Difficulties Nurses Report in Caring for Patients with Bone Metastases and Their Expectations after Participating in a Bone Metastasis Cancer Board: A Questionnaire Study.

BACKGROUND: Patients with bone metastases often face physical, mental, and social challenges that require multidisciplinary management. To improve treatment and practice, we conducted a questionnaire survey to assess nurses' opinions of problems related to caring for patients with bone metastases. In addition, we investigated nurses' perceptions of bone metastases after participating in a Bone Metastasis Cancer Board (BMCB). METHODS: An anonymous questionnaire survey on problems in bone metastasis treatment and the BMCB was conducted. The respondents were nurses with more than 1 year of clinical experience working in wards where patients with bone metastases were admitted. RESULTS: The number of valid responses was 224. Almost all the nurses felt anxiety about the risk of pathological fracture and paralysis while caring for patients with bone metastases. To reduce this anxiety, about 90% of the nurses supported the suggestion that "patients should be referred to an orthopedic surgeon in advance to obtain opinions on load restrictions". Nurses who had participated in the BMCB had higher expectations regarding treatment, multidisciplinary collaboration, and sharing and accumulating knowledge and experience. CONCLUSION: To improve treatment and nursing care for patients with bone metastases, it is important to make regular BMCB meetings more functional and to actively consult with specialists.

Risk of Pathological Fracture and Paralysis during Rehabilitation for Patients with Bone Metastases: A Questionnaire-Based Study.

BACKGROUND: Bone metastases can cause severe pain, pathological fractures, and spinal cord paralysis, which interrupt treatment for tumors and cause patients to be bedridden. In this study, we aimed to clarify therapists' problems in the rehabilitation of patients with bone metastases and their countermeasures using the results of questionnaires to therapists and recommend safer and more rational rehabilitation. METHODS: Questionnaire forms were sent to 21 therapists in our department. The questionnaire was conducted anonymously about problems during the rehabilitation procedure such as the risk of pathological fractures and paralysis. RESULTS: All of the therapists had strong anxiety (43%) or some anxiety (57%) about the risk of pathological fractures or paralysis during a procedure. However, no therapist responded that this had ever occurred. Many of the respondents had changed a procedure to a milder one (81%) or interrupted a procedure (48%) due to the patient's condition on the day. Therapists chose many options to reduce the risk of pathological fractures and paralysis during the procedure. Among them, "pre-rehabilitation referral to orthopedic surgeon" (86%), "consultation with a doctor about changes in patient's symptoms and findings" (86%), and "regular cooperation between multiple occupations" (67%) were frequently selected. CONCLUSIONS: Our questionnaire survey of therapists regarding the treatment of patients with bone metastases found that there was considerable anxiety about the risk of pathological fractures and paralysis during treatment. Our findings suggest that it is necessary to strengthen cooperation with multiple occupations, especially those in the orthopedic field.

Solitary Chondrosarcoma of the Right Ring Finger: A Case Report.

We present a case of solitary chondrosarcoma arising from the proximal phalanx of the ring finger in an elderly man. The chondrosarcoma developed over a period of 14 years, during which the phalanx became progressively more deformed. Several radiographic investigations were carried out, but the patient declined further suggested diagnostic examinations (computed tomography, magnetic resonance imaging, biopsy). Eventually, the lesion became significantly enlarged, and radiographs showed osteolytic lesions in the phalangeal bone. Ray amputation of the finger was required to establish a wide resection of the chondrosarcoma. Most osteochondral tumors arising from the phalanges are benign tumors such as enchondromas, but primary chondrogenic malignant bone tumors (chondrosarcomas) occasionally occur. Chondrosarcoma of the phalanx is difficult to distinguish from enchondroma of the phalanx, because histological investigations of the two neoplasms often produce similar findings. Even with a combination of clinical, biopsy, and imaging findings, differentiating these neoplasms is still challenging, because the characteristic clinical and radiological features of chondrosarcoma do not appear until it becomes aggressive and starts to cause destructive changes. Once that happens, radical expanded resection of the tumor is essential. Therefore, longstanding enchondroma-like lesions should be actively treated in elderly patients, even if a definite diagnosis of chondrosarcoma cannot be made.

Malignant granular cell tumors: Combining cytological and pathological findings for a definitive diagnosis.

Malignant granular cell tumors (GCTs) account for less than 2% of all GCTs and mainly occur in the deep soft tissue of the thigh or trunk. Malignant GCTs are highly aggressive tumors with high rates of recurrence and metastasis. In this brief report, we describe a rare case of malignant GCT in a 64-year-old Japanese man who presented with a 14 × 20 cm mass in the left inguinal region. The cytologic findings of fine-needle aspiration (FNA) revealed atypical epithelial-like granular cells with granular substance in the background, which was difficult to differentiate from apocrine carcinoma or melanoma. The immunohistochemistry (IHC) findings of the needle biopsy revealed that the tumor cells were positive for S-100 and lysosomal marker CD68 which was suggestive of a GCT. However, the presence of crush artifacts made it challenging to identify cellular atypia, which is a characteristic of malignant tumor. Taken together, the FNA and needle biopsy results were suggestive of malignant GCT. The importance of preoperative diagnosis of malignant GCT is well known, but few reports have described its cytological findings. In our brief report, we show that combining cytological FNA and biopsy findings with IHC findings achieves an accurate diagnosis of malignant GCT.

Spinal Metastases without Pedicle Signs on Radiograph and their Associated Clinical and Radiological Features.

BACKGROUND: The pedicle sign is a radiographic indicator of spinal metastases. However, it is not only the pedicle sign that is important in radiographic diagnosis of bone metastases. In the present study, the radiological features of symptomatic spinal metastases in patients without the pedicle sign were retrospectively examined. MATERIALS AND METHODS: Among 186 patients with symptomatic spinal metastases who visited our department between January 1, 2011, and December 31, 2017, 64 without the pedicle sign and with available computed tomography (CT) and magnetic resonance imaging (MRI) data in the first visit were enrolled and their data were analyzed. One author evaluated radiographs for findings suggestive of spinal metastases, CT to assess bone destruction, and MRI to evaluate the extent of lesions. Clinical variables were also examined and compared between patients with and without bone changes on radiography. RESULTS: Bone changes strongly suggesting bone metastasis, other than the pedicle sign, were observed in 31 out of 64 patients: bone cortical disappearance in 20, increased radiolucency of the central area in the vertebral body in 8, an irregular osteoblastic change in 5, and asymmetrical vertebral collapse in 10. An analysis of CT data revealed that intertrabecular, mildly osteolytic, and mildly osteoblastic types were more frequent in patients without any changes suggestive of bone metastases on radiographs. CONCLUSION: Radiographic findings other than the pedicle sign are useful for diagnosing bone metastases. The key to a radiographic diagnosis of spinal metastases is to pay attention to changes in the bone cortex of all vertebral components on radiographs in addition to the pedicle.

Marginal resection for patients with atypical lipomatous tumours of the extremities and trunk wall: a systematic review and meta-analysis.

BACKGROUND: This systematic review assessed and compared the efficacy of marginal resection to wide resection in patients with atypical lipomatous tumours (ALT) by evaluating the local recurrence rates, overall survival and adverse event rates. METHODS: We evaluated studies published between 1 January 1990 and 31 January 2019. The risks of bias in the selected studies were analyzed using the Cochrane Collaboration Risk of Bias Tool. The quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: Three case-control studies and three case series studies were identified. A meta-analysis was performed of six studies to evaluate the local recurrence rate after resection. Comparison of marginal and wide resections showed that the local recurrence rate was not significantly higher in the marginal resection group (14.2 and 1.4%, odds ratio: 2.88, 95% confidence interval 0.99-8.33, P = 0.05). We observed no difference in overall survival. In one study, the rates of adverse events were 14.7% in the marginal resection group and 45.4% in the wide treatment group (odds ratio, 0.32; 95% confidence interval 0.11-80.91, P < 0.05). CONCLUSIONS: In our analyses, five of six studies reported no recurrence for wide resection, compared to three to seven recurrences in the marginal resection group. One study reported only one case of recurrence for wide resection. Because ALT has a relatively good prognosis, the use of marginal resection is acceptable to preserve musculoskeletal function.

Association of Magnetic Resonance Imaging Features with Angioleiomyoma Histologic Subtype.

BACKGROUND: Angioleiomyomas typically present as small, painful, soft-tissue tumors less than 2 cm in diameter. The features of angioleiomyomas on magnetic resonance (MR) imaging are not well understood, and the association of MR findings with histologic subtype is unclear. In the present study, the MR features of angioleiomyomas of average size were compared in relation to histologic subtype. METHODS: This retrospective review of medical records analyzed MR imaging data and histologic specimens from 18 consecutive patients with angioleiomyomas that were resected at our hospital during the period from January 2006 through December 2013. RESULTS: On T1-weighted images, lesions exhibited homogeneous areas that were isointense with skeletal muscle. However, T2-weighted images of solid and venous angioleiomyomas showed heterogeneous areas that were isointense or slightly hyperintense, while cavernous angioleiomyomas exhibited hyperintensity. Most lesions had a hypointense rim, and two thirds had adjacent vessels. CONCLUSIONS: Our results suggest that MR findings for angioleiomyoma vary in relation to histologic subtype. T2-weighted images of solid and venous angioleiomyomas yielded specific MR findings that allowed for differentiation from other soft-tissue tumors, such as soft-tissue sarcomas. Most of these tumors exhibited isointense to slightly hyperintense regions, as compared with skeletal muscle, while findings for cavernous angioleiomyomas were nonspecific. Thus, clinical findings and MR imaging were almost sufficient for preoperative diagnosis of solid and venous angioleiomyomas.

Association of Pedicle Sign Type with Clinical and Radiological Features in Patients with Symptomatic Spinal Metastases.

BACKGROUND: Because of population aging in Japan, the number of cancer diagnoses is increasing rapidly. The pedicle sign is a valuable radiographic indicator of metastases, as the pedicle is the most commonly affected vertebral structure in radiographic assessment. However, few studies have carefully examined the morphological features of pedicle signs. To improve the capacity of medical professionals to diagnose symptomatic spinal metastases, we retrospectively examined the morphological characteristics of pedicle signs and their associations with clinical and radiological features. METHODS: 186 patients with symptomatic spinal metastases who visited our department during the period from January 1, 2011 through December 31, 2017 were enrolled. The pedicle sign was defined as a missing or obscured pedicle on an anteroposterior radiograph. Radiographs were evaluated for pedicles and other vertebrae structures. Clinical and other radiological features were compared in relation to the type of pedicle sign identified. RESULTS: Pedicle signs were classified as completely disappeared (complete, 26 patients), partially disappeared (partial, 40 patients), or obscured by the osteoblastic background (blastic, 28 patients). Disappearance of both the bone cortex and pedicle was observed in almost half of the patients with complete or partial pedicle signs. The complete pedicle sign was associated with significantly longer survival. CONCLUSION: Diagnosis of bone metastases requires understanding of pedicle sign types.

Optimal Treatment for Tenosynovial Giant Cell Tumor of the Hand.

This review examines the following aspects of tenosynovial giant cell tumors (TSGCTs): the use of multiple names, the complex relationship between tumor growth pattern and location, the high rate of postoperative recurrence, local invasiveness, use of nonsurgical therapy with molecularly targeted drugs, and best current treatments. This tumor has been referred to by various names, but is now most frequently referred to as TSGCT. TSGCT is classified as localized and diffuse, in accordance with its growth characteristics. Most TSGCTs of the fingers are localized. TSGCT is likely a neoplastic process arising from synovial lining cells, in which tumor cells express the colony stimulating factor 1 (CSF1) gene. The postoperative recurrence rate of TSGCT is approximately 15%. The intrinsic characteristics of recurrence are not clear, and complete resection of the lesion is still the treatment mainstay. Moreover, TSGCT commonly grows out of a pseudocapsule. Therefore, to perform complete resection of TSGCT, surgery must be performed cautiously after appropriate preparation, by using anesthesia, a tourniquet, surgical loupe, and surgical microscopy. After accurate preoperative diagnosis, meticulous planning by surgeons is necessary. The lesion should be resected along with approximately 1-mm of healthy tissue at the adhesion site. In addition, because satellite lesions might be present near the tumor, careful dissection and observation of the color of surrounding tissue are important. International clinical trials of CSF1 receptor inhibitors for TSGCT treatment are ongoing.

Combined Use of Magnetic Resonance Imaging and Fine-Needle Aspiration Cytology for Diagnosis of Soft-Tissue Tumors.

BACKGROUND: Magnetic resonance imaging (MRI) and fine-needle aspiration cytology (FNAC) are useful in the diagnosis of soft-tissue tumors and can be performed on outpatients. These modalities are complementary: MRI examines a large area, while FNAC assesses a highly specific region; MRI displays only signal intensities, while FNAC visualizes actual tumor cells. We investigated the combined use of these methods for differentiating malignant and benign tumors. METHODS: 148 patients (153 lesions: 137 benign, 16 malignant) underwent preoperative MRI and FNAC. A diagnosis was judged to be correct if one or both diagnoses were correct, incorrect if at least one diagnosis was incorrect, and indeterminate if both diagnoses were indeterminate or if MRI was indeterminate and the FNAC sample was insufficient. RESULTS: The diagnostic yields for MRI only, FNAC only, and their combination were 81.7%, 84.3%, and 92.2%, respectively, indicating that the diagnostic performance of MRI and FNAC was significantly improved when the methods were combined. CONCLUSIONS: As compared with either modality used alone, combined preoperative use of MRI and FNAC improved diagnosis of soft-tissue tumors.

Effect of Orthopedics Promotional Activities on Multidisciplinary Management of Patients with Bone Metastases.

BACKGROUND: The rapid aging of the Japanese population is leading to an increase in the number of patients with bone metastases. Since 2014, our orthopedics department has promoted multidisciplinary hospital activities, including offering lectures to hospital staff on multidisciplinary approaches for bone metastases and holding regular cancer board meetings on bone metastases. This study investigated whether these activities were effective in promoting multidisciplinary approaches and improving outcomes of patients with bone metastasis. METHODS: To investigate the effects of changes in medical practice on patients with bone metastases, we compared patient clinical characteristics after (January 2014 through December 2017) and before the start of the activities (January 2011 through December 2013). RESULTS: The semiannual numbers of first-visit, referral, and orthopedic surgical patients, the number of patients with slower growing primary cancers, and the number of patients with milder pain were significantly higher post-activity than pre-activity. The number of patients without paralysis was higher after the start of the activity than before the activity, but the difference was not significant. Survival after the first visit to the orthopedics department was significantly longer after the start of the activity than before the activity. CONCLUSIONS: The potential demand for a multidisciplinary approach to bone metastases is high, and orthopedic specialists should actively participate in this approach.

Natural Progression and Factors Predicting Growth of Retroperitoneal Schwannoma.

BACKGROUND: Although knowledge of the natural history of retroperitoneal schwannoma, including growth rate, would be useful when determining the indications and timing of surgical treatment for such nonpalpable tumors, the existing evidence is unclear. We examined the natural history of retroperitoneal schwannoma and assessed whether magnetic resonance imaging (MRI) and clinical findings predict future growth. METHODS: Among patients with retroperitoneal schwannoma treated in our department during the period from January 1, 2015 through December 31, 2015, eight who underwent follow-up assessment by MRI and did not undergo tumor resection for longer than 1 year were enrolled. Changes in lesion size were examined in relation to selected clinical and MRI findings. In cases of pressure erosion in the vertebral body, change in the size of the intraosseous region was compared to change in the size of the whole lesion. RESULTS: Median absolute growth rate (AGR) was 1.9 cm3 per year, median relative growth rate (RGR) was 5.6% per year, and median tumor volume doubling time (VDT) was 3.1 years. AGR, RGR, and VDT were not associated with any clinical variable. RGR and VDT values in the intraosseous region were about twice those of the whole lesions. CONCLUSIONS: The growth rates of retroperitoneal schwannomas varied. Additionally, no MRI or clinical findings predicted growth of retroperitoneal schwannoma. Therefore, careful follow-up is necessary for this tumor type, especially for lesions with bone erosion.

Symptoms Related to Moderate Skeletal-Related Events as Clues for the Diagnosis of Bone Metastasis.

BACKGROUND: Early diagnosis of bone metastasis is difficult. The aim of the present study was to determine whether symptoms related to skeletal-related events (SREs) can be used for the diagnosis of bone metastasis in the absence of screening tests. METHODS: We reviewed 81 patients with bone metastasis to evaluate their SREs at diagnosis. SREs were arbitrarily classified as moderate or severe. Moderate SREs included radiation to the bone before pathological fracture or paralysis, bone surgery before pathological fracture or paralysis, and hypercalcemia without dialysis. Severe SREs included pathological fracture, spinal cord compression, and hypercalcemia necessitating dialysis. RESULTS: The complication rates of SREs at the time the bone metastasis was diagnosed were 59.3% and 24.7% for severe and moderate SREs, respectively, and only 16.0% of cases were uncomplicated. The clinical factors that showed a significant relationship with the severity of SREs were age and history of malignancy. However, there was no significant relationship between the complication rate of total SREs and the presence or absence of a malignancy history (83.3% vs. 85.2%, respectively, p=0.83). CONCLUSION: The results of the present study suggest that symptoms related to SREs can be used to diagnose bone metastasis in the absence of a screening test. Bone metastasis should be diagnosed as often as possible based on symptoms related to moderate SREs and should be treated as soon as possible before patients develop severe SREs.

Development and Verification of Educational Material for Plain Radiographic Diagnosis of Bone Metastasis: A Preliminary Report.

Our previous studies showed that early diagnosis of painful bone metastasis is difficult and requires improvement in the diagnostic accuracy of plain radiography during an initial patient consultation. In this preliminary study, we evaluate the usefulness of educational material used to improve diagnosis of bone metastasis with plain radiography. This study included imaging data from 129 consecutive patients who visited our orthopedic clinic during the period January 2011 through December 2014. First, we prepared a test to measure the reading ability of orthopedic practitioners, after which the educational material was created. Then, the effectiveness of the educational material was verified by having orthopedic trainees take a pre-test and post-test. The test contained plain radiographic data from 12 patients with lesions and 6 without lesions. The educational material included plain radiographic data from 30 patients with typical findings of bone metastasis, as well as diagnostic magnetic resonance images or computed tomography scans, accompanied by a lecture. The accuracy and sensitivity of diagnosis significantly improved after the lecture; however, specificity decreased. Although the educational material was effective for improving the ability of orthopedic trainees to read plain radiographs of bone metastasis, some aspects of the program need to be improved and revised.

Diagnosis of Bone Metastasis in Patients Without a History of Cancer.

BACKGROUND: Diagnosing bone metastasis in patients without a history of cancer remains challenging. Diagnostic evaluation may be prolonged owing to difficulties in distinguishing between bone metastasis and common orthopedic diseases. We hypothesized that bone metastasis due to occult cancer would be more difficult to diagnose than bone metastasis in patients with a history of cancer. Few studies exist on the difficulty of diagnosing bone metastasis in patients without a history of cancer. Therefore, we reviewed the clinical course of patients with bone metastasis between January 2011 and December 2014. METHODS: We reviewed patients with bone metastasis to determine the diagnostic rate at first visit, period from symptom-onset to first visit, period from first visit to diagnosis, and presence of severe skeletal-related events at diagnosis, and compared these between 27 patients without a history of cancer (Group A) and 54 patients with a history of cancer (Group B). RESULTS: The diagnostic rate at first visit was significantly lower (11.5% vs. 52.4%, p=0.00069), the period from first visit to diagnosis was significantly longer (median, 7 weeks vs. 3 weeks, p=0.018), and the presence of severe skeletal-related events at diagnosis was significantly higher (81.4% vs. 50.0%, p=0.05) in patients without a history of cancer compared with those with a history of cancer. CONCLUSIONS: The results of this study indicate that it is difficult to diagnose bone metastasis in patients without a history of cancer. This must be considered in the early diagnosis of bone metastasis to prevent severe skeletal-related events.

Diagnostic Value of Plain Radiography for Symptomatic Bone Metastasis at the First Visit.

BACKGROUND: To prevent and minimize skeletal-related diseases, early diagnosis of bone metastases is important. However, previous reports have shown that plain radiography has low sensitivity and fails to screen multiple asymptomatic lesions. Limited investigations have been reported on the value of plain radiography in the diagnosis of symptomatic bone metastases. Therefore, this study aimed to investigate the diagnostic utility of plain radiography for symptomatic bone metastasis. METHODS: Two experienced orthopedic surgeons retrospectively evaluated the plain radiographs of 39 patients with symptoms during their first visit between 2011 and 2014 for bone metastases. Another 2 experienced orthopedic surgeons then reviewed the data using 2 reference standards, the clinical results and the retrospectively evaluated results, in a blinded manner. The data were then reviewed by 2 certified orthopedic surgeons and 7 orthopedic surgeons in training with differing years of experience in a blinded manner. RESULTS: The overall sensitivity of diagnosis of symptomatic bone metastasis using plain radiography at the clinic first visit was 71.4%. Upon blinded evaluation, the accuracy, sensitivity, and specificity were 55.8%, 54.3%, and 68.8% and 77.6%, 73.0%, and 85.7% for clinical results and results from 2 experienced orthopedic surgeons as a reference standard, retrospectively. There was a strong and significant correlation between the accuracy and observers' years of experience in orthopedic surgery among the orthopedic surgeons in training (R=0.942, p=0.0015). CONCLUSIONS: Plain radiography around the time of the first visit has a definitive role in the early diagnosis of symptomatic bone metastasis.

Challenges in the Diagnosis of bone Metastasis in Patients without a History of Malignancy at Their First Clinic Visit.

BACKGROUND: Many patients with bone metastases whose diagnoses came only after they had suffered aggravated conditions are still frequently encountered. However, there have been few studies regarding the early diagnosis of such metastases. We retrospectively reviewed the clinical courses of cases we experienced between 2004 and 2014 to clarify the practical situation of diagnosis of such bone metastases. METHODS: We undertook a retrospective review of 56 of our patients with bone metastasis who had no history of malignancy at their first visit, who visited our departments between 2004 and 2014. The initial diagnoses at the first visit to any clinic, the period from the first visit to any clinic to diagnosis of bone metastasis, the process to make the diagnosis, the frequency of severe skeletal-related events at diagnosis, and the examination serving as the basis for diagnosis were evaluated. RESULTS: The diagnosis of bone metastasis was made at the first visit in only 6 of the 56 patients. Pathological fractures, paralysis and/or calcemia were seen in 62.5% of the patients at diagnosis of bone metastasis. The median period from the first visit to any clinic to diagnosis was 7.0 weeks. Typically, the diagnosis of bone metastasis was made only after aggravation. The most frequent examination to serve as the basis of diagnosis was magnetic resonance imaging. CONCLUSIONS: Diagnosis of bone metastasis is challenging in patients without a history of malignancy at their first visit. For early diagnosis, it is important to recognize this challenge and to keep it in mind together with ongoing observation.

Subcutaneous angiolipoma: magnetic resonance imaging features with histological correlation.

PURPOSE: Despite producing pain, angiolipoma is sometimes misdiagnosed as an ordinary small lipoma, which is usually not associated with pain. Few reports have described magnetic resonance (MR) imaging findings of angiolipoma. The aim of the present study was to clarify the MR imaging features of angiolipoma. MATERIALS AND METHODS: The MR imaging findings of 11 lesions in 7 patients were reviewed and compared with histopathological findings. RESULTS: The MR imaging features of these lesions were the presence of fat nodules with or without areas of low signal intensity on T1- and T2-weighted images. The location of the low-signal-intensity areas varied. The low-signal-intensity areas were mainly in the peripheral portion of 3 lesions and in the central portion of 5 lesions. No or few low-signal-intensity areas were observed in 3 lesions. In the lesions with peripheral low-signal-intensity areas, lesion marginations were well defined, and the lesions were easily recognized as mass lesions. In the lesions with only central low-signal-intensity areas, marginations were poorly defined, and the lesions were not easy to recognize as mass lesions. In the lesions with few or without low-signal-intensity areas, marginations were invisible. Histopathological studies indicated that the low-signal-intensity areas on T1- and T2-weighted images corresponded to areas of dense capillary proliferation. In lesions with few or without low-signal-intensity areas on MR images, capillaries were thinly spread over almost the entire lesion area. CONCLUSION: The MR imaging features of angiolipoma are fat nodules with or without low-signal-intensity areas of various size and location on T1- and T2-weighted images.

Synthesis of 3',4'-difluoro-3'-deoxyribonucleosides and its evaluation of the biological activities: discovery of a novel type of anti-HCV agent 3',4'-difluorocordycepin.

Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF(2)/BF3 · OEt(2), the respective novel 3',4'-difluoro-3'-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the ß-face adducts as sole stereoisomers whereas α-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3'-deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity.

Primary structure and characterization of a non hemorrhagic metalloproteinase with fibrinolytic activity, from the snake venom of Protobothrops tokarensis (Tokara-habu).

A low molecular weight metalloproteinase, named PT-H2 protease, with fibrinolytic activity, was purified from the venom of Protobothrops tokarensis (Tokara-habu) by gel-filtration using Sephadex G-100, and ion-exchange chromatographies using CM-Sepharose Fast Flow and Mono S HR 5/5. By this procedure, about 85 mg of purified protein were obtained from 1.0 g of P. tokarensis venom. The purified protein showed a single protein band with a molecular weight of about 22.5 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. The pI of purified protein showed a single band of 6.8. This proteinase showed a strong fibrinolytic activity. Further, this proteinase showed fibrinogenase activity and proteolytic activity against synthetic substrates for matrix metalloproteinase, ADAM-17, and TACE (tumor necrosis factor converting enzyme). These proteolytic activities were inhibited by metalloproteinase inhibitors such as EDTA. PT-H2 protease consisted of 201 amino acid residues and had a calculated molecular weight of 22,994.7 Da. This protein showed conservation of the Zn²âº-binding HEXXHXXGXXHD sequence. PT-H2 protease showed high homology from 51.7 to 99.5% with amino acid sequences of other snake venom metalloproteinases.