Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of the patients with advanced prostate carcinoma have painful skeletal metastases, which are responsible for significant skeletal morbidity and disability. Most of these metastases are osteosclerotic, but it has been shown that the abnormal osteoblastic bone formation within metastases is preceded by osteoclastic activation, which appears to be associated with bone pain. This provides the rationale for using bisphosphonates, which are powerful and selective inhibitors of osteoclastic bone resorption. Several bisphosphonates have been shown to be clinically useful for the treatment of several conditions characterized by abnormal osteoclastic bone resorption, including Paget's disease, primary hyperparathyroidism, myelomatosis, and skeletal metastases. Its efficacy in relieving pain in patients with skeletal metastases due to prostate carcinoma has been confirmed in a few studies. The bisphosphonate clodronate was extensively investigated in the study unit. When infused intravenously i.v. (300 mg/day) relief of bone pain become appreciable within 3 days, sometimes preceded by a transient pain flare. These clinical results are very consistent and the residual pain usually is of extraosseous origin. Thus, with regard to pain of strictly bone origin, unresponsive patients are quite rare. Oral administration also is effective, but due to its limited intestinal absorption the effective dose is on the order of 1600-3200 mg/day. These doses usually are well tolerated, but they may be a problem for severely ill patients. Furthermore, the efficacy of treatment becomes apparent only after a few days. Thus, oral clodronate usually is adopted as a continuation of an i.v. course. The duration of the i.v. therapy should be individualized, but usually the more prolonged the treatment the longer the duration of the effect. For practical reasons, clodronate is infused daily for 5 days (Monday-Friday) and the treatment course is repeated at the time of any significant recurrence. The oral continuation prevents or delays the recurrence of bone pain in most patients, but in some patients this therapy has to be integrated occasionally with i.v. infusion. The duration of the effect for the same bioavailable dose is somewhat related to the degree of malignancy of the primary tumor. In an uncontrolled study, the author also evaluated the effectiveness of alendronate given either i.v. or orally. A single infusion of 5 mg alendronate i.v. produces roughly the symptomatic effect of 5 i.v. infusions of 300 mg clodronate. Alendronate, 40 mg orally/day, was effective in reducing bone pain in 11 of 12 patients with bone metastases due to prostate carcinoma but who were not confined to bed. In some patients with prostate carcinoma and a diffuse metastatic invasion of the skeleton, there is indirect biochemical and histologic evidence of osteomalacia. This can be aggravated by bisphosphonate administration because of the transient striking prevalence of osteoblastic activity over bone resorption, which also occasionally causes the appearance of symptomatic hypocalcemia. Therefore, the use of large oral supplements of calcium is recommended, particularly at the start of therapy. It is conceivable that these calcium supplements also may be able to improve the final clinical outcome of the bisphosphonate therapy. In conclusion, administration of large doses of bisphosphonates is one of the most cost-effective palliation treatments for patients with prostate carcinoma with bone metastases, both as first-line therapy and in the long term. With appropriate doses, a large proportion of patients can be maintained free of bone pain until death. Studies of the ability of lower doses to prevent skeletal morbidity in patients without metastases or with asymptomatic bone lesions are warranted.
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PMID:Bisphosphonates in prostate carcinoma. 936 35

We encountered an unusual case of extramammary Paget's disease (EMPD) recurring on the skin of the lower abdomen and entire right leg two and a half years after simple vulvectomy for minimally invasive Paget's disease of the vulva. Histologic examination of the skin metastases demonstrated that the proliferation of Paget cells was confined to the dermis, most of them were located in lymphatic vascular spaces. This case confirms that minimally invasive Paget's disease of the vulva may sometimes be an aggressive disease. We consider that lymphatic metastases already existed in this patient at the time of initial surgery; thus, the recurrence of EMPD on extragenital skin sites may have been prevented if initial treatment would have included radical vulvectomy and bilateral groin lymph node dissection instead of simple vulvectomy without groin lymph node dissection.
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PMID:Extramammary Paget's disease recurring on the skin of the lower abdomen and entire right leg two and half years after simple vulvectomy for minimally invasive Paget's disease of the vulva. 948 78

Perianal Paget's disease is rare, and its relationship to an associated internal regional cancer has been ill defined. We analyzed the histologic and immunohistochemical features of perianal Paget's disease in 11 patients to determine the frequency and relationship of associated regional internal carcinoma and to gain insight into its histogenesis. Of five patients with documented rectal adenocarcinoma, it was discovered synchronously with the Paget's disease in four and, subsequently, in one. Paget's cells of signet ring type predominated in four cases. Intraepithelial glands with intraluminal dirty necrosis were present in four cases. The immunophenotype in four cases studied was cytokeratin (CK)7+/CK20+/gross cystic disease fluid protein- (GCDFP) in both the intraepithelial Paget's cells and the invasive rectal adenocarcinoma. Six patients did not have documented rectal carcinoma. The Paget's cells in four were CK7+/CK20-/GCDFP15+. Three of these had purely intraepithelial Paget's disease, and invasive or metastatic disease developed in none after wide local excision. Bilateral inguinal lymph node metastases developed in the fourth patient, and the patient died 8 months after diagnosis of Paget's disease. In two patients, the Paget's cells were CK7+/CK20+/GCDFP15-. Recurrent intraepithelial perianal Paget's disease developed in one patient at 7 months; the patient was alive without disease at 24 months, and the other patient had several intraepithelial recurrences of perianal Paget's disease, and, subsequently, a large perianal tumor of uncertain cell type developed at 108 months, which led to the patient's death. We conclude that there are two types of perianal Paget's disease. One type has endodermal differentiation with gastrointestinal-type glands containing intraluminal dirty necrosis, numerous signet ring cells, CK20 positivity, and GCDFP15 negativity. Such cases are especially likely to be associated with synchronous or metachronous rectal adenocarcinoma. The other type is a primary cutaneous intraepithelial neoplasm in which the Paget's cells display sweat gland differentiation, including GCDFP15 positivity; it generally lacks gastrointestinal-type glands, intraluminal dirty necrosis, and CK20 positivity. The CK7 is a sensitive, albeit nonspecific, marker for Paget's cells.
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PMID:Perianal Paget's disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. 950 Feb 17

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.
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PMID:Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. 950 93

We report a case of recurrent extramammary Paget's disease of the vulva, which clinically, grossly, and microscopically mimicked an invasive lesion. A 76-year-old woman presented with recent onset of vaginal bleeding, a nodular vulvar lesion, and left inguinal lymphadenopathy. Following a vulvar biopsy and endometrial curettage, the patient underwent a total hysterectomy and bilateral salpingo-oophorectomy with lymph node dissection and a modified radical vulvectomy with left inguinal node dissection. Papillary serous adenocarcinoma was found involving the uterus and one right common iliac lymph node. Sections through the vulvar nodule revealed a marked intraepithelial proliferation, which resulted in a complex epidermal hyperplasia with deep invaginations. Tangential sections of rete pegs filled with Paget's cells and surrounded by papillary dermis displaced into the deep reticular dermis mimicked invasive nests of tumor cells. The loose fibrous tissue of the displaced papillary dermis resembled a desmoplastic reaction. No true stromal invasion was present, and none of the inguinal lymph nodes were involved by Paget's cells. The Paget's disease did not resemble the uterine carcinoma by histopathologic and immunohistochemical study. Recognition of the intraepithelial nature of Paget's disease has important clinical implications, inasmuch as stromal invasion can be associated with metastatic disease.
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PMID:Pseudoinvasive, nodular extramammary Paget's disease of the vulva. 959 51

Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen bridge has been replaced by carbon and diverse carbon side chains have generated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatment and prevention of osteoporosis, Paget's disease, hypercalcemia caused by malignancy, tumor metastases in bone, and other bone ailments. Selective action on bone is based on the binding of the BP moiety to the bone mineral. The molecular mode of action of BPs, which may differ from compound to compound, is unknown. However, at the tissue level, all BPs inhibit bone destruction and lead to an increase in bone mineral density by decreasing bone resorption and bone turnover. At the cellular level, the ultimate target of BP action is the osteoclast, the bone resorbing cell. In vitro evidence shows BP inhibition of osteoclast formation, via action on osteoblasts, and there is in vitro and in vivo evidence for BP inhibition of osteoclast activity. There is in vivo and in vitro evidence for increased apoptosis. The relative contribution of these various effects on the therapeutic action of BPs remains to be established. At the molecular level, it is not known if BPs act on a single or multiple targets. Enzymes in the cholesterol biosynthesis pathway and protein tyrosine phosphatases were shown to be inhibited by BPs.
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PMID:Mechanisms of action of bisphosphonates. 959 60

Since bone markers may reflect different aspects of bone disorders and cell function, and osteolytic and osteoblastic activities may be individually or concomitantly altered, determination of more than one marker type is generally appropriate. Also, the individual markers of a particular type do not necessarily show parallelism. For example, in osteomalacia from vitamin D deficiency, bone-specific alkaline phosphatase may be grossly elevated because of enhanced osteoblastic activity, whereas the vitamin D dependent osteocalcin may be decreased. With the exception of measurement of the bone enzymes, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase, bone marker measurements require complex and expensive immunoassays. As a general rule, the simple enzyme measurements can precede other investigation in most bone disorder> Bone-specific alkaline phosphatase measurement alone is generally adequate for the investigation of osteomalacia, Paget's disease and hyperparathyroidism but should be combined with measurement of tartrate-resistant acid phosphatase in suspected metastatic disease, and in multiple myeloma. Determination of both enzymes together may also be of value in the investigation of osteoporosis but in this disorder added benefit may be obtained by the addition of other bone markers, particularly urine deoxypyridinoline and possibly serum collagen telopeptide.
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PMID:Biochemical markers of bone turnover. 974 51

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.
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PMID:The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. 987 May 69

A 65-year-old man was referred to our hospital with a complaint of a scrotal mass which he first noticed 8 months ago. The mass was resected saving genital organs. Pathological diagnosis was extramammary Paget's disease with severe dermal invasion and many nuclear mitoses. The tumor was 15 mm in diameter, and 18 mm in thickness. The bilateral inguinal lymph nodes were dissected and multiple metastases were revealed in the right specimen. Since paraaortic lymph node metastases were detected later 5 cycles of chemotherapy consisting of cyclophosphamide, adriamycin and cisplatin (CAP) followed by radiation therapy were performed. However, only a partial response could be obtained, and multiple brain metastases were revealed on computed tomographic scan. He died 22 months after discovery of this disease. Since extramammary Paget's disease tends to grow slowly and horizontally, cases with such severe dermal invasion and early dissemination as in our case are unusual.
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PMID:[A case of genital Paget's disease with severe dermal invasion and early dissemination]. 1036 52

Extramammary Paget's disease is considered to be a malignant tumor originating from the sweat glands. Some cases of extramammary Paget's disease infiltrate the dermis and metastasize to the regional lymph nodes. No standard treatment has been established for advanced cases. Few previous studies of the treatment for metastatic Paget's disease have revealed an effective regimen. The prognosis of metastasized cases is very poor. We encountered a patient in whom extramammary Paget's disease had metastasized to the lymph nodes beyond the regional lymph nodes and systemic chemotherapy was partially effective. Combination chemotherapy consisted of mitomycin C 3.5 mg/m2 and epirubicin 50 mg/m2 on day 1, vincristine 0.6 mg/m2 on days 1 and 7, cisplatin 30 mg/m2 from days 1 to 3, and 5-fluorouracil 350 mg/m2 from days 3 to 7. After two courses of chemotherapy, the metastatic lymph nodes decreased in size by more than 90% compared to that before chemotherapy. We defined the treatment effect of this regimen as a partial response (PR). Microscopic examination of the resected lymph nodes revealed replacement of metastatic lesions by fibrous tissue, suggesting a therapeutic effect. Anorexia, alopecia, and leukopenia (neutropenia) have been reported as toxicities, but all were tolerated. Our results may provide useful indications for the management of this tumor. This particular combination chemotherapy is recommended for extramammary Paget's disease patients with systemic nodal metastases.
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PMID:A case of metastatic extramammary Paget's disease that responded to combination chemotherapy. 1038 Apr 32


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