Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

The Clinical Behavior and Recurrence Patterns of Oral Cavity Cancer in Oral Lichen Planus Patients.

OBJECTIVES: Oral lichen planus (OLP) is a chronic inflammatory disorder involving epithelia with squamous differentiation. Although described as a potential malignant precursor, the characteristics of malignancies arising among these patients are not widely described. Our goal was to describe the patterns of disease recurrence of patients with oral cavity squamous cell carcinoma (OSCC) arising on the background of OLP. METHODS: A retrospective analysis of all surgically treated patients with OSCC at a university-affiliated tertiary care center between 2000 and 2020. RESULTS: Two hundred seventy-nine patients with OSCC treated surgically were included. Forty (14.3%) had OLP. The mean age of patients with OLP was 70.9 years compared with 64.3 years for non-OLP patients (p = 0.03). OLP patients had a significantly higher rate of disease recurrence, persistence, or multiple primary disease (70% vs. 33.9%, p < 0.001). The mean number of sequential oncologic events for each patient with recurrence was also significantly higher among OLP patients (1.86 vs. 1.36, p = 0.03), a difference explained by a higher rate of multiple primary presentations (0.71 vs. 0.28, p = 0.008). A significant difference in disease-free survival (DFS) was demonstrated between the groups as patients with OLP had a lower 5-year DFS (34.7% vs. 61.3%, log-rank p value <0.001). On multivariate analysis, OLP was significantly associated with multiple primary events (p < 0.001, Odds ratio = 7.42, 95% confidence interval 2.9-19). CONCLUSIONS: OSCC patients with OLP background demand close clinical follow-up, as multiple primary disease is significantly more common and the DFS is significantly lower among these patients. A thorough clinical evaluation for all oral cavity subsites is mandatory. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3146-3151, 2024.

Risk factors contributing to early implant failure following sinus augmentation: A study of a challenging cohort.

BACKGROUND: Sinus augmentation has become a more predictable and successful procedure as the knowledge of its indications and complications increased. However, knowledge of risk factors leading to early implant failure (EIF) among challenging systemic and local conditions is insufficient. OBJECTIVES: The present study aims to assess risk factors for EIF following sinus augmentation in a challenging cohort. METHODS: A retrospective cohort study conducted during a period of 8 years in a tertiary referral centre providing surgical and dental health care. Implant and patient variables including age, ASA (American Society of Anesthesiology) physical status classification, smoking, residual alveolar bone, type of anaesthesia and EIF were collected. RESULTS: Cohort was comprised of 751 implants placed in 271 individuals. EIF rates at the implant and patient level were 6.3% and 12.5%, respectively. EIF was found to be higher among smokers (patient level: χ2 (1) = 8.74, p = .003), ASA 2 physical classification patients (patient level: χ2 (2) = 6.75, p = .03), sinuses augmented under general anaesthesia (patient level: χ2 (1)=8.97, p = .003), higher bone gain (implant level: W = 12 350, p = .004), lower residual alveolar bone height (implant level: W = 13 837, p = .001) and multiple implantations (patient level: W = 3016.5, p = 0.01). However, other variables such as age, gender, collagen membrane and implant's dimensions did not reach significance. CONCLUSIONS: Within the limits of the study, we can conclude that smoking, ASA 2 physical status classification, general anaesthesia, low residual alveolar bone height and numerous implants are risk factors for EIF following sinus augmentation in challenging cohorts.

Is the Risk to Develop Osteoradionecrosis of the Jaws Following IMRT for Head and Neck Cancer Related to Co-Factors?

Background and Objectives: Determine the contribution of coexisting factors to the risk to develop Osteoradionecrosis (ORN) of the jaws among patients who have received radiotherapy by intensity modulated radiation therapy (IMRT) for head and neck cancer (HNC) between 2013 and 2016, in a single medical center. Materials and Methods: The records of all patients treated with IMRT for HNC between 2013 and 2016 in The Davidoff Center for the treatment and Research of Cancer in Rabin Medical Center-Beilinson hospital, Petah-Tikva, Israel were screened. Patients who have received a minimum mean dose of 40 Gy to the oral cavity entered the research and their medical records were retrospectively reviewed. Collected background data included: age, gender, smoking, diabetes mellitus (DM), ASA score, mean and maximal radiation doses (Gy), and diseases characteristics including histological diagnosis, primary tumor site, and disease stage. Results: A total of 1232 patients were surveyed. Out of all screened patients, 93 received a minimum mean dose of 40 Gy to the oral cavity. Out of the 93 patients, 7 (7.52%) developed ORN (ORN+) and 86 did not develop ORN (ORN-). Tumor type in all seven patients in the ORN+ group was Squamous Cell Carcinoma (SCC). In three out of those seven patients (42.9%), the tumor was located in the mandible. Conclusions: within the limits of the relatively small cohort in the current study, we suggest that the development of ORN due to Radiation therapy (RT) with IMRT is related significantly only to the location of a tumor in the mandible. Other co-factors do not significantly increase the risk to develop ORN when RT is delivered via IMRT.

The unique characteristics of sialolithiasis following drug-induced hyposalivation.

OBJECTIVES: Assess clinical, imaging, operative, and post-operative characteristics of drug-induced vs. non-drug-induced sialolithiasis that are termed 'other etiologies of sialolithiasis.' MATERIALS AND METHODS: Data collected from a retrospective cohort of 96 patients who underwent intra-oral sialolith removal operations were categorized as patient disease characteristics, physical examination results, and imaging and therapeutic features. Patients were divided into two groups based on having drug-induced sialolithiasis (DIS) vs. other etiologies of sialolithiasis (OES). Patients who consumed any medication for chronic conditions were regarded as DIS. Statistical analyses were conducted to elucidate differences and similarities between the two groups. RESULTS: There were 60 patients in the DIS group and 36 in the OES group. DIS patients were significantly older (average age 57.9 vs. 39.8 years, respectively), with no gender predilection. Statins and anti-hypertensive medications were most commonly consumed. Presenting symptoms including number of past swellings, salty tasting saliva, pain, and antibiotic treatment were similar between the groups; mealtime-related swelling of the gland was noted in a higher proportion of OES patients (51.5% vs. 37%, respectively). Analysis of sialolith size and location from fixed anatomical landmarks on the mandible were not different between groups, and the most frequent sialolith location was the hilus gland in DIS vs. intra-glandular in OES patients. Sialolith removal operation time was significantly shorter for DIS patients (45 ± 11.5 vs. 61.1 ± 18.1 minutes). CONCLUSION: Drug-induced sialolithiasis may be regarded as a unique entity with a typical clinical age, presenting symptoms, imaging characteristics, and surgery duration. CLINICAL RELEVANCE: Clinicians should be aware of the above-mentioned differences when treating patients with sialolithiasis and anticipate a more challenging sialolith removal procedure for other etiologies of sialolithiasis, possibly due to underlying anatomical factors of the duct system. When treating drug-induced sialolithiasis, clinicians can expect a shorter operation time with a similar success rate and hospitalization time as with a younger, healthier population with other sialolithiasis etiologies.

Is inferior meatal antrostomy still relevant? A 12-year analysis of 93 oroantral fistulae closure with concomitant Caldwell-Luc operations.

OBJECTIVE: The aim of this study was to retrospectively evaluate clinical outcomes after closure of oroantral fistulae with concomitant Caldwell-Luc operations (OFCLOs) with or without inferior meatal antrostomy (IMA). STUDY DESIGN: Records from consecutive OFCLOs carried out over a 12-year period at the oral and maxillofacial surgery department at a single medical center were reviewed. Background data included age, sex, medical status, indications, and etiologies. Outcome data included operative time, hospitalization time, and postoperative use of analgesics and complications. RESULTS: From 2002 to 2013, 54 male patients (58%), 39 female patients (42%) (mean age 50 years; range 12-84 years) underwent OFCLOs. IMA was carried out in 66 cases (70%). All patients had minimal complications. We found statistically significant shorter operating times (72 vs 84 minutes), shorter postoperative hospitalization times (4.1 vs 5.6 days), lower need of analgesics (1.44 vs 2.88 per day), and fewer complications (11% vs 38%) when IMA was not used. CONCLUSIONS: IMA during OFCLOs carries increased morbidity without apparent benefits. Its routine use should, therefore, be discontinued.

Non-Autogenous Innovative Reconstruction Method Following Mandibulectomy.

BACKGROUND: Plexiform ameloblastoma is a locally aggressive odontogenic tumor, rare in the anterior mandible. The treatment of choice is resection with 1-3 cm free margins. In most of reported cases, the affected mandible is reconstructed by autogenic bone graft or osseocutaneous microvascular free flap in order to return function and esthetics. CASE DESCRIPTION: A 2 cm diameter exophytic ameloblastoma, located in the anterior mandible of a 50-year-old male was resected and reconstructed in a unique manner-allogenic bone block, recombinant human bone morphogenetic protein (rhBMP) and xenograft particles via transcutaneous submental approach. After bone maturation, dental implants were placed and restored by fixed prosthetics. PRACTICAL IMPLICATIONS: Mandible reconstruction modalities have a crucial influence on patient quality of life, function and esthetics. Allogenic bone block combined with rhBMP and xenograft particles can replace the traditional autogenous bone in certain circumstances. A submental transcutaneous "tent pole" approach can improve the success rate of the reconstruction procedure.

Evaluation of Surgical Treatment of Oroantral Fistulae in Smokers Versus Non-Smokers.

Background and Objectives: Smoking has been found to interfere with wound healing processes. Therefore, the purpose of this study was to compare surgical treatment of oroantral fistulae (OAFs) in smokers and non-smokers. Materials and Methods: Medical records of all consecutive patients who underwent surgical closure of OAFs between 2003 and 2016 at the oral and maxillofacial surgery department, Rabin Medical Center, Israel were reviewed. Patients' demographic data, preoperative signs and symptoms, surgical method of repair, and postoperative complications were recorded. Results: The cohort consisted of 38 smokers and 59 non-smokers. Age and gender distributions were similar in both groups. The main etiology in both groups was tooth extraction, followed by pre-prosthetic surgery in smokers and odontogenic infection in non-smokers (p = 0.02). Preoperative conditions were not significantly different between smokers and non-smokers in terms of size of soft tissue fistula and bony defect, chronic sinusitis and foreign bodies inside the sinus. OAFs were repaired by local soft tissue flaps without consideration of smoking status. Smokers experienced more moderate-severe postoperative pain (p = 0.05) and requested more weak opioids (p = 0.06). Postoperative complications included infection, delayed wound healing, residual OAF, pain, sensory disturbances and sino nasal symptoms. These were mostly minor and tended to be more frequent in smokers (p = 0.35). Successful closure of OAFs was obtained in all patients except one smoker who required revision surgery. Conclusions: Smokers may be more susceptible to OAFs secondary to preprosthetic surgery. In this cohort, there was no statistically significant difference in outcome between smokers and non-smokers in terms of failure. However, smokers tended to have more severe postoperative pain and discomfort and to experience more postoperative complications. Further studies with larger sample sizes should be conducted to validate these results.

Preoperative Maxillary Sinus Imaging and the Outcome of Sinus Floor Augmentation and Dental Implants in Asymptomatic Patients.

OBJECTIVES: Preoperative maxillary sinus imaging findings have been suggested to be associated with complications and outcomes of sinus lift and dental implant procedures; nonetheless the evidence is controversial. The aim of this study was to examine the association between preoperative maxillary sinus imaging findings and outcomes of sinus lift and dental implant procedures in asymptomatic patients. METHODS: We included all patients who underwent maxillary sinus lift and dental implant procedures between 2014 and 2017. Maxillary sinus imaging findings were extracted from pre-procedural dental computed tomography scans, and outcomes of the procedures were assessed. RESULTS: A total of 145 procedures were included. No sinonasal symptoms were reported preoperatively. In 46% of cases maxillary sinus imaging was abnormal. The most common imaging finding was peripheral mucosal thickening (38%). Sinus floor cyst/polyp was identified in 13% of the cases, of which 47% occupied more than 50% of the sinus volume. Partial or complete opacification of the maxillary sinus was documented in 3% of cases. The sinus ostium and ostiomeatal complex were obstructed in 7% and 1%, respectively. Mucosal perforation was documented in 22% of cases and was inversely related to mucosal thickening (P = 0.011). Other minor post-operative complications did not correlate with radiological findings. Post-surgical sinusitis was not observed in any of the patients regardless of pre-surgical imaging findings. CONCLUSIONS: Incidental maxillary sinus imaging findings such as mucosal swelling, cysts or polyps, regardless of their severity or size, and maxillary ostial obstruction may not need to be addressed prior to sinus augmentation and dental implant procedures in asymptomatic patients. Patients with complete sinus opacification should be referred to an otolaryngologist prior to surgery. Further controlled trials, in larger cohorts, are needed to corroborate our findings.

Metastatic tumors in oral mucosa and jawbones: Unusual primary origins and unusual oral locations.

AIM: To perform clinico-pathological characterization of a large series of oral metastases, collected from 3 main medical centers in Israel and compare findings to data on frequency of primary cancer types in the population. MATERIALS: Pathology archives were searched for cases of metastatic tumors to the oral soft tissues and jawbones, 1990 - 2016. Metastases to the skin of face or to major salivary glands have been excluded. Demographic data and histopathological features were analyzed. RESULTS: Study population included 60 patients, 35 females and 25 males (ratio of 1.4:1). The age range was 17-87 years, mean 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years, the remaining clustered predominantly in the 60-80 year age group. The mean age of females (59 + 13.84) was significantly lower than that of males (67.44 + 14) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (48.3% and 51.7%, respectively). The five most common organs from which metastases were distributed to the oral cavity and jawbones combined were kidney (20%), breast (15%), cutaneous (predominately melanoma, 13%), lung (11.7%) and soft tissue-sarcomas (8.3%). For comparison, Israel National Cancer Registry 2013 reported that the most frequent malignancies were breast (25.8%), colorectal cancer (16.3%), lung (12%) and prostate (10%). Malignant melanoma was 6th (5.4%), kidney malignancy was only 9th in frequency (4.2%). Although the gingiva and jawbones were the most frequent locations, some cases presented in unusual locations, (mandibular vestibule, lower lip, posterior dorsal tongue), without any specific clinical feature to suggest metastasis. CONCLUSIONS: The most frequent primary origins for oral metastasis do not correspond to the relative frequency of the primary tumors in the population, indicating that metastatic spread is not a random process. Although the majority of metastasis involves the gingiva and jawbones, any other oral mucosal location might be involved. Thus, in adult/older patients, metastasis from a distant site should be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.

Clinicopathologic evaluation of malignancy adjacent to dental implants.

OBJECTIVE: The aim of this study was to describe a new case series of peri-implant malignancy, review the literature, and discuss the implications of malignancies resembling peri-implantitis. STUDY DESIGN: This study was a retrospective analysis of cases from 2000 to 2016. RESULTS: Seven patients (two males and five females), aged 44 to 89 years, were included, representing 1.5% of oral malignancy cases. Five cases were squamous carcinoma, one of basal cell carcinoma, and one of carcinoma of metastatic origin. Six cases presented with nonulcerated overgrowth, with bone loss in three and massive osteolysis in one. Misinterpretation as peri-implantitis delayed diagnosis in six cases. Risk factors included previous oral malignancy (2), potentially malignant conditions (2), and smoking (1). Of the 47 cases in the English language literature, 85% were squamous cell carcinoma and 8.5% had distant metastasis. Most cases had one or more risk factors. CONCLUSIONS: Peri-implant malignancy may represent up to 1.5% of oral malignancy cases. Clinical features imitating peri-implantitis may delay diagnosis. Lesions failing to respond to treatment, especially in patients with pre-existing risk factors, should significantly increase suspicion. Histopathology is crucial for diagnosis.

The induction of tuftelin expression in PC12 cell line during hypoxia and NGF-induced differentiation.

The tuftelin protein isoforms undergo post-translation modifications, and are ubiquitously expressed in various tissues in embryos, adults, and tumors. Developmental and pathological studies suggested an apparent correlation between oxygen deprivation and tuftelin expression. The aim of the study was therefore to investigate the effect of a pathological insult (hypoxia) and a physiological growth factor (NGF), which antagonistically regulate HIF1 expression, on tuftelin expression using the neuronal PC12 cell model. In the present study, we first demonstrated the expression of tuftelin in PC12 cells, providing an experimental system to investigate the pathophysiological role of tuftelin. Furthermore, we demonstrated the induction of tuftelin during hypoxia by oxygen deprivation and during chemical hypoxia by cobalt chloride. Down-regulation of HIF1α mRNA blocked hypoxia-induced HIF1α expression, and reduced by 89% hypoxia-induced tuftelin expression. In mice, intraperitoneal injection of cobalt chloride significantly induced tuftelin mRNA and protein expression in the brain. During NGF-mediated PC12 differentiation, tuftelin expression was significantly induced in correlation with neurite outgrowth. This induction was partially blocked by K252a, a selective antagonist of the NGF receptor TrkA, indicating the involvement of the TrkA-signaling pathways in tuftelin induction by NGF. Revealing the physiological role of tuftelin will clarify mechanisms related to the "hypoxic genome," and NGF-induced neurotrophic and angiogenic effects.

Regeneration of bone and periodontal ligament induced by recombinant amelogenin after periodontitis.

Regeneration of mineralized tissues affected by chronic diseases comprises a major scientific and clinical challenge. Periodontitis, one such prevalent disease, involves destruction of the tooth-supporting tissues, alveolar bone, periodontal-ligament and cementum, often leading to tooth loss. In 1997, it became clear that, in addition to their function in enamel formation, the hydrophobic ectodermal enamel matrix proteins (EMPs) play a role in the regeneration of these periodontal tissues. The epithelial EMPs are a heterogeneous mixture of polypeptides encoded by several genes. It was not clear, however, which of these many EMPs induces the regeneration and what mechanisms are involved. Here we show that a single recombinant human amelogenin protein (rHAM(+)), induced in vivo regeneration of all tooth-supporting tissues after creation of experimental periodontitis in a dog model. To further understand the regeneration process, amelogenin expression was detected in normal and regenerating cells of the alveolar bone (osteocytes, osteoblasts and osteoclasts), periodontal ligament, cementum and in bone marrow stromal cells. Amelogenin expression was highest in areas of high bone turnover and activity. Further studies showed that during the first 2 weeks after application, rHAM(+) induced, directly or indirectly, significant recruitment of mesenchymal progenitor cells, which later differentiated to form the regenerated periodontal tissues. The ability of a single protein to bring about regeneration of all periodontal tissues, in the correct spatio-temporal order, through recruitment of mesenchymal progenitor cells, could pave the way for development of new therapeutic devices for treatment of periodontal, bone and ligament diseases based on rHAM(+).

Amelogenin expression in long bone and cartilage cells and in bone marrow progenitor cells.

The amelogenin protein is considered as the major molecular marker of developing ectodermal enamel. Recent data suggest other roles for amelogenin beyond structural regulation of enamel mineral crystal growth. Here we describe our novel discovery of amelogenin expression in long bone cells, in cartilage cells, in cells of the epiphyseal growth plate, and in bone marrow stromal cells.

Amelogenin, a major structural protein in mineralizing enamel, is also expressed in soft tissues: brain and cells of the hematopoietic system.

The amelogenin protein is considered as the major molecular marker of developing and mineralizing ectodermal enamel. It regulates the shape, size, and direction of growth of the enamel mineral crystallite. Recent data suggest other roles for amelogenin beyond regulation of enamel mineral crystal growth. The present study describes our recent discovery of amelogenin expression in soft tissues: in brain and in cells of the hematopoietic system, such as macrophages, megakaryocytes and in some of the hematopoietic stem cells. Reverse transcription-polymerase chain reaction (RT-PCR) followed by cDNA sequencing revealed, in mouse brain, two amelogenin mRNA isoforms: the full-length amelogenin including exon 4, and the isoform lacking exon 4. Immunohistochemistry revealed amelogenin expression in brain glial cells. Mouse macrophages were found to express the full-length amelogenin sequence lacking exon 4. Confocal microscopy revealed colocalization of amelogenin and CD41 (a megakaryocyte marker), as well as amelogenin and CD34 (a hematopoietic stem cell marker) in some of the bone marrow cells. The expression of amelogenin, a major structural protein of the mineralizing extracellular enamel matrix, also in cells of non-mineralizing soft tissues, suggests that amelogenin is multifunctional. Several different potential functions of amelogenin are discussed.