM was used to identify clusters of voxels associated with MID (P ≤.05 based on permutation testing). The result was externally tested on a cohort of 35 patients with head and neck cancer. Internally, we also performed a dose-volume histogram–based analysis by comparing the magnitude of the correlation between MID and the mean dose for the IBDM-identified cluster in comparison with 5 delineated masticatory structures. Results: A single cluster was identified with the IBDM approach (P s = −0.36, –0.35, −0.32; P =.001,.001,.002, respectively). External validation confirmed an association between mean dose to the IBDM cluster and MID (R s = −0.45; P =.007). Conclusions: IBDM bypasses the common assumption that dose patterns within structures are unimportant. Our novel IBDM approach for continuous outcome variables successfully identified a cluster of voxels that are highly associated with trismus, overlapping partially with the ipsilateral masseter. Tests on an external validation cohort showed an even stronger correlation with trismus. These results support use of the region in HNRT treatment planning to potentially reduce trismus.

PurposeMetastatic solid tumors to the oral cavity are rare, frequently indicative of an end-stage disease process, and associated with poor survival rates. We performed a 20-year retrospective clinical analysis of our institution's cases of solid metastases to the oral cavity, and investigated these patients' clinical outcomes.Material and methodsA retrospective study of patients with metastatic solid tumors to the oral cavity over a 20-year period (October 1996 to September 2015) was conducted at Memorial Sloan Kettering Cancer Center. Patients were selected if they had a histopathologically confirmed diagnosis. Demographic, pathologic, and clinical information were reviewed to identify patient outcomes.ResultsA total of 44 patients with metastatic non-melanocytic non-hematopoietic tumor to the oral cavity were identified: 24 males and 20 females (39 adults and 5 children) with a mean age of 54.3 years. In all, 24 cases involved the jaw and 20 cases involved the oral soft tissue. Eight patients (18.2%) had oral cavity metastases as the first indication of an occult malignancy. In adult patients, the common primary sites were the lungs (n=9, 20%), kidney (n=7, 16%), breast (n=5, 11%), and colon (n=4, 9%); and in pediatric patients the adrenal gland (3/5) was the most common site. Of the adult patients, 33 (84.6%) died of disease. From the time of metastasis diagnosis, patients with jaw metastases had a median and mean survival of 12 months and 27.7 months, respectively. In comparison, patients with oral soft tissue metastases had a median survival time of 5 months, and mean of 8 months. One pediatric patient (20%) died of disease 8 months after metastasis diagnosis.ConclusionMetastatic solid tumors to the oral cavity can be the first sign of a malignancy. Pediatric patients with oral cavity metastases have a better prognosis compared to adult patients. In this series, adults with oral soft tissue involvement had shorter survival times compared to patients with jaw involvement.

Osteoradionecrosis (ORN) remains an unintended debilitating complication of radiation therapy despite the advent of intensity-modulated radiation therapy (IMRT) which aims to deliver doses of radiation to the tumor site while minimizing doses to healthy tissues [[1], [2], [3], [4]. The etiopathogenesis of ORN has been attributed to the avascular effect of radiation to the bone resulting in hypoxia, hypovascularity, and hypocellularity [5], [6]. Radiation-induced fibrosis has also been implicated in the pathophysiology of ORN [7. Recent studies have placed reported incidences of ORN at 1–30% [2], [8], [9], [10], [11]. ORN of the jaw was defined as an area of exposed necrotic bone greater than 1 cm in an area of previous irradiation that failed to heal after 6 months [5]. This definition of ORN has been used for years and still remains the most widely used clinical criterion for the diagnosis of ORN though it fails to incorporate cases with radiologic evidence of necrosis with intact mucosa [5], [12], [13], [14], [15]. Although a report by Van Merkesteyn et al. described a case of ORN of the jaw with intact mucosa [16], subsequently only two series have likewise reported this condition. In 2000, Store and Boysen reported 17 patients with radiographic osteoradionecrosis of the jaw (rORN) with intact mucosa at initial diagnosis as did He et al. in a recent article where they described 16 patients presenting with rORN with intact mucosa [17], [18]Thus, it appears that rORN with intact mucosa is underdiagnosed. The objectives of this article are to: 1. Describe new cases of rORN with intact mucosa. 2. Correlate the dosimetric analyses of the involved area with the radiographic presentation and to determine the best predictor of rORN with intact mucosa. 3. Propose modification of Store and Boysen’s staging system of ORN. 4. Propose clinical guidelines for early identification of rORN with intact mucosa.

ObjectiveThe aim of this study was to investigate the relationship between type of antiresorptive medication and medication-related osteonecrosis of the jaw (MRONJ) onset and the role of premedication dental evaluation (PMDE) in the prevention of MRONJ.Study designOur database of patients with MRONJ was reviewed. The Kruskal-Wallis test was used to analyze the onset dose of the 3 frequent medication types associated with MRONJ. To evaluate the role of PMDE in the prevention of MRONJ, all patients on antiresorptive and/or antiangiogenic medications seen in the Dental Service of Memorial Sloan Kettering Cancer Center during a 10-year period were subclassified into 2 groups. Group I comprised patients seen for PMDE before the commencement of A/A and group II patients seen after prior exposure to antiresorptive and/or antiangiogenic medications. Fischer's exact test was used to compare the incidence of MRONJ in both groups.ResultsPatients on denosumab developed MRONJ earlier compared with zoledronate and pamidronate (P = .003). Group I had a significantly reduced incidence of MRONJ (0.9%) compared with group II (10.5%) (P

Head and neck high grade malignant peripheral nerve sheath tumors (HN-MPNSTs) are rare highly aggressive soft tissue sarcomas that show overlapping morphologic and immunophenotypic features with melanoma and other high grade sarcomas, resulting in diagnostic challenges, particularly in sporadic settings. Recent discoveries have implicated loss of function mutations in the polycomb repressive complex 2 (PRC2) components, including EED or SUZ12 genes, as one of the leading pathogenetic mechanisms in high grade MPNST. MPNSTs with PRC2 loss are associated with complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3), which emerged as a reliable immunohistochemical marker in the diagnosis of sporadic and radiation induced MPNST. As the diagnosis of MPNST in the HN is particularly challenging to distinguish from melanoma and other sarcoma types, we carried out a clinicopathologic analysis on HN-MPNST patients managed at our institution over a 20-year period (1997-2016), using the latest diagnostic criteria including H3K27me3 staining and other molecular investigations. The overall survival of HN-MPNST was compared with other HN soft tissue sarcomas. The diagnosis of HN-MPNST was confirmed in 13 patients (seven males and six females), with a mean age of 31 years; with 3 (23%) patients being of pediatric age. The most common site was the neck soft tissue (77%). Two-thirds of patients (n = 9) had stigmata of NF1, three had prior radiotherapy and only one developed a de novo MPNST. All except one tumor (86%) tested showed loss of H3K27me3 expression, including all non-NF1 patients. The 2 and 5-year DSS rates were 50 and 30%. The 2-year DFS rate was 21%. Adverse predictors on DSS included adult age (p = 0.011), prior-history of RT (p = 0.003) and recurrence (p = 0.003). Compared to other molecularly confirmed subsets of HN sarcomas (Ewing and Ewing-like sarcoma, rhabdomyosarcoma and synovial sarcoma), HN-MPNST had the worst overall survival (p

CIC-rearranged sarcoma (CRS) is a relatively new entity defined by its pathognomonic genetic signature and undifferentiated round cell phenotype, initially grouped together with the ‘Ewing sarcoma-like tumors’. However, increasing data suggest that these tumors should be regarded as a stand-alone pathologic entity. We conducted a clinicopathologic analysis on molecularly conformed Ewing sarcoma (ES) and CRS arising in the head and neck (HN) and compared to a well characterized cohort of ES and CRS from other locations. A total of 41 HN round cell sarcoma patients were selected from our institutional and consultation files, including 25 ES (median 20 years) and 16 CRS (median 29 years). Clinical follow-up information was available for all ES patients, ranging from 4 to 436 months (median 70 months), while for CRS, follow-up information was available in 11 patients (69%), ranging from 1 to 269 months (median 27 months). The most common location for ES was the facial and jaw bones (56%), while CRS occurred exclusively in the soft tissue, commonly in the neck. CRS showed variable CD99 staining in 75% of cases and diffuse WT1 (6/6) reactivity, while all ES expressed diffuse membranous staining for CD99 but none for WT1 (0/6). The 2-year overall survival (OS) rate for HN-CRS patients was 78%, while for HN-ES it was 100%. The OS of ES and CRS showed a trend toward a favorable outcome for HN-round cell sarcomas compared to other sites. Our findings suggest that HN-CRS have different clinical presentation and pathologic features compared to ES and should be classified as a stand-alone pathologic entity.

Objective To determine the prevalence and correlation of various risk factors [radiation dose, periodontal status, alcohol and smoking] to the development of osteoradionecrosis (ORN). Patients and methods The records of 1023 patients treated with IMRT for oral cavity cancer (OCC) and oropharyngeal cancer (OPC) between 2004 and 2013 were retrospectively reviewed to identify patients who developed ORN. Fisher exact tests were used to analyze patient characteristics between ORN patients with OCC and OPC. Paired Wilcoxon tests were used to compare the dose volumes to the ORN and contralateral non-ORN sites. To evaluate an association between ORN and risk factors, a case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by gender, tumor site and size. General estimation equations models were used to compare the risk factors in ORN cases and matched controls. Results 44 (4.3%) patients developed ORN during a median follow-up time of 52.5 months. In 82% of patients, ORN occurred spontaneously. Patients with OPC are prone to develop ORN earlier compared to patients with OCC (P = 0.03). OPC patients received a higher Dmax compared to OCC patients (P = 0.01). In the matched case-control analysis the significant risk factors on univariate analysis were poor periodontal status, history of alcohol use and radiation dose (P = 0.03, 0.002 and 0.009, respectively) and on multivariate analysis were alcohol use and radiation dose (P = 0.004 and 0.026, respectively). Conclusion In our study, higher radiation dose, poor periodontal status and alcohol use are significantly related to the risk of developing ORN.

CASE PRESENTATION In October 2012, a 70-year-old black woman presented to her ophthalmologist, who noted that she had a left parotid mass. She was subsequently referred to a hospital to have the mass evaluated. It was unclear how long the mass was present, but there were no symptoms. The patient reported no family history of malignancy, and her health was significant for type 2 diabetes mellitus, non-insulin-dependent. The patient had smoked 2 packs a day for 22 years, but she stated that she had quit 40 years ago. She stated she drank 1 to 2 alcoholic beverages per month. At an outside hospital, ultrasonography found a heterogeneously hypoechoic mass with irregular margins containing focal necrosis with possible deep extracapsular extension measuring 1.96 2.49 cm. No increased flow signal was seen on Doppler mode. A fine-needle aspiration (FNA) of the parotid mass was suspicious for acinic cell carcinoma. Within the same month, the patient was sent to Memorial Sloan Kettering Cancer Center. A computed tomography (CT) scan of the neck found an ill-defined, enhancing soft tissue mass in the left parotid tail with no deep parotid involvement, measuring 2.3 1.9 2.0 cm (Figure 1). No abnormal lymphadenopathy was noted in the neck. A second FNA taken of the left parotid found a salivary gland neoplasm with a cylindromatous pattern, which favored pleomorphic adenoma (Figure 2). The FNA slides from the previous hospital were also reviewed, and ultimately the diagnoses encompassed a differential diagnosis that included both acinic cell carcinoma and pleomorphic adenoma. A positron emission tomographyecomputed tomography scan found a 1.3 1.5-cm left parotid nodule with a maximum standardized uptake value of 2.7 (Figure 3). No hypermetabolic lymphadenopathy was noted in the neck.

Background and purpose To study internal and external generalizability of temporal dose–response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Material and methods Objective xerostomia was assessed in 121 patients (n Cohort1 =55; n Cohort2 =66) treated to 70Gy@2Gy in 2006–2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1 , and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p -values, and Hosmer–Lemeshow p -values (p HL )). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmean contra , Dmean ipsi ) were estimated from the generated dose–response curves. Results The observed xerostomia rate was 38%/47% (3months) and 19%/23% (11–12months) in Cohort1/Cohort2 . Risk of xerostomia at 3months increased for higher Dmean contra and Dmean ipsi ( Cohort1 : 0.17·Dmean contra +0.11·Dmean ipsi -8.13; AUC=0.90±0.05; p =0.0002±0.002; p HL =0.22±0.23; Cohort2 : AUC=0.81; p HL =0.27). The identified minimum Dmean contra thresholds were lower than in the QUANTEC guidelines ( Cohort1/Cohort2: Dmean contra =12/19Gy; Dmean contra , Dmean ipsi =16, 25/20, 26Gy). Conclusions Increased Dmean contra and Dmean ipsi explain short-term xerostomia following IMRT. Our results also suggest decreasing Dmean contra to below 20Gy, while keeping Dmean ipsi to around 25Gy. Long-term xerostomia was less frequent, and no dose–response relationship was established for this follow-up time.

ObjectiveTo determine clinicopathologic factors on survival in patients with head and neck synovial sarcoma.Patients and methodsWe retrospectively identified patients with molecularly confirmed synovial sarcomas of the head and neck (SS-HN), either by the presence of SS18-SSX fusion transcript by RT-PCR or SS18 gene rearrangement by FISH, who were managed at our institution over a 20-year period (1996-2015). Kaplan-Meier survival analysis and log-rank test were performed to evaluate variables related to disease specific survival (DSS). Fisher exact test was performed to evaluate variables related to local recurrence.ResultsThirty-four patients (20 males and 14 females, mean of 31years) with SS18-SSX fusion-positive SS-HN were identified. The parapharyngeal region of the neck was the most common site. The mean tumor size was 4.8cm (0.8-10cm). Two-thirds (n=23) of cases had a monophasic histology. The 2, 5 and 10-year DSS rates were 97%, 79% and 68%. The 5-year DSS rates for the adult/pediatric cohort were 74%/88%. Recurrence showed significant effect on DSS (p=0.021). There was no significant effect on DSS with age, therapy modality, tumor site, surgical margin, tumor size (⩽5cm vs. >5cm) and histopathologic subtype. Tumor site (i.e. skull base/paranasal sinus region) was associated with local recurrence (p=0.003).ConclusionIn our cohort DSS rate was associated with recurrence. Tumors located in the skull base/paranasal sinus region were associated with a higher rate of local recurrence. Thus appropriate selection of high risk patients who can benefit from multimodality therapies might improve survival.

Purpose Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteonecrosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. Patients and Methods Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. Results From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. Conclusions In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis.

Dentofacial developmental abnormalities have been reported in head and neck rhabdomyosarcoma (HNRMS) patients treated with conventional radiotherapy technique and chemotherapy. This current study investigates dentofacial long-term effects among HNRMS survivors managed with intensity-modulated radiotherapy (IMRT) and chemotherapy. In general, IMRT is a more effective 3D-conformal radiotherapy technique, which delivers high doses of radiation to the tumor target while minimizing doses received by the surrounding normal tissues. The medical records and radiographs were reviewed to identify the following: 1. Facial asymmetry and jaw hypoplasia. 2. Effects on the dental tissue causing tooth agenesis/hypodontia, root agenesis/stunting/malformation, and/or enamel hypoplasia. 3. Trismus, hyposalivation/xerostomia. Thirteen patients reviewed were evaluated at the dental service. Seven patients presented with facial asymmetry and jaw hypoplasia, 9 patients presented with effects on the dental tissue [root agenesis/stunting/malformation (9), tooth agenesis/hypodontia (7) and enamel hypoplasia (3)] and 7 patients developed trismus and /or xerostomia. All patients with facial asymmetry and jaw hypoplasia also developed dental abnormalities. Patients with dentofacial developmental abnormalities were ≤ 7 years of age at treatment. Our study shows that dentofacial developmental abnormalities are still a burden in the era of IMRT and as prognosis of childhood malignancy improves and more patients become long-term survivors, these late dentofacial sequelae among childhood cancer survivors will be common. To minimize these complications, dental oncologists should be integrated into the care of children with head and neck cancers.

PurposeThe aim of this study was to estimate the prevalence of trismus in oral and oropharyngeal cancer patients (OOPC) treated with intensity-modulated radiation therapy (IMRT) and to identify the role of risk factors in patients who developed trismus.Materials and methodsA retrospective cohort study of OOPC treated with IMRT in our institution from 2009 to 2014 was performed. Patients eligible for this study had pre-RT and post-RT maximal inter-incisal opening (MIO) measurements at 6-48 months post-RT, treated with high-dose radiation (≥60Gy) and pre-RT MIO ≥36mm. A descriptive analysis to identify the incidence of trismus, with trismus stated as MIO ≤35mm at or after 6 months post-RT measurement was performed. The role of risk factors such as age, gender, tumor site, tumor size (T), tumor stage, pre-RT MIO measurements and radiation dose to the tumor were assessed using Fisher exact test and the radiation doses to the ipsilateral muscles of mastication in patients who developed trismus were assessed by matching with control (non-trismus) patients using Wilcoxon Signed Rank test.ResultsThe study consisted of 54 patients with a median age of 55 years and 81% were males. The median follow-up time was 10 months. The prevalence of trismus was 14.8%. Patients with pre-RT MIO measurements ≤40mm were at risk of developing trismus (P&nbsp

BackgroundThe aims of this study were to investigate temporal patterns and potential risk factors for severe hyposalivation (xerostomia) after intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), and to test the two QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) guidelines.Patients and methodsSixty-three patients treated at the Memorial Sloan Kettering Cancer Center between 2006 and 2015, who had a minimum of three stimulated whole mouth saliva flow measurements (WMSFM) at a median follow-up time of 11 (range: 3-24) months were included. Xerostomia was defined as WMSFM ≤25% compared to relative pre-radiotherapy. Patients were stratified into three follow-up groups: 1

Objective Very few studies have evaluated the efficacy of pentoxifylline and tocopherol (PENT-E) in the management of medication-related osteonecrosis of the jaw (MRONJ), although some studies have shown the therapeutic and prophylactic benefit of PENT-E in the management of osteoradionecrosis. We report the outcomes of MRONJ managed with PENT-E in patients with metastatic bone disease or multiple myeloma. Study Design Seven patients diagnosed with established cases of refractory MRONJ caused by antiresorptive medications for the management of metastatic bone tumors or multiple myeloma were administered PENT-E for a mean period of 16.8 months (range 3-48 months). Results At the latest follow-up visit, all patients demonstrated relief of symptoms. There was radiographic evidence of new bone fill of prior radiolucent defect in all patients. Two patients had resolution of exposed bone, two patients had partial resolution, one patient had no change in exposed bone, and one patient with three sites of exposed bone before starting PENT-E had resolution in one site, partial resolution in another site, and no change in the third site. PENT-E was well tolerated in all patients. Conclusions Our case series demonstrated that PENT-E was well tolerated and may be an effective adjunct in the management of MRONJ.

Purpose Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated. Methods and Materials From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints. Results With a median clinic follow-up of 37.4 months (range, 0.8–89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n = 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT. Conclusions ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions.

Purpose Primary Ewing sarcoma of the jaw is rare. The aim of this study was to describe new cases of primary Ewing sarcoma of the jaw and investigate reported prognostic factors of Ewing sarcoma in this series and treatment outcome. Materials and Methods Six patients with primary Ewing sarcoma of the jaw were treated at the Memorial Sloan Kettering Cancer Center (MSKCC) from 1992 through 2013. Clinical data, pathology reports, treatment prescribed, treatment regimens, outcome, and follow-up information were reviewed. Results Five of 6 patients were female and 5 cases were in the mandible. No patient presented with metastatic disease at diagnosis. All cases were positive for CD99, and 3 patients with genetic confirmation were positive for EWS-FLI1 fusion or EWSR1 gene rearrangement. All patients received induction multiagent chemotherapy and surgical resection and 2 patients received adjuvant radiotherapy. Total (grade IV) or nearly total (grade III) tumor necrosis in 3 of 5 patients (60%) assessed for histologic response to chemotherapy indicated intense sensitivity. All patients were alive and free of disease, with no history of local recurrence, at a median follow-up period of 6.5 years. Conclusion Patients with primary Ewing sarcoma of the jaw have a good prognosis and metastasis is an uncommon occurrence at initial presentation.

Angiosarcomas are rare, malignant neoplasms of vascular origin that account for less than 1% of all soft tissue tumors. Angiosarcomas of the oral cavity are especially rare, and brachytherapy may be prescribed as a localized treatment to manage these malignancies. Intraoral brachytherapy requires collaboration between the radiation oncologist and a dental professional for the fabrication of the brachytherapy delivery prosthesis. The present clinical report describes an intraoral angiosarcoma and the fabrication of an intraoral brachytherapy prosthesis to manage this malignancy.

Background Bacterial infections have been linked to malignancies due to their ability to induce chronic inflammation. We investigated the association of oral bacteria in oral squamous cell carcinoma (OSCC/tumor) tissues and compared with adjacent non-tumor mucosa sampled 5 cm distant from the same patient (n = 10). By using culture-independent 16S rRNA approaches, denaturing gradient gel electrophoresis (DGGE) and cloning and sequencing, we assessed the total bacterial diversity in these clinical samples. Results DGGE fingerprints showed variations in the band intensity profiles within non-tumor and tumor tissues of the same patient and among the two groups. The clonal analysis indicated that from a total of 1200 sequences characterized, 80 bacterial species/phylotypes were detected representing six phyla, Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Actinobacteria and uncultivated TM7 in non-tumor and tumor libraries. In combined library, 12 classes, 16 order, 26 families and 40 genera were observed. Bacterial species, Streptococcus sp. oral taxon 058, Peptostreptococcus stomatis, Streptococcus salivarius, Streptococcus gordonii, Gemella haemolysans, Gemella morbillorum, Johnsonella ignava and Streptococcus parasanguinis I were highly associated with tumor site where as Granulicatella adiacens was prevalent at non-tumor site. Streptococcus intermedius was present in 70% of both non-tumor and tumor sites. Conclusions The underlying changes in the bacterial diversity in the oral mucosal tissues from non-tumor and tumor sites of OSCC subjects indicated a shift in bacterial colonization. These most prevalent or unique bacterial species/phylotypes present in tumor tissues may be associated with OSCC and needs to be further investigated with a larger sample size.

The aim of this study was to review the available literature and define clinical practice guidelines for the use of laser and other light therapies for the prevention and treatment of oral mucositis. A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. A new recommendation was made for low-level laser (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm2 (2 s/point)) for the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation conditioned with high-dose chemotherapy, with or without total body irradiation. A new suggestion was made for low-level laser (wavelength around 632.8 nm) for the prevention of oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer. No guideline was possible in other populations and for other light sources due to insufficient evidence. The increasing evidence in favor of low-level laser therapy allowed for the development of two new guidelines supporting this modality in the populations listed above. Evidence for other populations was also generally encouraging over a range of wavelengths and intensities. However, additional well-designed research is needed to evaluate the efficacy of laser and other light therapies in various cancer treatment settings.

Objective We report long-term follow-up of patients with intravenous bisphosphonate–related osteonecrosis of the jaw (BRONJ). Study Design Medical and dental histories, including type and duration of bisphosphonate treatment and comorbidities, were analyzed and compared with clinical course of 109 patients with BRONJ at Memorial Sloan-Kettering Cancer Center Dental Service. Results Median onset of BRONJ in months was 21 (zoledronic acid), 30 (pamidronate), and 36 (pamidronate plus zoledronic acid), with a significant difference between the pamidronate plus zoledronic acid and zoledronic acid groups (P = .01; Kruskal-Wallis). The median number of doses for BRONJ onset was significantly less with zoledronic acid (n = 18) than pamidronte plus zoledronic acid (n = 36; P = .001), but not pamidronate alone (n = 29). An association between diabetes (P = .05), decayed-missing-filled teeth (P = .02), and smoking (P = .03) and progression of BRONJ was identified through χ2 test. Conclusions This long-term follow-up of BRONJ cases enhances the literature and contributes to the knowledge of BRONJ clinical course.

Objectives Osteoradionecrosis is a significant complication following head and neck radiotherapy. The purpose of this study was to determine the intensity-modulated radiation therapy (IMRT) dosages delivered to the tooth-bearing regions of the mandible. Study Design A total of 28 patients with base of tongue cancer with the following stages: T1-2/N2-3 (n = 10), T3-4/N2-3 (n = 10), and T1-4/N0 (n = 8), treated with IMRT, were included. Average mean and maximum doses were calculated for the anterior, premolar, and molar regions. Results Lower doses were seen in anterior bone with smaller tumors. Large tumors, regardless of laterality, resulted in high doses to the entire mandible, with anterior bone receiving more than 6000 cGy. Conclusions Tumor size is important in preradiation dental treatment planning. This information is important in planning pre- and postradiation dental extractions. Dosimetric analyses correlating mean and maximum point dose with clinical presentation and outcomes are needed to determine the best predictor of osteoradionecrosis risk.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.

Lung neoplasms commonly develop in patients previously treated for head and neck carcinomas. The derivation of these tumors, either as new primary lung cancers or as metastatic head and neck cancers, is difficult to establish based on clinical or histopathologic criteria since both are squamous cell carcinomas and have identical features under light microscopy. However, this distinction has significant treatment and prognostic implications. Gene expression profiling was performed on a panel of 52 sequentially collected patients with either primary lung (n = 21) or primary head and neck (n = 31) carcinomas using the Affymetrix HG_U95Av2 high-density oligonucleotide microarray. Unsupervised hierarchical clustering with Ward linkage and the Pearson correlation metric was performed. To assess robustness, bootstrap resampling was performed with 1,000 iterations. A t test of the normalized values for each gene was used to determine the genes responsible for segregating head and neck from lung primary carcinomas, and those with the most differential expression were used for later analyses. In the absence of a large “test” set of tumors, we used a supervised leave-one-out cross-validation to test how well we could predict the tumor origin. Once a gene expression profile was established, 12 lung lesions taken from patients with previously treated head and neck cancers were similarly analyzed by gene expression profiling to determine their sites of origin. Unsupervised clustering analysis separated the study cohort into two distinct groups which reliably remained segregated with bootstrap resampling. Group 1 consisted of 30 tongue carcinomas. Group 2 consisted of 21 lung cancers and 1 tongue carcinoma. The clustering was not changed even when normal lung or tongue profiles were subtracted from the corresponding carcinomatous lesions, and a leave-one-out cross-validation showed a 98% correct prediction (see Supplementary Data 1). A minimum set of 500 genes required to distinguish these groups was established. Given the ability to segregate these lesions using molecular profiling, we analyzed the lung tumors of undetermined origin. All cases clearly clustered with either lung or tongue tumor subsets, strongly supporting our hypothesis that this technique could elucidate the tissue of origin of metastatic lesions. Although histologically similar, squamous cell carcinomas have distinct gene expression profiles based on their anatomic sites of origin. Accordingly, the application of gene expression profiling may be useful in identifying the derivation of lung nodules and consequently enhances treatment planning.

Amplification at chromosome 3q26.3 is a common and crucial event in head and neck squamous cell carcinoma (HNSCC), impacting significantly on tumor progression and clinical outcome. Two novel oncogenes, namely squamous cell carcinoma (SCC)-related oncogene (SCCRO) and PIK3CA (gene encoding phosphatidylinositol-3 kinase catalytic alpha-polypeptide), have been identified as targets of 3q26.3 amplification. This study aimed to delineate the role of SCCRO and PIK3CA in the pathogenesis of oral tongue SCC.The association between gene copy number for SCCRO and PIK3CA measured by fluorescence in situ hybridization and level of mRNA expression quantitated by real-time reverse transcription-PCR was assessed in a panel of human HNSCC cell lines. In addition, gene expression in 49 consecutive primary SCCs of the oral tongue was determined and correlated with clinicopathological characteristics and outcome.The mRNA level of SCCRO and PIK3CA was significantly correlated to the gene copy number in nine HNSCC cell lines. In addition, the expression level of SCCRO and PIK3CA was significantly greater in malignant tissues compared with those in histologically normal mucosae (2.17- and 2.46-fold, respectively; P0.001). Matched tumor normal control analysis revealed that 24.5 and 69.4% of patients expressed high levels of SCCRO and PIK3CA, respectively. Univariate analyses demonstrated that SCCRO overexpression correlated with nodal metastases (P = 0.05) and advanced stage (P = 0.02), whereas PIK3CA overexpression was associated with vascular invasion (P = 0.04). Only SCCRO overexpression was associated with disease-specific (P = 0.04) and overall survival (P = 0.02). Furthermore, SCCRO overexpression remained an independent predictor for cervical nodal metastasis on multivariate regression analysis (chi(2) likelihood ratio = 4.38; P = 0.04).Although both SCCRO and PIK3CA may play a role in the pathogenesis of oral tongue SCC through amplification at 3q26, SCCRO appears to be a significant predictor of regional metastasis and may be a marker for tumor aggressiveness and clinical outcome.

Background The present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling. Methods The gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR. Results Hierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (PHSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4 mRNA expression failed to show correlation with any of the relevant parameters. Conclusion The characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.