Broad subcutaneous emphysema with airway obstruction during robot-assisted partial nephrectomy: A case report and literature review.

Introduction: Subcutaneous emphysema is a relatively common complication in laparoscopic surgery. However, airway obstruction secondary to subcutaneous emphysema is rare. Case presentation: A 63-year-old woman with a 56-mm left renal tumor underwent a robot-assisted partial nephrectomy. The operative time was 155 min, the insufflation time was 108 min, and the estimated blood loss was 70 mL. The pneumoperitoneum pressure was maintained at 12 mmHg, except at 15 mmHg for 19 min during tumor resection. The end-tidal CO2 was <47 mmHg throughout the procedure. Postoperatively, broad subcutaneous emphysema from the thigh to the eyelid was observed. Computed tomography revealed airway obstruction, and extubation was aborted. On postoperative day 1, emphysema around the trachea and neck improved and the intubation tube was successfully removed. Conclusion: Both laryngeal emphysema and physical compression secondary to emphysema can cause airway obstruction. To reduce gas-related complications, the risk of developing subcutaneous emphysema should be properly assessed during robot-assisted laparoscopic surgery.

Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 2A inhibitor, PDM-631.

Recently, we identified a novel phosphodiesterase 2A (PDE2A) inhibitor, PDM-631 ((S)-3-cyclopropyl-6-methyl-1-(1-(4-(trifluoromethoxy)phenyl)propan-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one). PDM-631 showed potent inhibitory activities for human and rat PDE2A with IC50 values of 1.5 and 4.2nM, respectively and more than 2000-fold selectivity against other phosphodiesterases. In rat studies, PDM-631 showed oral bioavailability and good brain penetration, and increased the cGMP levels in the cortex. These data indicate that PDM-631 is a potent, selective, orally active, and brain-penetrable PDE2A inhibitor. In behavioral studies using rat models, PDM-631 (3-30mg/kg) resulted in better discrimination between a novel object and a familiar one 48h after the acquisition phase in the novel object recognition test, thus indicating that PDM-631 increased object recognition memory. In contrast, PDM-631 did not attenuate the conditioned avoidance response at the same dose range (3-30mg/kg) in rats, indicating that PDM-631 did not show an antipsychotic-like effect. In test for extrapyramidal side effect, PDM-631 had no effect on catalepsy at the effective doses (10 and 30mg/kg) in the novel object recognition test, while haloperidol caused catalepsy at a dose of 3mg/kg. Our results suggest that PDM-631 is a good pharmacological tool that can be used to investigate the role of PDE2A and may have therapeutic potential for the treatment of cognitive impairments associated with schizophrenia and neurodegenerative disorders, without any extrapyramidal side effects.

Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors.

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice.

The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms against oxidative stress. Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is characterized by progressive demyelination and neurodegeneration induced by inflammation and oxidative stress. The induction of Nrf2 signaling has been shown to inhibit disease development and progression in the experimental autoimmune encephalomyelitis (EAE) model of MS in mice. In the present study, we performed a high-throughput screening assay using a chimeric construct of the N-terminal portion of Nrf2 fused to LacZ. Using this approach, we identified the novel Nrf2 inducer TFM-735. Using human primary cell profiling systems, we found that TFM-735 inhibited T cell proliferation and exerted immuno-modulatory effects by inhibiting the production of IL-6 and IL-17. TFM-735 also inhibited IL-17 secretion from human peripheral blood mononuclear cells stimulated with anti-CD3 and anti-CD28. In EAE mice treated with TFM-735, the expression of the Nrf2 target gene Nqo1 increased in the brain and spleen, disease severity was ameliorated, and plasma IL-17 levels decreased. Furthermore, TFM-735 inhibited luciferase activity in Wim-6 transgenic EAE mice expressing the human interleukin 6-luciferase (hIL6-BAC-Luc) reporter. Therefore, these findings indicate that TFM-735 is a potent Nrf2 inducer that inhibits inflammatory cytokine production and disease progression in mice with EAE and that TFM-735 is a promising therapeutic agent for MS.

Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist.

Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

Dopamine D1 signaling involvement in the effects of the phosphodiesterase 10A inhibitor, PDM-042 on cognitive function and extrapyramidal side effect in rats.

Inhibition of phosphodiesterase 10A (PDE10A) results in activation of a dopamine D1 receptor-mediated direct pathway in addition to a dopamine D2 receptor-mediated indirect pathway in the striatum. Therefore, PDE10A inhibitors could be novel therapeutics for schizophrenia, which differ from the currently available antipsychotics that directly block the dopamine D2 receptor. Previously, we found that a novel PDE10A inhibitor, PDM-042, had antipsychotic-like activity similar to currently available antipsychotics and minimal cataleptic effects in rats. The purpose of the present study was to examine the pharmacological effects of PDM-042 on cognitive function and extrapyramidal side effect. In addition, we aimed to examine whether these effects were mediated by activation of dopamine D1 signaling in rats. PDM-042 (1-3mg/kg) resulted in better discrimination of a novel object from a familiar one 48h after the acquisition trial, suggesting that PDM-042 increased object recognition memory. A dopamine D1 receptor antagonist, SCH23390 (0.1mg/kg), significantly blocked the enhancement of the object recognition memory induced by PDM-042 (3mg/kg) without affecting the recognition index by itself. We also found that the cataleptic effect of PDM-042 (1mg/kg) was significantly enhanced by SCH23390 (0.01-0.03mg/kg). These results indicate that PDM-042 has the potential to increase object recognition memory and that the cognitive enhancing and cataleptic effects of PDM-042 are mediated at least by activation of dopamine D1 signaling.

Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine] in rats: potential for the treatment of schizophrenia.

Recently, we identified a novel phosphodiesterase 10A (PDE10A) inhibitor, PDM-042 ((E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine). PDM-042 showed potent inhibitory activities for human and rat PDE10A with IC 50 values of less than 1 nmol/L and more than 1000-fold selectivity against other phosphodiesterases. Tritiated PDM-042, [3H]PDM-042, had high affinity for membranes prepared from rat striatum with a Kd value of 8.5 nmol/L. The specific binding of [3H]PDM-042 was displaced in a concentration-dependent manner by PDM-042 and another structurally unrelated PDE10A inhibitor, MP-10. In rat studies, PDM-042 showed excellent brain penetration (striatum/plasma ratio = 6.3), occupancy rate (86.6% at a dose of 3 mg/kg), and good oral bioavailability (33%). These data indicate that PDM-042 is a potent, selective, orally active, and brain-penetrable PDE10A inhibitor. In behavioral studies using rat models relevant to schizophrenia, PDM-042 significantly antagonized MK-801-induced hyperlocomotion (0.1-0.3 mg/kg) without affecting spontaneous locomotor activity and attenuated the conditioned avoidance response (CAR) (0.3-1 mg/kg). In tests for adverse effects, PDM-042 had a minimal effect on catalepsy, even at a much higher dose (10 mg/kg) than the minimal effective dose (0.3 mg/kg) in the CAR. Furthermore, PDM-042 had no effect on prolactin release or glucose elevation up to 3 mg/kg, while risperidone increased prolactin release and olanzapine enhanced glucose levels at doses near their efficacious ones in the CAR. Our results suggest that PDM-042 is a good pharmacological tool that can be used to investigate the role of PDE10A and may have therapeutic potential for the treatment of schizophrenia.

Vascular malformations of the head and neck.

OBJECTIVE: Vascular malformations may appear anywhere in the body; 14-65% are in the head and neck. There are several treatments (sclerotherapy, surgery, laser treatment, and embolization, etc.), but standardized guidelines for these treatments are lacking. We conducted a retrospective review of venous or capillary malformations of the head and neck, and analyzed the epidemiology, pathology and treatment. METHODS: We retrospectively reviewed 67 patients with pathologically diagnosed venous or capillary malformations of the head and neck; we analyzed the location, pathology and treatment, as well as recurrent/residual cases. RESULTS: The oral cavity (59%) and nasal cavity (35%) were the most common locations. The frequency of each pathological type depended upon location. Surgery was undertaken in 65 cases, and sclerotherapy done in one patient. Sixty-one cases (92%) had resectable lesions. However polycystic masses (≥3 cysts) and large masses (diameter, ≥5cm) were significantly difficult to cure by single treatment. CONCLUSIONS: Surgery is indicated for localized small vascular malformations. However if the lesions ≥5cm or polycystic lesions were more likely to recur after surgery alone in our study population.

Primary intraosseous squamous cell carcinoma of the jaw: two new cases and review of the literature.

BACKGROUND: Primary intraosseous squamous cell carcinoma is very rare. We report two cases of primary intraosseous squamous cell carcinoma of the jaw, one arising from an odontogenic cyst and the other arising de novo. METHODS AND RESULTS: The first case was a 76-year-old man with right mandible pain. A panoramic radiography and computed tomography revealed a large mandibular radiolucency. A biopsy revealed squamous cell carcinoma, and radiotherapy and hemimandibulectomy were performed. The second case was a 50-year-old man with lymph node swelling on the left neck. Squamous cell carcinoma of the lymph node was suspected after fine needle biopsy. After left neck dissection, histological testing of the odontogenic cyst revealed squamous cell carcinoma, of which the mandible was thought to be the primary site. CONCLUSION: Our two cases have no recurrence, and panoramic radiography was a useful tool in the detection of mandible disease.

Tumor-induced osteomalacia originating from the temporal bone: a case report.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare clinical entity in which secondary osteomalacia is induced by tumor-related products. Fibroblast growth factor 23 (FGF-23) mRNA is overexpressed in the tumor tissue, leading to impaired reabsorption of phosphorus in the renal tubules and hypophosphatemia. Curative treatment is considered to be total resection of the tumor. METHODS AND RESULTS: A 53-year-old woman had experienced systemic bone pain and muscle weakness for several years. She had refractory hypophosphatemia and marked elevation of serum FGF-23 level. Whole body imaging eventually revealed a hypervascular mass in the right temporal bone, leading to a diagnosis of TIO. She underwent skull-base surgery after embolization of the tumor. After the en bloc resection, FGF-23 became undetectable, phosphate reabsorption normalized, and all symptoms resolved. CONCLUSIONS: We discuss the clinical features and treatment options for this rare disease.

Organized hematoma in the paranasal sinus and nasal cavity--imaging diagnosis and pathological findings.

OBJECTIVES: The "organized hematoma" is a non-neoplastic, hemorrhagic lesion, which can develop in the paranasal sinus and nasal cavity. This is the first report on the relationship between the imaging and pathological findings. METHODS: We diagnosed organized hematoma, based on three criteria: no existence of neoplastic cells; consistency of hematoma and fibrosis; and development from the paranasal sinus and nasal cavity. We retrospectively investigated six cases from the patients' medical records. RESULTS: On the imaging findings, the central part of the lesion was enhanced more strongly than the lesion periphery. All of the pathological findings were hematoma at the center, and fibrosis at the periphery. In three of the cases, dilated vessels were found but not in the other three. CONCLUSION: We found that the biphasic appearance of the imaging findings correlated with that of the pathological findings. There are two pathological types--the dilated vessel type and the non-dilated vessel type.

Recurrent cancer of the parotid gland: how well does salvage surgery work for locoregional failure?

PURPOSE: Many articles have discussed the clinical features of previously untreated parotid cancer, but the clinical characteristics and treatment of recurrent parotid cancer have not yet been fully described. MATERIALS: We retrospectively reviewed 20 patients with recurrent parotid cancer and analyzed the therapeutic strategies and the prognostic factors. RESULTS: Twelve patients (60%) underwent definitive surgery, including 3 who underwent skull base surgery. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) in the surgery group were 66.7 and 64.1%. In the definitive surgery group, the presence of lymph node metastasis and high-grade malignant histopathology were associated with a poor prognosis (p < 0.01). On the other hand, the presence of facial palsy at presentation, the surgical margin, the time of relapse and the T stage did not affect the DFS in our series. CONCLUSIONS: The results suggest that aggressive definitive surgery may be justified for the treatment of recurrent parotid cancer. The presence of lymph node metastasis and the histopathological malignancy grade are poor prognostic factors for OS and DFS.

Synovial sarcoma of the head and neck: rare case of cervical metastasis.

BACKGROUND: Synovial sarcoma is a rarely encountered soft tissue sarcoma. Surgery with a wide surgical margin is the treatment of choice. However, there is no consensus on the treatment of head and neck synovial sarcoma in patients with cervical metastasis. METHODS: A 20-year-old man was seen with a palpable mass in the right neck. He had been diagnosed with synovial sarcoma of the right tonsil and treated by surgery 1 and a half years before; therefore, the mass detected was thought to be a cervical metastasis of synovial sarcoma. We performed a modified radical neck dissection with no postoperative treatment. The pathological diagnosis was confirmed by detecting the SS-specific fusion gene SYT-SSX1. RESULTS: The patient remains free of recurrence or metastasis 2 years and 10 months after the surgery. CONCLUSIONS: We encountered a case of head and neck synovial sarcoma with cervical metastasis that was successfully treated.

Oral pilocarpine (5mg t.i.d.) used for xerostomia causes adverse effects in Japanese.

OBJECTIVE: To evaluate Japanese tolerability to pilocarpine of 5 mg t.i.d. METHODS: From January 2006 to July 2006, 39 patients with xerostomia received 5 mg t.i.d. pilocarpine for at least for 12 weeks unless they had experienced unacceptable adverse effects. All patients received radiotherapy that included the parotid glands in the radiation field >50 Gy. The body weights of the patients ranged from 42 to 73 kg (median 60 kg). RESULTS: Thirty-six of the 39 patients were evaluable. The tolerated rate was only 47%. Of the 25 patients whose body weights were less than 65 kg, the tolerated rate was 36%, whereas the rate of the 11 patients whose body weights were 65 kg or above was 72% (p=0.050). The most common adverse effect was sweating with an incidence of 64%. Response rate, which was defined as the total number of patients with an increase of at least 25 mm from the baseline in the VAS score divided by the number of maintaining patients among those who started pilocarpine after more than 4 months from the start of radiotherapy, was 40% at 12 weeks (n=15). CONCLUSION: For Japanese, 5mg t.i.d. pilocarpine caused a high incidence of unacceptable adverse effects. A lower dose of pilocarpine needs to be considered.

Characterization of binding affinity of CJ-023,423 for human prostanoid EP4 receptor.

In order to characterize the receptor binding pharmacology of CJ-023,423, a potent and selective EP4 antagonist, we performed a radioligand receptor binding assay under various assay conditions. An acidic (pH 6) and hypotonic buffer is a conventional, well-known buffer for prostaglandin E2 receptor binding assays. CJ-023,423 showed moderate binding affinity for human EP4 receptor under conventional buffer conditions. However, its binding affinity was greatly increased under neutral (pH 7.4) and isotonic buffer conditions. In this report, the binding mechanism between CJ-023,423 and human EP4 receptor is discussed based on the binding affinities determined under various assay conditions.

Long-term outcome following radical temporal bone resection for lateral skull base malignancies: a neurosurgical perspective.

OBJECT: Primary temporal bone malignancy is a rare form of tumor for which the therapeutic strategy remains controversial. In this study, the authors reviewed their experience with radical temporal bone resection (TBR) of such lesions and analyzed the long-term results to provide treatment recommendations. METHODS: Between 1994 and 2006, 17 patients (10 men and 7 women) underwent total or subtotal TBR for primary temporal bone malignancies. Tumors were graded according to the University of Pittsburgh system. The effects of surgical margins and tumor extensions on patient survival were analyzed using the Kaplan-Meier method. RESULTS: All tumors, except 1, were graded T4 (most advanced). Subtotal TBR was performed in 14 patients, and total TBR was performed in 3. The surgical margin was tumor negative in 10 patients and tumor positive in 7. For large tumors extending into the infratemporal fossa or encroaching on the jugular foramen, orbitozygomatic (3 patients) and posterior transjugular (4 patients) approaches were combined with the standard approach, and en bloc resection with a negative margin was achieved in all cases but 1. The follow-up time ranged from 0.3-11.6 years (mean 3.3 years). The 5-year recurrence-free and disease-specific survival rates were 67.5 and 60.1%, respectively. When a negative surgical margin was achieved, the survival rates improved to 100 and 89%, respectively. CONCLUSIONS: The neurosurgical skull base technique could improve the probability of en bloc resection with a tumor-free margin for extensive temporal bone malignancies, which would cure a subset of patients. The active participation of neurosurgeons would improve patient care in this field.

Planned simultaneous cervical skin reconstruction for salvage total pharyngolaryngectomy.

BACKGROUND: Salvage surgery after definitive radiotherapy with or without chemotherapy is still controversial, especially in cases of hypopharyngeal cancer because of the poor prognosis and surgical complications. Irradiation of the skin results in loss of flexibility of the skin and impairment of the normal healing processes, thereby increasing the risk of wound infections, which could be potentially life-threatening. In an attempt to diminish the risk of major complications, we performed planned cervical skin replacement with salvage total pharyngolaryngectomy (TPL). METHODS: From 2005 to 2006, six patients underwent salvage TPL and cervical reconstruction with a deltopectoral flap at our hospital. The cervical skin replacement was determined pre-operatively and not according to the intraoperative status. RESULTS: There were no major post-operative complications. Both the prolongation of the operation time and of the duration of hospitalization were within acceptable limits. CONCLUSION: Planned cervical skin reconstruction appears to be an appropriate and acceptable procedure with salvage pharyngolaryngectomy to avoid major complications.

Highly malignant submandibular extraskeletal osteosarcoma in a young patient.

Osteosarcoma is the most common primary malignant neoplasm of the bone. Rarely, osteosarcomas occur at sites other than the bone, so-called extraskeletal osteosarcoma (ESOS). ESOS is a rare malignancy that accounts for approximately 1% of all tissue sarcomas and present most commonly as a large soft tissue mass in the extremities. The patient was an 18-year-old Japanese man who presented with a stony hard mass in the left submandibular region. Fine-needle aspiration biopsy could not be performed due to the firmness of the mass. The patient underwent left selective neck dissection after enlargement of the mass. Three months after operation, the patient developed massive local recurrence of the tumor. We removed the tumor, encased by the muscles. Postoperatively, the patient received a course of radiotherapy. However, 4 months after the second operation, the patient developed left facial nerve palsy and complained of sudden hearing loss on the left side. The patient developed metastases and died after acute intracranial hemorrhage. To the best of our knowledge, this is the first report of a submandibular ESOS in a young man without history of radiotherapy or trauma.

In vitro pharmacological characterization of CJ-042794, a novel, potent, and selective prostaglandin EP(4) receptor antagonist.

Activation of the prostaglandin E(2) (PGE(2)) EP(4) receptor, a G-protein-coupled receptor (GPCR), results in increases in intracellular cyclic AMP (cAMP) levels via stimulation of adenylate cyclase. Here we describe the in vitro pharmacological characterization of a novel EP(4) receptor antagonist, CJ-042794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid). CJ-042794 inhibited [(3)H]-PGE(2) binding to the human EP(4) receptor with a mean pK(i) of 8.5, a binding affinity that was at least 200-fold more selective for the human EP(4) receptor than other human EP receptor subtypes (EP(1), EP(2), and EP(3)). CJ-042794 did not exhibit any remarkable binding to 65 additional proteins, including GPCRs, enzymes, and ion channels, suggesting that CJ-042794 is highly selective for the EP(4) receptor. CJ-042794 competitively inhibited PGE(2)-evoked elevations of intracellular cAMP levels in HEK293 cells overexpressing human EP(4) receptor with a mean pA(2) value of 8.6. PGE(2) inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha) in human whole blood (HWB); CJ-042794 reversed the inhibitory effects of PGE(2) on LPS-induced TNFalpha production in a concentration-dependent manner. These results suggest that CJ-042794, a novel, potent, and selective EP(4) receptor antagonist, has excellent pharmacological properties that make it a useful tool for exploring the physiological role of EP(4) receptors.

Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation.

Recent study suggests that the proinflammatory and nociceptive effects of prostaglandin E(2) are mediated by prostanoid receptor subtype EP(4) and prostanoid EP(4) receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP(4) receptor antagonist, CJ-042,794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl) oxy] phenyl} carbonyl) amino] ethyl} benzoic acid) in comparison with piroxicam (non-steroidal anti-inflammatory drug) or rofecoxib (cyclooxygenase-2 inhibitor). CJ-042,794 competitively antagonized cAMP accumulation with a pA(2) value of 8.7 in HEK293 cells overexpressing rat prostanoid EP(4) receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED(50) value of 4.7 mg/kg (11 micromol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 micromol/kg p.o.). When CJ-042,794 and rofecoxib were administered to adjuvant-induced arthritis rats on Days 12-22 twice daily, both compounds reversed paw swelling to normal levels. These results suggest that a pharmacological blockade of the prostanoid EP(4) receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.