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[Hepatic infusion of docetaxel using PEIT for a patient with stage IV breast cancer].

Hepatic infusion of docetaxel using PEIT was performed for a patient with stage IV breast cancer. Docetaxel was effective to a solitary liver metastatic lesion. A 64-year-old woman was admitted to our hospital because of a left breast mass that was bleeding. She was diagnosed with stage IV breast cancer. Surgery was performed on February 16th. The pathological diagnosis was invasive ductal carcinoma, and hormone receptors were negative. Two weeks after operation, monthly docetaxel injections were given together with doxifluidine 400 mg/day p.o., cyclophosphamide 50 mg/day p.o., and fadrozole hydrochloride hydrate 2 mg/day p.o. After two courses, hepatic infusion of docetaxel was performed using PEIT after informed consent. The patient's high serum CEA and CA15-3 level returned to the normal range. A metastatic lesion on CT changed to a cystic pattern. These results suggest that PEIT is worth trying in patients with solitary liver metastasis from breast cancer.

Antineoplastic Agents, Phytogenic↗

Vascular basophilia in ocular and orbital tumors.

The occurrence of vascular basophilia in ocular tumors has been a selective histologic feature of retinoblastomas. We recently observed a metastatic oat-cell carcinoma to the choroid which also demonstrated such a vascular hematoxyphilia. Histologic review of a variety of ocular and orbital metastatic carcinomas failed to yield a similar basophilic pattern. Examination of 100 consecutive retinoblastomas for vascular basophilia revealed an incidence of 6.0%. Similar material was not seen in any of 125 melanomas, including 10 with areas of necrosis. Histochemical studies showed the basophilic material to be DNA, and electron microscopy revealed the nuclear debris of pyknotic tumor cells to be continuous with identical material surrounding the adjacent blood vessels. The pathogenesis of vascular deposition of DNA in these two ocular tumors remains unclear. This finding most likely represents a form of tumor activity requiring comparatively healthy blood vessels to adequately precipitate liberated nucleic acids being filtered from the necrotic and degenerating tumor tissue.

Basophils↗

[Pathologic characteristics and the rational surgical treatment of rectal carcinoma].

122 cases with rectal carcinoma were operated by radical resection. The 5 year survival rate was 60.3%. The patho-biological characters of the rectal carcinoma were studied. The results showed that the prognosis of the rectal carcinoma was much better than that of gastric carcinoma due to the fact that most of the rectal carcinoma was localized with low metastatic rate to the lymphatics and its growth patterns are pushing and nest-like. For rational surgical treatment, it is necessary to have a clear understanding of the patho-biologic characters, staging and location of the rectal carcinoma preoperatively.

Adolescent↗

Clinical applicability of acid phosphatase isoenzyme assay.

We compared electrophoretic evaluation of acid phosphatase isoenzymes with spectrophotometric determination of prostatic acid phosphatase in terms of clinical utility. In all of 33 cases of prostatic carcinoma, an increased prostatic fraction was detected; in nine prostatectomized patients, this fraction returned to normal as measured by either technique. Abnormal spectrophotometric results were also seen in 10 cases of benign prostatic hypertrophy and seven cases of non-prostatic disorders, but only two benign prostatic hypertrophy and one non-prostatic case showed a prostatic band (band 2) in an electrophoretogram. Band 2 was not demonstrated in 463 patients affected by a great variety of diseases but without prostatic disorders. A weak band 5 was seen in patterns for most patients, except for cases with metastatic bone tumor and Gaucher's disease, whose serum showed a strong band 5. The specificity of bands 2 and 5 seems to be confirmed by this large series of patients. Measurement of acid phosphatase isoenzymes is recommended as a routine screening test for patients whose serum acid phosphatase is abnormally high, because the isoenzyme study not only indicates the presence or absence of prostatic cancer but also whether or not there is bony metastasis. Other disorders such as Gaucher's disease, different kinds of leukemias, and thrombocythemia may also be detected and distinguished by this screening technique.

Acid Phosphatase↗

[Biological characteristics and the surgical indications in organ metastasis of esophageal cancer patients].

Indications of surgical therapy for esophageal cancer patients with metastasis are limited. The reasons are as follows: patients undergoing radical surgery can not tolerate further surgery for metastatic tumors which ordinarily appear in major organs within two years (85% of cases) after the first surgery. Moreover, such tumors are originally malignant and no satisfactory results have been obtained by use of surgical procedures. One patient survived 11 years after such surgery for brain metastasis which occurred one year after the first operation for carcinoma of the thoracic esophagus. The few cases which may possibly benefit from surgical treatment for metastatic tumors are indicated by the DNA histogram patterns, degrees of vascular invasion and round cell infiltration of the tumor tissues in the primary lesions, and the grade of sinus histiocytosis in regional nodes. The vascular structure of human esophageal cancers transplantable to nude mice is variable and shows sinusoid like pattern. The diameters of cells of human esophageal cell lines range from 14 to 23 mu and are larger than the caliber of the capillary. Five of 9 cell lines have an effect on platelet aggregation, in contrast to normal cells which have no such effect. Seven of 9 cell lines show the dominant effect of procoagulant activity of cultured cells. The value of cAMP in cells is in reverse correlation to the sialic acid in those cells.

Animals↗

[Lymphogenic metastasis of malignant ovarian tumors (bases on lymphographic data)].

Lymphogenous dissemination of malignant ovarian tumor was studied by means of direct radiopaque lymphography in 113 primary patients. Lymph node metastases were detected in 63 cases (55.8%). Positive lymphographic results matched histological findings on distant lymph nodes in 76.0 +/- 8.7 and negative in 96.3% +/- 3.7 of cases. Most frequent sites of metastases were regional paraaortal lymph nodes (87.7%). Pelvic nodes were affected in 63.2%; since in 10.5% of cases separate metastases were found, it may be supposed that these lymph nodes are regional to ovaries, too. Inguinal nodes ranked third as metastatic sites (17.5%). Frequency of metastatic dissemination was found to depend on histological pattern of tumor tissue: they occurred in 46.3% cases of epithelial tumors, 73.9% - germinogenous and 50.0% of tumors of genital cord stroma. Metastases into lymph nodes were detected in 28.6% of patients with stage I tumors. Control lymphograms showed metastases in regression following chemotherapy in 56.6% of patients.

Adult↗

Prostate cancer treatment strategies based on tumor-specific biological principles: future directions.

Prostate cancer represents a heterogeneous disease entity with varying degrees of behavior, aggressiveness, patterns of metastasis, and response to therapy. Progressive metastatic prostate cancer is associated with a formidable array of morbidity that ultimately contributes to death of the patient. Thus far, there has been no convincing evidence to support routine use of non-hormonal chemotherapeutic agents or combinations over symptomatic treatment only. Furthermore, no single compound or combination has shown a dramatic improvement in conventional quality of life parameters over symptomatic treatment only. Androgen ablation remains the primary systemic therapeutic modality for this disease, yet the intense delineation of mechanisms involved in tumor cell metastasis has lead to new therapeutic strategies, ranging from cytotoxic to cytostatic, including immunomodulators. Among those strategies currently being studied are granulocyte-macrophage colony-stimulating factor-transduced prostate cancer vaccines, differentiation therapy, gene therapy, inducers of apoptosis, antimetastatic agents, angiogenesis inhibitors, radiation therapy (local and systemic), and systemic approaches targeted at prostate cancer morbidity. The difficult issue is which agents should be developed and how should we best assess the response using standard and newly identified endpoints. Certainly, the future of advanced prostate cancer therapy will undergo dramatic changes as a result of the continued interaction between the laboratory and the clinic.

Antineoplastic Agents↗

[Relationship between the abnormal expression of CD44 gene and bladder cancer].

Reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization were used to detect exon V6-containing isoforms of CD44 gene in 42 surgical bladder specimens (20 cases of bladder cancer, 10 cases of corresponding normal bladder tissue, 8 non-neoplastic bladder tissue from the benign prostatic hyperplasia, and 4 cystitis). All samples of bladder cancer tissue showed over-expression of many abnormal alternatively-spliced products containing transcripts from exon V6 of the CD44 gene except those from 22 non-neoplastic tissue. Furthermore, the band pattern permitted differentiation between the 2 cases of metastatic bladder tumors and the 18 cases of non metastatic tissue. Our results suggest that there is a remarkable relationship between the abnormal CD44 gene expression (inappropriate splicing and overexpression) and malignant phenotype and metastasis of bladder cancer. The CD44 splice variants may prove to be a more ideal tumor marker for the early diagnosis of bladder cancer and for the early detection of metastatic potential in surgical biopsy specimens, which deserves further evaluation.

Adult↗

Diagnostic utility of CD10 in differentiating hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration biopsy (FNAB) of the liver.

The differential diagnosis between hepatocellular carcinoma (HCC) and metastatic carcinoma, especially in moderate-poorly differentiated (MPD) HCC and poorly differentiated carcinoma, can be challenging in fine-needle aspiration biopsy (FNAB) of the liver. Recent studies demonstrate that canalicular staining for CD10 appears to be a highly specific marker for hepatocytic differentiation. The objective of this study was to test the utility of CD10 in differentiating HCC from metastatic carcinoma in FNAB of the liver. Formalin-fixed, paraffin-embedded cell blocks of 55 cases (22 HCC, 23 metastases, and 10 benign hepatic lesions) of FNAB of the liver were immunostained using monoclonal antibody against CD10, with microwave oven antigen retrieval, followed by a standard ABC method. Nineteen (86%) of 22 HCC cases were positive for CD10 with a canalicular staining pattern. Among them, 9 (82%) of 11 well-differentiated (WD) HCC and 10 (91%) of 11 MPD HCC were positive for CD10. Three (13%) of 23 metastatic carcinomas were positive for CD10, demonstrating a contrasting cytoplasmic and membranous staining pattern. The three positive cases were metastatic renal cell carcinoma (RCC), choriocarcinoma, and adenocarcinoma of the lung. All 10 cases of benign hepatic lesions showed positivity for CD10 with a canalicular and focal membranous staining pattern. In conclusion, CD10 appears to be a useful marker in discriminating between HCC and metastatic carcinoma when applied to FNAB of the liver. CD10 does not provide discrimination between WD HCC and benign hepatocytes.

Biomarkers, Tumor↗

Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior.

The aggressive and highly metastatic behavior observed in pancreatic ductal adenocarcinoma (PDAC) may be due to autocrine and/or paracrine interactions (tumor/stromal) involving altered expression of peptide growth factors and their corresponding receptors. The neurotrophin (NT) growth factor family and their cognate receptors have been demonstrated to play a role in the invasiveness, chemotactic behavior and tumor cell survival of both neuronal and non-neuronal cancers. We hypothesized that aberrant expression of the NTs and/or the Trk receptors may contribute to the malignant phenotype of PDAC, specifically tumor cell invasiveness, through autocrine and/or paracrine interactions. In this study, we examined the expression of NTs, Trks and p75NGFR by immunohistochemical and in situ hybridization analyses in both normal (n=14) and neoplastic pancreas (n=47) and PDAC-derived cell lines (n=6). Further, we evaluated the effects of various NTs on the in vitro invasive and chemotactic behavior on 6 human PDAC-derived cell lines in a modified Boyden chamber assay. Brain-derived nerve growth factor (BDNF), NT-3, NT-4/5 and Trks A, B and C exhibited diffuse cytoplasmic and membranous immunostaining patterns in both the ducts and the acini of the exocrine pancreas and the islets of the endocrine pancreas of both normal and PDAC specimens. NT expression was primarily within the stromal compartment of the tumor, while Trk expression was weak or absent. We observed a 68%, 64% and 66% increase in the expression of Trks A, B and C, respectively, in the ductal elements of the PDAC samples examined compared with the normal adjacent tissue. Invasiveness of 4 of 6 PDAC cell lines was significantly inhibited (p<0.05) when the cells were incubated with 100 ng/ml NT. However, when select cell lines were incubated with lower concentrations of NT-3 and BDNF (0, 1, 5, 25 and 50 ng/ml), invasiveness was significantly stimulated (p<0.05) through the Matrigel matrix. Collectively, our data suggest the possibility that paracrine and/or autocrine NT-Trk interactions may influence the phenotype (possibly the invasive behavior) of PDAC.

3T3 Cells↗

Unusual interleukin-4 and -13 signaling in human normal and tumor lung fibroblasts.

IL-4 and IL-13 act on human lung fibroblasts through specific receptors differing in their composition. Indeed, the gammac chain is constitutively expressed in tumor lung myofibroblast but not in normal cells. Here, we have analysed the signal transduction induced by IL-4 and IL-13 in both cell types, in order to better understand the molecular mechanisms underlying tumor stromal development. The IL-4Ralpha chain is constitutively phosphorylated and pre-associated with the JAK1 protein in both cell types. In normal cells, we detected the activation of the classic IRS-2 or JAK1/STAT6 pathways, the phosphorylation of JAK2, while Tyk2 was constitutively phosphorylated and not modified by both cytokines. In addition to these pathways, in lung tumor myofibroblasts, IL-4 and IL-13 induced the phosphorylation of JAK3 and increased the phosphorylation of Tyk2. Interestingly, in both cell types IL-4 and IL-13 triggered an unusual pattern of STAT1 and STAT3 activation. These events probably correspond to a tissue-specific signaling important for the immunoregulatory functions of airways fibroblasts. Indeed, the inflammatory-like pattern of STATs signaling triggered by IL-4 and IL-13 in these cells may favor the homing of inflammatory and/or metastatic cells. In lung myofibroblasts, these properties could be modified through the different pattern of JAK activation.

DNA-Binding Proteins↗

Xanthorrhizol, a natural sesquiterpenoid from Curcuma xanthorrhiza, has an anti-metastatic potential in experimental mouse lung metastasis model.

Xanthorrhizol is a sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhiza. In this study, the anti-metastatic activity of xanthorrhizol was evaluated by using an in vivo mouse lung metastasis model and a tumor mass formation assay. Interestingly, xanthorrhizol dramatically inhibited the formation of tumor nodules in the lung tissue and the intra-abdominal tumor mass formation. Next, to examine the mechanism of the anti-metastatic action of xanthorrhizol in the mouse lung metastasis, expression patterns of the several intracellular signaling molecules were evaluated using the lung tissues with tumor nodules. Higher expression levels of cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and phosphorylated extracellular signal-regulated kinase (ERK) were observed in the metastatic group compared with control, but these were attenuated by the treatment of xanthorrhizol. In conclusion, xanthorrhizol exerts anti-metastatic activity in vivo and this effect could be highly linked to the metastasis-related multiplex signal pathway including ERK, COX-2, and MMP-9.

Animals↗

[The role of magnetic resonant tomography in the diagnosis of primary and metastatic brain tumors].

1035 patients of suspected brain formations have been examined in a low-field magnetic resonance tomography (MPT) study. Various patterns of brain tumors were identified in 772 cases and diagnosis was verified by other procedures. Among the most frequent were neuro-epithelial tumors (157), meningiomas (161) and metastatic lesions (136). The MRT technique condition suggest histological pattern. Although less expensive and easier to service, low-field MRT's yield as much information for brain tumor diagnosis as medium- and high-field tomographs do.

Adult↗

Evaluation of the CD34 and CD10 immunostains using a two-color staining protocol in liver fine-needle aspiration biopsies.

Fine-needle aspiration (FNA) biopsies of liver masses may need immunohistochemistry to resolve difficult cases. We examined liver FNAs with CD10 and CD34 using a two-color staining protocol. Fifty-one cases of hepatocellular carcinoma (HCC) and 23 cases of liver metastases were stained first with CD10 using diaminobenzidine as a chromogen and then with CD34 using Fast Red. All cases were reviewed in a blinded fashion by two of the authors (R.I.Z. and Z.B.). Diagnoses were unblinded and staining patterns evaluated. Forty-eight of 51 cases of HCC stained for CD34 in a peripheral pattern and no cases of metastases stained for CD34 Seven of 23 cases of metastatic disease stained for CD10 in a diffuse cytoplasmic distribution and 29 of 51 HCCs stained in a canalicular pattern. Overall, the sensitivity of the CD10/CD34 combination was 98% and the specificity was 100% for HCC when appropriate staining patterns were observed. Two-color immunostaining with CD10 and CD34 may prove useful in distinguishing HCC from metastases.

Antigens, CD34↗

Regional heterogeneity and complementation in the expression of the tumor-associated glycoprotein 72 epitopes in colorectal cancer.

We analyzed the immunohistochemical expression of three epitopes of the tumor-associated glycoprotein 72 (TAG-72) in whole cross-sections of primary colorectal carcinomas and in regional lymph node metastases using monoclonal antibodies (MAbs) B72.3, CC-49, and CC-83, which recognize distinct carbohydrate antigenic determinants. B72.3, CC-49, and CC-83 reacted with 13 of 27 (48%), 25 of 27 (92%), and 21 of 27 (77%) carcinomas, respectively. The immunoreactivity with lymph node metastases followed a similar pattern; MAb CC-49 was again the most reactive of the three antibodies, since it labeled 13 of 15 metastatic lesions. Positive reactions of the MAbs with the primary tumors were not always predictive of the immunorecognition of their metastases. Distinct areas within whole cross-sections of TAG-72-positive primary carcinomas demonstrated marked differences in the expression of the three epitopes. CC-49 tended to react with the highest number of areas and with the highest percentages of carcinoma cells within each area. In no instances did B72.3 demonstrate reactivity superior to that of either CC-49 or CC-83. Tumors negative for the CC-49 epitope in any area also did not express the other two TAG-72 epitopes. However, the comparison of the immunostaining obtained with each MAb in TAG-72-positive primary lesions revealed areas where CC-83 was clearly more reactive than CC-49. Moreover, one lymph node metastasis, negative for CC-49, was recognized by CC-83. Thus, the combined use of MAbs CC-49 and CC-83 resulted in additive immunostaining of primary and metastatic colorectal carcinoma cells. The study provides evidence of intratumoral heterogeneity in the glycosylation pattern of the TAG-72 antigen in colorectal cancer and emphasizes the advantages of cocktails of anti-tumor-associated antigen MAbs in the immunodetection of colorectal tumor cells.

Antibodies, Monoclonal↗

Molecular cytogenetic characterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17).

The pediatric tumor neuroblastoma is characterized by a very variable, and at times unpredictable, pattern of clinical behavior, ranging from a benign localized tumor to an aggressive malignancy with poor prognosis. Standard clinical and pathological assessments do not always differentiate reliably between tumor subtypes and, therefore, genetic markers are now playing an increasingly important role in treatment decisions. MYCN oncogene amplification, for example, provides a useful marker of poor prognosis. However, less than one-half of all patients who present with, or who later develop, metastatic disease show MYCN amplification. Consequently, the identification of characteristic patterns of genetic alteration in the remaining tumors is of importance. In this report, we describe two new cell lines that we have established from metastatic, non-MYCN amplified, advanced stage neuroblastomas. These cell lines show a number of features in common, including unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and gain of 17q. Therefore, they provide a valuable resource for the characterization of genetic pathways leading to aggressive tumor growth in non-MYCN amplified neuroblastomas.

Adrenal Gland Neoplasms↗

Loss of cell-contact regulation and altered responses to autocrine motility factor correlate with increased malignancy in prostate cancer cells.

Tumor cell migration and proliferation in new organ environments are critical steps in cancer progression and can be modulated by tumor- and host-secreted molecules. Autocrine motility factor (AMF) is a tumor-secreted cytokine which regulates growth and motility by a receptor-mediated pathway. The AMF receptor, a 78-kDa cell surface glycoprotein (gp78), is regulated by cell contact in normal fibroblastic and bladder cells; however, this mechanism is disrupted during tumor progression. A prostatic carcinoma cell line which is low- to non-metastatic in nude mice (PC-3) and a derived metastatic variant (PC-3M) were examined to determine if gp78 cell density regulation is involved in prostate cancer progression. Both cell lines expressed gp78 and, although the basal migration of the parental PC-3 cells was higher than that of the metastatic variant, only the PC-3M cells were capable of responding to tumor-derived AMF with increased motility. Furthermore, these cells exhibited differential patterns of wound closure in an experimental system whereby the low-metastatic PC-3 cells migrated primarily along the wound edge while individual high-metastatic PC-3M cells entered the cell-free wound area directly. Cell surface gp78 distribution distinguished the cell populations with a markedly concentrated display of gp78 in polarized capped regions on the surface of the metastatic cells. Cell-cell contact down-regulated gp78 expression in the parental, but not the metastatic, cells, and mitogenic responses to exogenous AMF differed between these cell lines as well. In this model, metastasis appears to be associated with aberrant regulation of gp78 expression and distribution, coupled with enhanced exploitation of AMF's locomotory and proliferative effects.

Cell Movement↗