Publications by authors named "Hiroyuki Kawashima"

136 Publications

Synthesis and Properties of an 18π Aromatic Norcorrole P(V) Complex.

Org Lett 2021 Apr 22;23(7):2826-2830. Epub 2021 Mar 22.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan.

[16]Norcorrole is an antiaromatic ring-contracted porphyrinoid. Here, we show that the phosphorus insertion of the free-base [16]norcorrole switches its antiaromaticity to aromaticity. The treatment of a free-base -dimesityl[16]norcorrole with phosphorus tribromide in pyridine afforded an [18]norcorrole P(V) complex, which exhibited porphyrin-like absorption and fluorescence spectra. The phosphorus center adopted a distorted tetragonal pyramidal coordination geometry. The distinct aromatic nature of the [18]norcorrole P(V) complex was corroborated both experimentally and theoretically.
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http://dx.doi.org/10.1021/acs.orglett.1c00823DOI Listing
April 2021

Minimally Invasive Spinal Stabilization with Denosumab before Total Spondylectomy for a Collapsing Lower Lumbar Spinal Giant Cell Tumor.

Acta Med Okayama 2021 Feb;75(1):95-101

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences.

A 21-year-old man consulted our hospital for treatment of a spinal giant cell tumor (GCT) of Enneking stage III. Lower lumbar-spine tumors and severe spinal canal stenosis are associated with high risk for surgical mor-bidity. Stability was temporarily secured with a percutaneous pedicle screw fixation in combination with deno-sumab, which shrank the tumor. Total en bloc spondylectomy was then performed 6 months after initiation of denosumab, and the patient was followed for 3 years. There was no local recurrence, and bony fusion was obtained. Minimally invasive surgery and denosumab allowed safer and easier treatment of a collapsing lower lumbar extra-compartmental GCT.
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http://dx.doi.org/10.18926/AMO/61442DOI Listing
February 2021

Standard Treatment Remains the Recommended Approach for Patients with Bone Sarcoma Who Underwent Unplanned Surgery: Report from the Japanese Musculoskeletal Oncology Group.

Cancer Manag Res 2020 12;12:10017-10022. Epub 2020 Oct 12.

Department of Orthopaedic Surgery, Osaka National Hospital, Chuo-ku, Osaka 540-0006, Japan.

Background: The outcomes of unplanned surgery for bone sarcomas have not been frequently discussed. However, it is important to recognize patterns, treatment, and clinical outcomes of unplanned surgeries for patients with bone sarcomas. This multicenter study aimed to characterize the clinical outcomes of patients with bone sarcomas who underwent unplanned surgeries.

Patients And Methods: Data of 43 patients with bone sarcomas who underwent unplanned surgery between 2006 and 2017 were obtained from 23 hospitals in Japan. These included 18 cases of osteosarcoma, 9 of Ewing sarcoma, 8 of chondrosarcoma, and 6 of undifferentiated pleomorphic sarcoma. The study included 28 men and 15 women, with a mean age of 46 years. The mean follow-up duration was 59 months.

Results: The main primary tumor sites were the femur (n = 19), spine (n = 6), pelvis (n = 5), tibia (n = 3), and humerus (n = 3). The primary diagnoses were benign bone tumor (n = 24), trauma (n = 7), bone metastasis (n = 5), osteomyelitis (n = 4), degeneration (n=2), and unknown (n = 1). As unplanned surgeries, curettage, with or without bone graft, was performed in 26 patients; internal fixation was performed in 7; spinal surgery in 5; arthroplasty in 4; and arthroscopy in one. Thirty-eight patients received additional standard treatments. Thirty-four of these patients underwent surgical tumor resections, including amputation (n = 10), and the remaining 4 received radiotherapy or carbon ion radiotherapy as additional standard treatments. The 5-year disease-specific survival (DSS) rates in patients with osteosarcoma, Ewing sarcoma, and chondrosarcoma were 65.5%, 58.3%, and 72.9%, respectively. Twelve (27.9%) patients developed local recurrences (LR); among the total 43 patients studied, the 5-year DSS rates were significantly worse for those who developed LR compared to those who did not (p = 0.03). The 5-year DSS rates in patients with and without LR were 44% and 73.8%, respectively.

Conclusion: We recommend that patients who have undergone unplanned surgery be administered standard treatment, including the option of amputation because herein, LR was shown to be a risk factor for decreased DSS.
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http://dx.doi.org/10.2147/CMAR.S270178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567545PMC
October 2020

The medial inclination of the proximal tibia is associated with the external knee adduction moment in advanced varus knee osteoarthritis.

Knee Surg Sports Traumatol Arthrosc 2020 Oct 16. Epub 2020 Oct 16.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, 1-757 Asahimachi-dori Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: Whether the inclined articular surface on the medial proximal tibia and the external knee adduction moment (KAM) correlate remains unclear. The hypothesis was that a steeper inclined articular surface correlated with a larger KAM in advanced knee osteoarthritis (OA).

Methods: A total of 44 females (non-OA, 9 knees; early OA, 14 knees; advanced OA, 21 knees; mean age, 58 ± 16 years) were examined. Three-dimensional (3D) assessment was used on biplanar long-leg radiographs and 3D bone models using a 3D to 2D image registration technique. The approximation plane in the proximal tibia was determined using the least-square method. The joint moments were mathematically calculated in a gait analysis, applying a motion capture system and force plates. The main evaluation parameters were the femorotibial angle (FTA), the coronal inclination of the approximation plane in the medial proximal tibia (coronal inclination), and internal knee joint moments. The KAM means the external moments balanced with the internal knee abduction moments.

Results: The advanced OA showed a larger internal abduction moment (p = 0.017) at the loading response than the other groups. The larger FTA and steeper coronal inclination correlated with the larger internal abduction moment (FTA, p < 0.001; coronal inclination, p = 0.003) at the loading response.

Conclusions: As the clinical relevance, the association among the coronal inclination of the medial proximal tibia, lower extremity alignment, and KAM is one of the key factors to help better understand the etiology of knee OA.

Level Of Evidence: III.
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http://dx.doi.org/10.1007/s00167-020-06323-8DOI Listing
October 2020

Cortical thickness of the tibial diaphysis reveals age- and sex-related characteristics between non-obese healthy young and elderly subjects depending on the tibial regions.

J Exp Orthop 2020 Oct 6;7(1):78. Epub 2020 Oct 6.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, 1-757 Asahimachi-dori Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: This study aimed to evaluate the age- and sex-related characteristics in cortical thickness of the tibial diaphysis between non-obese healthy young and elderly subjects as reference data.

Methods: The study investigated 31 young subjects (12 men and 19 women; mean age, 25 ± 8 years) and 54 elderly subjects (29 men and 25 women; mean age, 70 ± 6 years). Three-dimensional estimated cortical thickness of the tibial diaphysis was automatically calculated for 5000-9000 measurement points using the high-resolution cortical thickness measurement from clinical computed tomography data. In 12 assessment regions created by combining three heights (proximal, central, and distal diaphysis) and four areas of the axial plane at 90° (medial, anterior, lateral, and posterior areas) in the tibial coordinate system, the standardized thickness was assessed using the tibial length.

Results: As structural characteristics, there were no differences in the medial and lateral thicknesses, while the anterior thickness was greater than the posterior thickness in all groups. The sex-related difference was not shown. As an age-related difference, elderly subjects showed greater or lesser cortical thickness than the young subjects, depending on the regions of the tibia.

Conclusions: Cortical thickness was different depending on sex, age, and regions in the tibia. The results of this study are of clinical relevance as reference points to clarify the causes of various pathological conditions for diseases.

Level Of Evidence: Level 3.
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http://dx.doi.org/10.1186/s40634-020-00297-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538524PMC
October 2020

Diagnosis and management of genital injuries in girls: 14-year experience.

Pediatr Int 2020 Aug 27. Epub 2020 Aug 27.

Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, Japan.

Background: Pediatric patients with genital injuries are often recommended to receive an examination under general anesthesia; however, detailed clinical data of such patients are rarely reported.

Methods: A single-center retrospective review was conducted in 45 girls less than 16 years of age with genital injuries between January 2005 and December 2018.

Results: The median patient age was 5.0 years. Forty-two patients were hospitalized, of whom 38 required an examination under general anesthesia and all consequently required surgical repair. The diagnosis obtained after a thorough examination under general anesthesia was inconsistent with the diagnosis obtained at the emergency room in five patients. In 20 patients, the source of bleeding was not clarified at the time of initial examination at the emergency room; four of these patients were later revealed to have vaginal or rectal injuries that had been overlooked during the examination at the emergency room. Injuries occurring in the bathroom were the most frequent and tended to be serious. Multiple injuries were found in 10 patients. The exterior of the labia minora was the most commonly injured site, found in 18 patients.

Conclusions: We analyzed the clinical data of girls with genital injuries in detail, which allowed us to find a detailed classification of injured sites and the characteristics of serious cases, and to re-recognize the importance of a thorough examination under general anesthesia.
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http://dx.doi.org/10.1111/ped.14448DOI Listing
August 2020

Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients with extra-abdominal desmoid-type fibromatosis: a systematic review.

Jpn J Clin Oncol 2020 Oct;50(11):1274-1281

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: The treatment modality for desmoid-type fibromatosis has shifted from surgery to conservative treatment. The guideline committee for clinical care of extra-abdominal desmoid-type fibromatosis in Japan conducted a systematic review of treatment with doxorubicin-based chemotherapy for desmoid-type fibromatosis.

Methods: We searched the pertinent literature. Two reviewers evaluated and screened it independently for eligibility and extracted data. They rated each report according to the grading of recommendations development and evaluation methodology. Based on the 'body of evidence', which the reviewers created, the clinical guideline committee decided a recommendation for the clinical question, 'Is doxorubicin-based chemotherapy effective for patients with extra-abdominal desmoid-type fibromatosis?'

Results: Fifty-three articles were extracted by the literature search, and one from hand search. After the first and second screenings, five articles were subjected to the final evaluation. There were no randomized controlled trials. According to response evaluation criteria in solid tumors criteria, the response rates of doxorubicin-based regimens and liposomal doxorubicin were 44% (28.6-54) and 33.3% (0-75) on average, respectively. In two reports, the response rates of doxorubicin-based regimens were higher than those of non-doxorubicin-based ones; 54% vs 12%, 40% vs 11%, respectively. The rates of G3 or G4 complications according to common terminology criteria for adverse events were 28% and 13% with doxorubicin-based and liposomal doxorubicin chemotherapy, respectively, including neutropenia or cardiac dysfunction. None of the reports addressed the issue of QOL.

Conclusion: Although the evidence level was low in the evaluated studies, doxorubicin-based and liposomal doxorubicin chemotherapy was observed to be effective. However, doxorubicin-based chemotherapy is associated with non-ignorable adverse events, and is not covered by insurance in Japan. We weakly recommend doxorubicin-based chemotherapy for patients with extra-abdominal desmoid-type fibromatosis in cases resistant to other treatments.
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http://dx.doi.org/10.1093/jjco/hyaa125DOI Listing
October 2020

A 2-to-2' 18-to-18' doubly linked Ni(ii) norcorrole dimer: an effectively conjugated antiaromatic dyad.

Chem Commun (Camb) 2020 Jun 20;56(50):6846-6849. Epub 2020 May 20.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8603, Japan.

The synthesis and properties of a 2-to-2' 18-to-18' doubly linked Ni(ii) norcorrole dimer are described. It adopts a highly planar structure, resulting in effective electronic interactions between the constituent norcorrole units. Nevertheless, each norcorrole unit exhibits substantial antiaromaticity, which stands in sharp contrast to stacked norcorrole dimers.
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http://dx.doi.org/10.1039/d0cc02543gDOI Listing
June 2020

What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma?

Clin Orthop Relat Res 2020 Nov;478(11):2537-2547

R. Nakayama, N. Asano, Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.

Background: Clear cell chondrosarcoma is an extremely rare chondrosarcoma subtype; thus, its treatment outcomes and associated factors have not been widely studied. Knowing more about it is potentially important because clear cell chondrosarcomas are often misdiagnosed as other benign lesions and subsequently treated and followed inappropriately.

Questions/purposes: (1) What are the patient- and tumor-related characteristics of clear cell chondrosarcoma? (2) What proportion of patients with clear cell chondrosarcoma initially had a misdiagnosis or a misleading initial biopsy result? (3) What is the survivorship of patients with clear cell chondrosarcoma free from death, local recurrence, and distant metastasis, and what factors are associated with greater survivorship or a reduced risk of local recurrence?

Methods: Between 1985 and 2018, 12 Japanese Musculoskeletal Oncology Group (JMOG) hospitals treated 42 patients with a diagnosis of clear cell chondrosarcoma. All 42 patients had complete medical records at a minimum of 1 year or death, and were included in this multicenter, retrospective, observational study. No patients were lost to follow-up within 5 years of treatment but four were lost to follow-up greater than 5 years after treatment because their physicians thought their follow-up was sufficient. Clinical data were collected by chart review. The median (range) follow-up period was 69 months (2 to 392). In general, when a possibly malignant bone tumor was found on imaging studies, the histological diagnosis was made by biopsy before initiating treatment. Once the diagnosis had been made, the patients were treated by surgery only, complete resection if technically possible, because chondrosarcomas are known to be resistant to chemotherapy and radiotherapy. Unresectable tumors were treated with particle-beam radiation therapy. When patients with chondrosarcoma were referred after unplanned surgical procedures with inadequate surgical margins, immediate additional wide resection was considered before local recurrence developed. This diagnostic and treatment strategy is common to all JMOG hospitals and did not change during the study period. Primary wide resection was performed in 79% (33 of 42) patients, additional wide resection after initial inadequate surgery in 12% (five of 42), curettage and bone grafting in 5% (two of 42) patients, and radiotherapy was administered to 5% (two of 42). Surgical margins among the 40 patients who underwent surgery at JMOG hospitals were no residual tumor in 93% (37 of 42) of patients, microscopic residual tumor in 2% (one of 42), and macroscopic residual tumor or state after curettage or intralesional excision in 5% (two of 42). The oncological endpoints of interest were 5- and 10- year overall survival, disease-free survival, survival free of local recurrence, and survival free of distant metastases; these were calculated using the Kaplan-Meier method and compared using the log-rank test. Risk ratios with their respective 95% confidence intervals (CIs) were estimated in a Cox regression model. The Bonferroni adjustment was used for multiple testing correction.

Results: The sex distribution was 74% men and 26% women (31 and 11 of 42, respectively), with a mean age of 47 ± 17 years. Eighty one percent (34 of 42) of tumors occurred at the ends of long bones, and the proximal femur was the most common site accounting for 60% (25 of 42). The mean size of the primary tumors was 6.3 ± 2.7 cm. Definite pathologic fractures were present in 26% (10 of 42) and another 26% (10 of 42) had extraskeletal involvement. None had metastases at presentation. Twenty four percent (six of 25) tumors in the proximal femur were misdiagnosed as benign lesions and treated inadequately without biopsy. Twenty nine percent (10 of 35) patients had initial misdiagnoses by biopsy and core needle biopsies had a greater risk of resulting in inaccurate histological diagnoses. The study patients' 5- and 10-year overall survival rates were 89% (95% CI 74 to 96) and 89% (95% CI 74 to 96), respectively; 5- and 10- year disease-free survival rates 77% (95% CI 58 to 89) and 57% (95% CI 36 to 75), respectively; 5- and 10-year local recurrence-free survival rates 86% (95% CI 68 to 95) and 71% (95% CI 49 to 86), respectively; and 5- and 10-year distant metastasis-free survival rates 84% (95% CI 67 to 93) and 74% (95% CI 53 to 88), respectively. Notably, bone metastases (17%, seven of 42) were as common as pulmonary metastases (14%, six of 42); four patients developed both bone and pulmonary metastases. The difference between 10-year overall survival rates and 10-year disease-free survival indicated very late recurrence more than 5 years after the initial treatment. After controlling for multiple comparisons, the only factor we found that was associated with local recurrence-free survival was initial treatment (positive margin versus primary wide resection) (risk ratio 8.83 [95% CI 1.47 to 53.1]; p = 0.022 after the Bonferroni adjustment). Additional wide resection reduced the risk of local recurrence.

Conclusions: The femoral head was the most common location of clear cell chondrosarcoma and had a high risk of misdiagnosis as common benign lesions that resulted in initial inadequate surgery and a consequent high risk of local recurrence. Immediate additional wide resection should be considered in patients who had initial inadequate surgery to reduce the risk of local recurrence. Because clear cell chondrosarcoma can recur locally or distantly in the bones and lungs in the long term, patients should be informed of the risk of very late recurrence and the necessity of decades-long with surveillance for local recurrence and lung and bone metastases.

Level Of Evidence: Level IV, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000001266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594916PMC
November 2020

The HDAC inhibitor OBP-801 suppresses the growth of myxofibrosarcoma cells.

J BUON 2020 Jan-Feb;25(1):464-471

Drug Discovery and 2Surgery, Division of Plastic and Reconstructive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto.

Purpose: Myxofibrosarcoma is characterized by a high rate of recurrence after surgery. Since myxofibrosarcoma is refractory to conventional cytotoxic chemotherapy, the established radical treatment is primary wide resection. The effects of histone deacetylase (HDAC) inhibitors on myxofibrosarcoma have not yet been investigated. Therefore, the main purpose of the present study was to examine the effects of a HDAC inhibitor on myxofibrosarcoma.

Methods: The effects of the HDAC inhibitor OBP-801 on human myxofibrosarcoma cells were examined using cell viability assay, flow cytometric analysis of the cell cycle and apoptosis, and Western blotting. The effects of combinations of OBP-801 with pazopanib or Akt-mTOR inhibitors were also investigated using cell viability assay.

Results: OBP-801 inhibited the growth of myxofibrosarcoma NMFH-1 and NMFH-2 cells. It also induced cell cycle arrest at the G2 phase and apoptosis in both cell lines. The inhibitory effects of pazopanib and Akt-mTOR inhibitors on the growth of myxofibrosarcoma cells were enhanced by the combination with OBP-801.

Conclusions: The present results demonstrated that OBP-801 exerted therapeutic effects in myxofibrosarcoma in both single and concomitant administrations. Therefore, OBP-801 has potential as a novel treatment for myxofibrosarcoma.
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December 2020

<Editors' Choice> mRNA expression in soft-tissue tumors.

Nagoya J Med Sci 2020 Feb;82(1):85-92

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Stanniocalcin-1 () is a glycoprotein that was originally identified as a calcium-regulating hormone in bony fish, and that has been shown to also critically mediate cell growth, proliferation and differentiation, etc. in humans. Increased expression levels have been previously detected in different human cancer samples, such as those isolated from lung, breast, ovary, colon, pancreas, and liver tumors; thus, the present study evaluated expression in various soft-tissue tumors. mRNA isolated from 16 cell lines and 186 clinical soft-tissue tumor specimens were analyzed via quantitative real-time PCR, and the calculated expression levels were normalized to those exhibited by -expressing MDA-MB-231 cells. The results of these analyses did not reveal any specific histological tumor types that displayed significantly increased expression; however, they did not indicate that expression was significantly higher in malignant compared to benign soft-tissue tumors. Furthermore, in adipocytic tumors, expression in dedifferentiated liposarcomas was found to be highest and lowest in lipoma tissues, respectively, suggesting that adipocytic tumors may express increasely high levels of mRNA as they become histologically more advanced. expression correlates with the malignancy grade in soft-tissue tumors.
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http://dx.doi.org/10.18999/nagjms.82.1.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103862PMC
February 2020

The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3.

J Orthop Surg Res 2020 Mar 4;15(1):87. Epub 2020 Mar 4.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan.

Background And Aim: The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management.

Methods: We investigated the effect of administering a low dose (1000 μM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived 2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS).

Results: Low-dose NAC (1000 μM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 μM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 μM) to RA-FLS suppressed MMP-3.

Conclusions: We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.
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http://dx.doi.org/10.1186/s13018-020-01595-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371465PMC
March 2020

Regioselective Oxidative Ring Cleavage of Antiaromatic Nickel(II) Norcorrole to Dialkoxybis(dipyrrin)s.

Chempluschem 2019 06 15;84(6):561. Epub 2019 May 15.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.

Invited for this month's cover is the group of Prof. Dr. Hiroshi Shinokubo at Nagoya University, Japan. The front cover shows the oxidative ring opening reaction of an antiaromatic porphyrinoid, norcorrole, into dipyrrin dimers. The background with the map of Japan represents the venue of ISNA-18, which will be held in Sapporo, Japan in July 2019. Read the full text of the article at 10.1002/cplu.201900068.
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http://dx.doi.org/10.1002/cplu.201900242DOI Listing
June 2019

Regioselective Oxidative Ring Cleavage of Antiaromatic Nickel(II) Norcorrole to Dialkoxybis(dipyrrin)s.

Chempluschem 2019 Jun 4;84(6):623-626. Epub 2019 Apr 4.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.

The Ni(II) complex of meso-dimesitylnorcorrole is a stable 16π antiaromatic porphyrinoid. We have previously reported that the reaction of the norcorrole Ni(II) complex with m-chloroperbenzoic acid resulted in oxygen insertion to afford the corresponding 10- oxacorrole Ni(II) complex, which is an 18π aromatic porphyrinoid. In sharp contrast, we have found that treatment of the norcorrole Ni(II) complex with bis[(trifluoroacetoxy)iodo]benzene in the presence of a variety of alcohols induced a ring-opening reaction to furnish the corresponding dialkoxybis(dipyrrin)s through regioselective oxidative C-C bond cleavage. Furthermore, dihydroxybis(dipyrrin) exhibited solvent-dependent absorption and emission behavior through keto-enol tautomerization of the hydroxy groups.
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http://dx.doi.org/10.1002/cplu.201900068DOI Listing
June 2019

Prolonged Myelosuppression due to Progressive Bone Marrow Fibrosis in a Patient with Acute Promyelocytic Leukemia.

Case Rep Hematol 2019 27;2019:1616237. Epub 2019 Nov 27.

Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Tokyo, Japan.

A 34-year-old woman was diagnosed with acute promyelocytic leukemia. Chemotherapy was administered following the JALSG APL204 protocol. Induction therapy with all-trans retinoic acid resulted in complete remission on day 49. She developed coccygeal pain from day 18, which spread to the spine and cheekbones and lasted 5 weeks. She had similar bone pain on days 7-10 of the first consolidation therapy and on days 4-12 of the second consolidation therapy. Oral loxoprofen was prescribed for pain relief. On day 33 of the third consolidation, white blood cell and neutrophil counts were 320/L and 20/L, respectively. After she developed epigastralgia and hematemesis, she developed septic shock. Gastroendoscopy revealed markedly thickened folds and diffusely damaged mucosa with blood oozing. Computed tomography revealed thickened walls of the antrum and the pylorus. Despite emergency treatments, she died. Bacterial culture of the gastric fluid yielded and enterococci growth. Collectively, she was diagnosed with phlegmonous gastritis. Retrospective examination of serial bone marrow biopsy specimens demonstrated progressive bone marrow fibrosis, which may have caused prolonged myelosuppression. Thus, evaluation of bone marrow fibrosis by bone marrow biopsy after each treatment cycle might serve as a predictor of persistent myelosuppression induced by chemotherapy.
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http://dx.doi.org/10.1155/2019/1616237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900957PMC
November 2019

Experimental arthritis and Porphyromonas gingivalis administration synergistically decrease bone regeneration in femoral cortical defects.

Sci Rep 2019 12 27;9(1):20031. Epub 2019 Dec 27.

Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Porphyromonas gingivalis infection can lead to periodontitis and dysbiosis, which are known risk factors for rheumatoid arthritis (RA). We investigated whether P. gingivalis administration affected bone regeneration in mice with or without arthritis. We administered P. gingivalis to male DBA/1 J mice that were or were not sensitised to type II collagen-induced arthritis (CIA). All mice underwent drilling of bilateral femurs. We histologically evaluated new bone regeneration (bone volume of the defect [BVd]/tissue volume of the defect [TVd]) using micro-computed tomography (micro-CT), osteoclast number/bone area, and active osteoblast surface/bone surface (Ob.S/BS). We measured serum cytokine levels and bone mineral density of the proximal tibia using micro-CT. CIA resulted in significantly reduced bone regeneration (BVd/TVd) at all time-points, whereas P. gingivalis administration showed similar effects at 2 weeks postoperatively. CIA resulted in higher osteoclast number/bone area and lower Ob.S/BS at 2 and 3 weeks postoperatively, respectively. However, P. gingivalis administration resulted in lower Ob.S/BS only at 2 weeks postoperatively. During later-stage bone regeneration, CIA and P. gingivalis administration synergistically decreased BVd/TVd, increased serum tumour necrosis factor-α, and resulted in the lowest bone mineral density. Therefore, RA and dysbiosis could be risk factors for prolonged fracture healing.
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http://dx.doi.org/10.1038/s41598-019-56265-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934576PMC
December 2019

Reconstruction of knee extensor with patellar tendon autograft following intraoperative radiotherapy.

Knee 2020 Jan 5;27(1):257-262. Epub 2019 Dec 5.

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.

Background: Patellar tendon autograft after intraoperative extracorporeal radiotherapy has been used for reconstruction of the extensor mechanism following limb-sparing wide tumor resection around the knee. The purpose of this study was to determine the clinical outcome of this reconstruction technique.

Methods: We retrospectively reviewed six consecutive patients with peripatellar tendon and proximal tibial sarcoma who underwent reconstruction of the knee extensor mechanism. The resection area was planned to be contained with the patellar tendon in order to obtain a wide margin. First, the patella was osteotomized at the midline, and the inferior half of patella, patellar tendon, and tibial tuberosity were excised en bloc. The resected segments were devitalized with intraoperative extracorporeal radiotherapy and reimplanted into the original site. A follow-up evaluation included an assessment of the range of motion, extensor lag, the International Society of Limb Salvage score, and complications.

Results: Six patients were followed up for 121-270 months. One patient underwent an additional reconstruction with total knee arthroplasty due to a collapse of the tibial subchondral bone. A supracondylar fracture of the femur occurred in two patients, and a delayed union of the osteosynthesis site of the tibial shaft was observed in one patient. At the latest follow up, extensor lag had a median of five degrees, and International Society of Limb Salvage scores had a median of 83%. No local recurrence or rupture of the patellar tendon was observed.

Conclusions: Reconstruction of the knee extensor mechanism using a patellar tendon treated with intraoperative radiotherapy is a reliable and successful method.
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http://dx.doi.org/10.1016/j.knee.2019.10.008DOI Listing
January 2020

Expression Profiling of Receptor-Activator of Nuclear Factor-Kappa B Ligand in Soft Tissue Tumors.

Tohoku J Exp Med 2019 06;248(2):87-97

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences.

Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.
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http://dx.doi.org/10.1620/tjem.248.87DOI Listing
June 2019

Forced expression of NR4A3 induced the differentiation of human neuroblastoma-derived NB1 cells.

Med Oncol 2019 Jun 10;36(8):66. Epub 2019 Jun 10.

Division of General Medicine, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi, Tokyo, 173-8610, Japan.

Nuclear receptor subfamily 4, group A, member 3 (NR4A3) is a member of the NR4A subgroup of orphan nuclear receptors, implicated in the regulation of diverse biological functions, including metabolism, angiogenesis, inflammation, cell proliferation, and apoptosis. Although many reports have suggested the involvement of NR4A3 in the development and/or progression of tumors, its role varies among tumor types. Previously, we reported that DNA hypomethylation at NR4A3 exon 3 is associated with lower survival rate of neuroblastoma (NB) patients. As hypomethylation of this region results in reduced expression of NR4A3, our observations suggested that NR4A3 functions as a tumor suppressor in NB. However, the exact mechanisms underlying its functions have not been clarified. In the present study, we analyzed public databases and showed that reduced NR4A3 expression was associated with shorter survival period of NB in two out of three datasets. An in vitro study revealed that forced expression of NR4A3 in human NB-derived cell line NB1 resulted in elongation of neurites along with overexpression of GAP43, one of the differentiation markers of NB. On the other hand, siRNA-mediated knockdown of NR4A3 suppressed the expression level of GAP43. Interestingly, the forced expression of NR4A3 induced only the GAP43 but not the other molecules involved in NB cell differentiation, such as MYCN, TRKA, and PHOX2B. These results indicated that NR4A3 directly activates the expression of GAP43 and induces differentiated phenotypes of NB cells, without affecting the upstream signals regulating GAP43 expression and NB differentiation.
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http://dx.doi.org/10.1007/s12032-019-1289-6DOI Listing
June 2019

Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients.

J Orthop Sci 2020 Mar 30;25(2):319-323. Epub 2019 May 30.

The Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

Background: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined.

Methods: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone.

Results: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis.

Conclusions: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear.
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http://dx.doi.org/10.1016/j.jos.2019.04.008DOI Listing
March 2020

Aortic mural leiomyosarcoma with spinal involvement.

J Thorac Cardiovasc Surg 2020 04 24;159(4):e249-e254. Epub 2019 Apr 24.

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

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http://dx.doi.org/10.1016/j.jtcvs.2019.04.015DOI Listing
April 2020

The natural history of incidental retroperitoneal schwannomas.

PLoS One 2019 15;14(4):e0215336. Epub 2019 Apr 15.

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata, Japan.

The natural history of asymptomatic retroperitoneal schwannomas is poorly understood. This study aimed at investigating the natural history of incidental retroperitoneal schwannomas. The medical charts and imaging studies of 22 asymptomatic patients under observation for at least 12 months for retroperitoneal schwannomas were reviewed. The duration of follow-up ranged between 13 and 176 months (mean 48 months). In the 22 patients managed by the "wait and see" approach, the average tumor size at initial presentation was 51 mm, which increased to 57 mm at final follow-up. During the final follow-up, 2 patients required surgical treatment for tumor enlargement, while the remaining patients remained asymptomatic without surgery. The average growth rate of the tumors was 1.9 mm/year (range: -1.9 to 8.7 mm/year). The majority of asymptomatic retroperitoneal schwannomas demonstrate minimal growth and may be suitable for management with the "wait and see" approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215336PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464223PMC
January 2020

Symptom Burden and End-of-Life Palliative Treatments during the Last Two Weeks of Life in Patients with Advanced Musculoskeletal Sarcoma.

J Palliat Med 2019 08 14;22(8):908-914. Epub 2019 Feb 14.

1Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Musculoskeletal sarcomas (MSSs) are rare cancers and often aggressive tumors that originate from mesenchymal tissue. Patients with advanced MSS often report difficulties with symptom burden, which can reduce their health-related quality-of-life. The aim of this study was to describe the patterns of the physical symptoms of MSS patients in the palliative setting and to detail the palliative treatment used in the last two weeks of life. Retrospective study using the electronic patient records from a single institution. A retrospective study was carried out in a sample of 46 consecutive MSS patients with locally advanced/metastatic disease, who were hospitalized and died in our department. The median age of these patients was 56 years at death. Symptom burden and medical intervention during the last two weeks of life were collected. The most frequent physical symptoms were pain and dyspnea in 93% and 78% of patients, respectively, while only 17% of patients suffered from nausea. A total of 98% of patients required opioids, and most patients were treated with morphine through either subcutaneous or intravenous continuous injection. Nonsteroidal anti-inflammatory drugs and acetaminophen were administered to 79% of patients. Corticosteroids were administered for the relief of dyspnea to 83% of patients. Of the patients, 46% received palliative chemotherapy within the last two weeks of life, and the oral treatment was continued until a median of 5.6 days before death. In addition, 39% of patients received a sedative treatment during the last two weeks of life for uncontrolled refractory symptoms. The symptom burden experienced by advanced MSS patients is profound at the end of life for all palliative approaches. Therefore, palliative medicine is an important and even crucial component of the continuum of care, allowing for aggressive symptom management with a variety of medical interventions, including palliative sedation.
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http://dx.doi.org/10.1089/jpm.2018.0415DOI Listing
August 2019

Successful resuscitation from cardiac arrest due to histologically revealed tumor embolism following bilateral intramedullary nailing of metastatic femoral lesions.

J Orthop Sci 2018 Oct 4. Epub 2018 Oct 4.

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

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http://dx.doi.org/10.1016/j.jos.2018.09.009DOI Listing
October 2018

Prognostic impact of the tumor immune microenvironment in synovial sarcoma.

Cancer Sci 2018 Oct 16;109(10):3043-3054. Epub 2018 Sep 16.

Division of Orthopedic Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

The association between the immune status within the tumor microenvironment and prognosis in synovial sarcoma is not well understood. We aimed to investigate the tumor immune microenvironment and analyze its prognostic impact for patients with synovial sarcoma. A total of 36 primary patients who were treated in our institution were retrospectively evaluated. Infiltration of lymphocytes (CD4+, CD8+, and FOXP3+), CD163+ macrophages, and expression of human leukocyte antigen (HLA) class I and programmed death ligand 1 (PD-L1) were evaluated by immunohistochemistry. Moreover, we investigated PD-L1 and programmed death ligand 2 (PD-L2) mRNA expression in 19 of the 36 cases, using real-time PCR. The Kaplan-Meier method was used to estimate overall survival and progression-free survival. Infiltration of lymphocytes and macrophages varied among the patients. Furthermore, the expression of HLA class I was negative or downregulated in 11 specimens. No PD-L1 expression was observed using immunohistochemistry. Moreover, although PD-L1 mRNA expression was observed in 18 of 19 specimens, the expression level was low. A higher infiltration of CD8+ or FOXP3+ lymphocytes in patients was associated with a favorable overall survival. In addition, a higher infiltration of CD163+ macrophages indicated a significantly worse overall and progression-free survival. Infiltration of CD4+ lymphocytes, HLA class I, PD-L1, and PD-L2 expression were not associated with patient prognosis. This represents the first report investigating the tumor immune microenvironment as a prognostic factor in synovial sarcoma, indicating that CD163+ macrophages are associated with tumor progression. Our results underscore the clinical significance of the tumor immune microenvironment in synovial sarcoma.
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http://dx.doi.org/10.1111/cas.13769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172059PMC
October 2018

Prognostic factors of Erdheim-Chester disease: a nationwide survey in Japan.

Haematologica 2018 11 5;103(11):1815-1824. Epub 2018 Jul 5.

Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo

Erdheim-Chester disease is a rare histiocytosis with insufficient clinical data. To clarify the clinical features and prognostic factors of Erdheim-Chester disease, we conducted a nationwide survey to collect the detailed data of 44 patients with Erdheim-Chester disease in Japan. The median age of onset of the participants was 51 (range: 23-76) years, and the median number of involved organs per patient was 4 (range: 1-11). The existence of central nervous system disease was correlated with older age (=0.033), the presence of cardiovascular lesions (=0.015), and an increased number of involved organs (=0.0042). The median survival from the onset was 10.4 years, and >3.0 mg/dL C-reactive protein level at onset was associated with worse outcome (median survival, 14.6 7.4 years; =0.0016). In a multivariate analysis, age >60 years (hazard ratio, 25.9; 95% confidence interval, 2.82-237; =0.0040) and the presence of digestive organ involvement (hazard ratio, 4.74; 95% confidence interval, 1.05-21.4; =0.043) were correlated with worse survival. Fourteen patients had available histological samples of Erdheim- Chester disease lesions. V600E mutation was detected in 11 patients (78%) by Sanger sequencing. A correlation between mutation status and clinical factors was not observed. Our study revealed that age and digestive organ involvement influence the outcome of Erdheim-Chester disease patients, and an inflammatory marker, such as C-reactive protein, might reflect the activity of this inflammatory myeloid neoplasm.
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http://dx.doi.org/10.3324/haematol.2018.190728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278973PMC
November 2018

NRP1 knockdown promotes the migration and invasion of human neuroblastoma-derived SK‑N‑AS cells via the activation of β1 integrin expression.

Int J Oncol 2018 Jul 7;53(1):159-166. Epub 2018 May 7.

Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan.

Neuropilin 1 (NRP1) is a transmembrane glycoprotein, which regulates many aspects of cellular function by functioning as co-receptor of various ligands. Recent studies have suggested that NRP1 promotes tumorigenesis, not only by activating the growth of tumor vessels, but also by activating the growth or migration of tumor cells themselves. The present study was performed to elucidate the roles of NRP1 in the development and/or progression of neuroblastoma (NB). In contrast to previous observations in various types of cancer, the analysis of public datasets indicated that lower levels of NRP1 expression were significantly associated with a shorter survival period of patients with NB. Consistent with this finding, wound-healing assay and Matrigel invasion assay revealed that NB cells in which NRP1 was knocked down exhibited increased migratory and invasive abilities. Further analyses indicated that β1 integrin expression was markedly increased in NB cells in which NRP1 was knocked down, and NB cells in which β1 integrin was knocked down exhibited decreased migratory and invasive abilities. The results presented herein indicate that NRP1 exerts tumor suppressive effects in NB, at least in part by regulating the expression of β1 integrin.
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http://dx.doi.org/10.3892/ijo.2018.4397DOI Listing
July 2018

The Diagnostic and Prognostic Value of Hematological and Chemical Abnormalities in Soft Tissue Sarcoma: A Comparative Study in Patients with Benign and Malignant Soft Tissue Tumors.

Ann Clin Lab Sci 2018 Jan;48(1):11-17

Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata.

The value of routine blood tests in malignant soft tissue tumors remains uncertain. To determine if these tests can be used for screening, the routine pretreatment blood test findings were retrospectively investigated in 359 patients with benign and malignant soft tissue tumors. Additionally, the prognostic potential of pretreatment blood abnormalities was evaluated in patients with soft tissue sarcomas. We compared clinical factors and blood tests findings between patients with benign and malignant soft tissue tumors using univariate and multivariate analysis. Subsequently, patients with malignant tumors were divided into two groups based on blood test reference values, and the prognostic significance of each parameter was evaluated. In the univariate analysis, age, tumor size, and tumor depth were significant clinical diagnostic factors. Significant increases in the granulocyte count, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and γ-glutamyl transpeptidase (γ-GTP) levels were found in patients with malignant soft tissue tumors. Multiple logistic regression showed that tumor size and ESR were independent factors that predicted malignant soft tissue tumors. The Kaplan-Meier survival analysis revealed that granulocyte counts, γ-GTP levels, and CRP levels correlated significantly with overall survival. Thus, pretreatment routine blood tests are useful diagnostic and prognostic markers for diagnosing soft tissue sarcoma.
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January 2018

Denosumab as a potential therapeutic option for leiomyosarcoma with osteoclast-like giant cells: A case report.

Mol Clin Oncol 2018 Jan 6;8(1):30-33. Epub 2017 Nov 6.

Department of Orthopedic Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Niigata 951-8510, Japan.

Bone leiomyosarcoma is a rare primary osseous malignant tumor with a high metastatic potential. Similar to other bone sarcomas, high histological grade and tumor stage are predictive of a poor outcome. We herein present our experience with treating a 64-year-old woman with bone leiomyosarcoma accompanied by multiple bone metastases. A biopsy revealed occasional osteoclast-like giant cells. In addition to radiation therapy, the osteoclastogenesis inhibitor denosumab was administered but the patient did not undergo adjuvant chemotherapy or surgery. Good clinical and short-term radiological responses to denosumab have been observed for 2 years. Therefore, denosumab may represent a viable treatment option without the need for adjuvant chemotherapy.
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http://dx.doi.org/10.3892/mco.2017.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769267PMC
January 2018

Acid-Mediated Migration of Bromide in an Antiaromatic Porphyrinoid: Preparation of Two Regioisomeric Ni(II) Bromonorcorroles.

J Org Chem 2017 10 21;82(19):10425-10432. Epub 2017 Sep 21.

Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.

The regioselective halogenation of porphyrinoids is critical for their selective functionalization, which enables the fine tuning of their electronic and optical properties. Here we report the synthesis of two regioisomeric Ni(II) bromonorcorroles on the basis of the acid-induced migration of the bromo substituent. Treatment of Ni(II) dimesitylnorcorrole with N-bromosuccinimide (NBS) selectively afforded Ni(II) 3-bromonorcorrole, which was further converted into Ni(II) 2-bromonorcorrole upon treatment with hydrogen bromide. In addition, the reaction of Ni(II) dimesitylnorcorrole with an excess amount of NBS afforded the octabrominated product. The reaction mechanism of the bromination reaction of Ni(II) dimesitylnorcorrole was investigated by theoretical calculations.
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http://dx.doi.org/10.1021/acs.joc.7b01899DOI Listing
October 2017