Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas.

Matrix metalloproteinases are believed to play an important role in tumor invasion and metastasis. To examine the expression of the stromelysin 3 (ST3) gene, a new member of the matrix metalloproteinase gene family, 111 head and neck squamous cell carcinomas and 21 metastatic lymph nodes were analyzed by Northern blot. ST3 gene expression was observed in 106 carcinomas and 19 metastatic nodes, but in only 2 of 60 samples of corresponding normal tissue tested in parallel. ST3 RNA, by in situ hybridization, and ST3 protein, by immunohistochemical analysis, were specifically detected in fibroblastic cells immediately surrounding invasive cancer cells. This fibroblastic expression of the ST3 gene is characteristic among the matrix metalloproteinase genes known to be overexpressed in head and neck carcinomas, since stromelysin 2 transcripts were specifically detected in neoplastic cells, and type I collagenase transcripts in both neoplastic cells and stromal fibroblasts. Furthermore, there was a highly significant positive correlation (P < 0.0001) between ST3 RNA levels and local invasiveness by the cancer cells, suggesting that enhanced expression of the ST3 gene may contribute to the neoplastic phenotype in head and neck carcinomas.

Phase I study of liposomal MTP-PE-activated autologous monocytes administered intraperitoneally to patients with peritoneal carcinomatosis.

We have conducted a phase I study with autologous monocytes activated ex vivo and administered intraperitoneally in nine patients with peritoneal carcinomatosis. Blood monocytes were collected by leukapheresis and then purified by counterflow elutriation (up to 10(9) cells, with a purity of greater than 90%). Ex vivo activation was obtained by incubating these cells with 1 micrograms liposomal MTP-PE/10(6) monocytes for 18 hours in hydrophobic culture bags at 37 degrees C in 5% carbon dioxide humidified air. The activated monocytes were then infused in the peritoneal cavity once a week for 5 consecutive weeks through an implanted peritoneal infusion system, Port-A-Cath (Pharmacia Deltec, St Paul, MN), on an intrapatient dose-escalating schedule (10(7) to 10(9) monocytes). No severe adverse reactions occurred. Toxicity was mild, the chief acute reactions being fever (27%), chills (13%), and abdominal pain (25%). None of the side effects led to dose reduction. No consistent change in hemostatic function, liver function, or renal function was observed. Significant increases in granulocyte counts, neopterine, and acute phase reactants (fibrinogen, C-reactive protein) occurred in the peripheral blood. In vitro monocyte activation was demonstrated by the relapse of procoagulant activity and monokines (interleukin-1 [IL-1], IL-6, and tumor necrosis factor-alpha [TNF alpha]) in the supernatants of cultured monocytes. Evidence for in vivo monocyte activation was provided by the increase of these monokines in the peritoneal fluids. Kinetic studies with indium-111 (111In)-labeled activated autologous monocytes in five patients suggest that these infused monocytes may remain in the peritoneal cavity for up to 7 days. This locoregional immunotherapeutic approach seems to be encouraging in view of adjuvant therapeutic modality in ovarian cancer patients with minimal residual intraabdominal disease following second-look laparotomy.

Modulation of human breast cancer cell adhesion by estrogens and antiestrogens.

In order to study the effect of estrogens and antiestrogens on the adhesive properties of human breast cancer cells, the attachment on endothelial cells (EC), on subendothelial extracellular matrix (ECM) and on ECM components (collagen I and IV, laminin, fibronectin) of estrogen-dependent (MCF-7, ZR75-1) and estrogen-independent (BT-20) breast cancer cell lines was investigated. The cells were grown under conditions of controlled exposure to estrogen [17 beta-estradiol (E2)] and/or antiestrogens [tamoxifen (Tam) or 4-hydroxytamoxifen (OH-Tam)]. Treatment by E2 enhanced the ability of ZR75-1 cells to adhere to the various substrates, which contrasts with the observed absence of effects with the BT-20 cells. Similarly, Tam or OH-Tam induced a reduction of the adhesion of ZR75-1 tumor cell, but not of BT-20 cells. This effect was reversed by competing concentrations of E2. The effects on MCF-7 cell adhesion were similar to those described for ZR75-1 cells, but could not be reproducibly observed. Adhesion assays carried out with ZR75-1 cells grown in the absence or presence of phenol red, a pH indicator which behaves as a weak estrogen, led to a similar pattern of cell attachment. Conditioned media harvested from E2- or Tam-treated ZR75-1 cells failed to induce any effect on adhesion of other ZR75-1 cells grown in E2-deprived medium, suggesting that secretory activities are not required for the control of cell adhesiveness. The results suggest that estrogens and antiestrogens can control the adhesive behavior of breast tumor cells through their hormone responsive structures possibly by regulating expression of cell adhesion proteins and/or their cell surface receptors.

Amplification of 11q13 DNA markers in head and neck squamous cell carcinomas: correlation with clinical outcome.

This study was performed on 282 patients with primary head and neck squamous cell carcinomas to evaluate the prognostic importance of 11q13 amplification. Amplification of the 11q13 DNA markers, HST-1/FGF-4 and BCL-1, evaluated by Southern and slot blot hybridisation, was detected in 52% of tumours. 11q13 amplification was associated with tumour site since this alteration occurred in 76% of tumours arising in the hypopharynx, versus 40% in the other sites (P = 0.0007). 11q13 amplification was also significantly related to the presence of involved neck lymph nodes (P = 0.013). The relationship between 11q13 amplification and risk of progression was studied in two subgroups of head and neck cancer patients with regard to treatment modalities. The presence of 11q13 amplification in the tumour was not significantly associated with a shorter event-free survival (P = 0.82) and crude survival (P = 0.61) of the 201 patients treated by surgery and postoperative radiotherapy. Similarly, absence of a relationship was observed for the group of 79 patients treated by surgery alone. These results confirm that 11q13 amplification is a prominent event in head and neck squamous cell carcinoma, indicating that it may be a common genetic event in the development of these neoplasms, but is not a reliable prognostic marker.

Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy.

The aim of this study was to evaluate the predictive value of five different biological factors in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy: (1) tumour grade scored according to the Elston-Ellis classification, (2) hormonal receptor (HR) status; (3) tumour cell proliferation evaluated by Ki-67 staining, (4) HER-2 and topoisomerase II alpha (TopoIIalpha) expression evaluated by immunohistochemistry (IHC), (5) HER-2 and TopoIIalpha amplification evaluated by real-time polymerase chain reaction (PCR). 119 patients with operable breast cancer were treated with six cycles of FEC (100 5-fluorouracil (5-FU) 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2). Tumour response was assessed clinically and by computed tomography (CT) scan, then by pathological assessment. The clinical overall response (OR) was 80%, with 19% of complete responders (CR). The radiological OR was 71%, with 16% of CR. A pathological CR was demonstrated in 13% of the patients according to the Sataloff classification. In the multivariate analysis, the absence of HR expression and Ki-67 > or = 20% were predictive for a clinical CR. A high tumour grade was predictive for a pathological CR. Overexpression or amplification of HER2 or Topollcalpha were not predictive of response.

Platelet regeneration time after aspirin ingestion and platelet survival time after labelling with 51chromium or 111indium oxine--a comparative study.

A simultaneous investigation of platelet regeneration time (PRT) based upon malondialdehyde (MDA) recovery after a single oral intake of 500 mg of aspirin and of platelet survival time (PST) after labelling with 51chromium or 111indium oxine was performed in 25 cancerous patients. A pilot study conducted with 9 healthy volunteers demonstrated that the MDA assay was highly reproducible and specific for the platelet cycloxygenase activity. The pattern of MDA recovery after aspirin ingestion was linear in the healthy volunteers and in the patients presenting both a normal and an accelerated platelet turnover. PST were calculated using the four mathematical models recommended by the International Committee for Standardization in Hematology; the best fit was given by the multiple hit model in 22 cases and by the linear regression model in 3 cases. The mean results obtained in the patients investigated with the 51chromium were consistently shorter than those obtained in the patients investigated with the 111indium oxine while the mean PRT were almost identical in the two groups. An excellent correlation between PRT and PST was observed after 111indium oxine labelling and using the weighted mean method for PST determination. These results suggest that the 111indium oxine technique is a better method for platelet labelling and that the results provided by the weighted mean method reflect more closely the in vivo platelet turnover than those provided by the multiple hit model.

Rflp analysis of the L-myc oncogene in head and neck-cancer - relationship study with susceptibility and disease progression.

The L-myc DNA restriction fragment length polymorphism (RFLF), revealed by EcoRI digestion, has been evaluated in a case-control study including 161 head and neck cancer (HNSCC) patients and 160 normal healthy individuals with similar smoking and alcohol habits. No significant difference in the distribution of L-myc genotypes (LL, LS or SS) was found between the two populations implying thus no predisposition to head and neck tumour by either allele. There was no significant association between L-myc genotypes and the usual clinicopathological features such as T staging, differentiation status and lymph node involvement. Moreover, follow-up data from 154 patients was obtained and correlated with the L-myc pattern. No significant difference was observed in metastasis occurrence, multiple cancer incidence and survival data in the patients classified according to the L-myc genotypes; only a trend to preferentially develop metastasis in lung for patients with S allele was noted. In conclusion, our data shows that the L-myc typing does not contribute to HNSCC risk or prognosis assessment. A review of L-myc RFLP published studies shows contradictory results even on the same type of tumour and emphasizes the lacunae in understanding the biological role of L-myc for valid interpretation of L-myc allelic associations with cancer susceptibility or prognosis.

Frequency and intensity of crack use as predictors of women's involvement in HIV-related sexual risk behaviors.

Recent trends in the progression of the AIDS epidemic in the United States indicate that women's rates of acquiring HIV are escalating more rapidly than are men's. Consequently, there has been both an increasing interest in and a need for research targeting substance-abusing women's involvement in HIV risk behaviors. In recent years, strong suggestive evidence has arisen to suggest that women who use crack cocaine are at an elevated risk for acquiring HIV, probably as a result of their involvement in high-risk sexual behaviors. The present study is based on a sample of 1723 women from 22 locales around the United States who used crack cocaine at least once during the previous 30 days but who reported never having injected drugs at any point in their lifetime. Women were divided into four groups based on their frequency and intensity of using crack. In subsequent analyses, this grouping was used to predict the extent to which female crack users engage in five sexual risk behavior measures (number of sexual partners, number of drug-injecting sexual partners, number of times having sexual relations while high on alcohol and/or other drugs, number of times trading sex for drugs and/or money, and proportion of all sexual acts involving the use of protection). The data revealed that the women who used crack with the greatest frequency and the greatest intensity were the most heavily involved in risky sexual behaviors. They differed quite sharply from their lower-intensity and/or lower-frequency crack-using counterparts in terms of their HIV risk behavior involvement and in terms of their actual HIV seroprevalence rates.

Immunoradiometric assay for human thyroglobulin and variations in thyroid pathology.

A specific and sensitive double antibody radioimmunoassay for measuring human serum thyroglobulin (Tg) has been developed. Serum Tg levels are reported for patients with differentiated and undifferentiated thyroid carcinomas, post-treated and untreated hyperthyroidism, thyroiditis, and cold nodular goiters. We have studied results of serum Tg levels in the follow-up and care of patients who have undergone total thyroidectomy for differentiated thyroid carcinomas. Tg has no diagnostic value in the detection of thyroid cancer, but is a reliable index of metastatic growth in the follow-up of patients with differentiated carcinomas. In addition, serum Tg determination might be helpful in the aetiological diagnosis of bone or lung metastases of unknown origin.

Alteration of the C-met oncogene locus in human head and neck-carcinoma.

The c-met proto-oncogene encodes the receptor for the hepatocyte growth factor/scatter factor (HGF/SF) which induces eel proliferation and motility. We have analysed the genetic alteration involving the c-met locus on chromosome 7q31 using the pMet H polymorphic probe, in tumor and normal DNA from 87 patients with head and neck squamous cell carcinomas (HNSCC). We report the observation of loss of heterozygosity (LOH) at this locus in 23% of informative cases, contrasting with the previously reported 40% LOH detected in breast cancer. Further, gain of genetic material was also observed in 13% of the HNSCCs. The alterations of c-met gene were not significantly associated with standard pronostic features including tumor size and lymph node status. Involvement of the c-met locus in allelic imbalance, either loss or gain of genetic material, is relatively consistent with complex karyotype patterns detected in head and neck squamous cell carcinomas through previous cytogenetic studies.

[Circulating immune complexes in breast cancer]. / Complexes immuns circulants dans le cancer du sein.

The occurrence of circulating immune complexes (CIC) was investigated in serum samples from 139 patients with breast cancer, using the 125I-C1q binding test. In the 85 cases of regional forms, the level of Clq binding activity did not appear to be correlated with the clinical TN stage, nor with the local treatment of the tumor. Conversely it was clearly elevated in the 13 cases of inflammatory breast tumors, and the decrease of CIC at the post-chemotherapy, but pre-surgical stage may involve the inflammatory signs in this augmentation of CIC. Frequency of occurrence and levels of CIC were slightly increased in the 41 metastatic breast cancer patients when compared to the cases of local breast carcinoma. In the disseminated forms, increase, no change, or decrease of CIC levels showed a poor correlation to progression, stabilisation, or improvement of the disease. CIC seems to be of slight prognostic value in breast cancer with local forms, but regarding progression of the disease, metastatic breast cancer patients with elevated CIC did not prove to be unfavorable group. So far, CIC did not appear to be a tumor marker or an evident prognostic factor of clinical relevance in breast cancer. Assays for antigen-specific CIC might be of greater clinical significance, in breast cancer, than the antigen non specific assays available at present.

Apheresis-elutriation program for adoptive immunotherapy with autologous activated monocytes in cancer patients.

Human blood monocytes (Mo) and monocyte-derived macrophages (M phi) are known to be potent antitumor cytotoxic effector cells through activation with recombinant human interferon gamma (rIFN-gamma), bacterial muramyldipeptide or the synthetic derivative muramyltripeptide phosphatidylethanolamine entrapped in liposomes (L-MTP-PE). Large-scale generation of ex vivo activated Mo from the blood of cancer patients proved feasible. We report our experience with a fixed rotor speed counterflow centrifugation elutration (CEE) procedure using the newly available Beckman high capacity JE-5.0 rotor system that reproducibly isolates up to 1.0-1.5 x 10(9) Mo with greater than 90% purity, in suspension and functionally intact derived from peripheral blood mononuclear cell-enriched suspensions obtained by leukapheresis (LP) from healthy volunteers and cancer patients. The semiclosed, easy to handle CCE system, was adapted to a sterile technique that permitted clinical trials in adoptive monocyte immunotherapy. Freshly isolated Mo did not lose morphological or functional integrity and had no spontaneous activation. Their abilities to become activated to the cytotoxic state after 18-h stimulation with 500 U/ml rIFN-gamma or 1 microgram/ml L-MTP-PE and to differentiate into matured M phi in vitro were not altered. The system was therefore used to isolate large numbers of Mo for a phase I clinical trial of intraperitoneal immunotherapy with L-MTP-PE activated autologous Mo in nine patients with peritoneal carcinomatosis. Each patient received weekly Mo infusions (n = 5) with an intrapatient dose escalation schedule (from 10(7) to 10(9) Mo). Toxicities were mild including fever, chills and abdominal pain. There was no treatment-induced thromboembolic event or capillary leak syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized study of on-line plasma perfusion over protein A-sepharose and 5-fluorouracil chemotherapy in patients with metastatic colorectal carcinoma.

To evaluate the safety of on-line plasma perfusion over protein-A sepharose and the therapeutic advantage of combining plasma perfusion (PP) over protein-A sepharose with 5-fluorouracil (5-FU) chemotherapy in patients with metastatic colorectal carcinoma (MCRC), thirty patients were randomized after surgery of primary CRC to receive a combination of 5-FU and PP over protein-A sepharose (group A), or a combination of 5-FU and PP over sepharose (group B), or 5-FU alone (group C). Bi-weekly on-line PP over 200 ml protein-A sepharose gel (group A) or 200 ml sepharose gel (group B) were performed with a Cobe 2997 blood cell separator for a maximum of 19 treatments per patient. 5-FU was given at 1000 mg/m2/d on days 1-5 of a 4-weekly cycle until progression. PP was well tolerated and no severe or life-threatening toxicity was observed. Mild clinical side-effects consisted of fever and chills (36% in group A, 23% in group B). The most common biological effects of PP over protein-A sepharose were significant drops in IgG (66% of pre-PP values), CH50 and C3 (73% of pre-PP values) and a significant generation of C3a and C5a anaphylatoxins. Tumor response rates were 40% for group A, 0% for group B and 20% for group C. The median survival times tended to be longer in group A (17 months) than in group B (10 months) and in group C (9 months). This is the first randomized trial showing some therapeutic advantage in combining PP over protein-A sepharose with conventional chemotherapy in MCRC.

[Left intraventricular thrombosis. From diagnosis to treatment]. / Thrombose intraventriculaire gauche. Du diagnostic au traitement.

Left ventricular thrombi are the source of much concern in numerous conditions affecting the ventricles. Refinement in echocardiographic and isotopic techniques is enabling earlier diagnosis and a more rational approach to therapy. These thrombi occur very frequently, and are most often asymptomatic (more than 2 to 3 times out of 4), and their natural course is not well known. Recent studies have dealt with acute ischemic cardiopathies, but these should not obscure the fact that thrombi occur with similar frequency in chronic conditions, in particular, hypokinetic cardiomyopathies. Three recent cases emphasize this, demonstrate the frequency of these thrombi, and help illustrate available diagnostic methods and a practical approach to this condition. These recent developments only confirm the importance of effective anticoagulation in all patients at risk and the necessity of optimal treatment with inotropic agents which do not suppress thrombus formation, but appear to prevent their complications.

Erotized transference reconsidered: expanding the countertransference dimension.

A reconsideration of the erotized transference from a contemporary perspective has been presented utilizing detailed case material provided by Stoller. The main thesis is that this type of transference, traditionally conceived as a product of a particular kind of patient often felt to be borderline, is better understood as arising in a specific intersubjective context involving both participants in the psychoanalytic situation. The focus is on the intricate interaction of analyst and patient, recognizing that either may serve as a selfobject for the other. This view assumes a more expanded countertransference role than recognized in the earlier literature. The psychoanalytic situation can be erotized by either or both participants. A corollary thesis is that the details of a patient's fantasy should also be viewed as codetermined and that imbedded within it might be the patient's subjective experience of the psychoanalytic interaction. Alluded to peripherally is that the erotized transference in the interaction between male analyst and female patient is, in part, a manifestation of traditional roles assumed in situations involving a male authority figure in close engagement with a female who perceives herself as relatively powerless. This issue has recently received considerable attention from writers who have addressed themselves to the important gender issues in psychoanalysis.

Chemistry and biological activity of essential oils from Piper claussenianum (Piperaceae).

Analyses of essential oils obtained from fresh and dried leaves and inflorescences of Piper clausenianum were performed using GC-FID, GC-MS and NMR techniques. Forty compounds were detected for these four oils with the total of identified constituents ranging from 88.7% for the dried inflorescences to 97.7% for the dried leaves. Sesquiterpenes were the main constituents in the volatile fraction from leaves with a high percentage of (E)-nerolidol (up to 83%). However, monoterpenes were identified in greater amount in the inflorescences, with linalool percentages from 50% up. The essential oils from fresh leaves and inflorescences were submitted to anti-parasitic activity against a strain of Leishmania amazonensis. Both samples showed biological activity, but the essential oil from P. claussenianum fresh leaves, which was rich in (E)-nerolidol, showed effective growth inhibition of L. amazonensis due to the high percentage of this metabolite in the mixture.