AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer.

Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the ß-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.

Osteonecrosis of the jaw under palbociclib: A case series description.

INTRODUCTION: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. MATERIALS AND METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. CONCLUSION: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Medication-related osteonecrosis of the jaw: Evaluation of a therapeutic strategy in oral surgery.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse illness linked to antiresorptive therapies (ART), for which there is no therapeutic gold standard. Many factors can influence MRONJ evolution such as cancer type, treatment, comorbidities, and accumulated dose of ART. The aim of this study was to determine the influencing factors of MRONJ treatments success. METHODS: This retrospective study focused on patients treated for MRONJ in a French tertiary centre. Non-operative therapy was always applied, ART were suspended if appropriate, and surgery (MRONJ removal and musculo-mucosal flap reconstruction) was performed in the absence of contraindication. The evaluation criteria were bone and mucosal healing 3 months after surgery. RESULTS: 81 MRONJ were included; medical treatment alone was administered to 26 % while the remaining 74 % received additional surgery. Therapeutic success reached 86.7 % (52/60) for surgery compared to 42.9 % (9/21) for medical treatment alone (p < 0.001). Age (OR=1.08, p = 0.014) and the absence of infection (OR=5.32, p = 0.042) were in favour of success, while medical treatment alone (OR=0.03, p < 0.001) was highly unfavourable. CONCLUSION: MRONJ healing is influenced by age, non-infectious stages, and surgery. Additional surgery in MRONJ treatment should be advised if the health of the patient permits.

Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.

Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance.

Management options for dental extraction in hemophiliacs: a study of 55 extractions (2000-2002).

OBJECTIVE: Dental extraction in hemophiliacs is associated with a high risk of bleeding. It requires a multidisciplinary approach and stringent protocol. The current trend is to simplify these protocols. In this study we review the efficacy of a protocol using systemic treatment--factors/dihydro-D-arginine vasopressin (DDAVP)--and simplified local hemostatic measures to control bleeding, to limit patient discomfort, and to minimize hospital length of stay. STUDY DESIGN: This retrospective study of 55 dental extractions was performed during 19 interventions in 16 patients with hemophilia A or B to assess the efficacy of a protocol combining general management via the injection of factor concentrates or DDAVP and local hemostasis using biological glue and gelatin packing. Compressive, hemostatic splints, which have been in use by some for many years, are replaced by intermittent tranexamic acid compression during the first 3 days after surgery. RESULTS: We recorded 6 instances of postsurgical bleeding, 4 of which occurred after the compression period. In 2 cases repetition of the local hemostasic measures was required along with the injection of an antihemophilic factor concentrate. In the other 4 cases, the patients' condition reverted to normal following injection of the factor concentrate and the reapplication of the compression. CONCLUSION: The adopted protocol produced a reliable outcome, limiting the duration of the hospital stay to 24 hours in most cases, and improving postsurgical comfort thanks to a combination of systemic treatment and local hemostasic measures including intermittent tranexamic acid compression.

Clinical results comparing high-oxygen and low-oxygen permeable soft contact lenses in France.

PURPOSE: This article reports clinical results comparing a high-oxygen permeable (HDk) silicone hydrogel soft contact lens with a low-oxygen permeable (LDk) soft hydroxyethyl methacrylate contact lens when worn on an extended-wear basis. METHODS: Six practitioners in France enrolled 134 subjects in this 4-month, open-label, multicenter, prospective, randomized, cross-over study. Subjects were randomized to receive either an HDk lotrafilcon A or an LDk etafilcon A soft contact lens. Subjects crossed over to the alternative lens after either 3 months' experience with the HDk lens or 1 month's experience with the LDk lens. Clinical and subjective data were collected at scheduled follow-upvisits. RESULTS: The subjective data has been reported in a separate article. Both types of lenses gave similar performance for visual acuity. Biomicroscopic examination findings averaged below grade 1 (trace) for both lenses throughout the study. A statistically significant difference for limbal redness was found at 1 week (HDk = 0.11; LDk = 0.33; paired-t test, P < 0.05). Eight of 10 biomicroscopic signs improved within 1 week when subjects changed from the LDk lens to the HDk lens. Deposits for both lenses remained below grade 1, and wetting was nearly perfect for both lenses throughout the study. Over 90% of fittings for both lenses were acceptable or optimal. CONCLUSION: The improvements in biomicroscopy signs seen with the HDk lens may provide practitioners an alternative to LDk contact lenses for extended wear.

Subjective experience with high-oxygen and low-oxygen permeable soft contact lenses in France.

PURPOSE: This article reports the subjective results of a study comparing extended-wear high-oxygen permeable (HDk) silicone hydrogel soft contact lenses with low-oxygen permeable (LDk) hydroxyethyl methacrylate lenses. METHODS: Six practitioners in France enrolled 134 subjects in this 4-month, open-label, multicenter, prospective, randomized, cross-over study. Subjects were randomized to receive prescriptions of either an HDk lotrafilcon A or an LDk etafilcon A soft contact lens. Subjects then crossed over to the alternative lens after either 3 months' experience with the HDk lens or 1 month's experience with the LDk lens. Clinical and subjective data were collected at scheduled follow-up visits. RESULTS: The clinical data has been reported in a separate article. After 1 month of wear. HDk lenses were rated better than LDk lenses for all aspects of comfort and overall average symptoms. Subjects were satisfied with both lenses, and lens features were comparable through 1 month. The preference was higher for HDk lenses after crossing over, either from or to LDk lenses. Eighty-six percent of HDk and 85% of LDk subjects reported wearing their lenses while sleeping for 7 nights per week during the study. Seventy-seven percent of HDk and 21% of LDk subjects reported wearing their lenses while sleeping for 22 to 31 nights during the study. CONCLUSIONS: Based on subjective results, therefore, the HDk lens offers another option to patients and practitioners for extended-wear or continuous-wear soft contact lenses.