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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.

Background Bisphosphonates, such as zoledronic acid, are commonly used to treat bone metastasis from malignant conditions, such as multiple myeloma, or from solid tumors, such as breast or prostate cancer. Medication-related osteonecrosis of the jaw (MRONJ) is one of the complications of bisphosphonate treatment. The reported incidence of MRONJ among patients with cancers and bone metastases treated with zoledronic acid is 1.3%. MRONJ has been reported to have an incidence rate of up to 18.5%. The clinical and radiographic presentations of MRONJ are very similar to those of bone metastases, making early diagnosis and timely treatment challenging. This is a case report of a patient with multiple myeloma with a history of treatment with zoledronic acid and whose initial presentation of an intraoral lesion made it challenging to distinguish between bone metastasis and MRONJ. Case Summary This is a case report of a 67-year-old female with multiple myeloma, with a history of zoledronic acid, 28 doses taken from 2013 to 2016 and the disease in remission. The patient initially presented with a 1-week history of firm gingival swelling buccal and lingual to a fixed partial denture (FPD) in the left mandible. Panoramic radiography showed a well-defined radiolucent lesion. Considering her history of antiresorptive treatment, MRONJ was considered as one of the diagnoses. However, because of the unusual hyperkeratotic nature of the buccal gingiva, relapsed disease was included in the differential diagnosis. Because of the unconventional clinical manifestation and concerns about relapsed disease, computed tomography guided bone biopsy was performed, and it revealed plasma cell neoplasm and necrotic bone. The patient was treated with palliative radiation therapy and antibiotics, which resulted in a significant decrease in her symptoms. Eventually, a portion of the FPD was removed, and an exposed bony site with a mobile bony sequestrum was revealed. Removal of the sequestrum led to complete gingival healing of the exposed site. Conclusions Maxillofacial manifestation of bone metastasis is common but is often overlooked. Therefore, it should be considered in the differential diagnosis when a patient with a history of antiresorptive medications presents with a gingival mass and/or exophytic bone. Good clinical judgment and well-timed bone biopsy and diagnostic imaging can lead to the correct diagnosis and optimal treatment.

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.

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.

Objectives Osteoradionecrosis (ORN) is a complication of head and neck radiation therapy (RT) and is associated with significant morbidity. The incidence of ORN is variable, and it has been speculated to be lower with advanced RT techniques. Risk factors that have been associated with the development of ORN mainly include trauma and a radiation dose to the head and neck region greater than 60 Gy. However, in a study conducted by our group, ORN developed spontaneously (without any known history of trauma or dentoalveolar procedure) in 82% of the ORN cohort following intensity-modulated radiation therapy (IMRT).The purpose of this study was to characterize spontaneous ORN and to compare spontaneous ORN with nonspontaneous ORN (e.g., related to trauma or dentoalveolar procedures). Study Design Following approval by the Institutional Review Board of the Memorial Sloan Kettering Cancer Center (MSKCC), the treatment records of 44 patients with spontaneous ORN (group A) and 24 patients with nonspontaneous ORN (group B) treated with IMRT at the MSKCC for head and neck cancer (HNCa) were identified and retrospectively reviewed. Average prescribed mean and maximum radiation doses for the region of ORN were calculated by using MSKCC's proprietary radiation treatment planning software. Furthermore, Fischer's exact test was used to compare patient characteristics, such as primary site, tumor stage, smoking status, and other comorbidities, between the spontaneous ORN group and the nonspontaneous ORN group. Results According to preliminary data from 12 patients in group A and 6 patients from group B, the patients in group A appeared to have been exposed to higher radiation doses (Dmax; greater than 70 Gy) compared with group B. Furthermore, no statistical significance was noted between the 2 groups with regard to primary tumor, tumor stage, smoking status, and comorbidities, such as cardiovascular disease and hypertension (P > .05). However, statistical significance was evident for diabetes in group B (P Conclusions Collection of data on the expanded cohort of patients from each group, as well as other variables, such as radiation therapy fractionation, is ongoing. Our initial data indicates that increased radiation dose greater than 70 Gy may be associated with the development of spontaneous 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.

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.

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.

A 52-year-old male with history of metastatic melanoma of unknown primary, stage IV with metastases to the left iliac region as well as pancreatic head was diagnosed in early 2014. The metastatic melanoma to the iliac bone presented as a large painful lesion and radiologically as a large lytic lesion. He was treated with palliative radiotherapy, 27 Gy in 3 fractions completed in March 2014 and at about the same time started on Ipilimumab at 3 mg/kg intravenous (230 mg) every 3 weeks for a total of 4 doses, the last one in May 2014. Six days following the second dose of Ipilimumab, the patient presented with a gingival swelling on the lingual aspect of the right mandible. On examination, there was a swelling of the lingual gingiva adjacent to the right mandibular molars, localized bleeding on probing, mild discomfort, and a small amount of purulent discharge was expressed from the gingival sulcus on palpation (Fig. 1A). Panoramic and periapical radiographs showed no obvious radiopaque or radiolucent lesions. The area was irrigated with 0.12% chlorhexidine. He was advised to irrigate the area 3 times per day with chlorhexidine. One week later, he presented for a follow-up, at which time he said “it doesn't feel better”. On examination, the swelling had progressed, a fistula was noted from the lingual area of the right mandibular second molar to the mylohyoid space, and on palpation purulence was expressed from the fistula with slight discomfort. Nevertheless, the patient had excellent oral hygiene. He was prescribed Augmentin 875 mg bid for 7 days. A month later, he presented with a complaint of “my other doctor thought he saw some exposed bone in the area that we have been watching”. He stated that it was asymptomatic; however his tongue noticed something rough. On examination, there was a 2 × 2 mm exposed necrotic-appearing bone on the lingual aspect of the right mandibular second molar (Fig. 1B), there was slight purulence on palpation and the bone was mobile but no tenderness or sensitivity on manipulation. The patient was instructed to continue with the chlorhexidine rinse. In 3 weeks, he returned with the complaint of “the bone is moving around now and bothering my tongue”. There was no history of pain from that area. On examination, an area of exposed necrotic bone measuring 10 × 5 mm was present (Fig. 1C); the bone was very mobile and easily removed with cotton forceps with no associated pain or bleeding on removal. The patient was advised to continue the chlorhexidine rinse. The specimen was submitted for histopathologic evaluation (Fig. 1D), which was reported as a non-vital bone (sequestrum) with bacterial colonies consistent with actinomyces species associated with acute inflammatory cells (Fig. 1E). At his 2 month follow-up examination, the area had fully resolved and healed with no purulent discharge or pain on palpation (Fig. 1F). Fig. 1 Clinical picture at initial presentation showing a gingival swelling (A), clinical picture a month later showing a 2 × 2 mm area of exposed bone (B), clinical picture 3 weeks later showing a 10 × 5 mm area of exposed necrotic bone (C), ... The clinical findings of bone exposure of the jaw with histopathologic diagnosis of sequestrum with actinomyces and neutrophils are similar to osteonecrosis of the jaw (ONJ) in patients treated with anti-resorptive or antiangiogenic agents. With no history of radiation therapy to the jaw or metastasis of the tumor to the jaw, this can be termed medication related osteonecrosis of the jaw (MRONJ) [1]. Since 2003, there has been an increase in ONJ cases related to anti-resorptive medications such as Alendronate (oral bisphosphonate), Pamidronate and Zolendronate (intravenous bisphosphonate), Denosumab (humanized monoclonal antibody) and anti-angiogenic medications such as Sunitinib (tyrosine kinase inhibitor) and Bevacizumab (humanized monoclonal antibody), which targets the vascular endothelial growth factor pathway [[2], [3], [4], [5], [6], [7]]. This patient had not used any of the aforementioned class of medications. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma both in naive or post-chemotherapy treated patients. Ipilimumab is a humanized monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is expressed in activated T-cells and in suppressor T-regulatory cells which bind to antigen presenting cells thereby lessening T-cell responses. Blocking the CTLA-4 increases the antitumor responses by activated T-cells. Ipilimumab has demonstrated clinical benefits in the management of melanoma [[8], [9]]. The adverse toxicities of Ipilimumab have been attributed to increased immune-reactivity against normal tissues causing pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies [10]. Bone necrosis was not reported. We suggest that Ipilimumab may have been involved in the process of bone necrosis in this patient. Ipilimumab increases systemic activated T-cells presence. CTLA4 deficient activated T-cells have been shown to be associated with osteonecrosis, as activated T-cells may elicit osteoclastogenesis via osteoprotegerin ligand resulting in bone loss [11]. Trauma from regular oral activity (chewing or tooth brushing) could increase the demand on this vulnerable bone to mend itself, resulting in localized bone necrosis. To our knowledge, this is the first report of ONJ in a patient treated with Ipilimumab. Thousands of patients have been treated with Ipilimumab. If osteonecrosis is an associated complication, it is probably rare and maybe because patients are treated for a short time. As this is a relatively new medication with great promise for management of melanoma and other advanced-stage malignancy clinicians involved in the care of patients managed with Ipilimumab should be aware of this complication.