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1.
Pediatr Infect Dis J ; 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38920375

ABSTRACT

A multicenter cross-sectional diagnostic study was carried out including 45 children with nontuberculous mycobacterial cervicofacial lymphadenitis and controls. The tested immunoassay, detecting M. avium-specific anti-glycopeptidolipid-core immunoglobulin A antibodies, had inadequate diagnostic performance in the studied population and seems to be of no additional value in detecting cases of nontuberculous mycobacterial cervicofacial lymphadenitis.

2.
Facial Plast Surg ; 40(1): 68-79, 2024 Feb.
Article in English | MEDLINE | ID: mdl-36878677

ABSTRACT

Wound healing is a complex biological process subject to complications that might jeopardize the patient's postoperative care. Appropriately approaching surgical wounds after head and neck surgery positively influences the quality and speed of wound healing and increases patient comfort. A large variety of dressing materials currently exist that allow the care of different types of wounds. Nevertheless, there is limited literature on the most suitable types of dressings after head and neck surgery. The objective of the present article is to review the most commonly used wound dressings, their benefits, indications, and disadvantages, and to provide a systematic approach for wound care within the head and neck. The Woundcare Consultant Society distinguishes wounds into three groups: black, yellow, and red. Each type of wound represents distinctive underlying pathophysiological processes with unique needs. Utilizing this classification along with the TIME model allows a proper characterization of wounds and the identification of potential healing barriers. This evidence-based and systematic approach can facilitate and guide the head and neck surgeon in selecting a wound dressing upon acknowledging their properties, which are herein reviewed and exemplified with representative cases.


Subject(s)
Surgical Wound Infection , Surgical Wound , Humans , Bandages , Wound Healing , Neck/surgery
3.
Oral Oncol ; 149: 106677, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38142550

ABSTRACT

OBJECTIVE: The aim of this project is to create an interactive online patient decision aid (PDA) for oropharyngeal cancer (OPSCC) patients, eligible for transoral (robotic) surgery with an ultimate goal to assist both physicians and patients in making treatment choices. MATERIALS AND METHODS: Following the International Patient Decision Aid Standards, a mixed-methods approach was employed. The study involved semi-structured in-depth interviews with patients and physicians, thinking-out-loud sessions, and study-specific questionnaires. Thematic coding and analysis were conducted on verbatim transcriptions of audio-recorded interviews. RESULTS: The PDA drafts were evaluated by twenty OPSCC survivors and twenty multidisciplinary specialists. Significant revisions were made after phase 1 to enhance readability and reduce text, whilst incorporating videos and graphics. Following all phases, both patients and specialists rated the PDA as comprehensible, feasible, and a valuable addition to regular counseling. CONCLUSION: This study showcases the development of a PDA for early stage oropharyngeal cancer patients considering surgery and radiotherapy options. The decision aid emphasizes the disparities in short- and long-term side effects between the two treatments. Patients and physicians found the decision aid to be understandable, user-friendly, and helpful for future patients. The PDA is available on https://beslissamen.nl/.


Subject(s)
Carcinoma , Oropharyngeal Neoplasms , Robotic Surgical Procedures , Humans , Netherlands , Oropharyngeal Neoplasms/surgery , Oropharyngeal Neoplasms/radiotherapy , Decision Support Techniques
4.
Case Rep Dent ; 2023: 2347855, 2023.
Article in English | MEDLINE | ID: mdl-38020961

ABSTRACT

Cherubism is an autosomal dominant disease with variable expression. Aggressive forms of untreated cherubism may lead to severe malformation of the maxillofacial skeleton, developing tooth germs and teeth. Scarcely described and empirically applied interventional therapies during active stages of the disease try to limit the damage and deformation caused by progression of expanding intraosseous lesions. The final goal is to minimize the need for corrective surgeries once progressive growth has halted and disease enters its quiescent phase. New insights into the pathophysiology of cherubism hypothesize a potential role for dental development and jaw growth in the (hyper)activation of the disease. Theoretically, this could guide the ideal moment of pharmacological interventions. In this case report, the off-label use of systemic calcitonin treatment is described, stressing particularly the potential importance of its appropriate timing and duration of treatment.

5.
J Bone Miner Res ; 38(12): 1822-1833, 2023 12.
Article in English | MEDLINE | ID: mdl-37823782

ABSTRACT

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Subject(s)
Calcitonin , Cherubism , Child , Humans , Male , Female , Calcitonin/adverse effects , Cohort Studies , Cherubism/drug therapy , Retrospective Studies , Minerals
6.
Oncologist ; 28(11): 1005-e1104, 2023 Nov 02.
Article in English | MEDLINE | ID: mdl-37449658

ABSTRACT

BACKGROUND: Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab as GCTB. The primary objective of this study was to determine the efficacy of denosumab in patients with GCRTB that have recurred or require morbid surgery. METHODS: In this open-label, multicenter, phase II trial, patients with GCRTB were included (June 2018-March 2020). Recruitment was stopped because of low accrual. Patients received denosumab (120 mg) subcutaneously (SC) on day 1 of every 4-week cycle with a loading dose of 120 mg SC on days 8 and 15. RESULTS: Three patients were enrolled. One withdrew consent before start of study. The remaining patients had central giant cell granuloma of the jawbone (CGCG). Median treatment duration was 15 cycles (range 12-18). In both subjects, improvement in ossification of lesions was seen. Median follow-up was 28.5 months (range 20-37). One patient developed a recurrence for which surgery was performed. CONCLUSION: Due to critical emerging real-world data of denosumab in GCRTBs, the study was prematurely stopped and not supportive of use of denosumab for this indication. (ClinicalTrials.gov Identifier: NCT03605199).


Subject(s)
Bone Density Conservation Agents , Bone Neoplasms , Giant Cell Tumor of Bone , Humans , Denosumab , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/drug therapy , Giant Cell Tumor of Bone/drug therapy , Giant Cells/pathology
7.
Histopathology ; 83(2): 326-329, 2023 Aug.
Article in English | MEDLINE | ID: mdl-36939112

ABSTRACT

AIMS: Simple Bone Cysts (SBCs) predominantly occur in long bones and 59% harbour NFATC2 rearrangements. Jaw SBC is rare and was previously referred to as traumatic bone cyst. It can rarely occur in association with cemento-osseous dysplasia (COD). To determine whether jaw SBCs represent the same entity as SBC of the long bones, or if they have a different molecular signature, we collected 48 jaw SBC cases of 47 patients to assess NFATC2 rearrangement. METHODS AND RESULTS: Out of the 48 cases, 36 could be used for fluorescence in-situ hybridization (FISH), of which nine (two of which associated with COD) were successful using an NFATC2 split probe. The remaining cases failed to show adequate FISH signals. All nine cases lacked NFATC2 rearrangement and five of these showed no detectable gene fusions using Archer FusionPlex. CONCLUSION: In our study, NFATC2 rearrangement is absent in solitary jaw SBC (n = 7) and COD-associated SBC (n = 2). Our findings suggest that SBC presenting in the jaw is molecularly different from SBC in long bones. Future molecular studies may confirm the absence of clonal molecular aberrations in SBC of the jaw which would support a non-neoplastic, reactive origin.


Subject(s)
Bone Cysts , NFATC Transcription Factors , Odontogenic Tumors , Humans , Bone Cysts/genetics , Odontogenic Tumors/genetics , NFATC Transcription Factors/genetics
8.
J Pediatr Surg ; 58(9): 1770-1775, 2023 Sep.
Article in English | MEDLINE | ID: mdl-36809867

ABSTRACT

BACKGROUND: Nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis is a rare infection which almost exclusively occurs in children, most commonly children 0-5 years old. It can leave scars in highly visible areas. The present study aimed to evaluate the long-term esthetic outcome of different treatment modalities for NTM cervicofacial lymphadenitis. METHODS: This retrospective cohort study included 92 participants with a history of bacteriologically proven NTM cervicofacial lymphadenitis. All patients were diagnosed at least 10 years prior and were aged >12 years upon enrollment. Based on standardized photographs, the scars were assessed by subjects with the Patient Scar Assessment Scale, and by five independent observers with the revised and weighted Observer Scar Assessment Scale. RESULTS: The mean age at initial presentation was 3,9 years and the mean follow-up time was 15.24 years. Initial treatments included surgical treatment (n = 53), antibiotic treatment (n = 29) and watchful waiting (n = 10). Subsequent surgery was performed in two patients, due to a recurrence after initial surgical treatment, and in 10 patients initially treated with antibiotic treatment or watchful waiting. Esthetic outcomes were statistically significantly better with initial surgery, compared to initial non-surgical treatment, based on patient scores of scar thickness, and based on observer scores of scar thickness, surface appearance, general appearance and the revised and weighted sum score of all assessment items. CONCLUSIONS: The long-term esthetic outcome of surgical treatment was superior to non-surgical treatment. These findings could facilitate the process of shared decision making. LEVEL OF EVIDENCE: Level III.


Subject(s)
Lymphadenitis , Mycobacterium Infections, Nontuberculous , Child , Humans , Infant , Infant, Newborn , Child, Preschool , Cicatrix/etiology , Cicatrix/therapy , Retrospective Studies , Lymphadenitis/microbiology , Lymphadenitis/surgery , Anti-Bacterial Agents/therapeutic use , Lymph Node Excision , Mycobacterium Infections, Nontuberculous/diagnosis , Mycobacterium Infections, Nontuberculous/surgery , Treatment Outcome
9.
Mod Pathol ; 36(1): 100013, 2023 01.
Article in English | MEDLINE | ID: mdl-36788065

ABSTRACT

Psammomatoid ossifying fibroma (PsOF), also known as juvenile PsOF, is a benign fibro-osseous neoplasm predominantly affecting the extragnathic bones, particularly the frontal and ethmoid bones, with a preference for adolescents and young adults. The clinical and morphologic features of PsOF may overlap with those of other fibro-osseous lesions, and additional molecular markers would help increase diagnostic accuracy. Because identical chromosomal breakpoints at bands Xq26 and 2q33 have been described in 3 cases of PsOF located in the orbita, we aimed to identify the exact genes involved in these chromosomal breakpoints and determine their frequency in PsOF using transcriptome sequencing and fluorescence in situ hybridization (FISH). We performed whole RNA transcriptome sequencing on frozen tissue in 2 PsOF index cases and identified a fusion transcript involving SATB2, located on chromosome 2q33.1, and AL513487.1, located on chromosome Xq26, in one of the cases. The fusion was validated using reverse transcription (RT)-PCR and SATB2 FISH. The fusion lead to a truncated protein product losing most of the functional domains. Subsequently, we analyzed an additional 24 juvenile PsOFs, 8 juvenile trabecular ossifying fibromas (JTOFs), and 11 cemento-ossifying fibromas (COFs) for SATB2 using FISH and found evidence of SATB2 gene rearrangements in 58% (7 of 12) of the evaluable PsOF cases but not in any of the evaluable JTOF (n = 7) and COF (n = 7) cases. A combination of SATB2 immunofluorescence and a 2-color SATB2 FISH in our index case revealed that most tumor cells harboring the rearrangement lacked SATB2 expression. Using immunohistochemistry, 65% of PsOF, 100% of JTOF, and 100% of COF cases showed moderate or strong staining for SATB2. In these cases, we observed a mosaic pattern of expression with >25% of the spindle cells in between the bone matrix, with osteoblasts and osteocytes being positive for SATB2. Interestingly, 35% (8 of 23) of PsOFs, in contrast to JTOFs and COFs, showed SATB2 expression in <5% of cells. To our knowledge, this is the first report that shows the involvement of SATB2 in the development of a neoplastic lesion. In this study, we have showed that SATB2 rearrangement is a recurrent molecular alteration that appears to be highly specific for PsOF. Our findings support that PsOF is not only morphologically and clinically but also genetically distinct from JTOF and COF.


Subject(s)
Bone Neoplasms , Fibroma, Ossifying , Matrix Attachment Region Binding Proteins , Humans , Fibroma, Ossifying/genetics , In Situ Hybridization, Fluorescence , Bone Neoplasms/genetics , Immunohistochemistry , Gene Rearrangement , Transcription Factors/genetics , Matrix Attachment Region Binding Proteins/genetics
10.
Article in English | MEDLINE | ID: mdl-36529675

ABSTRACT

Sporadic central giant cell granulomas of the jaws (GCGJ) are often solitary lesions, characterized by KRAS, FGFR1, and TRPV4 somatic mutations. Multifocal lesions may occur and are associated with hyperparathyroidism or underlying syndromes such as cherubism, which is marked by SH3BP2 mutations, and RASopathies, which are caused by mutations in the FGFR-RAS-RAF-MEK-ERK signaling cascade. The diagnosis of multiple GCGJ can be challenging. The present case reports a 14-year-old boy with multiple central GCGJ and no obvious syndromic trait. Sanger sequencing-based analysis revealed wild-type sequences for SH3BP2 (exon 9), KRAS (exons 2-4), and FGFR1 (exons 9 and 10) genes. A rare TRPV4 somatic mutation (p.Val708Met) was detected in the lesion on the right side of the mandible, whereas the other tumor and the normal oral mucosa revealed wild-type TRPV4 sequences. This report expands the spectrum of TRPV4 somatic mutations in central GCGJ.


Subject(s)
Granuloma, Giant Cell , Male , Humans , Adolescent , Granuloma, Giant Cell/genetics , TRPV Cation Channels/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Mutation/genetics , Jaw/pathology
11.
Eur J Cancer ; 175: 263-273, 2022 11.
Article in English | MEDLINE | ID: mdl-36174298

ABSTRACT

BACKGROUND: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). METHODS: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. RESULTS: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. CONCLUSION: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.


Subject(s)
Bone Density Conservation Agents , Bone Neoplasms , Giant Cell Tumor of Bone , Bone Density Conservation Agents/adverse effects , Bone Neoplasms/drug therapy , Cohort Studies , Denosumab/adverse effects , Female , Giant Cell Tumor of Bone/diagnostic imaging , Giant Cell Tumor of Bone/drug therapy , Giant Cells/metabolism , Giant Cells/pathology , Humans , Male , Neoplasm Recurrence, Local/drug therapy , Retrospective Studies
12.
Virchows Arch ; 481(4): 671-675, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35612673

ABSTRACT

Non-ossifying fibroma (NOF) and central giant cell granuloma (CGCG) are both benign tumours of bone with overlapping morphology and similar mutations in the RAS/MAPK pathway. However, NOF is located in the long bones with regression after puberty in contrast to CGCG which is located in the jaw bones and does not regress spontaneously. We hypothesised that endocrine regulation by oestrogen plays a role in the spontaneous regression in NOF. Therefore, we examined the expression of ERα in a series of NOF and CGCG. ERα expression (EP1) was determined using immunohistochemistry on 16 NOFs (whole slides), and 47 CGCGs (tissue microarrays (TMA's n = 41 and whole slide n = 6)). As comparison, we included TMAs of other giant cell containing bone lesions: giant cell tumour of bone (n = 75), chondroblastoma (n = 12), chondromyxoid fibroma (n = 12), aneurysmal bone cyst (n = 6) and telangiectatic osteosarcoma (n = 6). All 16 NOF samples demonstrated ERα protein expression, while all 47 CGCG and all other giant cell containing bone tumours were negative. Most NOF samples had moderate staining intensity and between 24 and 49% of the spindle cells were ERα-positive. Our findings further support the role of endocrine regulation via oestrogen in the spontaneous regression in NOF. Whether oestrogen signalling at puberty is involved in the induction of senescence in the neoplastic cells of NOF harbouring RAS/MAPK pathway mutations needs further research. Since ERα expression was not observed in other giant cell containing bone lesions with overlapping morphological features, positive ERα expression may favour the diagnosis of NOF in challenging diagnostic cases.


Subject(s)
Bone Neoplasms , Fibroma , Giant Cell Tumor of Bone , Bone Neoplasms/pathology , Estrogen Receptor alpha , Estrogens , Fibroma/genetics , Fibroma/pathology , Giant Cell Tumor of Bone/diagnosis , Giant Cell Tumor of Bone/genetics , Giant Cells/pathology , Humans , Receptors, Estrogen , Receptors, Immunologic
13.
Radiother Oncol ; 168: 16-22, 2022 03.
Article in English | MEDLINE | ID: mdl-35065998

ABSTRACT

PURPOSE: We aim to identify the dosimetric and clinical impact of reducing the total GTV-CTV-PTV margins in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. MATERIALS AND METHODS: The acute and late toxicity and outcomes of 155 consecutive patients treated between February 2017 and March 2019 with GTV-CTV-PTV margins of 9 mm were compared to those of 155 consecutive patients treated with total margin of 15 mm margin, before April 2015. All patients were treated with VMAT with daily-image guidance using CBCT. RESULTS: Reducing the GTV-CTV-PTV by 6 mm resulted in significant reduction of total irradiated volume (PTV-total) by a median of 28.1% and significant reduction of doses to all salivary glands (largest reduction ipsilateral parotid gland; median -9.6 Gy) and constrictor muscle (-6.1 Gy) with subsequent reduction of the incidence of overall acute grade 3 toxicity (47.7% for 9 mm and 66.5% for 15 mm groups, p = 0.001), grade 3 mucositis (18.1% vs. 35.5%, p < 0.001) and feeding tube-dependency at the end of treatment (24.5% vs. 40%, p = 0.005). The incidence of late grade ≥ 2 xerostomia and dysphagia were also significantly lower in the 9 mm group (31.7% vs. 58.6% p < 0.001, and 15.4% vs. 26.7%, p = 0.04). The 2-year rates of loco-regional control, disease-free and overall survival were 78.8% vs.75.8%, 70.9% vs. 64.4%, and 83.8% vs. 67.6%, (p > 0.05, all). CONCLUSION: Reduction of the total GTV-CTV-PTV margins from 15 to 9 mm in HNSCC significantly reduced the irradiated volumes and the dose to salivary glands and constrictor muscle with significant reduction of radiation-related toxicity. The loco-regional control rates of both groups were comparable.


Subject(s)
Head and Neck Neoplasms , Radiation Injuries , Radiotherapy, Intensity-Modulated , Head and Neck Neoplasms/complications , Humans , Radiation Injuries/etiology , Radiation Injuries/prevention & control , Radiometry , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Intensity-Modulated/adverse effects , Radiotherapy, Intensity-Modulated/methods , Squamous Cell Carcinoma of Head and Neck/radiotherapy
14.
J Oral Maxillofac Surg ; 80(3): 537-544, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34758350

ABSTRACT

PURPOSE: Information on long-term treatment outcome for nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in children is scarce. The purpose of this study is to evaluate long-term outcome for surgical treatment, which is the mainstay treatment modality. METHODS: This case series describes recurrence rates of surgically treated NTM cervicofacial lymphadenitis patients with a follow-up of at least 10 years. The current study data were partially collected from a randomized, prospective, multicenter, multidisciplinary trial (CHIMED study), which was conducted between 2000 and 2006 to determine the optimal treatment for NTM cervicofacial lymphadenitis in children. After the CHIMED trial inclusion ended, our institute continued to serve as a referral center. This enabled us to enlarge the surgical CHIMED cohort by adding patients who were treated during 2007 to 2010 in our center and collect the rest of the current study data. RESULTS: About 427 children with chronic cervicofacial lymphadenopathy were analyzed. Among these, 290 had microbiologically confirmed cervicofacial mycobacterial infections (n = 3 Mycobacterium tuberculosis, n = 1 Mycobacterium bovis, n = 286 NTM). Of these 286 children with NTM cervicofacial lymphadenitis, 189 were treated surgically (median age: 41 months, range: 9-144, 46.0% males). The affected lymph nodes were excised in 151 children (79.9%), and curettage was performed in 38 children (20.1%). One patient (0.07%) experienced a reactivation/recurrence 2 years after surgical excision and required another surgical excision. Three children (7.9%) experienced infection reactivation/recurrences after curettage, confirmed by redness or a draining fistula, within the first year after healing. Two of these 3 patients were treated with additional surgical excisions. CONCLUSION: The long-term outcome of surgical excision for NTM cervicofacial lymphadenitis is favorable with a low recurrence rate. Curettage or a conservative wait-and-see approach can be considered an alternative in advanced and surgically challenging cases. However, healing will take longer, and late recurrences are possible.


Subject(s)
Lymphadenitis , Tuberculosis, Lymph Node , Child , Child, Preschool , Female , Humans , Infant , Lymph Node Excision , Lymph Nodes , Lymphadenitis/microbiology , Lymphadenitis/surgery , Male , Prospective Studies
15.
Nat Commun ; 12(1): 7348, 2021 12 22.
Article in English | MEDLINE | ID: mdl-34937871

ABSTRACT

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.


Subject(s)
Head and Neck Neoplasms/drug therapy , Immunotherapy , Ipilimumab/therapeutic use , Neoadjuvant Therapy , Nivolumab/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Aged , Biomarkers, Tumor/metabolism , Female , Fluorodeoxyglucose F18/chemistry , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Immune Checkpoint Inhibitors/therapeutic use , Male , Middle Aged , Positron-Emission Tomography , Squamous Cell Carcinoma of Head and Neck/diagnostic imaging , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/surgery , Exome Sequencing
16.
Case Rep Dent ; 2021: 9938672, 2021.
Article in English | MEDLINE | ID: mdl-34055424

ABSTRACT

Pleomorphic adenoma is the most common salivary gland tumor but is extremely rare in pediatric patients. The parotid gland is the most affected salivary gland, and the minor salivary glands are rarely affected. Here, we report a case of a 12-year-old boy with a pleomorphic adenoma of the palate.

17.
Bone ; 149: 115935, 2021 08.
Article in English | MEDLINE | ID: mdl-33771761

ABSTRACT

The majority of giant cell lesions of the jaw present as a solitary focus of disease in bones of the maxillofacial skeleton. Less frequently they occur as multifocal lesions. This raises the clinical dilemma if these should be considered distinct entities and therefore each need a specific therapeutic approach. Solitary giant cell lesions of the jaw present with a great diversity of symptoms. Recent molecular analysis revealed that these are associated with somatic gain-of-function mutations in KRAS, FGFR1 or TRPV4 in a large component of the mononuclear stromal cells which all act on the RAS/MAPK pathway. For multifocal lesions, a small group of neoplastic multifocal giant cell lesions of the jaw remain after ruling out hyperparathyroidism. Strikingly, most of these patients are diagnosed with jaw lesions before the age of 20 years, thus before the completion of dental and jaw development. These multifocal lesions are often accompanied by a diagnosis or strong clinical suspicion of a syndrome. Many of the frequently reported syndromes belong to the so-called RASopathies, with germline or mosaic mutations leading to downstream upregulation of the RAS/MAPK pathway. The other frequently reported syndrome is cherubism, with gain-of-function mutations in the SH3BP2 gene leading through assumed and unknown signaling to an autoinflammatory bone disorder with hyperactive osteoclasts and defective osteoblastogenesis. Based on this extensive literature review, a RAS/MAPK pathway activation is hypothesized in all giant cell lesions of the jaw. The different interaction between and contribution of deregulated signaling in individual cell lineages and crosstalk with other pathways among the different germline- and non-germline-based alterations causing giant cell lesions of the jaw can be explanatory for the characteristic clinical features. As such, this might also aid in the understanding of the age-dependent symptomatology of syndrome associated giant cell lesions of the jaw; hopefully guiding ideal timing when installing treatment strategies in the future.


Subject(s)
Cherubism , Hyperparathyroidism , Adaptor Proteins, Signal Transducing/genetics , Adult , Giant Cells , Humans , Mutation , Signal Transduction , Young Adult
18.
Am J Surg Pathol ; 45(5): 690-693, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33653978

ABSTRACT

Cementoblastomas are rare odontogenic tumors developing in close proximity to the roots of teeth. Due to their striking morphologic resemblance to osteoblastomas of the peripheral skeleton, we set out to determine whether cementoblastomas harbor the same FOS rearrangements with overexpression of c-FOS as has recently been described for osteoblastomas. In total, 16 cementoblastomas were analyzed for FOS expression by immunohistochemistry and for FOS rearrangements by fluorescence in situ hybridization (FISH). We observed strong and diffuse staining of c-FOS in 71% of cementoblastomas and identified a FOS rearrangement in all cases (n=3) applicable for FISH. In the remaining cases, FISH failed due to decalcification. Cementoblastomas harbor similar FOS rearrangements and show overexpression of c-FOS like osteoblastomas, suggesting that both entities might represent parts of the spectrum of the same disease.


Subject(s)
Biomarkers, Tumor , Bone Neoplasms , Dental Cementum , Gene Rearrangement , Odontogenic Tumors , Osteoblastoma , Proto-Oncogene Proteins c-fos , Tooth Root , Adolescent , Adult , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Bone Neoplasms/chemistry , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Child , Dental Cementum/chemistry , Dental Cementum/pathology , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Netherlands , Odontogenic Tumors/chemistry , Odontogenic Tumors/genetics , Odontogenic Tumors/pathology , Osteoblastoma/chemistry , Osteoblastoma/genetics , Osteoblastoma/pathology , Proto-Oncogene Proteins c-fos/analysis , Proto-Oncogene Proteins c-fos/genetics , Switzerland , Tooth Root/chemistry , Tooth Root/pathology , Young Adult
19.
Radiother Oncol ; 147: 56-63, 2020 06.
Article in English | MEDLINE | ID: mdl-32240908

ABSTRACT

BACKGROUND AND PURPOSE: Bilateral elective nodal irradiation (ENI) remains the standard treatment for head and neck squamous cell carcinoma (HNSCC). Unilateral ENI could reduce treatment toxicity and improve health-related quality-of-life (HRQOL). This prospective proof-of-principle trial (NCT02572661) investigated the feasibility, safety and clinical benefits of SPECT/CT-guided ENI of the node-negative contralateral neck. MATERIALS AND METHODS: Patients with lateralized T1-3N0-2bM0 HNSCC of the oropharynx, oral cavity, larynx and hypopharynx underwent SPECT/CT after peritumoral 99mTc-nanocolloid injection. Patients without contralateral lymph drainage received ipsilateral ENI only. If lymph drainage to only one contralateral hot spot was visible, ENI to the contralateral neck would be limited to only the level containing the hot spot. The primary endpoint was the incidence of contralateral regional failure (CRF) at 2 years. Toxicity and HRQOL were compared with a 1:1 matched historical cohort that received standard bilateral ENI (B-ENI) with identical planning and treatment techniques. RESULTS: Fifty patients were treated with SPECT/CT-guided ENI. After a median follow-up of 33 months (range 18-45), CRF was observed in one patient (2%; 95% confidence interval: 0-6%). Compared to the matched B-ENI group, patients treated with SPECT/CT-guided ENI had significantly lower incidences of grade ≥2 dysphagia (54% vs. 82%; p < 0.001), tube feeding (10% vs. 50%; p < 0.001) and late grade ≥2 xerostomia (9% vs. 54%; p < 0.001). Significant and clinically relevant HRQOL benefits of SPECT/CT-guided ENI were observed on the EORTC QLQ-C30 summary score, and QLQ-HN35 swallowing and dry mouth subscales. CONCLUSION: SPECT/CT-guided ENI is associated with a low risk of contralateral regional failure. Compared to B-ENI, SPECT/CT-guided ENI significantly reduces dysphagia, feeding tube placement, and late xerostomia and improves HRQOL.


Subject(s)
Head and Neck Neoplasms , Xerostomia , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/radiotherapy , Humans , Prospective Studies , Single Photon Emission Computed Tomography Computed Tomography , Squamous Cell Carcinoma of Head and Neck/radiotherapy
20.
Photochem Photobiol ; 96(2): 405-416, 2020 03.
Article in English | MEDLINE | ID: mdl-31907934

ABSTRACT

Previous dosimetric studies during photodynamic therapy (PDT) of superficial lesions within a cavity such as the nasopharynx, demonstrated significant intra- and interpatient variations in fluence rate build-up as a result of tissue surface re-emitted and reflected photons, which depends on the optical properties. This scattering effect affects the response to PDT. Recently, a meta-tetra(hydroxyphenyl)chlorin-mediated PDT study of malignancies in the paranasal sinuses after salvage surgery was initiated. These geometries are complex in shape, with spatially varying optical properties. Therefore, preplanning and in vivo dosimetry is required to ensure an effective fluence delivered to the tumor. For this purpose, two 3D light distribution models were developed: first, a simple empirical model that directly calculates the fluence rate at the cavity surface using a simple linear function that includes the scatter contribution as function of the light source to surface distance. And second, an analytical model based on Lambert's cosine law assuming a global diffuse reflectance constant. The models were evaluated by means of three 3D printed optical phantoms and one porcine tissue phantom. Predictive fluence rate distributions of both models are within ± 20% accurate and have the potential to determine the optimal source location and light source output power settings.


Subject(s)
Light , Nose Neoplasms/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Animals , Cone-Beam Computed Tomography , Disease Models, Animal , Humans , Nose Neoplasms/pathology , Swine
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