Redox Activity of IrIII Complexes with Multidentate Ligands Based on Dipyrido-Annulated N-Heterocyclic Carbenes: Access to High Valent and High Spin State with Carbon Donors.

Synthetic strategies to access high-valent iridium complexes usually require use of π donating ligands bearing electronegative atoms (e. g. amide or oxide) or σ donating electropositive atoms (e. g. boryl or hydride). Besides the η5 -(methyl)cyclopentadienyl derivatives, high-valent η1 carbon-ligated iridium complexes are challenging to synthesize. To meet this challenge, this work reports the oxidation behavior of an all-carbon-ligated anionic bis(CCC-pincer) IrIII complex. Being both σ and π donating, the diaryl dipyrido-annulated N-heterocyclic carbene (dpa-NHC) IrIII complex allowed a stepwise 4e- oxidation sequence. The first 2e- oxidation led to an oxidative coupling of two adjacent aryl groups, resulting in formation of a cationic chiral IrIII complex bearing a CCCC-tetradentate ligand. A further 2e- oxidation allowed isolation of a high-valent tricationic complex with a triplet ground state. These results close a synthetic gap for carbon-ligated iridium complexes and demonstrate the electronic tuning potential of organic π ligands for unusual electronic properties.

An aggressive nodular fasciitis lesion protruding from the palm (USP6 gene fusion helps differentiate from sarcomas): A case report.

Nodular fasciitis is a mesenchymal lesion, which has been viewed as a reactive process. The MYH9-USP6 fusion gene was recently detected in nodular fasciitis, and nodular fasciitis is now considered to be a self-limiting neoplastic process. Recently, a case of nodular fasciitis that recurred a number of times and metastasized to soft tissues was reported, and the features of aggressive cases of nodular fasciitis are currently under investigation. Here, a case of locally aggressive nodular fasciitis is presented, in which the lesion grew rapidly and caused ulnar nerve palsy. The lesion was locally controlled via marginal excision, and no metastasis was identified at 24 months post-operation. Histologically, the lesion was consistent with nodular fasciitis, and the detection of the MYH9-USP6 fusion gene supported the diagnosis. Although most nodular fasciitis lesions are benign, some may be locally aggressive or even metastasize. In the case outlined in the present study, marginal excision was sufficient to locally control the lesion.

Cognitive insight and functional outcome in schizophrenia; a multi-center collaborative study with the specific level of functioning scale-Japanese version.

The Specific Levels of Functioning Scale (SLOF) has been reported to provide a measure of social function in patients with schizophrenia. The aim of this multi-center study was to determine convergent validity of the Japanese version of SLOF, and if cognitive insight would be associated with social function. Fifty-eight patients with schizophrenia participated in the study. Social function, neurocognition, and daily activity skills were evaluated by the Social Functioning Scale (SFS), Brief Assessment of Cognition in Schizophrenia (BACS) and UCSD Performance-based Skills Assessment-Brief (UPSA-B), respectively. We also assessed cognitive insight with the Beck Cognitive Insight Scale (BCIS). Significant relationships were noted between scores on the SLOF vs. those of the SFS, BACS, UPSA-B, and BCIS. Specifically, the correlation between performance on the UPSA-B and SLOF scores was significantly more robust compared to the correlation between performance on the UPSA-B and scores on the SFS. Similarly, the correlation between scores on the BACS and SLOF tended to be more robust than that between the BACS and SFS. Importantly, while the correlation between scores on the BCIS and SLOF reached significance, it was not so between scores on the BCIS and SFS. The SLOF Japanese version was found to provide a measure of social consequences in patients with schizophrenia. Importantly, this study is the first to indicate the relationship between cognitive insight and social function evaluated by the SLOF. This finding is consistent with the observation that SLOF scores were considerably associated with performances on objective functional measures.

Prospective Evaluation of Zoledronic Acid in the Treatment of Bone Metastases from Differentiated Thyroid Carcinoma.

PURPOSE: The objectives of this study were to prospectively delineate the efficacy and safety of zoledronic acid for treating bone metastases (BM) from differentiated thyroid carcinoma (DTC), and to evaluate the relationships between levels of bone metabolic markers and occurrence of skeletal-related events (SREs). METHODS: This was a prospective, single-arm, single-center study. Nineteen patients with BM from DTC were assigned to receive zoledronic acid therapy every 4-5 weeks. Imaging studies for sites of BM were conducted every 6 months, and levels of bone metabolic markers, including serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide of type I collagen (NTx), were assessed every 3 months. To evaluate the efficacy of zoledronic acid use, data of SREs were compared with those of 16 historical controls. RESULTS: SREs developed in eight patients (42 %), but metastatic spinal cord compression (MSCC) appeared in only one patient. Pain scores were ameliorated in five patients, but aggravated in six patients. Ten patients had stable disease, six showed progressive disease, and none showed partial or complete response during the observation period. Decreases in levels of bone metabolic markers were observed in ten patients for BAP and 15 for NTx. However, no significant correlations were identified between changes in bone metabolic marker levels and development of SREs. CONCLUSIONS: Zoledronic acid may offer a mainstay of multidisciplinary treatment for patients with BM for the purpose of reducing SREs. Levels of serum BAP and urinary NTx do not appear reliable as indicators of amelioration of BM symptoms.

Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma.

BACKGROUND: Currently bisphosphonates are often administered to patients with osteolytic bone metastases from several neoplasms. Based on favorable experience in other cancers with bone metastases and the lack of effective treatment, we started to use zoledronic acid (ZA), a recently developed synthetic bisphosphonate drug, in the treatment of this disease. In the present study, we retrospectively evaluated the efficacy of ZA for bone metastases from differentiated thyroid carcinoma. METHODS: The study consisted of 50 patients with bone metastases from differentiated thyroid carcinoma treated at the Cancer Institute Hospital of Tokyo between 1976 and 2008. Among them, 28 patients who did not undergo bisphosphonate therapy were defined as group A and 22 patients who received ZA therapy were defined as group B. The primary efficacy endpoint for ZA treatment was the reduction in the percentage of patients who developed skeletal-related events (SREs), including bone fracture, spinal cord compression, and hypercalcemia. A secondary endpoint was the interval between a presentation of bone metastases and appearance of SREs. RESULTS: SREs occurred in significantly lower frequency in group B (3 of 22 patients, 14%) than group A (14 of 28 patients, 50%) (p = 0.007). The use of ZA significantly retarded the onset of the first SRE (p = 0.04). Two group-B patients developed bisphosphonate-related osteonecrosis of the jaw. CONCLUSION: Treatment with ZA was effective in reducing SREs or delaying their appearance in patients with bone metastases from differentiated thyroid carcinoma.

[Diagnosis and treatment for bone metastases--multidisciplinary team medicine by cancer board].

With the recent progress in cancer treatment making longer survival possible, the need of treatment for bone metastases has become indispensable to assure patient QOL(quality of life). Treatment and prevention of fracture and spinal cord injury are very important not only to maintain good QOL but also to improve survival. Early diagnosis of the risks and the prevention and treatment of fracture and spinal cord injury are necessary. An orthopedics-based team approach to establishing an effective and intensive diagnosis and treatment system for bone metastases is called for Cancer Board.

A Japanese patient with Li-Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene.

We describe a patient who had nine primary malignant tumors and a germline mutation in the p53 tumor-suppressor gene, characteristically found in the Li-Fraumeni syndrome (LFS). A 15-year-old girl with no family history of cancer was referred to our hospital because of pain and swelling of the right knee. Osteosarcoma was diagnosed. The patient received chemotherapy followed by surgery and had a remission. After the age of 28 years, nine primary malignant tumors developed successively, including right breast cancer, colon cancer, malignant fibrous histiocytoma (MFH) of the abdominal wall, right lung double cancers, bilateral breast cancers, and MFH of the left thigh. This is the second highest number of types of primary malignant tumors to be reported in LFS. All tumors were treated by a multidisciplinary approach, including surgery. Genetic analysis revealed a germline missense mutation in the p53 gene (c.659 A > G), resulting in Y220C, which has been reported in three families with LFS. The patient died of lung metastasis from MFH at the age of 37 years. Despite the multiple tumors, repeated induction of remissions resulted in long survival. Our findings suggest that a multidisciplinary approach to treatment, including surgery, is beneficial in patients with LFS.

Definition of the target sign and its use for the diagnosis of schwannomas.

UNLABELLED: The target sign is one of the characteristic imaging findings in schwannomas that distinguishes it from other soft tissue tumors, but its definition has varied in past studies. We defined the characteristic target sign on MRI and clarified its sensitivity and specificity based on histology. Of the 199 schwannomas reviewed, 162 (81%) showed biphasic macroscopic and microscopic patterns of central Antoni A and peripheral Antoni B cells; 118 (59%) also showed a biphasic pattern on MRI. Gadolinium-enhanced T1-weighted images showed central high intensity and peripheral low intensity, whereas T2-weighted images showed peripheral high intensity and central low intensity. Seventy-eight cases had cystic, hemorrhagic, or necrotic degeneration, which corresponded to high intensity on T2-weighted images and low intensity on gadolinium-enhanced T1-weighted images. Nine cases in which the degenerative area was only in the central portion of Antoni A showed a triphasic pattern. We defined the target sign as the biphasic or triphasic pattern on MRI, and the sign correlated with macroscopic and microscopic findings. The specificity of the target sign in schwannoma was 100% and the sensitivity was 59%; therefore, the target sign was characteristic of and helpful for the diagnosis of schwannomas. LEVEL OF EVIDENCE: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Surgery for dedifferentiated liposarcoma, presenting two radiologically and pathologically distinctive patterns.

In this paper, we report three cases with dedifferentiated liposarcoma in the lower extremities, presenting two patterns that are distinctively different radiologically and pathologically. The first case was a 67-year-old male who had discovered a mass in his left thigh, which was shown as a low and iso density mass between the muscles on computed tomography (CT). The second case was a 61-year-old male who had suffered from an intramuscular tumor with a non-fatty sarcomatous area within the fatty components as shown on magenetic resonance imaging (MRI). The third case was a 52-year-old female who had presented with an intramuscular tumor of the left thigh, consisting of a mass with fat and another soft tissue tumor adjacent to the lipomatous component as detected with CT and MRI. The final pathological diagnoses of the resected specimens in all three cases were concluded to be dedifferentiated liposarcoma, composed of well-differentiated liposarcomas and spindle and/or pleomorphic sarcomas, compatible with malignant fibrous histiocytoma. In all three cases, wide resection of the tumor was successfully carried out, and all patients have been continuously disease-free up to the most recent follow-up. Evaluation of the surgical margins for the resected specimens indicated that the safety margin for a dedifferentiated lesion should be accomplished as an adequate margin or more, and a marginal margin or more could be considered as safe only for the confined part of a well-differentiated liposarcoma.

Malignant change secondary to fibrous dysplasia.

BACKGROUND: Malignant change in fibrous dysplasia (FD) is very rare. This study was carried out to establish some characteristic clinical information about this disorder. METHODS: Four cases with a malignant change in FD out of 128 cases with FD were surgically treated and followed up for a median period of 61.3 months. The mean age of the patients was 39.8 years. Clinical features, radiological findings, and the outcome were analyzed for each of the four cases. RESULTS AND CONCLUSION: The sites of the lesions were tibia (2 cases), femur (1 case), and rib (1 case). The forms of FD were monostotic in one case and polyostotic in three cases. Radiologically, plain films and computed tomography (CT) showed osteolytic lesions with poorly delineated margins within and/or near areas having a ground-glass appearance. In the osteolytic lesions, simple cystic changes associated with old FD could be excluded by enhanced magnetic resonance imaging (MRI). Histopathologically, two cases were osteosarcoma, one case was malignant fibrous histiocytoma (MFH), and one case was fibrosarcoma. The management of this disease should be decided according to the type of primary high-grade bone sarcoma. One patient, with MFH, was dead of lung metastasis 13 months after surgery. The others are alive without disease.

Oncologic outcome of parosteal osteosarcoma.

BACKGROUND: This retrospective review evaluated the clinical features and surgical outcomes of parosteal osteosarcoma (POS). METHODS: Nine patients were surgically treated and followed up. Their mean age was 30.8 years. Clinical information and oncologic outcomes of each case were analyzed. RESULTS: Sites of involvement were all in the femur, and all tumors arose from the metaphyseal area of the distal femur. Biopsies for definite diagnoses were performed in just two of the nine cases. Wide resection was applied for all tumors. Surgical evaluations were a 1-cm-wide procedure in six cases and a 2-cm-wide procedure (or more) in three cases. All patients were found to be continuously disease free during the follow-up period of 115.1 months. CONCLUSION: POS showed characteristic findings on radiographic images. Therefore, wide resection without biopsy could be performed in 77.8% (7/9) of the cases. This procedure may contribute to attaining better limb function, because of preventing contamination of healthy surrounding tissue and minimizing the extent of resection. The safety margin was evaluated as a 1-cm-wide procedure. For the choice of reconstruction, indication of autobone grafting (3/9) or total knee replacement (TKR) (6/9) depended on tumor size, location, and shape. With no adjuvant treatments, all cases have shown good clinical courses during the entire follow-up period of about 10 years.

Report of four cases with high-grade surface osteosarcoma.

High-grade surface osteosarcoma is the rarest of the three types of surface osteosarcoma. Four cases with high-grade surface osteosarcoma arising from the distal femur and tibia are reported in this study. One patient was previously diagnosed with Turner's syndrome. Radiologically, three cases presented characteristic appearances suggesting high-grade bone-forming sarcoma arising from the bone surface; however, one case was similar to other juxtacortical lesions such as periosteal and parosteal osteosarcoma, which typically have a better prognosis than high-grade surface osteosarcoma. Therefore, all cases underwent biopsy to determine a definitive diagnosis. Our strategy of treatment for high-grade surface osteosarcoma was a combination of wide resection and pre-/post-operative chemotherapy, equivalent to the treatment for conventional intramedullary osteosarcoma. At the last follow-up, two cases were still undergoing chemotherapy, one case was continuously disease free during the follow-up period of 81 months, and one patient was living with no evidence of disease 60 months after surgery. The aim of this study is to report the clinical information, oncological outcome and appropriate treatment for high-grade surface osteosarcoma.

Surgical treatment of bone metastasis: indications and outcomes.

Due to advances in cancer treatment that prolong survival, there has been a noticeable increase in the prevalence of bone metastasis. Consequently, the likelihood of orthopedic surgeons encountering such tumors and the need for effective surgical treatment are also expanding. Although bone metastasis constitutes only one possible type of metastatic lesion, and while local control at a bone metastatic site alone may have little effect on total curability, the quality of life (QOL) of the patient cannot be ensured if local control is ignored. Therefore, it is important to achieve local control through multidisciplinary treatments aimed at both reduced surgery and at conservation of limb function. Surgical treatment may be indicated after a series of more conservative treatments. Among the main indications are pathologic fracture or a high risk of fracture of limb bones. Acute spinal cord injury caused by acute compression fracture from spinal metastasis is a relative indication. The occurrence of a solitary metastasis, for which extended survival may be anticipated, is also an indication for surgery to achieve local control. Appropriate local control is required to realize a predicted survival period. As well, the surgical method, resection margin, and supplementary treatments, and immediately effective reconstruction method should be selected accordingly.

[Surgical treatment for bone and soft tissue sarcoma].

There are many kinds of wide excision or wide resection, which are methods to remove the tumor with surrounding tissues. The curability of wide resection depends on the range and characteristics of the normal surrounding tissues. The fascia, periosteum and perivascular sheath act as barriers against invasion of tumors. Therefore, evaluation of the surgical margin is essential in surgery for malignancy. Some sarcomas characteristically show invasive growth patterns while others have a discrete border. Causes of the local recurrence are 1) insufficient surgical margin, 2) skip metastasis, 3) tumor thrombus, and 4) lymph node metastasis. The so-called "Safety surgical margin" is the margin that prevents local recurrence due to insufficient surgical treatment. Local recurrence due to other causes can not be treated by surgery alone as chemotherapy is also required. For example, the infiltrative type of malignant fibrous histiocytoma requires a curative procedure. On the other hand, non-infiltrative types of sarcoma or high-grade sarcoma, which are good responders to preoperative treatment, are locally controlled by an adequate wide margin procedure. When the tumor is close to the bone, main vessels and/or nerves, it is sometimes very difficult to preoperatively decide whether or not to sacrifice these important organs. A new surgical method, "In Situ Preparation (ISP)," is a useful method to solve such problems. ISP makes it possible to evaluate the surgical margin without contamination. And additional procedures including alcohol soaking or pasteurization can be achieved according to the surgical margin. Because ISP can prevent overtreatment, the number of our cases that require resection of the nerves or vessels have decreased. After a wide resection, there have been many possible complications, including infection, deep venous thrombosis, loosening of prosthesis, skin necrosis, and arterial occlusion. Once postoperative complications occur, patients must remain in the hospital for a long time. To prevent this, the preservation of normal tissue, meaning reduction of surgical margin, is important.

The concept of curative margin in surgery for bone and soft tissue sarcoma.

To clarify the safety margin in excision of bone and soft tissue sarcomas, a new evaluation method for surgical margins was drafted by the Bone and Soft Tissue Committee of the Japanese Orthopaedic Association in 1989. This new evaluation system was applied to 1329 patients with bone and soft tissue sarcomas, of whom 492 were excluded because of insufficient details, leaving 837 patients (901 surgeries) for the current study. Based on the results derived from analyzing these registered surgical margins, predictable safety margins under different conditions could be determined. When preoperative treatment is not done or is ineffective in high-grade sarcoma, a margin greater than 3 cm wide is necessary. When the preoperative modality is effective, a 2-cm wide margin is permissible. However, for recurrent sarcoma, whether low-grade or high-grade, a curative procedure is necessary. For low-grade sarcoma, obtaining an adequate wide margin is essential but partial marginal margins are acceptable at sites where barriers exist. When the margin is insufficient, radiotherapy should be used regardless of the tumor grade. Making a safety margin definitive through this system, an optimum treatment can be obtained and unnecessary adjunctive modalities can be avoided.

Pasteurized autologous bone graft in surgery for bone and soft tissue sarcoma.

For skeletal reconstruction in surgery for bone tumors, pasteurization of bone has been used with favorable results over autoclaving or boiling. Twenty-three patients with primary malignant bone tumors and two patients with soft tissue sarcoma invading bone reconstruction surgery with pasteurized autologous bone graft comprised the study group. There were 16 females and nine males, between 7 and 77 years of age who were followed up for at least 3 years (mean, 52 months). The International Society of Limb Salvage graft evaluation method was used for evaluation of the radiographs. Fifteen patients (60%) had complete incorporation of the graft and eight patients (32%) had partial incorporation. Viability of the grafts was evaluated by bone scintigraphy. Of 22 patients evaluated, uptake was detected in 17 patients from approximately 6 months postoperatively after which it increased gradually. The functional results were assessed by the system of the Musculoskeletal Tumor Society, and the mean functional rating was 86%. Eighteen patients have been disease-free and seven have died of disease. Fracture (12%) and infection (20%) were the main complications. No local recurrence was detected. These results indicate that pasteurization of bone may be a useful option for reconstruction after resection of malignant bone tumors. The advantages of extracorporeal pasteurization include convenience of use, avoidance of intraspecies infection and allogenic reactions, and satisfactory bone remodeling.