[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

Impact of Zoledronic Acid and Denosumab Treatment on Growth Factor Concentration in Platelet Rich Fibrin of Patients With Osteolytic Bone Metastases.

BACKGROUND/AIM: Side effects of zolendronic acid (ZA) and RANKL inhibitors (RANKL-I) include impaired wound healing and osteonecrosis of the jaw. Platelet rich fibrin (PRF) enhances wound healing and bone remodelling in vivo and in vitro. However, the topical use PRF in the surgical treatment of patients with medicament-related osteonecrosis of the jaw is relatively new and not thoroughly investigated. Furthermore, the potential attenuation of the PRF effect following antiresorptive treatment remains unclear. Therefore, we investigated the concentration of growth factors within the PRF in healthy volunteers and in patients with antiresorptive treatment. PATIENTS AND METHODS: Blood samples from healthy volunteers and patients were used to produce PRF. The levels of EGF, VEGF, PDGF-BB, TGF-ß1, BMP-2, and CD31 in the PRF was investigated by ELISA. RESULTS: ZA treatment induced a significant decrease in EGF and TGF-ß1 levels, whereas RANKL-I caused lower TGF-ß1 levels. CONCLUSION: Reduced EGF levels in PRF after ZA treatment may explain the delayed wound healing and question the positive effect of PRF in these patients. PRF use in patients undergoing RANKL-I treatment seems to be more justified.

The antitumor effect of liposome-encapsulated cisplatin on rat osteosarcoma and its enhancement by caffeine.

BACKGROUND: Drug delivery systems are for the purpose of targeting a drug to a specific tissue selectively and at the same time preventing a drug from accumulating in healthy organs. Liposomes have been proposed as useful drug carriers in targeted drug delivery system and are under investigation in several therapeutic fields. Caffeine has been identified as belonging to the group of xanthines that enhances the action of cisplatin. MATERIALS AND METHODS: In this study, liposomes containing polyethylene glycol encapsulated cisplatin (CDDP-L) were prepared. The action of CDDP-L on rat osteosarcoma and the enhancing action of caffeine on the antitumor effect of CDDP-L were evaluated. Using osteosarcoma-bearing rats, the retention of CDDP-L in the blood, its intratumor concentration, cytoreductive effect and the enhancing action of caffeine on its antitumor effect were examined. RESULTS: The liposomes were able to remain in the systemic circulation for a long time and to be concentrated in the osteosarcoma, but that action did not produce an effect corresponding to the quantity of cisplatin which was encapsulated reaching the tumor. In rats administered CDDP-L, it was discovered that the antitumor effect was not only enhanced by the coadministration of caffeine but also further enhanced when the dosing period of caffeine was increased. CONCLUSION: CDDP-L combined with caffeine treatment can produce better results for osteosarcoma.

[A case of osteonecrosis of the lower jaw due to bisphosphonates in a breast cancer patient with bone metastasis].

Recently, osteonecrosis of the jaw (ONJ) with bisphosphonates is frequently reported. ONJ due to bisphosphonate is an adverse event in the treatment of breast cancer with bone metastasis. We report a case of ONJ due to bisphosphonates. A 66-year-old woman was admitted to our hospital due to right advanced breast cancer with bone metastasis. She received neo-adjuvant chemotherapy consisting of paclitaxel 70 mg/m2, qw, trastuzumab 2 mg/m2, qw. After chemotherapy, we performed modified mastectomy for local control. Postoperative adjuvant chemotherapy was added with bisphosphonate for bone metastasis of breast cancer. After bisphosphonate was used 14 times, she had a pain and pus-discharge in her lower jaw. The dentists' diagnosis was ONJ. We treated her with antibiotics and local minor curettage. The inflammatory symptoms almost disappeared. In this case, the administration of bisphosphonates was thought to be a major risk factor for ONJ. We think that special precautions for ONJ should be taken in patients administered bisphosphonates for bone metastasis of breast cancer.

Circulating Candidate Biomarkers in Giant Cell Tumors of Bone.

PURPOSE: Approximately 5% of giant cell tumors (GCT) of bone develop pulmonary metastases. Although many biomarkers have been proposed, identification of circulating low abundance molecules may be useful to predict malignant progression. EXPERIMENTAL DESIGN: The hydrogel nanoparticle technique followed by MS was used to detect low molecular weight serum proteins or protein fragments in serum of 20 GCT patients with different clinical course and in ten healthy sera used as control. The most representative low-abundant de novo or differentially abundant proteins were submitted to String database that recognized interconnected activated pathways including protein activation cascade, wound healing, cell-substrate adhesion, and response to stress. Statistics were performed for identification of candidate prognostic factors. RESULTS: Proteome cluster analysis separated metastasis-free from metastatic GCT patients in two well-defined groups where serum levels of signaling transduction mediators and regulators of kinase activity presented a high discriminatory power. Increased expression of proteins STAT5B, GRB2, and OXSR1 was related to a higher probability of metastasis. Multivariate analysis demonstrated that tumor grade and STAT5B were independent prognostic factors. CONCLUSIONS AND CLINICAL RELEVANCE: By using a noninvasive technique, we identified differentially abundant serum candidate biomarkers, also providing prognostic information in patients with GCT of bone.

Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study.

INTRODUCTION: Neoadjuvant chemotherapy has become the treatment of choice for locally advanced breast cancer. Zoledronic acid (ZA) is a bisphosphonate initially used in the treatment of bone metastases because of its antibone resorption effect. Antitumor effects of ZA, including the inhibition of cell adhesion to mineralized bone or the antiangiogenic effect, have been demonstrated. However, the clinical significance of these effects remains to be determined. MATERIALS AND METHODS: We undertook a multicenter open-label randomized trial to analyze the value of adding ZA to neoadjuvant chemotherapy for TNM clinical stage T2/T3 breast cancer. The primary endpoint was the evolution of serum VEGF. RESULTS: The data from 24 patients were included in the ZA group and 26 in the control group. The evolution of serum VEGF was slightly in favor of ZA at 5.5 months (-0.7% vs. +7.5%), without reaching statistical significance (P = .52). The secondary endpoints were the breast conservation rate (higher with ZA; 83.3% vs. 65.4%; P = NS), pathologic complete response (no effect), and circulating tumor cells (odds ratio, 0.68 in favor of ZA; 95% confidence interval, 0.02-24.36). No cases of jaw necrosis or severe renal failure were observed in either group. CONCLUSION: ZA is an antitumor drug of interest because of its multiple effects on tumor biology. Larger trials with longer follow-up that include additional endpoints such as relapse and survival rates would be of interest.

Apparent interaction of dimethyl sulfoxide with cisplatin released from polymer delivery devices injected subcutaneously in dogs.

Local tissue toxicity, systemic toxicity and platinum pharmacokinetics were evaluated in 6 normal healthy beagle dogs injected subcutaneously with two formulations of a polylactide biodegradable polymer (Atrigel) system containing cisplatin. Dogs were injected 4 times at 30 day intervals at platinum dosages of 70, 105 and 157.5 mg/m2 (dose escalation). Once pharmacokinetics were established, 29 dogs with spontaneous stage IIb appendicular osteosarcoma were treated with 4 injections of the same polymer system containing cisplatin at 70 mg/m2 (20 dogs) and 100 mg/m2 (9 dogs) to establish efficacy against micrometastatic disease. Local tissue toxicity was variable. Systemic toxicity, as judged by clinicopathologic evaluation was not noted at any dose level or injection number. Interim (6 month) survival analysis revealed a median disease-free interval of 180 days. Consistent platinum release characteristics were found, however, the lack of toxicity and decreased disease-free-interval raised concerns over the biologic activity of the cisplatin. Prior to completion of the study, it was discovered that dimethyl sulfoxide, the solvent used in the co-polymer system, may be responsible for biologic inactivation of cisplatin. This was subsequently demonstrated in tissue culture assays. The clinical trial was suspended and dogs were treated with traditional chemotherapy.

Two cases of multiple ossifying fibromas in the jaws.

BACKGROUND: The clinicopathologic characteristics of multiple ossifying fibroma (OF) are unclear due to the condition's rarity, making diagnosis challenging. Sporadic multiple OFs must be distinguished from hyperparathyroidism-jaw tumour syndrome (HPT-JT) related OF and other fibro-osseous lesions. METHODS: Multiple OF cases were identified from ossifying fibroma cases. Clinical data including age, sex, anatomic site, radiographic features, clinical impression, treatment and available follow-up data as well as serum calcium, phosphorus, and parathyroid hormone (PTH) were recorded. GNAS and HRPT2 genetic mutations were examined in the two present cases. Case reports of sporadic multiple ossifying fibroma and HPT-JT-related OF were also reviewed. RESULTS: The two present cases were confirmed as sporadic multiple OF, with no genetic GNAS and HRPT2 mutations found. The incidence of sporadic multiple ossifying fibroma was 2.0% (2/102). The total 18 sporadic multiform OF cases were characterized as followed: 13 (72.2%) female; 5 (27.8%) male; mean age 28.6 years; 2/16 (11.1%) cases only in the mandible; 4/18 (22.2%) cases only in the maxilla; and 12/18 (66.7%) cases in both the maxilla and mandible. Radiographically, the lesions were radiolucent in 5/18 (27.8%) cases and mixed density in 13/18 (72.2%) cases. Along with 24 cases of HPT-JT related OF were reviewed, sixteen (66.7%) patients were diagnosed with a single lesion, and 8 patients (33.3%) were diagnosed with multiple jaw lesions. CONCLUSIONS: Sporadic multiple OFs are very rare, but must be distinguished from HPT-JT related OF. We strongly recommend that patients diagnosed with multiple ossifying fibromas receive serum PTH testing and mutation screening of HRPT2. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/1194507146115753.

Biodistribution of antisense nanoparticles in mammary carcinoma rat model.

Efficient and specific delivery of antisenses (ASs) and protection of the sequences from degradation are critical factors for effective therapy. Sustained release nanoparticles (NP) offer increased resistance to nuclease degradation, increased amounts of AS uptake, and the possibility of control in dosing and sustained duration of AS administration. The biodegradable and biocompatible poly(D,L-lactic-co-glycolic acid) copolymer (PLGA) was utilized to encapsulate AS directed against osteopontin (OPN), which is a promising therapeutic target in mammary carcinoma. Whole body biodistribution of OPN AS NP was evaluated in comparison to naked AS, in intact and mammary carcinoma metastasis model bearing rats. Naked and NP encapsulated AS exhibited different biodistribution profiles. AS NP, in contrast to naked AS, tended to accumulate mostly in the spleen, liver, and at the tumor inoculation site. Drug levels in intact organs were negligible. The elimination of naked AS was faster, due to rapid degradation of the unprotected sequence. It is concluded that AS NP protect the AS from degradation, provide efficient AS delivery to the tumor tissue, and minimize AS accumulation in intact organs due to the AS sustained release profile as well as the favorable NP physicochemical properties.

Methotrexate loaded acrylic cement in the management of skeletal metastases. Biomechanical, biological, and systemic effect.

Skeletal metastases occur commonly, and frequently are complicated by the development of an impending or pathologic fracture. In the majority of instances, these patients are best treated by internal stabilization, frequently supplemented by methylmethacrylate, to relieve pain and maintain the patient's mobility. The underlying tumor may continue to grow, and if this occurs the progressive lysis may result in loosening and subsequent failure of the implant. To prevent additional local growth, postoperative radiotherapy is recommended, and many patients also receive endocrine or chemotherapy, but the adjuvant therapy is not always successful in preventing progressive local tumor induced osteolysis. It is possible that the addition of chemotherapeutic agents to the methylmethacrylate may inhibit local growth. This study was performed to determine the biomechanical, biologic, and systemic effects of adding methotrexate to methylmethacrylate. The results show that the addition of methotrexate in as much as a concentration of 2 g methotrexate per 40 g cement did not significantly alter the biomechanical characteristics of the bone cement. The incorporated methotrexate was released continuously from the loaded bone cement, and in the amount and concentration used did not have any toxic effects on the host animal. The methotrexate did not appear to be affected by the heat of polymerization and had a significant systemic effect. There was a significant reduction in pulmonary metastases with methotrexate loaded cement as compared with unloaded cement, the effect being dependent on the concentration of methotrexate in the cement. The results of these studies indicate that methotrexate loaded cement may have an important role to play as part of the orthopaedic management of impending and pathologic fractures.

Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulin-like growth factor-1 serum levels.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies. STUDY PURPOSE: To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS. DESIGN/METHODS: A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily. RESULTS: There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% ( < 0.0001, n = 21) and 53% ( = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (DeltaAUC) for arginine-stimulated GH serum levels at week two was lower than baseline ( < 0.01). At weeks two and eight, GH peak values were lower than baseline ( < 0.0001 and = 0.002, respectively). CONCLUSIONS: A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.

Cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of metastatic prostate cancer. A Southwest Oncology Group study.

BACKGROUND: Hormone-refractory metastatic prostate cancer remains a therapeutic challenge. Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), a drug combination that is active in solid tumors, was evaluated using specific response criteria. METHODS: Fifty-two eligible patients with measurable (19), evaluable (29), or bone scan only (4) metastatic prostate cancer were treated with cyclophosphamide, 100 mg/m2 every day by mouth, methotrexate, 15 mg/m2 intravenously weekly, and 5-fluorouracil, 300 mg/m2 intravenously weekly. Treatment was given continuously unless interrupted by toxicity or disease progression. RESULTS: There were two partial responses (7%) among the evaluable patients. Six (32%) measurable patients and four (14%) evaluable patients had stable disease. Median time to progression was 3.2 months for measurable and 2.8 months for evaluable disease patients. Median survivals were 10.9 and 10.2 months, respectively. There was no difference between the two groups with regard to response rate or survival. Toxicity was acceptable and consisted primarily of myelosuppression. CONCLUSIONS: CMF is minimally active in hormone-refractory metastatic prostate cancer.