Tumor-agnostic plasma assay for circulating tumor DNA detects minimal residual disease and predicts outcome in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing. PATIENTS AND METHODS: A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, ß = 0.9). RESULTS: We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011). CONCLUSIONS: Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.

Medication-related osteonecrosis of the jaw, a risk to reassess in osteoporotic patients.

INTRODUCTION: The use of antiresorptive drugs concerns many medical specialties either in relation to their prescription for osteoporosis or cancer, or in relation to the treatment of their side effects. In the literature, less than 10% of medication-related osteonecrosis of the jaw are related to patients treated for osteoporosis, while 90% are found in patients treated for cancer. Despite the increasing number of osteoporotic patients taking high doses of antiresorptive drugs, only few studies describe this topic. The main aim of this study was to highlight the occurrence of medication-related osteonecrosis of the jaw in osteoporotic patients compared to cancer patients. The second aim was to highlight risk factors in the two groups, to try to understand the high number of osteoporotic patients in our population. MATERIALS AND METHODS: A retrospective study was conducted between December 2004 and March 2021 to identify all cases of medication-related osteonecrosis of the jaw in our department with emphasis on the osteoporotic population. Demographic, systemic and local risk factors were collected as well as the type, dose and duration of the anti-resorptive drugs treatment. Evolution and follow-up were also recorded. RESULTS: One hundred sixty five patients presented with medication-related osteonecrosis of the jaw, of whom 67 (40,6%) were osteoporotic. Seventeen (25,4%) patients were males and 50 females (74,6%). Risk factors were tobacco consumption (28,4%), anemia (20,9%), alcohol consumption (19,4%). Use of corticoids or anticoagulant/antithrombotic therapy was related in 20,9% and 16,4%, respectively. The mean age at MRONJ diagnosis was 74,4 (50-98). The mean follow up time was 23,7 months (1-110). CONCLUSION: Unlike the literature where medication-related osteonecrosis of the jaw in osteoporotic patients represents less than 10%, the rate in our series was much higher and represents 40% of the patients. This highlights the importance of a complete dental examination before and during antiresorptive drugs treatment, even in the case of osteoporotic patients.

Dental prevention of maxillo-mandibular osteoradionecrosis: A ten-year retrospective study.

INTRODUCTION: Osteoradionecrosis (ORN) remains a frequent complication of radiotherapy in head and neck cancer. As ORN management is often complex, it is essential to focus on its prevention, mainly by dental prophylaxis. The objectives of this study were to evaluate a dental preventive approach based on ORN data and to highlight individual risk factors statistically associated with time-to-ORN. MATERIALS AND METHODS: A retrospective study (January 2004-December 2013) included 415 patients with head and neck cancer who received radiotherapy in their treatment with at least 50 Grays on maxillo-mandibular bones. Pre-radiotherapy dental assessment (clinical and radiological) and prevention (with standardised extraction protocol) were performed. RESULTS: The ORN rate was 7.5%, with a dental origin in 35.5% of cases, mainly represented by dental infection in exclusive mandibular locations. More than 90% of patients were partially or completely dentate, and more than 70% had poor oral hygiene. Dental extractions were performed in 67.9% of patients before radiotherapy and in 42.9% after radiotherapy. Statistically significant risk factors associated with time-to-ORN were addictions (tobacco and alcohol), diabetes, oropharyngeal tumour location, combination of surgery followed by radiotherapy and post-radiotherapy dental extractions. DISCUSSION AND CONCLUSION: Considering that ORN implies severe disabilities and complex management, the rate of 7.5% is unacceptable. A better dental prevention could reduce this rate by one-third. Dental extractions could be systematic in high-dose irradiation mandibular areas in patients presenting with poor oral hygiene and/or statistically significant risk factors for the occurrence of ORN. Moreover, favourable oral condition after radiotherapy should be maintained.

Medication-related osteonecrosis of the jaw related to epacadostat and pembrolizumab.

MRONJ is a well-known side effect of various medications, such as antiresorptive drugs, anti-angiogenic agents, immunomodulators and immunosuppressants. MRONJ related to immunotherapy is rarely described, with only one case related to ipilimumab. The interaction between the immune system and osteoclast lineage cells is well known. T cells release factors and cytokines that control osteoclastogenesis, and osteoclasts produce factors with an action on T cells. We attempted to explain how immunotherapy could cause MRONJ through the case report of a young patient with metastatic melanoma who developed maxilla MRONJ after pembrolizumab and epacadostat treatment.

Axillary lymph node metastasis in second oropharyngeal cancer.

BACKGROUND: The risk of metastasizing in axillary lymph node is occasional in the head and neck cancers. This pattern of spread is difficult to explain and totally unpredictable even for these lymphophilic cancers. OBSERVATION: A 72-year-old patient benefited, 11 years ago, of surgical oncology care associated with adjuvant radiotherapy for squamous cell carcinoma of the left floor of the mouth (pT4 pN2b M0). He presented a second primary malignancy at the right oropharyngeal level. Pet CT revealed a right infraclinic axillary metastasis. The metastatic origin was confirmed by pathological analysis. DISCUSSION: The current management of head and neck cancers is based on the histological pattern of infiltration, the size of the primary tumor and the pattern of metastasizing lymph nodes and potential distant spreading. Current tests allow us to diagnose most distant metastases even outside the usual area of lymphatic drainage. Involvement of axillary lymph node, probably through retrograde lymphatic spreading is not so rare in recurrences of oropharyngeal cancer (T3-T4, N2…) as we have observed in the literature. In this review, we raise some degree of similarity between such oncological progression and factors related to this aberrant spreading.

Successful treatment of grade III osteoradionecrosis with mandibular fracture with pentoxifylline, tocopherol and clodronate.

Osteoradionecrosis (ORN) is one of the most severe complications after head and neck radiotherapy. Once established, ORN is difficult to manage and is traditionally considered to be irreversible. Since the recent understanding of the pathophysiology of ORN is based on the concept of radiation-induced fibrosis, a new therapeutic medical regimen has been proposed comprising the combination of pentoxifylline, tocopherol and clodronate (PENTOCLO). A 55-year-old woman presented with grade III ORN with large intraoral bone exposure, a fracture of the left posterior horizontal branch and an orocutaneous fistula. Because she refused surgery, medical treatment with PENTOCLO was proposed. After 55months of treatment, there was complete mucosal coverage and complete consolidation of the fracture site around the orocutaneous fistula. PENTOCLO treatment can help some patients with grade III disease, as in this case. Further prospective randomized controlled trials are needed to confirm this result.

Buccal paraneoplastic pemphigus multi-resistant: Case report and review of diagnostic and therapeutic strategies.

Paraneoplastic pemphigus is a rare autoimmune blistering disease generally associated with malignancy. The clinical presentation consists typically of painful and diffuse erosive stomatitis that may be accompanied by polymorphic skin lesions and systemic involvement. Diagnosis is based on clinical manifestations and confirmed by histology and immunological testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents. We report a case of buccal paraneoplastic pemphigus resistant to ibrutinib and rituximab successfully treated with azathioprine and polyclonal immunoglobulins.

[Etiologic diagnosis of jaw osteonecrosis, other than bisphosphonate and radiotherapy related osteitis]. / Diagnostic étiologique des ostéonécroses maxillomandibulaires, ostéites à bisphosphonates et ostéoradionécroses exceptées.

Our purpose was to highlight the various etiologies of maxillo-mandibular osteonecrosis, other than radiotherapy and biphosphonate related osteitis that have been abundantly reported. We performed a PubMed search from August 1, 1972 to August 1, 2012 using the following MeSH terms: "osteonecrosis", "bone", "necrosis", "jaw", "maxilla", "mandible", "palate", "oral", "avascular necrosis", NOT "bisphosphonate" NOT "osteoradionecrosis". Most cases of osteonecrosis were iatrogenic. Viral, mycotic, or bacterial infections were less frequent causes. Cocaine abuse, Wegener's granulomatosis, and N/K lymphoma were other etiologies. It is important to identify the various etiologies rapidly to manage this sometimes very mutilating condition adequately.

Etiologic diagnosis of jaw osteonecrosis, other than bisphosphonate and radiotherapy related osteonecrosis.

Our purpose was to highlight the various etiologies of maxillo-mandibular osteonecrosis, other than radiotherapy and biphosphonate related osteitis that have been abundantly reported. We performed a PubMed search from August 1, 1972 to August 1, 2012 using the following MeSH terms: "osteonecrosis", "bone", "necrosis", "jaw", "maxilla", "mandible", "palate", "oral", "avascular necrosis", NOT "bisphosphonate" NOT "osteoradionecrosis". Most cases of osteonecrosis were iatrogenic. Viral, mycotic, or bacterial infections were less frequent causes. Cocaine abuse, Wegener's granulomatosis, and N/K lymphoma were other etiologies. It is important to identify the various etiologies rapidly to manage this sometimes very mutilating condition adequately.

Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Cetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography ((18)FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls. RESULTS: Cetuximab given 24 h before surgery was safe. Ninety percent of patients had (18)FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than -25% or less than -50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003). CONCLUSIONS: Short-course pre-operative administration of cetuximab is safe and shows a high rate of (18)FDG-PET response. (18)FDG-PET response was correlated with residual tumour cellularity suggesting that (18)FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN.

[Recurrent maxillo-mandibular odontogenic keratocysts: prevention and treatment]. / Kératokystes odontogéniques maxillo-mandibulaires récidivants: prévention et traitement.

Keratocyst is an odontogenic cyst with an aggressive clinical behavior and a high recurrence rate. Our work describes a 62 year-old patient with Gorlin's syndrome presenting advanced recurrent maxillo-mandibular keratocysts. He already had multiple resections of these lesions. Early diagnosis and treatment of keratocysts is crucial to reduce the extension of the cysts and minimize their malignant transformation especially when they are part of a Gorlin's syndrome.

[Solitary bone cyst of the mandible and platelet rich fibrin (PRF)]. / Kyste osseux solitaire de la mandibule et fibrine riche en plaquettes (PRF).

INTRODUCTION: Solitary maxillary or mandibular bone cysts are rare benign lesions. They are usually localized in the mandible of young men. In some cases, a traumatic risk factor can be documented. OBSERVATION: A young 13-year-old female patient consulted in the orthodontics unit. An orthopantomogram showed a large cystic lesion in the ramus and posterior part of the left mandible corpus. No reossification of the cavity was observed one year after curettage. A second curettage was performed combined with PRF filling. Six months later, the cavity was completely reossified. DISCUSSION: Curettage is the first line treatment of isolated cystic lesions and generally followed by complete reossification of the cavity. Incomplete healing is observed in 20% of the cases. PRF may induce the healing of non-reossified cystic cavity by supplying local growth factors.

[Osteoporosis, bisphosphonates and jaws osteochemonecrosis]. / Ostéoporose, bisphosphonates et ostéochimionécrose maxillo-mandibulaire.

Bisphosphonates are widely used in the treatment of nonmalignant bone disease like osteoporosis, Paget's disease and malignant disease like malignant hypercalcemia, osteolytic metastasis from breast and prostate cancer and multiple myeloma. Jaws osteonecrosis is described since 2003 and is more often associated with the intraveinous use than oral use. Higher risk of osteonecrosis is noted after 3 years of osteoporosis treatment. The precipitating event is often a tooth extraction or other invasive procedure. There is no effective treatment for this pathology. Careful oral examination is necessary before prescribing bisphosphonates and dental treatment must be achieved before the initiation of treatment.

[Melanoma of the oral mucosa]. / Mélanome de la muqueuse buccale.

INTRODUCTION: The oral melanoma (OM) account for 1% of all melanomas. The prognosis is poor despite an adequate locoregional control of the disease. CLINICAL CASE: A 45-year-old woman presented with submandibular lymph nodes, having metastised from a melanoma. Oral cavity examination revealed a pigmented lesion of the gingiva in front of tooth 12, with satellite spots. Surgical treatment, radiotherapy, chemotherapy, and immunotherapy failed and the patient died 16 months after diagnosis. DISCUSSION: Oral melanomas have a poor prognosis probably because they are generally detected late. The most common sites for oral melanomas are the palate and maxillary gingiva. About 30% of OM is preceded by areas of oral pigmentation for several months or years. The prognosis is poor with a 5% to 20% five-year survival rate.

[Osteochemonecrosis of the jaws and bisphosphonates: a case report and literature review]. / Ostéochimionécrose maxillo-mandibulaire et bisphosphonates. A propos d'un cas et revue de la littérature.

Jaws osteonecrosis were, in most cases, caused by external irradiation. It was otherwise a rare occurrence. However, bisphosphonates have recently been associated with osteonecrosis of the mandible or the maxilla. Bisphosphonates are widely used in the treatment of osteoporosis, multiple myeloma and osteolytic bone metastases. They inhibit bone resorption by osteoclasts and disrupt the bone turnover. The so-caused bone expositions are painful and prone to surinfection. Even after cessation of the bisphosphonates, the results of medical and surgical treatment are very inconsistent. A thorough dental check-up is recommended before initiating a course of bisphosphonates.

[Avascular mandibular necrosis]. / Nécrose avasculaire de la mandibule.

INTRODUCTION: Jaw osteonecrosis is, in most cases, caused by external irradiation. It is otherwise a rare occurrence. OBSERVATION: A 52-year-old patient was referred to this hospital for several tooth extractions. In the procedure follow-up, the external aspect of the mandible was more and more exposed. This led to the spontaneous loss of a voluminous bone fragment. The patient had never undergone radiotherapy or a course of bisphosphonates but had a long-term cardio-vascular history. He had undergone endarterectomy of both carotids, an ilio-femoral by-pass, and a coronary dilatation. The diagnosis of bone infarction on a chronic osteomyelitis was made. DISCUSSION: Blood coagulation disorders are responsible for most cases of bone infarction. Other risk factors include local trauma, chemotherapy, corticoids, and bisphosphonates. Necrosis of the jawbones is rare even though these are prone to trauma and infections. Symptoms are not specific and imaging is contributive late in the evolution. The results of medical treatment (antibiotherapy, vasodilators, and hyperbaric oxygenotherapy) and surgical debridement are very inconsistent.

[Bisphosphonates and maxillo-mandibular osteo(chemo)necrosis]. / Bisphosphonates et ostéo(chimio)nécrose maxillo-mandibulaire.

INTRODUCTION: Maxillo-mandibular osteonecrosis is exceptional outside a context of cervico-facial radiotherapy. Bisphosphonates are non-metabolized pyrophosphate analogues which inhibit osteoclastic activity. Bisphosphonates are prescribed for the treatment of malignant hypercalcemia, osteolysis associated with metastatic bone disease, Paget's disease and osteoporosis. Maxillomandibular osteonecrosis with bisphosphonates can be observed in 1/10000 patients, but is probably underestimated due to lack of dental examination. MATERIAL AND METHODS: We describe six cases of mandibular necrosis associated with bisphosphonates: five of them as part of their treatment regimen for a neoplastic condition and one for osteoporosis. RESULTS: Two patients developed spontaneous bone necrosis. In two others, tooth extraction preceded the onset of osteonecrosis. In the last two patients, we noted a preexisting dental infection. All the histopathological examinations showed necrotic bone colonized by Actinomyces. DISCUSSION: Bisphosphonate-induced osteonecrosis is only found in the maxillomandibular area because the jaws are the only bone in the skeleton exposed to the external environment. The mandible is rendered particularly prone to necrosis even after minor trauma because of its terminal vascularization. Careful oral examination is recommended before prescribing bisphosphonate therapy.

[Oral verrucous carcinoma]. / Le carcinome verruqueux oral.

Verrucous carcinoma is a rare, low-grade, well-differentiated form of squamous cell carcinoma seen on skin and mucosa. It is a slow-growing and locally aggressive tumor whose standard treatment is surgery. A case of strongly invasive oral verrucous carcinoma is presented with the medical history. The differential diagnosis of this neoplasm is difficult and requires clinic and pathologic data confrontation. In this paper, the importance of knowing the malignant potential of this lesion is stressed. Indeed, in 20% of verrucous carcinoma, foci of squamous cell carcinoma can be found. A review of literature and a differential diagnosis of verrucous carcinoma are presented.

[Central reparative giant cell granuloma of the maxilla. Apropos of a case]. / Granulome réparateur central à cellules géantes des maxillaires. A propos d'un cas.

Central giant cell granulomas are uncommon, locally aggressive and benign tumors of the maxillofacial skeleton. The authors report a case of tumor arising from the maxilla and present a review of essential characteristics of the lesion.