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.

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.

Heart rate regulation by G proteins acting on the cardiac pacemaker channel.

Heart rate is determined by pacemaker currents, of which the most important is the hyperpolarization-activated current I(f). Heart rate and I(f) are increased by beta-adrenergic agonists and decreased by muscarinic agonists released from cardiac sympathetic and vagal nerves, respectively. The hypothesis that the receptors for each agonist are directly coupled to I(f) channels by G proteins was tested. Under substrate-free conditions, preactivated G protein Gs stimulated and preactivated G protein G(o) inhibited I(f) channels of sinoatrial node pacemaker cells. These effects were mimicked by the corresponding preactivated alpha subunits of the G proteins. Unexpectedly, the two G proteins acted simultaneously, with G(o) being the more potent. This result may explain in molecular terms the classical observation in cardiac physiology, that vagal inhibition of heart rate is much greater on a background of sympathetic stimulation.

[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.

[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.

Risk factors for complications after partial splenic embolization for liver cirrhosis.

BACKGROUND: Partial splenic embolization (PSE) in patients with cirrhosis can achieve a prolonged increase in blood cell count. However, there is little information on the risk factors for complications after PSE for liver cirrhosis. METHODS: Seventy patients (41 men and 29 women) with cirrhosis-induced hypersplenism underwent PSE. Based on the Child-Pugh classification, 30, 35 and five patients had class A, B and C disease respectively. Risk factors for complications after PSE were examined retrospectively by logistic regression analysis. RESULTS: The mean splenic infarction rate was 77.1 per cent. Twelve patients (17 per cent) had complications following PSE. In univariable analysis, Child-Pugh class C, total bilirubin level of 1.4 mg/dl or more, serum albumin level of 2.8 g/dl or less and infarcted splenic volume of 540 ml or more were significantly associated with complications after PSE. In multivariable analysis, Child-Pugh class C (P = 0.012) and infarcted splenic volume of 540 ml or more (P = 0.031) were identified as risk factors, with an odds ratio of 22.92 and 5.01 respectively. CONCLUSION: Child-Pugh class C and a large splenic infarction volume are risk factors for complications after PSE for liver cirrhosis.

[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.

[Paravertebral muscle metastasis from lung cancer; report of a case].

A 69-year-old man had undergone right S6 segmentectomy for lung cancer (poorly differentiated adenocarcinoma, pT2N0M0, stage IB). One years later, computed tomography (CT) showed abnormal shadow in the right paravertebral muscle of 7 x 5 cm in size. The patient underwent resection of the tumor. The tumor was white, solid and elastic hard mass. Histopathologically, the tumor was paravertebral muscle metastasis from lung cancer. The patient was discharged on 23rd postoperative day, but died of other disease after 1 and a half month postoperatively.

[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 infection which need to distinguish from lung cancer].

A 42 year old female was admitted to our hospital due to abnormal shadow on her chest X-ray. She had no symptoms. Chest X-ray and computed tomography (CT) scan revealed solitary nodule on left S10. Bronchofiberscopy was perfomed, but it could not establish pathological diagnosis. Thoracoscopic surgery was performed. It revealed that solitary nodule was Mycobacterium avium infection. Majority cases of Mycobacterium avium infection showed multiple nodules or infiltration shadows on bilateral lungs. But in our case, CT scan showed a solitary nodule, causing differential diagnosis from lung cancer to be difficult.

[Mycobacterium avium complex (MAC) infection needed differential diagnosis of the recurrence after surgery for double lung cancer; report of a case].

A 62-year-old woman had undergone video-assisted thoracic surgery (VATS) -right upper lobectomy and right S8 segmentectomy for double lung cancers (papillary adenocarcinoma and bronchioloalveoler carcinoma, stage IA). Four years later, chest computed tomography (CT) showed abnormal shadow, 20 mm in size, along the staple-suture line. The 3 months later, new lesion, 15 mm in size, was observed in right lower lobe. CT-guided biopsy revealed no malignancy. The patient underwent partial resection of the right lower lobe and tumorectomy. The tumor was solid and cystic mass. Histopathologically, the tumor was granuloma infected by Mycobacterium avium. The patient was discharged on 17th postoperative day, and doing well without new lesion for 9 months postoperatively.

[Malignant solitary fibrous tumor of the pleura; report of a case].

A 68-year-old female was admitted to our hospital for further examination of abnormal shadow on chest X-ray. Needle biopsy could not establish pathological diagnosis. Three years later, chest computed tomography (CT) revealed the tumor was enlarged. We suspected it was a malignant tumor, and resected by video-assisted thoracoscopy. The tumor occurred from the right middle lobe, and intraoperative diagnosis was malignant tumor. We added middle lobectomy. Histological examination revealed that tumor was malignant solitary fibrous tumor.

[Lung metastasis of malignant peripheral nerve sheath tumor: report of a case].

A 37-year-old man with von Recklinghausen's disease admitted to our hospital because of chest abnormal shadow. He had underwent extended radical tumorectomy for malignant peripheral nerve sheath tumor (MPNST) in left lower limb 33 months before. Chest X-ray and computed tomography (CT) scan revealed solitary tumor on right S10. Tumor was resected under thoracoscopic surgery. Histological diagnosis was metastasis of MPNST. MPNST with lung metastasis showing very poor prognosis. The patient is doing well 2 years after pulmonary resection without recurrence. Careful follow up is important for MPNST.

Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide.

BACKGROUND: Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-alpha (TNF-alpha) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-alpha production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock. METHODS AND RESULTS: Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-). The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-alpha and expression of TNF-alpha mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor DIP-APC, an active site-blocked APC, showed any effect on these ET-induced changes. Both inhibition of TNF-alpha production by leukocytopenia and treatment with anti-rat TNF-alpha antibody produced effects similar to those induced by APC. Aminoguanidine, a selective inhibitor of iNOS, inhibited both the hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) in this animal model. CONCLUSIONS: These observations strongly suggest that APC inhibits iNOS induction by decreasing TNF-alpha production, leading to the prevention of ET-induced hypotension. Furthermore, such effects of APC were not dependent on its anticoagulant effects but rather on its serine protease activity.

The nature and origin of spontaneous noise in G protein-gated ion channels.

Arrival of agonist is generally thought to initiate the signal transduction process in G protein-receptor coupled systems. However, the muscarinic atrial K+ (K+[ACh]) channel opens spontaneously in the absence of applied agonist, giving a noisy appearance to the current records. We investigated the nature and origin of the noise by measuring single channel currents in cell-attached or excised, inside-out membrane patches. Guanosine triphosphate (GTP) produced identical single channel currents in a concentration- and Mg(2+)-dependent manner in the presence or absence of carbachol, but the requirements for GTP were greater in the absence of agonist. Hence the agonist-independent currents appeared to be produced by an endogenous G protein, Gk. This prediction was confirmed when an affinity-purified, sequence-specific Gi-3 alpha antibody or pertussis toxin (PTX) blocked the agonist-independent currents. Candidate endogenous agonists were ruled out by the lack of effect of their corresponding antagonists. Thus agonist-independent currents had the same nature as agonist-dependent K+[ACh] currents and seemed to originate in the same way. We have developed a hypothesis in which agonist-free, empty receptors prime Gk with GTP and Gk activates atrial K+ [ACh] channels producing basal currents or noise. Agonist-independent activation by G proteins of effectors including ion channels appears to be a common occurrence.

Parathyroid-hormone-related protein induces expression of receptor activator of NF-{kappa}B ligand in human periodontal ligament cells via a cAMP/protein kinase A-independent pathway.

UNLABELLED: Periodontal ligament (PDL) cells play important roles in root resorption of human deciduous teeth by odontoclasts (osteoclast-like cells). However, it is unclear how PDL cells regulate osteoclastogenesis. We examined the effects of PTHrP, TGF-beta, and EGF, which are all secreted by the tooth germ, on tartrate-resistant acid-phosphatase-positive (TRAP+) cell formation using co-cultures of human PDL cells and mouse spleen cells. Only PTHrP promoted TRAP+ cell formation in co-cultures. PTHrP induced receptor activator of NF-kappaB ligand (RANKL) mRNA expression and slightly reduced osteoprotegerin (OPG) expression in PDL cells. The cAMP/PKA inhibitors Rp-cAMP, H89, and PKI did not affect PTHrP-induced TRAP+ cell formation. The PKC inhibitor, Ro-32-0432, suppressed RANKL expression in PDL cells and PTHrP-induced TRAP+ cell formation. However, this inhibitor directly modulated the number of osteoclast precursors. Thus, PTHrP induces osteoclastogenesis by increasing the relative expression level of RANKL vs. OPG in PDL cells via a cAMP/PKA-independent pathway. ABBREVIATIONS: PTHrP, parathyroid-hormone-related protein; TGF-beta, transforming growth factor-beta; EGF, epidermal growth factor; RANKL, receptor activator of NF-kappaB ligand; OPG, osteoprotegerin; PDL, periodontal ligament; TRAP, tartrate-resistant acid phosphatase; PKA, protein kinase A; PKC, protein kinase C; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; cAMP, cyclic Adenosine 3'5'-Monophosphate.

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.

Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models.

Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo.