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PubMed1981

The diagnostic dilemma of the "small round cell neoplasm": catecholamine fluorescence and tissue culture morphology as markers for neuroblastoma.

Small round cell neoplasms, which include neuroblastoma, Ewing's sarcoma, embryonal rhabdomyosarcoma, oat cell carcinoma, and lymphoma, are often confused with one another histologically. The advent of successful but distinct therapeutic approaches for different neoplasms has increased the need for precise diagnosis. The use of techniques ancillary to routine histologic or ultrastructural analysis allows better definition of the specific tumor type. Four cases of small cell tumor are described in which the initial working diagnosis was incorrect. The application of two diagnostic procedures for neuroblastoma was of great value to clarifying the proper diagnosis. These tests were a rapid fluorescence assay for intracellular catecholamines and a tissue culture assay for neurite outgrowth. Both of these methods are highly sensitive for neuroblastoma and distinguish neuroblastoma from other small round cell neoplasms. Their use confirmed this unsuspected diagnosis in three cases and excluded neuroblastoma in the fourth case.

Adult↗

PubMed1978

Ultrastructural observations on the histogenesis of alveolar rhabdomyosarcoma.

Ultrastructural examination of an alveolar rhabdomyosarcoma revealed that the bulk of the tumor was composed of small polygonal cells containing polyribosomes, short strands of rough endoplasmic reticulum, and variable amounts of glycogen; the cells were joined by small desmosome-like structures. Similar cells, as well as a variety of larger forms which appeared to be derived from the small cells, were observed along the septa; the larger forms developed a copious cytoplasm and occasionally produced myofilaments. Some of these cells were separated from the septa by basement membranes. Giant cells were also present in the alveolar spaces; these formed neither basement membranes nor myofilaments. The septa themselves were composed largely of collagen and fibroblasts. It is suggested that the commonly proposed correspondence of alveolar rhabdomyosarcoma to the myotube stage of muscle differentiation is incorrect; if anything, the overall pattern of the tumor is epithelial-like, and may correspond to the organization of mesenchymal cells at the stage of somite differentiation. The resemblance of the masses of small tumor cells to the cells of Ewing's sarcoma is discussed.

Basement Membrane↗

PubMed2000

All-trans retinoic acid and interferon-alpha in the treatment of a patient with resistant metastatic osteosarcoma.

BACKGROUND: A boy age 14 years who was in complete remission from Stage IIB small cell osteosarcoma, which was misdiagnosed as Ewing sarcoma and consequently was treated, developed inoperable lung metastases when he was off therapy. He received second-line treatment for recurrent Ewing sarcoma, including chemotherapy and radiotherapy, and obtained only a temporary response. A compassionate treatment with all-trans retinoic acid (ATRA) and interferon-alpha (IFNalpha) was then undertaken. METHODS: The patient initially was treated according to the national SE91 protocol for nonmetastatic Ewing sarcoma. After a bilateral pulmonary recurrence, he received second-line chemotherapy and irradiation of the largest metastasis, with a temporary partial response. The patient was then treated with a combination of oral ATRA (90 mg/m(2) for 3 days per week) and subcutaneous IFNalpha (3 x 10(6) U/m(2) 5 days per week) for 4 months. The same therapy also was administered for the control of residual disease after surgery for a total duration of 1 year of ATRA/IFN treatment. During the first 3 weeks of therapy, ATRA pharmacokinetics were studied. RESULTS: After progression of the patient's disease, despite the administration of first-line and second-line chemotherapy, combined treatment with ATRA/IFNalpha yielded a partial remission, which allowed surgical resection of the largest metastasis. The same therapy was effective in preventing tumor recurrence after incomplete removal of the remaining metastases. Treatment was well tolerated, and the patient is in stable complete remission 14 months after the end of therapy. The pharmacokinetics results confirmed the indication of an intermittent schedule for oral ATRA therapy. CONCLUSIONS: ATRA/IFNalpha treatment may be considered as an alternative approach in the treatment of patients with metastatic osteosarcoma who have disease that is resistant to conventional chemotherapy and in the treatment of patients with minimal tumor residue.

Adolescent↗

PubMed1976

Characteristics of hematopoietic cell line established from human myelomonocytic leukemia.

The peripheral blood of an acute myelomonocytic leukemia patient has been cultured for 16 months. The culture is at present at the 140th population doupling level. The cultured cells have the characteristics of so-called lymphoblastoid cells and proliferate actively as individual cells in small clusters, or in large clumps consisting of large mononuclear cells. Some of these cells appeare to be lymphoid, but the majority are immature mononuclear cells with a tendency to lobulate. They gave a weakly positive peroxidase reaction at the beginning of cultivation, and have given a strongly positive esterase reaction persistently. The cytoplasm shows ciliary or tail-like projections as the cell matures. Complement (C3) receptor and IgG receptors are found on the cell surface, and active phagocytosis is mannifest. Colloidal iron particles or viable red blood cells attached to the cell membrane suggesting possible differentiation to reticulum cells or macrophages. The cultured cells are mostly diploid but some cells show chromosome abnormality. Herpes type virus was foun in the nucleus, cytoplasma and on the cell membrane. The transplanatation of cultured cells to the cheek pouch of hamsters produced small tumors with histological findings resembling reticulum cell sarcoma.

Adult↗

PubMed1988

Primary tumours of the thymus in the rat.

The features of 192 primary thymic tumours occurring in the rat are described. Of these neoplasms, 170 were classified as benign thymomas, one as a benign fibrous histiocytoma, 20 as various types of malignant thymoma, 3 lympho-epithelioma-like carcinomas, one mixed small cell undifferentiated-squamous cell carcinoma, one sarcoma-like carcinoma, 4 undifferentiated carcinomas, 11 squamous cell carcinomas and the one remaining tumour as a carcinoid. A mouse, anti-epithelial, monoclonal antibody, lu-5, was used to confirm the epithelial nature of the malignant thymomas, and neuron-specific enolase to confirm the diagnosis of carcinoid. The tumours showed many features in common with those reported in man.

Animals↗

PubMed2006

Desmoplastic small round cell tumour: obstetric and gynecological presentations.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare sarcoma primarily affecting young men. We report two cases in young women mimicking gynaecological malignancy. CASES: A 23-year-old woman underwent caesarean section for obstructed labour. At surgery, multiple tumour deposits were found throughout abdomen and pelvis. Histology and PCR confirmed DSRCT. Despite chemotherapy, the patient relapsed and died 27 months after diagnosis. A 29-year-old woman presented with abdominal distension and elevated Ca125. Imaging demonstrated widespread tumour within abdomen and pelvis. Histology confirmed DSRCT. Although attaining a complete response to chemotherapy, she relapsed within 2 months and died 11 months after diagnosis. CONCLUSION: DSRCT should be considered in the differential diagnosis of young women presenting with abdominal distension and multiple masses on imaging.

Abdominal Neoplasms↗

PubMedDate not supplied

A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells.

Aberrant activation of the Wingless-type (Wnt)/beta-catenin signaling pathway is associated with a variety of human cancers. Little is known regarding the role that Wnt ligands play in human carcinogenesis. To test whether a Wnt-1 signal is a survival factor in human cancer cells and thus may serve as a potential cancer therapeutic target, we investigated the effect of inhibition of Wnt-1 signaling in a variety of human cancer cell lines, including non small cell lung cancer, breast cancer, mesothelioma, and sarcoma. Both monoclonal antibody and RNA interference (RNAi) were used to inhibit Wnt-1 signaling. We found that incubation of a monoclonal anti-Wnt-1 antibody induced apoptosis and caused downstream protein changes in cancer cells overexpressing Wnt-1. In contrast, apoptosis was not detected in cells lacking or having minimal Wnt-1 expression after the antibody incubation. RNAi targeting of Wnt-1 in cancer cells overexpressing Wnt-1 demonstrated similar downstream protein changes and induction of apoptosis. The antibody also suppressed tumor growth in vivo. Our results indicate that both monoclonal anti-Wnt-1 antibody and Wnt-1 siRNA inhibit Wnt-1 signaling and can induce apoptosis in human cancer cells. These findings hold promise as a novel therapeutic strategy for cancer.

Antibodies, Monoclonal↗

PubMed2004

Camptothecin and taxol: historic achievements in natural products research.

The research team of Dr. Monroe E. Wall and Dr. Mansukh C. Wani of Research Triangle Institute discovered two first-in-class life-saving chemotherapeutic agents. Camptothecin, first isolated and identified from Camptotheca acuminata, was found to kill cancer cells uniquely via topoisomerase I poisoning. Presently, two first-generation analogues of camptothecin are used to treat ovarian, colorectal, and small-cell lung cancers, and several second-generation analogues are in clinical trials. Taxol, first isolated and identified by Wall and Wani from Taxus brevifolia, was found to inhibit cancer cell growth via the stabilization of microtubules. In 1992, taxol was approved for refractory ovarian cancer and today is used against breast and non-small cell lung cancers and in Kaposi's sarcoma. While there have been numerous reviews of these molecules individually, this review offers an integrated account of the research team of "Wall and Wani" and the significance of their discoveries to chemistry, biology, and clinical medicine.

Antineoplastic Agents, Phytogenic↗

PubMed1986

Composite lymphoma with immunoblastic features and Langerhans' cell granulomatosis (histiocytosis X).

A 50-year-old male with a history of tonsillar and right axillary lymph node enlargement due to atypical lymphoid hyperplasia presented two years later with marked bilateral axillary and inguinal lymphadenopathy. The lymph node biopsy showed a composite lymphoma (follicular, mixed, small and large cell plus B-immunoblastic sarcoma) with associated focal Langerhans' cell granulomatosis (LCG) (Histiocytosis X). The diagnosis of composite lymphoma was supported by the immunohistochemical demonstration of two different monoclonal patterns in the follicular and diffuse areas. The typical Birbeck's granules were demonstrated ultrastructurally in LCG areas, which also stained with S-100 protein. LCG may coexist with malignant lymphoma, however, it appears to be confined to the neoplastic nodes with no tendency to systemic spread. It is important to recognize this association so that the impact of this apparently benign lesion (LCG) not be overestimated and that the subsequent management of the patient be directed according to the type of the coexisting malignant lymphoma.

Antibodies, Monoclonal↗

PubMed2001

Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors.

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.

Adult↗

PubMedDate not supplied

Monitoring apoptosis in real time.

Many therapeutically active anticancer treatments exert their effect by the induction of apoptosis and necrosis. Serial biopsies in breast cancer patients have suggested that response to therapy correlates with early posttreatment increases in tumor apoptotic index. Radiolabeled technetium Tc 99m-recombinant human (rh) annexin V provides a noninvasive technique for imaging treatment-induced cell death. Annexin V is a naturally occurring human protein that binds avidly to membrane-associated phosphatidylserine (PS). PS is normally found only on the inner leaflet of the cell membrane double layer, but it is actively transported to the outer layer as an early event in apoptosis and becomes available for annexin binding. Annexin also gains access to PS as a result of the membrane fragmentation associated with necrosis. In vitro studies of apoptosis using fluorescein annexin have shown good correlation with assessments of apoptosis documented by nuclear DNA degradation and caspase activation. In vivo localization of intravenously administered Tc 99m-annexin V has been demonstrated in numerous preclinical models of apoptosis, including anti-Fas-mediated hepatic apoptosis, rejection of allogeneic heterotopic cardiac allografts, cyclophosphamide treatment of murine lymphoma, cyclophosphamide-induced apoptosis in bone marrow, and leukocyte apoptosis associated with abscess formation. Scintigraphic studies in humans using Tc 99m-rh annexin V have demonstrated the feasibility of imaging cell death in acute myocardial infarction, in tumors with a high apoptotic index, and in response to anti-tumor chemotherapy of non-small cell lung cancer, small-cell lung cancer, breast cancer, lymphoma, and sarcoma. Increased localization of Tc 99m-rh annexin V within 1 to 3 days of chemotherapy has been noted in some, but not all, subjects with these tumors. To date, most subjects showing increased Tc 99m-rh annexin V uptake after the first course of chemotherapy have shown objective clinical responses. A single site study in 15 subjects with 1-year follow-up has suggested that increased posttreatment Tc 99m-rh annexin uptake is associated with improved time to progression of disease and survival time. In vivo imaging of cell death may have the potential to improve the treatment of cancer patients by allowing rapid, objective, patient-by-patient assessment of the efficacy of tumor cell killing.

Animals↗

PubMed2000

DX-8951f: summary of phase I clinical trials.

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.

Animals↗

PubMed1991

Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer.

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.

Drug Evaluation↗

PubMed1997

Enzyme immunoassay of glioma cell tenascin secretion and augmentation by tumor necrosis factor-alpha.

Expression of tenascin, an extracellular matrix glycoprotein, was measured in glioma cell lines using a newly established enzyme immunoassay. Secreted tenascin was found at concentrations greater than 800 ng/ml in eight of 14 glioma, three small cell lung carcinoma, two melanoma, and one sarcoma cell lines. The remaining six glioma and other carcinoma cell lines, and cell lines originating from normal tissues demonstrated low levels or no secretion into the supernatant. The glioma cell line, U-251-MG nu/nu, which has almost 100% transplantability in nude mice, had the highest expression level of tenascin among the glioma cell lines examined. Even low secretor glioma cell lines released high concentrations of tenascin, detectable by assaying the NP-40 solubilized cell lysates. Flow cytometric analysis revealed that tenascin was located on both the cell surface and primarily in the cytoplasm of glioma cells. When the glioma cell lines were exposed to tumor necrosis factor-alpha (TNF-alpha), levels of secreted tenascin increased between 36% and 380%, whereas transforming growth factor-beta induced only minimal changes. These results suggest that glioma cell lines may be classified according to the degree of tenascin secretion/expression: high secretor type, low secretor type, and non-expressing type. The increase in tenascin secretion by TNF-alpha suggests that the expression of tenascin in glioma growth and development may be mediated through a cytokine network.

Animals↗

PubMed1975

Biologic properties of transplantation immune sera. IV. Influence of the course of immunization, dilution and complexing to antigen on enhancing activity of Ig classes.

The influence of the course of immunization on the facilitating-enhancing activity of antibody classes has been studied by passive enhancement of growth of A/JAX sarcomas in CBA and IC mice and of C57BL/6 EL 4 leukemia in BALB/c mice. The influence of dilution of antibodies and complexing to antigens was also studied. During immunization (with several boosters), the enhancing capacity of sera increased together with 7S IgG antibody activity, but showed no correlation with 19S IgM antibody activity. It also was mercaptoethanol resistant. IgG1 to be more enhancing than an equal number of hemagglutinating units of IgG2a. When concentrated on a small amount (10(5)) of target sarcoma I cells, complement-fixing IC anti-A antibodies were even inhibitory on Sa I allografted to IC recipients. Progressive dilutions reversed this situation, IgG1 activity disappearing and IgG2 acquiring enhancing activity. After complexing to corresponding antigens IgG2 also (and immune sera with inhibitory properties) acquired enhancing properties. These results may provide a basis for understanding the discrepancies between the results of several groups of authors studying the class(es) of enhancing anibodies.

Animals↗

PubMed2005

Anorectal malignant melanoma: report of two cases from Buddhachinnaraj Hospital.

Anorectal malignant melanoma is a rare disease and has a uniformly poor prognosis. The following are two reported cases from Buddhachinaraj Hospital. A 55-year-old and a 65-year-old female patients presented with rectal bleeding. Large anorectal masses with regional lymph node involvement were detected initially. They exhibited different histological features which were atypical round cell resembling lymphocytes or were small cell appearance and spindle cell appearance similar to sarcoma. The diagnosis was confirmed by expression of S100 protein and HMB45. Abdominoperineal resection (APR) was the treatment of choice in both patients. The former case died in the fourth month after diagnosis because of distance metastasis and congestive heart failure. The latter case is receiving postoperative adjuvant therapy.

Aged↗

PubMedDate not supplied

Fine needle aspiration biopsy diagnosis of rhabdomyosarcoma. An immunocytochemical study.

Specific antibodies against desmin, skeletal muscle actin and myosin were assessed for their usefulness in the cytodiagnosis of five rhabdomyosarcomas: one well-differentiated, two moderately differentiated and two poorly differentiated lesions. Acetone-fixed smears from fine needle aspiration biopsies and the avidin-biotinyl-peroxidase complex technique were used. All aspirates were positively immunostained with antibodies against desmin and actin. Myosin could only be detected in the moderately and well-differentiated tumors. The percentage of tumor cells positive for any of the three proteins was positively correlated with the overall degree of differentiation. However, the number of positive tumor cells decreased in the sequence desmin-actin-myosin. The results indicate the value of antibodies, especially those against skeletal muscle actin, in aiding in the cytodiagnosis of rhabdomyosarcoma, particularly with respect to its differential diagnosis from small round cell tumors in children and pleomorphic sarcomas in adults.

Actins↗

PubMed2002

Thalidomide in cancer.

Thalidomide has immunomodulatory and anti-angiogenic properties which may underlie its activity in cancer. After its success in myeloma, it has been investigated in other plasma cell dyscrasias, myelodysplastic syndromes, gliomas, Kaposi's sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Thalidomide causes responses in 30-50% of myeloma patients as a single agent, and acts synergistically with corticosteroids and chemotherapy. Thalidomide results in the reduction or elimination of transfusion-dependence in some patients with myelodysplastic syndrome. Responses have also been seen in one-third of patients with Kaposi's sarcoma, in a small proportion of patients with renal cell carcinoma and high-grade glioma, and in some patients with colon cancer in combination with irinotecan. The drug is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation, and fatigue are common side effects, whereas peripheral neuropathy and skin rash are seen in one-third. A minority of patients experience bradycardia. Thrombotic phenomena are especially common when thalidomide is combined with chemotherapy. Adverse effects severe enough to necessitate cessation of therapy are seen in around 20% of patients. A therapeutic trial of thalidomide is essential in all patients with relapsed or refractory myeloma. In other cancers, the best way to use the drug is in the setting of clinical trials. In the absence of access to studies or alternative therapeutic options, thalidomide could be considered singly or in combination with standard therapy.

Angiogenesis Inhibitors↗