Incidence of antiresorptive agent-related osteonecrosis of the jaw: A multicenter retrospective epidemiological study in Hyogo Prefecture, Japan.

Background/purpose: The incidence of medication-related osteonecrosis of the jaw is increasing worldwide, mostly due to the use of antiresorptive agents (ARAs) such as bisphosphonate (BP) and denosumab (Dmab). However, the proportion of BP-related osteonecrosis of the jaw (BRONJ) and Dmab-related osteonecrosis of the jaw (DRONJ) among all ARA-related osteonecrosis of the jaw (ARONJ) cases is not clear; this hinders appropriate treatment, recurrence-prevention planning, and avoidance of unnecessary Dmab withdrawal. Moreover, the causative drug administered at each disease stage remains unknown. Therefore, we conducted a retrospective study of patients with ARONJ who visited oral and maxillofacial surgery departments at hospitals in Hyogo Prefecture, Japan, over 3 years to classify and compare patient characteristics with those having BRONJ and DRONJ. We sought to identify the proportion of DRONJ in ARONJ. Materials and methods: After excluding stage 0 patients, 1021 patients were included (471 high-dose; 560 low-dose). ARA treatment for bone metastases of malignant tumors and multiple myeloma was considered high dose, while that for cancer treatment-induced bone loss and osteoporosis was low dose. Results: Low doses of BP and Dmab accounted for >50% patients; the results differed from those in other countries. DRONJ accounted for 58% and 35% of high-dose and low-dose cases, respectively. Stage 3 ARONJ cases comprised 92 (19.5%) low-dose BRONJ, 39 (20.1%) high-dose BRONJ, 24 (30%) low-dose DRONJ, and 68 (24.5%) high-dose DRONJ. Eighty-nine patients who received switch therapy were divided into BRONJ or DRONJ, but there was no difference in the ratio of each stage compared to the non-switch therapy. Conclusion: To the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, causative drug, and its doses by disease stages. DRONJ accounted for approximately 30% of the ARONJ, approximately 60% of which was due to high doses.

Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,ß-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the ß-amino ester derivative.

A Facile and Convenient Synthesis of Trisubstituted (E)-α,ß-Unsaturated Esters by Tandem Acetylation-E1cB Reaction.

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.

A literature review of perioperative antibiotic administration in surgery for medication-related osteonecrosis of the jaw.

PURPOSE: Few studies exist that focus on the details of perioperative antibiotic administration for surgery to treat medication-related osteonecrosis of the jaw (MRONJ). The regime and duration of perioperative antibiotics applied in published studies were reviewed to clarify appropriate perioperative antibiotic use in MRONJ surgery. METHODS: A literature search was conducted using the MEDLINE database via PubMed. RESULTS: The search resulted in 453 hits on PubMed. After reading the downloaded full-text articles, 17 articles met the inclusion and exclusion criteria. The most common perioperative antibiotic used for MRONJ surgery was a combination of penicillin-based antibiotics and ß-lactamase inhibitor (52.9%), and the second most common regime was penicillin-based antibiotics with metronidazole (17.6%). The duration of administration was 2 weeks postoperatively in nine studies, whereas four studies applied long-term administration (2-6 weeks postoperatively). CONCLUSIONS: Oral and maxillofacial surgeons mostly prefer penicillin-based antibiotics plus ß-lactamase inhibitor or metronidazole for MRONJ surgery. The duration of administration of these medications may be based on empirical experience.

Green Synthesis of (R)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids.

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

Retrospective study of treatment outcomes after postoperative chemoradiotherapy in Japanese oral squamous cell carcinoma patients with risk factors of recurrence.

BACKGROUND: The purpose of this study was to investigate the feasibility of postoperative concomitant chemoradiotherapy (CRT) with cisplatin (CDDP), and compare the prognosis in 3 groups-without postoperative therapy (S-only), with radiotherapy (RT) alone (S+RT), and with CRT (S+CRT)-in oral squamous cell carcinoma (OSCC) patients at high risk of recurrence. METHODS: Clinicopathologic data and treatment modality were investigated. Endpoints evaluated were locoregional control (LRC), relapse-free survival, overall survival (OS), and type of recurrence. RESULTS: The S+CRT group was associated with a better LRC rate than the S-only (P < .001) and S+RT groups (P = .044). However, there was no significant difference in OS rates between the S+RT and S+CRT groups. CONCLUSION: The addition of concomitant CDDP to postoperative RT improved LRC. However, there may be no benefit from the addition of concomitant CDDP to postoperative RT for improvement of distant metastasis and OS rates in OSCC patients.

Palladium-Catalyzed 1,3-Difunctionalization Using Terminal Alkenes with Alkenyl Nonaflates and Aryl Boronic Acids.

A Pd-catalyzed 1,3-difunctionalization of terminal alkenes using 1,1-disubstituted alkenyl nonaflates and arylboronic acid coupling partners is reported. This transformation affords allylic arene products that are difficult to selectively access using traditional Heck cross-coupling methodologies. The evaluation of seldom employed 1,1-disubstituted alkenyl nonaflate coupling partners led to the elucidation of subtle mechanistic features of π-allyl stabilized Pd-intermediates. Good stereo- and regioselectivity for the formation of 1,3-addition products can be accessed through a minimization of steric interactions that emanate from alkenyl nonaflate substitution.

Magnitude-based Asymmetric Fourier Imaging (MagAFI).

PURPOSE: We propose and assess 2 novel asymmetric Fourier imaging (AFI) techniques, magnitude-based AFI (MagAFI) and MagAFI combined with projection on to convex sets (POCS) (MagAFI+POCS). MagAFI does not require phase information because it uses only the magnitude image with zero-filling. MagAFI+POCS requires phase information but further reduces image errors. MATERIALS AND METHODS: We initially compared phase maps obtained using asymmetrically sampled data for the whole of the k-space and symmetrically sampled data for the low frequency part of the k-space. We used one-dimensional simulation data and 3-dimensional gradient echo data for 2 different echo times (TEs) of the brains of volunteers and assessed the differences between the image reconstructed from the full k-space data and AFI images reconstructed from truncated k-space data. We generated AFI images in this study using the zero-filling, Margosian (homodyne), Margosian+POCS (standard POCS), MagAFI, and MagAFI+POCS techniques. RESULTS: We confirmed the assumption of smaller phase errors for the full k-space data than for the symmetric low frequency k-space data. Our proposed MagAFI technique provides images with smaller phase-induced errors than those obtained using conventional methods, including standard POCS methods, which have been regarded as the best methods. MagAFI+POCS improves image quality as well as robustness. CONCLUSION: Our proposed MagAFI technique achieves a practical balance of image quality and simplicity to perform better than conventional methods using only the 0-filled magnitude image. Combined with POCS, this technique can produce images of even better quality.

Multicenter Retrospective Study of Adjuvant Therapy for Patients with Pathologically Lymph Node-Positive Oral Squamous Cell Carcinoma: Analysis of Covariance Using Propensity Score.

BACKGROUND: The presence of pathologically positive lymph nodes (pN+) is a well-known prognostic factor in oral squamous cell carcinoma (OSCC). The aims of this retrospective multicenter study were to assess the prognosis of OSCC patients with pN+ disease; to compare the prognosis of patients with pN+ disease who underwent surgery plus radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) with that of patients who underwent surgery only; and to account for biases associated with treatment selection of adjuvant RT or CCRT. METHODS: The records of 313 OSCC patients with pN+ disease were retrospectively reviewed. The main outcome measures were 5-year disease-specific survival (DSS) and overall survival (OS) rates. To reduce selection biases associated with retrospective data, the treatment groups were evaluated by Cox proportional hazard analysis with propensity score as a covariate. RESULTS: The 5-year OS and DSS survival rates for the entire patient cohort were 51.8 and 59.2 %, respectively. T3-4 stage, closed (<5 mm) margin distance, ≥4 involved nodes, and extracapsular spread were significant poor prognostic factors for OS and DSS. In the propensity score analysis, postoperative RT/CCRT significantly improved OS and DSS compared to surgery only. However, OS and DSS were not significantly different between patients who received postoperative RT and CCRT. CONCLUSION: The addition of cytotoxic chemotherapy to RT does not provide additional survival benefit in OSCC patients with pN+ disease. Alternative strategies, such as molecular targeted therapies, are needed to further improve the survival of high-risk OSCC patients with pN+ disease.

Vascular endothelial growth factor C (VEGF-C) expression predicts metastasis in tongue cancer.

OBJECTIVE: We evaluated predictive factors for cervical lymph node metastasis of tongue squamous cell carcinoma (SCC). STUDY DESIGN: We present a retrospective analysis of 90 patients with T1-2 N0 SCC who underwent primary excision as initial treatment without preoperative radiotherapy or chemotherapy. We examined the clinicopathologic factors (gender, age, clinical stage, surgical margin, grade of differentiation, lymphatic invasion, tumor depth of invasion, pattern of invasion [POI]) and immunohistochemical factors (vascular endothelial growth factor [VEGF]-A and VEGF-C expression) to predict the probability of lymph node metastasis. RESULTS: The local progression-free 5-year survival rate was 100%. Tumor depth of invasion (≥4 mm, P = .022), POI (score >4, P = .000), and VEGF-C expression (P = .008) were associated with the lymph node metastasis of tongue SCC in a multiple logistic regression analysis (odds ratios [ORs]: 5.075, 17.383, and 9.533, respectively). CONCLUSIONS: The local control rate of tongue SCC in the early stages has significantly improved as a result of development of surgical techniques. On the other hand, we believe that tumor depth of invasion (≥4 mm), POI, and VEGF-C expression all need to be considered in the preoperative and postoperative planning stages for tongue cancer treatment.

Tunnel Technique for the Closure of an Oroantral Fistula with a Pedicled Palatal Mucoperiosteal Flap.

BACKGROUND: Oroantral fistula may develop as a complication of tooth extraction owing to infection, trauma, or removal of maxillary cyst or tumors. Closure by using a palatal mucoperiosteal flap with the greater palatine vessels is a very traditional and basic technique. The palatal mucosa is thick and is firm. However, deformation can occur with shifting of the mucoperiosteal flap, survival of the flap may be unsuccessful, and patients may have substantial intraoral discomfort felt until healing of the eminence with the arcuation. As a method to relieve these problems, we present a mucoperiosteal tunnel technique for the closure of oroantral fistula by using a palatal mucoperiosteal flap pedicled with the greater palatine vessels. METHOD: A 42-year-old man and a 69-year-old woman each had a palatal fistula after palatal tumor resection and tooth extraction, respectively. We designed a mucoperiosteal flap pedicled with the left greater palatine vessel. We ablated the mucoperiosteum between the fistula and the mucoperiosteal flap, and passed this flap under the ablated mucoperiosteum as a tunnel. RESULT: One year after surgery, the fistula had not reappeared and the mucoperiosteal flap harvest did not generate dyskinesis of the soft palate. CONCLUSION: Tunnel technique for the closure of an oroantral fistula with a pedicled palatal mucoperiosteal flap is obtains good fructification.

Postoperative abnormal response of C-reactive protein as an indicator for infectious complications after oral oncologic surgery with primary reconstruction.

BACKGROUND: C-reactive protein (CRP) screening has been reported to be reliable for detection of infectious complications. Postoperative abnormal response of CRP can predict wound infection in colorectal surgery. This study aimed to determine the efficacy of CRP monitoring to detect infectious complications in oral oncologic surgery. METHODS: One hundred patients who underwent oral cancer resection with primary reconstruction were enrolled. Postoperative kinetics of CRP were classified into a normal or abnormal response. RESULTS: A normal CRP response after surgery was observed in 61 patients and an abnormal response was observed in 39. There were postoperative infectious complications in 21 patients, with surgical site infections in 13 patients (early onset in six and late onset in seven). Non-wound infections were found in nine patients. Sensitivity, specificity, the positive predictive value, and the negative predictive value for abnormal CRP response as a predictor for early infectious complications were 100%, 70.1%, 35.9%, and 100%, respectively. CONCLUSION: Postoperative serial CRP screening is a useful test as an indicator of infectious complications in oral oncologic surgery. Normal CRP responses can rule out almost all early infectious complications.

Origin of high E-selectivity in 4-pyrrolidinopyridine-catalyzed tetrasubstituted α,α'-alkenediol: a computational and experimental study.

We have developed 4-pyrrolidinopyridine catalysts for the geometry-selective (E-selective) acylation of tetrasubstituted α,α'-alkenediols. To elucidate the major factors of the high geometry selectivity, experimental and computational studies were carried out. The control experiments with respect to the substituent of the substrate indicated the fundamental hydrogen bonding of the acidic hydrogen of NHNs and the Z-OH in the substrate. Comparison between C2- and C1-symmetric catalysts exhibited the necessity of the C2-symmetric catalyst structure. The computationally proposed transition state (TS) model well explained the experimental results. Whereas the fundamental NH/amide-CO and the two-point free-OH/acetate anion hydrogen bonds stabilize the transition state (TS), affording the E-product, the steric repulsion between the N-protecting group and the amide side chain destabilizes TS, affording the Z-product. The role of the two amide side chains of the catalyst in a C2-symmetric fashion is the enhancement of the molecular recognition ability through the additional hydrogen bond in a cooperative manner.

Spindle Cell Carcinoma of the Oral Cavity: the Impact of Chemotherapy on Pulmonary Metastatic Tumor Doubling Time.

Spindle cell carcinoma (SpCC) an aggressive squamous cell carcinoma, variant, frequently metastasizes to regional lymph nodes and distant organs. Unfortunately, an effective treatment method for oral SpCC distant metastasis has not yet been established. Here we present 2 of oral SpCC cases that showed distant metastases after initial treatment, and 2 that showed distant metastases following during surgery. We calculated the tumor doubling time (TDT) and onset of the pulmonary metastatic and examined the TDT of the pulmonary metastatic tumor in patients with or without chemotherapy to determine the effect of anticancer drugs on oral SpCC. Tumor growth curves revealed that pulmonary metastasis likely grew to 1mm, 122 days before the initial examination, indicating that most oral SpCC patients should be treated for metastases. Three patients underwent chemotherapy for pulmonary metastatic tumor, complete response (CR) in one patient and no change (NC) in two. Thus, SpCC patients may have pulmonary micro-metastases even at the initial examination. We recommend wide resection for oral SpCC patients, followed by chemotherapy to prevent metastases.

Alteration of cell-cell junctions in cultured human lymphatic endothelial cells with inflammatory cytokine stimulation.

BACKGROUND: To maintain normal function, the lymphatic endothelium is regulated by cell-cell junctions. There have been few studies of lymphatic endothelial cell junctions using standard cell biological methods. This study had two purposes: to characterize cell junctions in cultured lymphatic endothelial cells and to investigate the effects of the inflammatory cytokine TNF-α on altered cell-cell junctions. METHODS AND RESULTS: Cultured human dermal lymphatic endothelial cells (HDLEC) were immunostained with the tight junction marker, ZO-1, and adherens junction markers, VE-cadherin and PECAM-1. In TNF-α-treated HDLEC, we evaluated changes in endothelial cell junctions by immunostaining and through the use of transendothelial electrical resistance (TER). Immunofluorescence staining of HDLEC revealed heterogeneity among the endothelial cell junctions, which could be classified into continuous and discontinuous junctions. In these cell junctions, ZO-1 and VE-cadherin were co-localized. Double immunofluorescence staining revealed the broad distribution of VE-cadherin at the cell periphery, where VE-cadherin and PECAM-1 were co-localized. TNF-α treatment decreased TER, caused a predominance in the appearance of discontinuous junctions with a reduction in the broad distribution of VE-cadherin at the cell periphery in HDLEC. CONCLUSIONS: The results indicate a heterogeneous distribution of cell junctions in HDLEC involving continuous and discontinuous junctions. Our data also suggest that TNF-α alters the normal distribution of cell junctions and affects the endothelial barrier of cultured lymphatic endothelial cells. The broad distribution of VE-cadherin at the cell periphery may reflect the lymphatic permeability.

Absence of the sternocleidomastoid muscle in a patient that underwent neck dissection for squamous cell carcinoma of the tongue.

The congenital absence of a skeletal muscle is a rare cause of congenital muscular torticollis, and the condition is associated with various unusual anatomical structures. We describe a rare case of congenital absence of the sternocleidomastoid muscle associated with squamous cell carcinoma of the tongue in a patient who underwent neck dissection. In this case, both the external jugular vein and the spinal accessory nerve were absent. However, we found that branches of the C3 nerve extended from the cervical plexus to the trapezius muscle and seemed to be acting as trapezius muscle motor nerves in place of the accessory nerve. After the operation, the patient was able to lift and abduct his right arm, and his shoulder did not droop.

Inhomogeneous noise correction combined with uniform filter and sensitivity map (INCUS) for multi-coil imaging including parallel imaging.

PURPOSE: We have developed and assess INCUS (inhomogeneous noise correction combined with uniform filter and sensitivity map), a novel technique to correct spatially inhomogeneous noise in surface-coil-based standard or parallel imaging in magnetic resonance (MR) imaging. MATERIALS AND METHODS: We employed a weighted summation of 2 images uniformly filtered with both a strong filter and a weak or no filter to achieve spatially nonuniform filtering by utilizing a coil-sensitivity and/or noise map to give greater weight to the strongly denoised components of the region with lower signal-to-noise ratio (SNR). We compared the image quality and difference between INCUS and standard uniform filter techniques employing several types of linear or nonlinear filter in abdominal or diffusion-weighted brain images each for 1 volunteer acquired on a 1.5-tesla magnetic resonance (MR) imager with parallel imaging after adding simulated noise. RESULTS: The INCUS technique inherently reduced inhomogeneous noise on multiple surface-coil imaging and minimized blur obtained with every filter type. Overall errors were smaller for the INCUS filter than the uniform filter when either of these was used in combination with any of the other filters. CONCLUSION: The INCUS technique provides a straightforward, higher degree of freedom, and computationally feasible implementation of a general purpose de-noising filter for surface coil-based imaging including parallel imaging in commercial MR imaging.

The observational study of delayed wound healing after tooth extraction in patients receiving oral bisphosphonate therapy.

INTRODUCTION: In this study, we investigated whether such a discontinuation of oral bisphosphonate (BP) for 3 months might influence the incidence of BP-related osteonecrosis of the jaw (BRONJ) and wound healing after tooth extraction in patients receiving oral BP therapy. MATERIAL AND METHODS: There were a total of 434 teeth in 201 patients (18 males and 183 females). The patients were divided into two groups depending on whether or not they underwent a 3-month discontinuation of BP therapy (BP- and BP+) before tooth extraction. In this observational study investigated delayed wound healing after tooth extraction in patients receiving oral BP therapy. RESULTS: In all cases of the BP- group, there were no BRONJ although there was delayed wound healing in two cases. However, in one case of the BP+ group, oral BP was continued because it was deemed high risk to discontinue treatment by the patient's physician. In this case, an intraoral fistula was still present with bone exposure at 120 weeks after extraction (BRONJ stage 1). CONCLUSION: This study supports the idea of a drug holiday and encourages further clinical research on this topic of tooth extraction in patients receiving oral BP therapy.

Retrospective study of ameloblastoma: the possibility of conservative treatment.

At our institutions, most cases of the solid or multicystic type were treated as conservatively as possible in order to avoid disadvantages of radical treatment. The aim of present study was to retrospectively analyze the ameloblastoma cases diagnosed at our two institutions, to classify them according to the criteria of the 2005 WHO classification, and to evaluate the possibility of using a conservative approach for the surgical treatment of ameloblastoma. Maxillary cases, unicystic cases, peripheral cases and resection-treated cases were excluded from this study. In 23 tumors of mandibular solid or multicystic ameloblastoma, a patient's age, gender, location, clinical signs, duration, radiographic appearance, preoperative diagnosis, ameloblastoma subtypes, treatment, and recurrence were investigated. The recurrence rate (48.7%) in this study was lower than the reported recurrence rate after conservative treatment for solid or multicystic ameloblastoma and was higher than the reported recurrence rate of ameloblastoma, inclusive of other types. However, all patients who were diagnosed with recurrences have maintained their quality of life and were satisfied for at least several years after the conservative treatment. In conclusion, we demonstrated one possibility that a conservative approach might be employed in the surgical treatment of ameloblastoma (even of the solid or multicystic type).

Influence of preoperative dental procedures on the prognosis of patients with squamous cell carcinoma of the gingiva.

Our aim was to investigate the prognosis of patients with squamous cell carcinoma (SCC) of the gingiva who had preoperative dental operations. We studied 102 patients who were being operated on for SCC of the gingiva with special reference to the effects of preoperative dental operations on the prognosis. Twenty-six patients had dental procedures such as tooth extraction, or incision, or curettage before they visited our hospital, while the remaining 76 had no such interventions. The percentage of patients with advanced T stage disease (T3 or T4) was higher among those who had interventions (17/26, 65%) than among those who had not (35/76, 46%). The difference was not significant. Histopathologically invaded nodes were detected in half the patients in the intervention group (13/26), while they were found in only 18/76 (24%) of those in the no intervention group (p<0.02). The incidence of nodal metastases with extranodal spread was significantly higher in the intervention group than in the no intervention group (p<0.05), and those in the intervention group were more likely to develop distant metastases than those in the other group (p<0.001). The 5-year survival in the two groups was 65% and 92%, respectively (p<0.01). Preoperative dental operations such as tooth extraction, incision, or curettage possibly lead to regional and distant metastases and therefore a poor prognosis in patients with SCC of the gingiva.