Efficacy and Safety of Radium-223 for Castration-resistant Prostate Cancer With Bone Metastasis Before and After Docetaxel.

BACKGROUND/AIM: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. PATIENTS AND METHODS: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. RESULTS: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). CONCLUSION: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.

Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid metabolites as therapeutic agents for BRONJ.

Hyperocclusion up-regulates CCL3 expression in CCL2- and CCR2-deficient mice.

UNLABELLED: Excessive mechanical stress (MS) during hyperocclusion is known to result in disappearance of the alveolar hard line, enlargement of the periodontal ligament (PDL) space, and destruction of alveolar bone, leading to occlusal traumatism. We have recently reported that MS induces predominantly C-C chemokine ligand (CCL) 2 expression in PDL tissues, leading, via C-C chemokine receptor (CCR) 2, to MS-dependent osteoclastogenesis in alveolar bone. Thus, we hypothesize that ablation of the CCL2/CCR2 signaling pathway should suppress MS-induced osteoclastogenesis-associated chemokines and alleviate occlusal traumatism. We examined the effect of MS on chemokine expression and osteoclastogenesis using in vivo and in vitro hyperocclusion models with CCL2-deficient (CCL2((-/-))) and CCR2-deficient (CCR2((-/-))) mice. Compared with that in wild-type mice, expression of CCL3 in PDL cells and TRAP-positive cells in alveolar bone from CCL2((-/-)) and CCR2((-/-)) mice was up-regulated, even in the absence of MS. Furthermore, the expression of CCL3 and TRAP-positive cells was significantly increased after both 4 and 7 days of hyperocclusal MS loading in CCL2((-/-)) and CCR2((-/-)) mice. Hyperocclusion induced compensatory CCL3 expression and promoted osteoclastogenesis to counterbalance deficient CCL2/CCR2 signaling, suggesting that co-expression of CCL3 with CCL2 may precipitate synergistic, MS-dependent alveolar bone destruction during occlusal traumatism. ABBREVIATIONS: MS, mechanical stress; PDL, periodontal ligament; CCL2, CC chemokine ligand 2 (MCP-1; monocyte chemoattractant protein-1); CCR2, CC chemokine receptor 2; CCL3, CC chemokine ligand 3 (MIP-1α); CCL5, CC chemokine ligand 5 (RANTES).

Maxillary stability after Le Fort I osteotomy with self-setting α-tricalcium phosphate and an absorbable plate.

The purpose of this study was to compare retrospectively postoperative differences in maxillary stability after Le Fort I osteotomy and fixation with an unsintered hydroxyapatite (u-HA)/poly-l-lactic acid (PLLA) plate with or without self-setting α-tricalcium phosphate (Biopex(®)) as interpositional material. Subjects comprised 45 patients diagnosed with mandibular prognathism with maxillary retrognathism and mandibular prognathism with bimaxillary asymmetry. All patients underwent Le Fort I osteotomy and bilateral sagittal split ramus osteotomy with fixation by uHA/PLLA plates. Patients were divided into 4 groups consisting of 9 maxillary impaction cases with Biopex(®) (group 1) to fill the gap between the bone segments, 14 maxillary advancement cases with Biopex(®) (group 2), 8 maxillary impaction cases without Biopex(®) (group 3) and 14 maxillary advancement cases without Biopex(®) (group 4). Changes in cepahalometric parameters at time intervals (1, 3 and 12 months) between the groups were compared. Results showed that stability did not depend on the use or otherwise of Biopex(®).

Maxillary stability after Le Fort I osteotomy using three different plate systems.

The purpose of this study was to compare postoperative changes in maxillary stability after Le Fort I osteotomy in three groups: with an unsintered hydroxyapatite (u-HA)/poly-L-lactic acid (PLLA) plate; a PLLA plate; and a titanium plate. Subjects comprised 60 Japanese patients diagnosed with mandibular prognathism. All patients underwent Le Fort I osteotomy and bilateral sagittal split ramus osteotomy. All patients were randomized in groups of 20 to a u-HA/PLLA group, a PLLA plate group and a titanium plate group. Changes in postoperative time intervals between the plate groups were compared using lateral and posteroanterior cephalography. The uHA/PLLA group had significantly larger values than the PLLA group regarding change of mx1-S perpendicular to SN between 3 and 12 months (T3) (P=0.0269). The uHA/PLLA group had a significantly larger value than the PLLA group regarding change of S-A perpendicular to SN between baseline and 1 month (T1) (P=0.0257). There was no significant difference in the other measurements. This study suggests that maxillary stability with satisfactory results could be obtained in the u-HA/PLLA, PLLA plate and titanium plate groups, although there was a slight difference between the u-HA/PLLA and PLLA plate systems in Le Fort I osteotomy.

Changes in the lip closing force of patients with class III malocclusion before and after orthognathic surgery.

The purpose of this study was to examine the changes in lip pressure before and after orthognathic surgery for skeletal class III patients. The subject groups were 32 female and 31 male patients diagnosed with mandibular prognathism and/or maxillary retrognathism who underwent orthognathic surgery. Control groups consisted of 20 women and 20 men with normal occlusion without dento-alveolar deformity. Maximum and minimum lip closing force was measured with Lip De Cum® for the control groups and subject groups preoperatively and 6 months postoperatively. The difference between the pre- and postoperative values of the groups was examined statistically. The maximum lip closing force in men was significantly larger than that in women in both the preoperative class III group (p=0.0330) and the control group (p=0.0097). The preoperative class III group was significantly smaller than the control group in maximum lip closing force in both men (p<0.0001) and women (p<0.0001). The postoperative maximum lip closing force was significantly larger than the preoperative value in both men (p=0.0037) and women (p=0.0273) in the Class III group. This study suggested that the maximum lip closing force increases after orthognathic surgery in Class III patients.

Hyperocclusion stimulates osteoclastogenesis via CCL2 expression.

Excessive mechanical stress (MS) during hyperocclusion is known to result in disappearance of the alveolar hard line, enlargement of the periodontal ligament (PDL) space, and destruction of alveolar bone, leading to occlusal traumatism. We hypothesized that MS induces expression of osteoclastogenesis-associated chemokines in PDL tissue, resulting in chemotaxis and osteoclastogenesis during occlusal traumatism. We examined the effect of MS on relationships between chemokine expression and osteoclastogenesis using in vivo and in vitro hyperocclusion models. In an in vitro model, intermittent stretching-induced MS was shown to up-regulate the expression of CC chemokine ligand (CCL)2, CCL3, and CCL5 in PDL cells. The expression levels of CCL2 in PDL tissues, its receptor CCR2 in pre-osteoclasts, and tartrate-resistant acid-phosphatase-positive cells in alveolar bone were significantly up-regulated 4-7 days after excessive MS during hyperocclusion in in vivo rodent models. Hyperocclusion predominantly induced CCL2 expression in PDL tissues and promoted chemotaxis and osteoclastogenesis, leading to MS-dependent alveolar bone destruction during occlusal traumatism.

Oral epithelial cells are activated via TRP channels.

Transient receptor potential (TRP) ion channels are critical contributors to the perception of various environmental stimuli. Although the oral cavity is the access point for various food types, the expression of TRP channels in oral mucosa remains unknown. We hypothesized that the oral epithelium itself may participate in sensing thermal, mechanical, and chemical conditions. The expression profiles of TRP channels exhibited regional differences among the buccal, palatal, and tongue epithelia. Changes in elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) in oral epithelial cells were found after stimulation of the TRP channels with capsaicin, camphor, 4α-phorbol-12,13 didecanoate (4α-PDD), 2-aminoethoxydiphenyl borate (2-APB), and menthol. These increases in Ca(2+) appeared dependent on the TRP channels, because [Ca(2+)](i) suppression was observed after the addition of the TRPV channel antagonist ruthenium red. These results demonstrate that the oral epithelia express various TRP channels and may have functional roles in sensory activities, together with neurons.

Conditional mutualism between Allodynerus delphinalis (Hymenoptera: Vespidae) and Ensliniella parasitica (Astigmata: Winterschmidtiidae) may determine maximum parasitic mite infestation.

Mutualism is a prominent interaction within ecosystems, yet most may actually be conditional. The symbiotic mite, Ensliniella parasitica Vitzthum, ingests the hemolymph of juvenile potter wasps, Allodynerus delphinalis (Giraud), but also protects them from a natural enemy, Melittobia acasta, and is transported to new nests in host pockets specialized for this purpose (i.e., acarinaria). Thus, two different antagonisms from the mite may arise: commensalistic cheating is expected without the natural enemy of the host, and parasitism is predicted with excessive numbers of the mite. However, facultative parasitism mediated by mutualism has rarely been studied in any organism. We found no significant differences in juvenile mortality, nesting rate, or fecundity between mite-free and naturally mite-laden juveniles. However, when overloaded with mites ( approximately 1.5-2.5 times more mites than the maximum number per wasp larva in the field), the developmental period of the male wasp was significantly delayed, and juvenile wasp mortality increased to 30%. These results show that mutualism mediated by parasitism may revert to parasitism, suggesting that either or both organisms in a mutualism mediated by parasitism need population control of the parasite to avoid the risk of parasitism.

PTHrP induces Notch signaling in periodontal ligament cells.

Periodontal ligament (PDL) cells are known to play important roles in tooth eruption and alveolar bone metabolism. We previously reported that PTHrP increases RANKL expression in human PDL cells, suggesting that it promotes odontoclastic root resorption during tooth eruption. While it is known that Notch-related genes play a key role during bone development, the role of the Notch signaling pathway in PDL cells during tooth and bone resorption is less clear. We hypothesized that PTHrP induces a Notch ligand in PDL cells and thereby regulates osteo- and odontoclastogenesis. We found that PTHrP increased Notch1 ligand Jagged1 expression in human PDL cells in a dose- and time-dependent manner. PTHrP-induced Jagged1 up-regulation was mediated by PKA activation, but not by PKC. Jagged1 also promoted RANKL-induced osteoclastogenesis. These results demonstrate that PTHrP induces Jagged1 expression in PDL cells, leading to osteo- and odontoclastogenesis, and thus likely promoting tooth and alveolar bone resorption.

[Malignant pleural mesothelioma in which many asbestos bodies were counted in its specimen].

A 53-years-old woman was admitted to our hospital because of pleural effusion. She underwent pleural biopsy and diagnosed as mesothelioma. Right extrapleuralpneumonectomy was performed. We counted asbestos bodies in the resected lung. 443,571 asbestos bodies were counted in 1 gram of dry lung. We thought that she was heavily exposed to asbestos. Since high risk of incidence of mesothelioma is suggested among her fellow worker, special investigation is necessary for asbestos exposure.

Early serial Q-switched ruby laser therapy for medium-sized to giant congenital melanocytic naevi.

BACKGROUND: Medium-sized to giant congenital melanocytic naevi (CMN) are difficult to treat, especially if the lesions appear on the face or extremities where treated areas are visible and cosmesis is important. OBJECTIVES: In infants, nests of pigmented naevus reside more superficially and the skin is more transparent than in adults, so we treated medium-sized to giant CMN with early serial Q-switched ruby laser therapy from infancy. PATIENTS AND METHODS: We treated nine patients with medium-sized to giant CMN on the face or upper limbs from 1 month of age with early serial Q-switched ruby laser therapy. The laser power was initially 5 J cm(-2) and increased in 0.5 J cm(-2) steps to a maximum of 10 J cm(-2). There were three treatment sites on the forehead, one on the temple, one on the cheek and four on the upper arm. RESULTS: It took 8-15 treatments for the CMN to become a colour similar to the surrounding skin. The mean number of treatments was 9.6. The colour was reduced to 0-20% of the colour of the baseline lesion in all nine patients. Partial slight repigmentation occurred in eight of these patients. These naevi were treated with an additional one or two Q-switched ruby laser irradiations and successfully lightened for at least 1 year. In the remaining patient, pigmentation returned to a level similar to the original lesion within 1 month of the last treatment. Therefore, the lesion was excised for cosmetic reasons. After the treatment series, the skin texture was fine and no patients had hypertrophic scarring. CONCLUSIONS: Although treatment of one patient with the Q-switched ruby laser therapy failed, the remaining patients responded well and had good to excellent skin texture without hypertrophic scarring. Early serial Q-switched ruby laser treatment, starting from infancy, is a promising treatment method for this condition.

The effects of changing position and angle of the proximal segment after intraoral vertical ramus osteotomy.

The authors evaluated changes in position and angle of the proximal segment, including the condyle, after intraoral vertical ramus osteotomy (IVRO) with and without a Le Fort I osteotomy to verify whether displacement of the proximal segment could induce postoperative complications. Changes in condylar angle, ramus angle, and displacement of proximal segment were measured pre- and postoperatively. The position of the temporomandibular joint (TMJ) disc was examined pre- and postoperatively. Trigeminal nerve hypoesthesia in the lower lip was assessed bilaterally. The postoperative horizontal condylar angle was significantly smaller than the preoperative one on the deviated and non-deviated sides (P<0.0001). The postoperative coronal condylar angle was significantly larger than the preoperative one on the deviated side (P=0.0483). The postoperative sagittal ramus angle was larger than the preoperative one on the deviated (P<0.0001) and non-deviated (P=0.00005) side. Most joints with an anteriorly-displaced disc with and without reduction improved on the non-deviated side; 5 of 16 joints improved on the deviated side. Results suggest the position and angle of the proximal segment, including the condyle, could change after IVRO. This could be associated with symptomatic improvement in TMJ, and extreme medial displacement of the proximal segment could delay recovery from lower lip hypoesthesia.

[Video-assisted thoracic surgery (VATS) for clinical stage I lung cancer in consideration of the diameters and characteristcs of each tumor and the technical limitations of VATS].

UNLABELLED: We planned an intervention study to investigate the late outcome of limited surgery for cStage IA lung cancer by several video-assisted thoracic surgery (VATS) procedures. METHODS: VATS partial resection was done for non-solid tumors less than 1.5 cm in maximum diameter with non-solid component on high resolution computed tomography (HRCT) [group A]. VATS segmentectomy with minor thoracotomy with ND1 + alpha lymph node dissection was done for tumors less than 2.0 cm in maximum diameter that was not included in the group A (group B). Tumors of less than 3.0 cm in diameter that did not fit into the other 2 groups were treated by VATS lobectomy with minor thoracotomy plus ND2 lymph node dissection (group C). RESULTS: A total of 159 patients were enrolled during the 5-year enrollment period (group A: 21 patients, group B: 43 patients, group C: 95 patients). The recurrence-free 5-year survival rate was 100% in the group A, 82.8% in the group B, and 78.4% in the group C, showing no significant differences between the groups. Twenty-eight % of patients was switched to surgical techniques involving more extensive resection in the group A and B. while 6% of the patients was switched to thoracotomy overall. The overall recurrence rate was 10.7% (n=17), while the locoregional and distant recurrence rate was 5.7% (n=9) and 5.0% (n=8), respectively. CONCLUSIONS: This controlled intervention study suggested that limited surgery by VATS approaches for cStage IA lung cancer are acceptable as cancer operation.

Involvement of tazarotene-induced gene 1 in proliferation and differentiation of human adipose tissue-derived mesenchymal stem cells.

OBJECTIVE: Mesenchymal stem cells (MSC) have both self-renewal and multilineage differentiation potential, and bone marrow-derived MSC have been applied for tissue regeneration and repair. Although adipose tissue-derived MSC (ASC) have emerged as an alternative cell source, little information is available regarding the biologic difference between ASC derived from visceral and subcutaneous fat. Therefore, we aimed to compare the proliferation and gene expression profile of cultured human visceral ASC (VASC) and subcutaneous ASC (SASC), and to identify a novel gene involved in proliferation and differentiation of ASC. MATERIALS AND METHODS: We performed microarray analysis of cultured VASC and SASC, and investigated the role of tazarotene-induced gene 1 (TIG1), a most differentially expressed gene, in the proliferation and differentiation of ASC. RESULTS: SASC proliferated faster than VASC for over 10 passages, and TIG1 expression was consistently up-regulated in VASC of humans, rats and mice. Overexpression of the TIG1 gene in human SASC inhibited cell proliferation, whereas knockdown of TIG1 expression by siRNA promoted cell proliferation. In addition, overexpression of the TIG1 gene in SASC enhanced their differentiation into adipocytes, and promoted up-regulation of peroxisome proliferators-activated receptor gamma and CCAAT/enhancer binding protein alpha. On the other hand, TIG1 overexpression in SASC inhibited their differentiation into osteocytes and the expression of osteocalcin. CONCLUSION: TIG1 plays an important role in regulating proliferation and differentiation of ASC.

The effect of mandibular setback or two-jaws surgery on pharyngeal airway among different genders.

Cephalometric studies show significant gender differences in the size of the pharyngeal airway space. This study aimed to investigate and compare morphologic changes after mandibular setback or two-jaws surgery on the pharyngeal airway in men and women using computed tomography (CT). The sample included 34 women and 13 men diagnosed with Class III skeletal deformities, who had been treated by mandibular setback or bimaxillary surgery (maxillary advancement and mandibular setback). Anteroposterior, lateral and cross-sectional area dimensions of the airway, at the level of soft palate and base of tongue, were measured pre- and postoperatively on CT images. In the mandibular setback group, the anteroposterior and cross-sectional area of the pharyngeal airway at the level of the soft palate and base of tongue were significantly reduced for men or women (P<.05). In the two-jaws surgery group, only midsagittal anteroposterior dimensions at the same levels were significantly decreased for men or women (P<.05). The difference between any values measured between men and women who received bilateral sagittal split ramus osteotomy setback surgery or two-jaws surgery for the treatment of class III anteroposterior discrepancy were not statistically significant (P>.05). This study suggests that oropharyngeal airway measurements, important for airway patency, do not demonstrate sex dimorphism.

[Granulocyte-colony stimulating factor producing tumor with high serum interleukin-6].

A 53-year-old man admitted to our hospital because of fever and chest abnormal shadow. Chest X-ray and computed tomography (CT) scan revealed large tumor on right upper lobe. Serum interleukin (IL)-6 and granulocyte-colony stimulating factor (G-CSF) were high. Right upper lobectomy and chest wall resection was performed. Histological diagnosis was large cell carcinoma. Immunohistological examination of lung tumor cells showed positive staining for G-CSF in only 1% of them. We diagnosed that tumor was G-CSF producing tumor and we thought that tumor produced IL-6.

[Mycobacterium avium complex disease after conservative therapy for 3 years; report of a case].

A 62-year old woman admitted to our hospital because of an abnormal shadow on chest X-ray. Chest X-ray and computed tomography (CT) scan revealed a 2 cm nodular shadow with cavity in the right upper lobe. Bronchofiberscopy was performed, and Mycobacterium avium complex was demonstrated bacteriologically. She had been followed-up for 3 years with chemotherapy, however slow but progressive enlargement of the lesion was noted on chest X-ray. Finally she reffered to our department for surgical treatment, and right upper lobectomy was performed. Ten months after operation, there is no sign of recurrence.

[Intrapulmonary and mediastinal, double bronchogenic cysts; report of a case].

A 59-year-old woman was pointed out abnormal shadows on chest film and has been followed up since 2001. In October 2006, she consulted our hospital for further examination. Computed tomography (CT) showed double cystic lesions located in the right lower lobe, and in the paraesophageal region. The patient underwent video-assisted thoracic surgery (VATS) right lower lobectomy and resection of the tumor in the mediastinum. The content of the tumor were greenish and whitish discharge. Histopathologically, both were bronchogenic cysts. The patient was discharged on 17th postoperative day and doing well for 6 months postoperatively.