C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction.

Myocardial infarction in humans provokes an acute phase response, and C-reactive protein (CRP), the classical acute phase plasma protein, is deposited together with complement within the infarct. The peak plasma CRP value is strongly associated with postinfarct morbidity and mortality. Human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. Here we show that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by approximately 40%. In vivo complement depletion, produced by cobra venom factor, completely abrogated this effect. Complement depletion also markedly reduced infarct size, even when initiated up to 2 h after coronary ligation. These observations demonstrate that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease.

Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vivo MRI studies demonstrate histopathologic correlation.

Improving the prevention and detection of preinvasive ductal carcinoma in situ (DCIS) is expected to lower both morbidity and mortality from breast cancer. Transgenic mouse models can be used as a 'test bed' to develop new imaging methods and to evaluate the efficacy of candidate preventive therapies. We hypothesized that despite its microscopic size, early murine mammary cancer, including DCIS, might be accurately detected by MRI. C3(1) SV40 TAg female mice (n=23) between 10 and 18 weeks of age were selected for study. Eleven mice were subjected to in vitro imaging using a T(2)-weighted spin echo sequence and 12 mice were selected for in vivo imaging using a T(1)-weighted gradient echo, a T(2)-weighted spin echo and high spectral and spatial resolution imaging sequences. The imaged glands were carefully dissected, formalin fixed and paraffin embedded, and then H&E stained sections were obtained. The ratio of image-detected versus histologically detected cancers was obtained by reviewing the MR images and H&E sections independently and using histology as the gold standard. MR images were able to detect 12/12 intramammary lymph nodes, 1/1 relatively large (approximately 5 mm) tumor, 17/18 small (approximately 1 mm) tumors and 13/16 ducts distended with DCIS greater than 300 microm. Significantly, there were no false positives--i.e., image detection always corresponded to a histologically detectable cancer in this model. These results indicate that MR imaging can reliably detect both preinvasive in situ and early invasive mammary cancers in mice with high sensitivity. This technology is an important step toward the more effective use of non-invasive imaging in pre-clinical studies of breast cancer prevention, detection and treatment.

Uptake and distribution of specific and control monoclonal antibodies in subcutaneous xenografts following intratumor injection.

Nude mice bearing s.c. xenografts of the human colon adenocarcinoma HT29 were given intratumor injections of a mixture of 125I-labeled specific antibody (AUA1) and 131I-labeled control antibody (HMFG1), or with the labels reversed. After dissection at 1 and 4 h postadministration, both specific and control antibodies had 47-63% of the injected dose (% ID) in the tumor. By 24 h, the tumor contained 43 +/- 11% ID of AUA1 which persisted at around this level for 5 days and remained at nearly 20% ID at 18 days. In contrast, the HMFG1 activity was 23 +/- 9% ID at 24 h, which continued to fall and was less than 5% ID by 7 days. Normal organ levels were less than 2% ID/g for both antibodies, with HMFG1 being higher than AUA1 at all times, resulting in specificity indices greater than 20 by 5 days. Autoradiography of tumors removed 2 h postinjection of 125I-labeled AUA1 or HMFG1 showed high levels of antibody at the injection site. At 48 h and 7 days postinjection, the specific antibody was bound to the surface of tumor cells in islands remote from the injection site, whereas the control antibody was found only in the stroma and blood vessels, or as diffuse nonspecific uptake. These data indicate that intratumor injection of radiolabeled monoclonal antibodies may achieve high radiation doses in accessible tumors without systemic irradiation.

Intravesical administration of radiolabeled antitumor monoclonal antibody in bladder carcinoma.

Tumor associated AUA1 monoclonal antibody and 11.4.1. nonspecific monoclonal antibody, which does not react with human tissues, were radiolabeled with 111In and administered intravesically to 23 patients undergoing cystoscopy for bladder carcinoma. The antibody solution remained in the bladder for 1 h and then was washed out prior to cystoscopy. Tumor and nontumor samples were obtained during cystoscopy and were counted in a gamma counter. Conventional and immunoperoxidase staining with both antibodies were also performed. AUA1 reacted with all bladder carcinomas while 11.4.1. was negative in all cases. The mean uptake of AUA1 at 2, 24, and 48 h after the instillation (expressed as 10(3) x percentage of injected dose/g of tissue) was: 6.12 +/- 5.50 (SD), 1.70 +/- 2.57, 0.30 +/- 0.17 in the tumors and 0.32 +/- 0.50, 0.22 +/- 0.30, 0 in the nontumor areas, and for 11.4.1. it was: 0.075 +/- 0.075, 0.025 +/- 0.025 in the tumors and 0.30 +/- 0.42, 0.15 +/- 0.26 in the nontumor areas. The uptake of AUA1 by the tumors correlated with the tumor grade. There was no radioactivity in the blood at 2 h, and at 1, 2, and 3 days after the instillation. Our results indicate that intravesical administration of radiolabeled monoclonal antibody AUA1 targets selectively to tumor tissue without any significant normal tissue uptake. This finding might allow the development of a nontoxic and specific therapeutic approach for superficial bladder carcinoma.

Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion.

We have used quantitative zymography to measure levels of the type IV collagenases matrix metalloproteinase (MMP)-9 and MMP-2 in 42 biopsies of transitional cell carcinoma and in 7 biopsies of normal bladder. Mean levels of MMP-9 were significantly higher in tumor compared with normal samples (P = 0.08). Levels of MMP-9 and active MMP-2 increased with tumor grade (test for trend, P = 0.002 and P = 0.05, respectively). Levels of MMP-9 and activated MMP-2 were also higher in invasive tumors than in superficial ones (P = 0.001 and P = 0.008, respectively). In situ hybridization studies showed that the mRNAs for both MMP-2 and MMP-9 were located chiefly in the stroma rather than epithelial tumor cells and were concentrated at the interface between the two tissues.

Fluid flow induces upregulation of synthesis and release of tissue factor pathway inhibitor in vitro.

Fluid flow modulates the synthesis and secretion by endothelial cells (ECs) of several proteins that control the hemostatic properties of the vessel wall. Tissue factor pathway inhibitor (TFPI), also synthesized by ECs, is the main downregulator of tissue factor-dependent procoagulant activity. In the present study, we investigated the effect of physiological shear stress on the expression, distribution, and release of TFPI in cultured ECs. The EA.hy926 cell line was grown in a hollow-fiber perfusion system and exposed for variable times to different shear values: 0.27 dyne/cm(2) (minimal flow), 4.1 dyne/cm(2) (venous flow), and 19 dyne/cm(2) (moderate arterial flow). Step increase of the shear stress from 0.27 to 19 dyne/cm(2) induced a sharp increase of TFPI released into the medium and a parallel decrease and redistribution of cell-associated TFPI, which suggests that an acute release of TFPI occurred from the cellular pools. During 24 hours of high shear stress, cell-associated TFPI antigen and mRNA increased time-dependently. Subjecting ECs to steady shear stress for 72 hours also upregulated the expression and production of TFPI, in direct correlation with the degree of the shear. The secretion of TFPI was enhanced 1.9-fold under venous flow and 2.4-fold under arterial flow compared with minimal flow. Equally, cell-associated TFPI antigen and cell surface TFPI activity increased proportionally with the shear stress. The expression of TFPI mRNA, as determined by Northern blotting, increased up to 2-fold in ECs under venous flow and up to 3-fold under arterial flow. These results suggest that shear forces regulate TFPI by modulating its release and gene expression in ECs in vitro.

Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS.

OBJECTIVE: To determine the safety and efficacy of the sulphated polysaccharide, dextrin 2-sulphate, when delivered to the lymphatic circulation by the peritoneal route. DESIGN: An open Phase I/II dose-escalation clinical study in which six patients with AIDS were treated with seven courses of dextrin 2-sulphate each lasting 1 month. METHODS: During each course of treatment, the drug was administered daily for 28 days using an intraperitoneal catheter. Viral load was measured at frequent intervals using a plasma tissue culture infectious dose (TCID) assay, a cellular TCID assay, p24 antigenaemia, HIV-1 RNA and HIV-1 DNA. Plasma beta-chemokine levels were also measured. RESULTS: Dose escalation was completed without toxicity. A total of 7 patient-months of treatment were completed. With increasing doses of dextrin 2-sulphate, the infectious plasma viraemia, cellular viraemia and p24 antigenaemia all fell during the period of drug administration, but with no significant change in HIV-1 RNA. This was associated with increased plasma levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Dextrin 2-sulphate accumulated in peritoneal macrophages and induced the release of MIP-1alpha and MIP-1beta from these cells in vitro. These beta-chemokines could have augmented the cell surface-mediated anti-HIV-1 effect of dextrin 2-sulphate in vivo by binding to and blocking the CC-chemokine receptor-5. A second fall in infectious plasma viraemia, cellular viraemia, p24 antigenaemia and HIV-1 RNA was seen at day 100 which was then sustained for several months. A clinical improvement in Kaposi's sarcoma was also seen. CONCLUSIONS: Our results suggest that the intraperitoneal administration of dextrin 2-sulphate can reduce the replication of HIV-1 in patients with AIDS. With increasing doses of dextrin 2-sulphate, the fall in viral load was seen during the period of drug administration and again 2 months after completing treatment.

Human endometrial fibroblasts immortalized by simian virus 40 large T antigen differentiate in response to a decidualization stimulus.

Human endometrial fibroblasts have been immortalized by infection with simian virus 40 large T antigen and established as a permanent cell line, St-2. Biochemical differentiation of this cell line has been demonstrated by the ability of a decidualizing stimulus, 8-bromo-cAMP plus medroxyprogesterone acetate (MPA), to induce PRL secretion and increase the enzymatic activity of estrone sulfatase. MPA, alone or in combination with estradiol, was unable to elicit this response, but potentiated the effect of 8-bromo-cAMP on PRL production and estrone sulfatase activity. The increase in PRL protein was accompanied by an increase in PRL messenger RNA and increased expression of the insulin-like growth factor-binding protein-1 messenger RNA. The St-2 cell PRL transcript was larger than the pituitary PRL transcript, suggesting its initiation from the distal, nonpituitary, PRL promoter. This was confirmed by reverse transcription-PCR analysis of PRL transcripts using primers specific for the additional sequences present only in the 5'-untranslated region of RNA initiated from the distal promoter. Transient transfection of a reporter construct containing 3000 bp of DNA 5' to the decidual-specific promoter of the human PRL gene demonstrated that cAMP was capable of activating this distal promoter in St-2 cells. In conclusion, this novel cell line provides an interesting new model in which to pursue aspects of biochemical differentiation of human endometrium in vitro.

Formation of endothelin by cultured airway epithelial cells.

Immunoreactivity to endothelin was detected in conditioned culture medium from both canine and porcine tracheal epithelial cells. Gel permeation chromatography and fast protein liquid chromatography were used to confirm the identity of the endothelin. The two peaks demonstrated on fast protein liquid chromatography co-eluted with endothelin 1 and endothelin 3 respectively.

3,3',4,4'-tetrachlorobiphenyl (TCB) can enhance DMBA-induced mammary carcinogenesis in the rat.

Polychlorinated biphenyls (PCBs) are fat-soluble environmental pollutants which can be stored in the fatty tissue of breast and secreted in milk. Previous studies have shown that PCBs can influence liver carcinogenesis in animal models but no such studies have been reported in breast. These experiments aimed to determine whether a PCB congener could influence mammary carcinogenesis using the rat DMBA-induced mammary tumour model system. 3,3',4,4'-Tetrachlorobiphenyl (TCB) enhanced the development of DMBA-induced mammary tumours in young female rats and did so in animals fed either a low-fat (5% w/w corn oil) or a high-fat (20% w/w corn oil) diet. The combination of TCB and high-fat diet resulted in tumours growing so fast that the experiment had to be terminated at 10.5 weeks for humane reasons. At termination the total numbers of tumours in each group of 20 rats were: 4 in the low-fat group, 22 in the low-fat plus TCB group, 25 in the high-fat group and 50 in the high-fat plus TCB group. Histopathological analysis confirmed that 98% of the tumours were mammary carcinomas, predominantly in situ ductal carcinomas, but, in addition, revealed that 13 of the tumours had an invasive phenotype of which 12/13 had all arisen in TCB-treated animals. This demonstrates, for the first time, that a PCB congener can influence mammary carcinogenesis.

Differential expression of mucin genes in mammary and extramammary Paget's disease.

Paget's disease (PD) of the skin is characterized by intraepidermal adenocarcinoma cells, which contain clear cytoplasm and abundant mucin. Nearly all cases of mammary PD (MPD) are associated with underlying ductal carcinoma of the breast, whereas in the majority of cases of extramammary PD (EMPD) no underlying regional malignancy is identified. Mucins are high molecular weight glycoproteins produced by epithelial cells. Different mucin genes are expressed in various types of tissues such as mammary glands, intestinal mucosa, and adnexal structures of the skin. We studied the immunohistochemical expression of apomucin MUC1, MUC2, MUC5AC in MPD, and EMPD. MUC1 is commonly expressed in most cases of PD. MUC5AC is a unique mucin that is exhibited in the majority of cases of EMPD, but not in any MPD. Of the 13 patients with MPD who all had associated breast ductal carcinoma, both Paget cells and underlying ductal carcinoma exhibited the phenotype (MUC1+MUC2-MUC5AC-). This mucin phenotype is also expressed by Toker cells, which have been identified in the epidermis of five of 50 nipples in mastectomies without MPD. Of the three patients with perianal PD who all had associated rectal adenocarcinoma, Paget's cells expressed MUC2 constantly but expressed MUC1 and MUC5AC variably. Seven patients with intraepidermal vulvar PD and two patients with scrotal-penile PD had no identifiable underlying malignancy. Paget cells from all of these nine cases of EMPD expressed a uniform phenotype of mucin (MUC1+MUC2-MUC5AC+). One case of vulvar PD associated with underlying apocrine carcinoma had a phenotype (MUC1+MUC2-MUC5AC-) identical to that of normal apocrine glands. The skin appendage and Bartholin's glands from 20 normal-appearing vulvar skin samples and anal glands from 10 hemorrhoidectomies were also studied. Only Bartholin's gland expressed a mucin phenotype identical to that of intraepidermal EMPD. The results of the present study indicate that 1) MPD may arise from either mammary glands or epidermal Toker cells, 2) intraepidermal EMPD in the anogenital areas may arise from ectopic MUC5AC+ cells originating from Bartholin's or some other unidentified glands, and 3) unique expression of MUC2 in perianal PD indicates its origin from colorectal mucosa. We conclude that the study of mucin gene expression is useful in identifying the histogenesis of PD.

Angiosarcoma of the ovary: clinicopathologic and immunohistochemical analysis of four cases with a broad morphologic spectrum.

Angiosarcoma most frequently occurs in the skin of the head and neck region of elderly persons, lymphedematous limbs, or in deep soft tissue but only rarely has been described to occur in the female genital tract. Four cases of angiosarcoma of the ovary are described herein. They occurred in patients 25 to 42 years old (median, 31 years). The most common clinical presentation was abdominal pain. All of the tumors were unilateral, hemorrhagic, and ranged from 3.5 cm to 14 cm (median, 13 cm). The histologic appearance of the tumors was varied, and often the vascular nature of the tumor was not apparent immediately. Some of the tumors had a fascicular growth pattern composed of spindle-shaped cells with ovoid nuclei and ample eosinophilic cytoplasm closely mimicking leiomyosarcoma. Other tumors resembled ovarian yolk sac tumor with a reticular growth pattern, whereas, in other areas, cystic structures lined by hobnailed hyperchromatic enlarged nuclei simulated clear cell carcinoma of the ovary. Despite these misleading morphologic findings, all cases were characterized, at least focally, by vasoformative channels or discrete cytoplasmic vacuoles, and all were immunoreactive for vascular markers. Two patients with spread of tumor outside of the ovary died 1 month and 2 years after initial diagnosis, respectively. Two patients with tumor confined to the ovary are alive without evidence of disease 3 and 14 months after diagnosis, respectively. The differential diagnosis of this unusual neoplasm is discussed, and the literature is reviewed.

"Proximal-type" epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series.

Eighteen examples of an unusual malignant soft-tissue neoplasm, the morphology of which ranged from that of "atypical" epithelioid sarcoma to that of a rhabdoid tumor or undifferentiated carcinoma (with transitional forms) are described. Patients included 11 males and seven females; their median age was 35.5 years with most patients aged 20 to 40 years. Development of a mass was the main presenting symptom. Six tumors developed in the pelvis and perineal region, four in the pubic region and vulva, three in the buttocks, one in the deep soft tissues of the left hip, one on the penis, one in left forearm, one in left axilla, and one on the occiput. Tumor size ranged from 1 to 20 cm (median, 4 cm). On microscopic examination, the tumor cells invaded the subcutaneous or deep soft tissues, had prominent epithelioid or rhabdoid features, had marked cytologic atypia, and grew in a multinodular pattern in half of the cases. Areas of necrosis were often seen. A granuloma-like pattern reminiscent of that observed in classic epithelioid sarcoma was observed in only two cases. Immunohistochemically, positivity for cytokeratin, epithelial membrane antigen, and vimentin was seen in all but one of the cases. Of 16 cases, 10 and eight tumors reacted with desmin and CD34, respectively; five of 15 reacted at least focally with smooth-muscle actin, whereas three of 13 and one of 10 reacted for HMB-45 and carcinoembryonic antigen, respectively. S-100 protein and CD31 yielded negative results. Seven tumors were investigated at the ultrastructural level, four of which showed prominent intracytoplasmic intermediate filament aggregates, often accumulating into paranuclear whorls, which is in keeping with the rhabdoid phenotype. Five tumors showed features of epithelial differentiation (i.e., tonofilament-like structures or desmosomes or both), whereas one tumor displayed features of myofibroblastic differentiation. Differential diagnoses include mainly conventional epithelioid sarcoma, extrarenal malignant rhabdoid tumor, epithelioid malignant peripheral nerve sheath tumor, melanoma, rhabdomyosarcoma, and undifferentiated carcinoma. Follow-up information on 14 patients (range, 4 months to 8 years; median, 19 months) revealed local recurrence in one case and metastatic dissemination in six patients, leading to death in five. In our opinion, the above-described neoplasms represent a usually "proximal-type" of epithelioid sarcoma. In contrast to the conventional, "distal-type" epithelioid sarcoma, the proximal variant is characterized by a predominantly large-cell, epithelioid cytomorphology, marked cytologic atypia, frequent occurrence of rhabdoid features, and lack of a granuloma-like pattern in most cases. It appears to be somewhat more aggressive (or at least metastasizes earlier) than usual epithelioid sarcoma.

A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation.

Of 143 consecutive patients who survived at least 6 months after bone marrow transplantation (allogeneic [n = 131]; syngeneic [n = 5]; or autologous [n = 7]) and whose pulmonary function was evaluated before and on at least 2 occasions after BMT, 29 (20%) developed a chronic pulmonary syndrome without evidence for an infectious etiology. Twenty-eight (97%) presented with cough and 22 (76%) with dyspnea; abnormal chest signs were crackles in 23 (79%) and wheeze in 22 (76%). Chest roentgenogram showed pulmonary infiltrates in 15 (52%) cases but was normal in 14 (48%). All patients had major reductions in lung volumes (forced expiratory volume in 1 sec [FEV1]; relaxed vital capacity [VC]; and alveolar volume [VA]), and/or diffusing capacity (pulmonary diffusing capacity [TLCO] and single-breath carbon monoxide coefficient [KCO]). The obstructive component varied with only 18 (62%) patients developing overt airways obstruction (FEV1/VC < 75%), and in 6 of this group the fall in lung volumes preceded the onset of airways obstruction. Open lung biopsy (n = 4) showed both bronchiolitis obliterans and chronic patchy interstitial pneumonitis. The development of this syndrome was associated with acute (P < 0.001) and chronic (P < 0.0001) graft-versus-host disease of other organ systems. Twenty-four (83%) patients had a partial or complete response to immunosuppressive agents. Six (21%) have died, five (17%) of pulmonary complications. We suggest that this syndrome may be a manifestation of chronic GVHD involvement of the lung.

Late-onset hemorrhagic cystitis associated with urinary excretion of polyomaviruses after bone marrow transplantation.

Hemorrhagic cystitis is a well known complication of allogeneic bone marrow transplantation (BMT) and is normally attributed to the use of high-dose cyclophosphamide in the preparative regimen. Hemorrhagic cystitis occurring late after BMT is unlikely to be due to the effects of this conditioning, and probably has an infective etiology. Three patients undergoing BMT for chronic granulocytic leukemia (CGL) developed terminal dysuria and hematuria at 38, 56, and 149 days post-BMT. Electron microscopy (EM) of urine voided at these times revealed large numbers of papovavirions, which were subsequently identified as BK virus. Urine samples inoculated onto human embryonic lung fibroblasts induced infection of the cells and replication of the virus as detected by EM of tissue culture fluid. Urine from one of these patients was examined by standard cytological techniques, and EM of urothelial cells showed nuclear inclusions consisting of nonencapsulated virus particles of diameter 40 nm, consistent with papovavirus. Five further patients were found to be excreting BK virus without symptoms of cystitis, although one of these patients did experience abnormalities of liver function that were otherwise unexplained. BK virus has already been implicated in hepatic dysfunction posttransplant, and in cystitis in nonimmunosuppressed children. We postulate that it may also be involved in the etiology of late hemorrhagic cystitis after BMT.

In vivo quantification of human pulmonary beta-adrenoceptor density using PET: comparison with in vitro radioligand binding.

UNLABELLED: A new method has recently been developed to quantify pulmonary beta-adrenergic receptors in vivo using PET. This study used in vitro radioligand binding assay (RLBA) as the gold standard to validate in vivo PET measurements. METHODS: Five male patients with lung cancer aged 57 yr (range 42-67 yr) were studied. PET scanning was performed the day before thoracotomy to determine regional pulmonary beta-receptor density. RLBA was carried out on cell membranes prepared from specimens of lung tissue obtained at the thoracotomy to measure beta-receptor density in vitro. In both cases, the hydrophilic nonselective beta-antagonist radioligand (S)-CGP-12177 was used. For PET studies, this was labeled with 11C and for RLBA with 3H. RESULTS: In the PET study, beta-receptor density (Bmax) was 9.43 +/- 1.32 pmole g-1 tissue. In the RLBA study, Bmax was 99.0 +/- 15.5 fmole mg-1 protein, equivalent to 9.90 +/- 1.55 pmole mg-1 tissue. These values are in good agreement with previously reported in vitro measurements on human lung membranes using 125I-iodocyanopindolol. A correlation was found between beta-adrenergic density obtained using PET and beta-adrenergic density obtained using RLBA (r = 0.92; p < 0.05). CONCLUSION: The results support the use of PET as a new method for imaging and the way for studies of physiological and pharmacological regulation of beta-adrenergic receptors through noninvasive serial measurements.

Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain.

Intracellular immunoglobulin crystal formation within plasma cells is an uncommon finding in multiple myeloma and other lymphoplasmacytic tumors. We present 12 cases of plasmacytic tumors with prominent crystal formation, including myeloma (5 cases), lymphoplasmacytic lymphoma (6 cases), and a nonneoplastic plasma cell proliferation. In all cases, crystal formation was associated with the proliferation of variable numbers of histiocytes containing similar inclusions. These cases showed a variety of appearances, sometimes obscuring the underlying plasma cell tumor and raising the differential diagnosis of a storage disorder, hemophagocytosis, or a mesenchymal lesion. In cases of lymphoplasmacytic lymphoma, patients typically presented with marked paraproteinemia and symptoms of hyperviscosity. Crystal-storing histiocytosis was not associated with other immunoglobulin deposition disorders, including amyloidosis, Mott cell tumors, or kappa-light chain deposition. In our cases and those previously reported, we found an overwhelming association of crystal-storing histiocytosis (CSH) with tumors expressing immunoglobulin kappa light chain with no consistent association with a particular heavy chain. These results suggest that CSH results from the ingestion of crystals produced by plasma cell tumors that either overproduce kappa light chain or express a structurally aberrant molecule. CSH persists in the marrow and other sites throughout the course of the disease and in our series was not highly associated with development of the adult Fanconi syndrome or rapid clinical deterioration.

The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines.

We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 +/- 80.5 fmol) than in benign (29.6 +/- 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.

Solid and papillary epithelial neoplasm arising in heterotopic pancreatic tissue of the mesocolon.

AIM: Solid and papillary epithelial neoplasm (SPEN) is an uncommon pancreatic tumour. Very rarely it has also been described outside the pancreas, usually arising from heterotopic pancreatic tissue. This report summarises all the published extrapancreatic SPENs and documents the sixth such case arising from heterotopic pancreatic tissue of the transverse mesocolon in a 15 year old girl. METHODS/RESULTS: Histological and immunohistochemical examination revealed typical papillary and solid areas composed of columnar, cuboidal, and round cells, which were focally positive for vimentin, cytokeratin, neurone specific enolase, carcinoembryonic antigen, alpha1-antitrypsin, alpha1-antichymotrypsin, and negative for neuroendocrine markers (neurofilament, PGP 9.5, chromogranin A, synaptophysin, and S100), p53, and oestrogen and progesterone receptors. Electron microscopy showed scant zymogen but no neurosecretory granules. In agreement with the flow cytometric result s of diploidy, comparative genomic hybridisation (CGH) did not reveal loss or gain of genetic material, and the in situ hybridisation analysis of the RB1 and p53 genes revealed no abnormality in the 13q and 17p arms. CONCLUSIONS: Immunohistochemical and electron microscopic data support exocrine differentiation. The CGH and the flow cytometric results suggest a subtle, yet unknown genetic change, rather than a large genetic alteration. RB1 and p53 in situ hybridisation ruled out the role of deletion at these sites in the pathogenesis of SPEN. Interestingly, review of the published and the present heterotopic pancreatic SPENs identified the mesocolon as the most common anatomical site (four of six), despite the very rare occurrence of ectopic pancreatic tissue at this site.

Antibody-guided irradiation of malignant ascites in ovarian cancer: a new therapeutic method possessing specificity against cancer cells.

Immunocytology of ascitic fluid of a patient with ovarian cancer demonstrated reactivity with two tumor-associated monoclonal antibodies, AUA1 and HMFG2. AUA1 radiolabeled with 48.6 mCi 131I was given intraperitoneally. There was a reduction in the rate of reaccumulation of ascites. Cytology of recurrent ascites revealed reactivity with antibody HMFG2 but not AUA1. The patient was further treated intraperitoneally with 39.0 mCi 131I-labeled HMFG2. There has been no reaccumulation of ascites. It is concluded that antibody-guided irradiation may be an effective treatment of malignant ascites secondary to ovarian cancer. Furthermore, this case illustrates the specificity of antibody interactions in the mediation of therapeutic effect and the possibility of tumor selection after irradiation with a single monoclonal antibody. If specificity plays a role, all major specificities should be covered by an appropriate panel of radioactively labeled antibodies. It is recommended that for comprehensive therapy of malignant ascites secondary to ovarian cancer, a mixture of antibodies such as HMFG2 and AUA1 should be used.