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Intracellular hydroxyl radical production induced by recombinant human tumor necrosis factor and its implication in the killing of tumor cells in vitro.

This study investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells (2 X 10(7) cells) in the presence of rhTNF (100 U), hydroxyl radical production as detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 h reaching 1.8 times that in the absence of rhTNF. This increase was dependent on the concentration of rhTNF and was effectively prevented by the simultaneous addition of anti-rhTNF monoclonal antibody III 2F3, which inhibited both the binding of rhTNF to its receptor and the cytotoxic activity of rhTNF. The addition of iron chelator 2,2'-bipyridine, which inhibits iron-catalized Fenton reaction and so inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. A similar increase in hydroxyl radical production in the presence of rhTNF was also detected with TNF-sensitive human myosarcoma-derived KYM cells, but no such increase was detected with TNF insensitive human embryonic lung fibroblast HEL cells. The results show that rhTNF induces increased hydroxyl radical production in TNF-sensitive cells, and suggest that this plays an important role in the mechanism of tumor cell killing by rhTNF.

2,2'-Dipyridyl↗

[A case of mucosal esophageal carcinoma with a large intramural metastasis in the stomach].

The prognosis of mucosal carcinoma of the esophagus is extremely good because of low frequency of lymphatic invasion compared with submucosal carcinoma. A 64-year-old male was admitted presented with dysphagia and weight loss. Roentgenogram and esophagoscopy revealed erosive lesions in the lower portion of the esophagus and a huge submucosal tumor that looked like the myosarcoma in the cardial portion. After total resection of thoracic esophagus and partial gastrectomy, esophagogastrostomy was done through the anterior thoracic route. During the operation, we found a few disseminative foci in the thoracic cavity (pl1) and direct invasion of cardial tumor to the celiac portion. Therefore, the operation was absolute by palliative. Histological examination of the resected specimen showed that the IIc-like lesion of the lower portion of the esophagus was a moderately differentiated squamous cell carcinoma invading the mucosa (mm), which was 2.0 x 1.6 cm in size, with marked lymphatic invasion, and intra-mural metastatic foci (7.0 x 5.0 cm) at the cardial portion. The patient died 3 months after the operation with mediastinal lymph node metastasis. In our 19 cases of resected mucosal carcinoma of the esophagus, lymphatic invasion was positive in 16%, and lymph node metastasis was positive in 16%, and intramural metastasis was in only one case. Frequency of intramural metastasis in esophageal carcinoma is about 10% in sm -a3 lesion, 5% in mm. In our experience, the prognosis of curatively resected mucosal carcinoma of the esophagus is generally good. We get long survivals, when curative operation is undergone, even if the lymphatic invasion is positive.

Carcinoma, Squamous Cell↗

[A case of primary malignant fibrous histiocytoma of the right lung].

A malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma found in adults, but a primary MFH of the lung is very rare. A chest X-ray taken of a 73-year-old man revealed a massive lesion in the right upper lobe, and a subsequent right upper lobe lobectomy uncovered a soft, light yellow tumor in the right S3 area, measuring 2.8 x 2.6 x 1.7 cm. Histologically, the tumor manifested a typical storiform pattern of spindle-sharp cells with no sign of a myosarcoma. As no abnormal lesion was detected in the abdomen and extremities, the tumor was diagnosed as a primary MFH of the lung.

Aged↗

[Implication of hydroxyl radical production in the killing of tumor cells by recombinant human tumor necrosis factor].

We investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells in the presence of rhTNF, hydroxyl radical production detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 hours reached 1.8 times of that in the absence of rhTNF. This increase of hydroxyl radical production was dependent on the concentration of rhTNF. The addition of iron chelator 2,2'-bipyridine which inhibits iron catalized Fenton reaction and inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. The increase of hydroxyl radical production stimulated by rhTNF was also detected in TNF sensitive human myosarcoma derived KYM cells as well as in L-M cells, but no change was detected in TNF insensitive human embryonic lung fibroblast HEL cells. These results suggest that rhTNF induced increase of hydroxyl radical production may play a significant role in the mechanism of tumor cell killing by rhTNF.

Cell Line↗

Chemically induced rhabdomyosarcomas in rats. Ultrastructural, immunohistochemical, biochemical features and expression of alpha-actin isoforms.

A series of 14 primary and two metastatic rat rhabdomyosarcomas (RMS) induced with nickel sulfide was studied by light microscopy, transmission electron microscopy, indirect immunofluorescence, avidin-biotin-peroxidase immunohistochemistry and two-dimensional gel electrophoresis. Monoclonal or affinity-purified polyclonal antibodies were used for the immunohistochemical demonstration of vimentin, desmin, alpha-smooth muscle (alpha-sm) actin and alpha-sarcomeric (alpha-sr) actin. By histological and ultrastructural studies, four categories of RMS were diagnosed on the basis of the neoplastic cell types. These were: (1) well-differentiated RMS (n = 2), (2) pleomorphic RMS (n = 8), (3) embryonal RMS (n = 4), and (4) embryonal myosarcomas (n = 2). Immunohistochemically, all these neoplasms expressed desmin and alpha-sr actin, reflecting their rhabdomyoblastic origin. Two dimensional gel electrophoresis performed on five neoplasms demonstrated alpha, beta and gamma actins spots in all cases. This study demonstrates that the alpha-sr actin antibody represents a good marker for rhabdomyoblastic differentiation is useful in the diagnosis of RMS since it was present in all morphologically confirmed RMS and in two ultrastructurally undifferentiated sarcomas positive for desmin. Neoplastic cells positive for alpha-sm actin were noted in 11 confirmed RMS. Double indirect immunofluorescence showed that all alpha-sm and alpha-sr positive cells also contained desmin. Co-expression of alpha-sr and alpha-sm actins was studied in serial sections of formalin-fixed, paraffin-embedded tumor tissue. Both alpha-sm and alpha-sr actins were localized in some rhabdomyoblasts. This study confirms our previous observations in human tumors and shows, for the first time, that alpha-sr and alpha-sm actins can be present in the same neoplastic cell in vivo.

Actins↗

Antibody specific to muscle actins in the diagnosis and classification of soft tissue tumors.

A series of soft tissue tumors, melanomas, carcinomas, and lymphomas were studied immunohistochemically for the presence of muscle actins (MA) with the monoclonal antibody HHF-35, and for the presence of desmin for comparison. In nonneoplastic tissues, MA immunoreactivity was present in skeletal and smooth muscle cells, in the pericytes of small vessels, and in the myoepithelial cells. Desmin immunoreactivity had a similar distribution, except that the pericytes of small vessels and myoepithelial cells were negative. All 17 rhabdomyosarcomas were positive for both MA and desmin. Of leiomyosarcomas, 31/32 were positive for MA, and 29/32 for desmin. In pleomorphic undifferentiated sarcomas (malignant fibrous histiocytomas) MA and desmin-positive cells were present in 9/35 and 5/35 cases, respectively. Three of five pleomorphic liposarcomas showed MA-positive tumor cells, which were also desmin-positive in one case. Desmoid tumors often showed a moderate number of both desmin- and MA-positive cells. Hemangiopericytoma, Kaposi's sarcoma, and endometrial stromal sarcoma showed MA-positive staining only in the pericytes and not in the neoplastic cells. In various types of carcinomas, melanomas, and lymphomas, MA- or desmin-positive neoplastic cells were not identified. MA, but not desmin, was present in the desmoplastic stroma in many carcinomas. Both MA and desmin are good markers for muscle differentiation and especially serve to identify rhabdomyosarcomas and leiomyosarcomas. These markers are also present in some sarcomas currently regarded as nonmuscle tumors. This may suggest that some of these tumors have differentiation properties related to true myosarcomas. The absence of muscle actin, a pericytic marker, in hemangiopericytoma does not confirm the concept of pericytic nature of this tumor.

Actins↗

Inhibition of human tumor colony formation by the new alkyl lysophospholipid ilmofosine.

The cytostatic-cytotoxic effect of the new thioether alkyl lysophospholipid analogue Ilmofosine (1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine, BM 41.440) on colony formation of 30 different spontaneous human tumors was investigated in vitro with the use of a methylcellulose monolayer assay. Twenty-five neoplasms were sensitive to Ilmofosine within the concentration range tested (0-16 micrograms/ml). The most susceptible tumors were 2 colon carcinomas, 2 squamous cell carcinomas and 1 small-cell carcinoma of the lungs, 2 myosarcomas, 2 ovarian carcinomas, 1 gallbladder carcinoma, and 1 pleural mesothelioma with 50% colony formation inhibition doses ranging from 1.5 to 4.0 micrograms/ml. Due to the sensitivity criteria of the U.S. National Cancer Institute (greater than or equal to 70% inhibition of colony formation at 10 micrograms/ml), 15 of 30 tumors tested have to be considered as susceptible to Ilmofosine.

Cells, Cultured↗

[Pseudomalignant, hyperacute circumscribed myositis. Contribution and limitations of echography. Review of the literature. Apropos of a case].

The very sudden onset of a painful muscular tumefaction was suggestive of a para-ostal osteosarcoma or myosarcoma. Ultrasound imaging showed a heterogeneous echogenic mass with several extending shadow cones, raising the possibility of the benign nature of the lesion, but urgent operation showed the pseudomalignant circumscribed myositis nature of the affection.

Adult↗

Photoimmunotherapy: treatment of animal tumors with tumor-specific monoclonal antibody-hematoporphyrin conjugates.

The term "photoimmunotherapy" describes an anti-cancer treatment that combines the phototoxic effects of chemical such as hematoporphyrin and the target-seeking ability of antibodies. Hematoporphyrin was chemically coupled to monoclonal antibodies directed to the DBA/2J myosarcoma M-1. Administration of anti-M-1-hematoporphyrin conjugates i.v. to M-1 tumor-bearing animals followed by exposure to incandescent light resulted in suppression of M-1 growth. The time interval between injection and light exposure was an important parameter in terms of tumor suppression. Tumor-bearing animals maintained in the dark for 96 to 196 hr after hematoporphyrin-antibody injection followed by 4-hr light exposure demonstrated significantly lower tumor incidence and longer latency periods, in comparison to conjugate-treated animals instantly exposed to light. The growth inhibiting properties of the conjugate appeared to be M-1-specific; it had no effect on the growth of a C57BL/6J lymphoma EL4. In addition, conjugates made with a nonspecific monoclonal antibody did not have any specific anti-tumor effect on M-1 growth. Treatment with equivalent doses of hematoporphyrin or antibody had no significant inhibiting effect on tumor growth. Clearly, the homing ability of the specific monoclonal antibody-hematoporphyrin conjugate was essential for effective drug delivery and inhibition of tumor growth.

Animals↗

[Ewing sarcoma. Diagnostic and therapeutic problems in children].

A pathological X-ray of the skeleton with the clinical correlation "painful swelling of soft tissue" is always an alarming sign in childhood. Radiology is our most important device to decide if the disease is of traumatic, inflammatory, incretory or neoplasmatic as well as of degenerative origin. Considering the group of "neoplasmatic alterations" there are more than 50 different entities. The differential diagnosis of a "bone tumor" requires large experience from the radiologist. Supporting the oncologist an experienced pathologist must be capable to distinguish a reticulosarcoma, a neuroblastoma metastasis, a leukemic bone-infiltrate or an embryonal rhabdo-myosarcoma from an Ewing's sarcoma. An experienced surgeon is of the same importance capable of not only collecting detritus out of necrotic tumor centres or altered tissues, but of gathering several samples from vital tumor tissue. This experienced team is especially required when children are in concern, as this age represents the peak of manifestation of malignant bone-sarcoma as Ewing's sarcoma or osteosarcoma. The quoted case-descriptions point our how difficult it may be to find the proper biopsy location and how initial false diagnosis lets valuable time pass by and prevents early diagnosis.

Adolescent↗

[Chemotherapy for metastatic lung cancer].

The effects of chemotherapy for lung metastasis in 284 cancer patients using various anti-tumor drugs, including classic ones and modern active agents for the past 18 years, were presented. Lung metastasis for lung cancer was excluded. The response was achieved in cervical carcinoma of the uterus (17/62, 27%), endometrial carcinoma of the uterus (1/7, 14%), colorectal cancer (6/39, 15%), breast cancer (5/28, 18%) and stomach cancer (4/28, 14%). A high response was achieved in myosarcoma (5/12, 42%), testicular cancer (5/11, 45%) and also in ovarian cancer (3/10, 30%). Though there were few cases, a high response was achieved in malignant melanoma (2/3), choriocarcinoma (2/4) and esophageal cancer (1/3). In total patients the response rate was 20%. In these cases a complete response was achieved in 4 cervical cancers; one testicular cancer, ovarian cancer, esophageal cancer and renal cancer, respectively. However, the effect was temporary and no longterm survivor was observed except for one case of renal cancer treated continuously with interferon (3 X 10(6) units daily) and showing complete remission after 7 months of therapy. The effect of chemotherapy for lung metastasis was compared between nodular metastasis (NM) and lymphagiosis carcinomatosa (LC). In cervical carcinoma of the uterus, the response rate in NM (39%) was higher than in LC (11%). However, no difference was observed in breast cancer (NM 15%, LC 13%) nor in stomach cancer (NM 13%, LC 18%).

Antineoplastic Agents↗

Carcinogenicity of nickel subsulfide for respiratory tract mucosa.

The carcinogenicity of nickel subsulfide, Ni3S2, for respiratory tract epithelium was studied in heterotopic tracheal transplants with doses of 1 and 3 mg Ni3S2 per trachea. Chemical determinations indicated that Ni3S2 persisted in the tracheas for seven to nine months. Ni3S2 showed marked toxicity for mucociliary epithelium, resulting in widespread atrophy and focal epithelial necrosis during the first two months of exposure. The submucosa showed mononuclear infiltration and signs of fibroblastic and capillary proliferation. Tumor studies indicated that Ni3S2 can induce carcinomas in tracheal epithelium. The carcinoma incidence was 10% at 1 mg and approximately 1.5% at 3 mg. The higher dose produced a 67% incidence of fibro- and myosarcomas. The data suggest that, compared to some carcinogenic polycyclic hydrocarbons, Ni3S2 may not be a strong carcinogen for the epithelium of conducting airways. The data are discussed in light of other experimental studies and of epidemiological findings on respiratory tract cancers in nickel workers.

Animals↗

The role of electron microscopy in the determination of tumour histogenesis.

In the majority of cases the histogenesis and classification of tumours can be unequivocally established by light microscopy, but in some instances the diagnosis remains ambiguous even after special staining techniques have been employed. So wide and varied are the situations in which the electron microscope can help establish a diagnosis that it is impossible to even mention them all in the brief time available. I will therefore present only a brief description of the manner in which one can resolve with the electron microscopy some well known diagnostic problems. This includes distinguishing: (1) an anaplastic carcinoma from a sarcoma; (2) an amelanotic melanoma from other tumours; (3) APUDomas from other tumors; (4) myosarcomas from other tumours; and (5) Ewing's tumour, neuroblastoma and lymphoma from each other.

Adenocarcinoma↗

[Non-urothelial tumors of the urinary tract].

Only about 2% of the urinary tract are not of urothelial origin. Our knowledge of their morphology and biology is mainly based on single case reports, and therefore apart from a few exceptions very poor. Generally, the most often affected site is the urinary bladder (79.2%), followed by the urethra (12.7%), pelvis (4.9%) and ureter (3.2%). The urinary bladder also is the only organ in which all different histological types of these tumors were described. According to their histogenesis non-urothelial tumors (NUT) can be classified by the following main groups: soft tissue tumors, mixed epithelial and non epithelial tumors (carcinosarcomas), neuroendocrine carcinomas, carcinoids, malignant lymphomas, malignant melanomas and extragonadal germ cell tumors. Moreover some very interesting tumor-like lesions, like malakoplakia and inflammatory pseudosarcoma, mainly occur in this region. About 75% of all NUT of the urinary tract belong to the soft tissue tumors. Rhabdomyosarcomas in children and leiomyomas and -myosarcomas in adults are the more frequent histological types. Leiomyosarcomas can easily be confused with other tumor types or even with inflammatory pseudotumors. The use of immunohistochemistry to achieve a correct diagnosis is mandatory but not always successful. A relatively frequent tumor occurring in the bladder of young adults is the paraganglioma (pheochromocytoma), which usually produces typical symptoms of catecholamine excess. Carcinosarcomas of the urinary bladder contain both epithelial and mesenchymal components. They have to be distinguished from collision tumors (coexistent but separate carcinoma and sarcoma), spindle cell transitional carcinomas as well as from carcinomas with osseous or cartilaginous metaplasia. Carcinoids and neuroendocrine carcinomas developed from the neuroendocrine cells scattered all over the transitional epithelium of the bladder. Neuroendocrine carcinomas of the bladder are also called "oat cell carcinomas" since they show the same histological features and immunoreactivity as the oat cell carcinomas of the lung. They share also the same poor prognosis. The affection of the urinary tract in generalized malignant lymphomas and leukemias occur in more than 30% of cases. Lymphomas, primarily localised in the urinary bladder are, however, extremely rare. The most frequent ones are low grade non Hodgkin lymphomas, although 3 cases of Hodgkin disease and a few cases of primary extramedullary plasmacytoma of the bladder have been reported, too.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma↗

Results obtained with fractionated ifosfamide massive-dose treatment in generalized malignant tumours.

In 409 sufferers from various malignant tumours, we used the cytostatic Ifosfamide (ASTAZ4942) in fractionated doses. The total i.v. dose averaging 300 mg/kg bodyweight, was either spread over 5 consecutive days (5 X 60 mg/kg i.v.) or over 10 consecutive days (10 X 30 mg/kg). At the same time, most patients were irradiated, the radiation dose usually being only one tenth the antitumour dose. Infections and electrolyte imbalance were first treated before Ifosfamide therapy was instituted. Cases of advanced cerebral sclerosis, thrombopenia below 75,000/cmm, cerebral metastases, impaired renal function and inadequate cooperation of the patient were excluded from the studies. To prevent and control side effects, various premedications and adjuvants are required: Antiemetics, prevention of cystitis and infections, cardiovascular agents etc. Corticosteroids are contraindicated. Out of 360 assessable patients 101 had a full remission, 150 a partial remission, 79 were failures; 30 cases were not evaluated. Good results were seen especially in ovarian carcinoma, mammary carcinoma and microcellular bronchial carcinoma. Particularly striking is the drug's effectiveness in testicular tumours including teratomas, osteosarcomas, chondrosarcomas and myosarcomas as well as in some adenocarcinomas of the gastro-intestinal tract, particularly pancreatic carcinoma. In lymphoreticular tumours and haemoblastoses, its potency is less pronounced. The side effects of Ifosfamide are the same as those of other alkylating agents. They are reversible and can usually be controlled or even avoided by adequate preventive measures. In the order of incidence we observed: Alopecia, leukopenia, fall in haemoglobin, cystitis, intercurrent infections, nausea and vomiting as well as cerebral disorders. Since haemorrhagic cystitis considerably interferes with Ifosfamide treatment, its prevention is of essential importance. Because of possible complications and specific premedication and adjuvant measures for their control, this type of treatment should for the present only be carried out by oncologists or special cancer centres.

Adolescent↗

[Antithrombogenic activity of blood vessel walls in the pathogenesis of metastasis in tumor-bearing animals].

The purpose of this work was to examine the relationship between the antiaggregatory activity of the vascular wall and the metastatic spread of experimental tumors. Rats with the tumor "Myosarcoma-1" displayed, on the average, a 30% reduction in the antiaggregatory activity of the aortic wall. Three-week of the animals with a combination of the drugs dipyridamole (0.84 mg/kg per os), phytin (14 mg/kg per os), glutamic acid (28 mg/kg per os) restored the antiaggregatory properties of the vascular wall virtually up to the control values. The similar result was observed with cordarone (60 mg/kg intraperitoneally): the antiaggregatory properties of the vascular wall increased on the average by 50%. The metastatic spread of tumor cells in mice with Lewis carcinoma of the lung decreased on the average twice while treating them with these agents. The findings point to the fact that drug correction of the antiaggregatory activity of the vascular wall reduces the rate of metastatic spread.

Animals↗

[Bladder leiomyosarcoma. Report of a new case].

Non-epithelial bladder tumours are rare and account for 1% to 5% of all vesical tumours. Among them, malignant muscular sarcoma, myosarcoma, leiomyosarcoma and rabdomyosarcoma account for 0.5% of all malignant vesical tumours. Because of their rarity, a new case of vesical leiomyosarcoma is presented. The clinical, diagnostic and therapeutical aspects are evaluated. Due to its aggressiveness and speed growth, there is no effective treatment, since in most cases both surgery, and radiation plus chemotherapy fall behind the tumour's evolution.

Humans↗

[Leiomyosarcoma of the small intestine and the colorectum. A case contribution].

Smooth muscle tumors of the alimentary tract are uncommon. A retrospective study was made of 7 patients treated for leiomyosarcoma of the small and large bowel to identify prognostic factors that influence results. The symptoms associated with these tumors varied according to the anatomic sites of the lesions and the position of the growth in relation to the intestinal lumen but the most common presenting clinical signs are bleeding or obstruction. The differential diagnosis between benign and malignant smooth muscle tumors is sometimes quite difficult. Clinical behavior of the myosarcomas of the gastrointestinal tract can be predicted to a large extent by the site of the tumor, the presence or absence of invasion of adjacent vital organs, and the histopathologic grade of malignancy. Although the mitotic activity of a gastrointestinal stromal tumor remains the most critical prognostic factor, tumors have been seen to recur locally and to metastasize even with rare or absent mitotic figures. Further studies are needed to pinpoint the factors that may be correlated to the prognosis.

Adult↗