Surgical management of epithelial ovarian cancer at community hospitals: A population-based study.

BACKGROUND AND OBJECTIVES: Accurate surgical staging and maximal tumor reduction are the basic management principles of epithelial ovarian cancer (EOC). The purpose of our study is to report on staging practices and the primary surgery of EOC in a region that has no tertiary oncological referral center and no surgical gynecological oncologist. METHODS: Between 1 January 1989 and 30 December 1995, the Valais Cancer Registry had registered 157 patients with ovarian cancer stage I-IV. Hospital case notes were reviewed retrospectively and patients who did not have a surgical abdominal exploration (n = 20), with borderline (n = 12) or non-epithelial tumors (n = 13), operated upon in other regions (n = 8) and without complete medical records (n = 2) were excluded. Therefore 102 patients were evaluated. RESULTS: The interventions have been performed in 7 regional hospitals and 1 private clinic by 24 obstetricians-gynecologists and 8 general surgeons. In early EOC, 9% random peritoneal biopsies and 3% retroperitoneal lymph node samplings have been performed. In advanced EOC, 40% of patients had total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy and 42% had cytoreductive surgery with a residual tumor of

How CA 125 is used in routine clinical practice.

The only role where the CA 125 test has proven utility is: (i) for monitoring ovarian cancer (OC); and (ii) for a preoperative test in patients with an ovarian mass. The aim of our study was to assess the clinical indications for CA 125 determinations in order to estimate the appropriateness of CA 125 use. During the period of 1 August 1993 through 31 December 1995 all CA 125 assays performed at the laboratory of the Institut Central des Hôpitaux Valaisans (ICHV) and the data of the patients receiving these tests were audited in order to identify the clinical indication for the test. We have considered as 'correct indication' a CA 125 test performed: (i) during follow-up monitoring of patients having an OC and; (ii) as a preoperative test of a suspect ovarian mass. 462 patients have received a total of 1057 CA 125 assays. 84 (18%) patients have received 537 (51%) tests for monitoring OC and 68 (15%) patients, 68 tests (6%) as a preoperative evaluation for an ovarian mass. 310/462 (67%) other patients have received 452/1057 (43%) CA 125 tests for screening purposes in various clinical situations. Therefore, only 33% (152/462) patients including 57% (605/1057) of tests, had CA 125 assessments done for the correct indication. The current pattern of practice shows that a great number of CA 125 requests were inappropriate. Educational actions aimed at laboratory users concerning the optimal use of CA 125 should be considered in order to develop a more rational approach.

[15 years CA-125 antigen: usefulness and limits. Apropos of 3 clinical cases]. / 15 ans de CA 125: utilité et limites. A propos de 3 situations cliniques.

Fifteen years ago, the first clinical assay of the serum tumour marker CA 125 was introduced as a commercial kit. This test is currently the most widely used tumour marker in gynaecologic oncology. Studies have shown that the CA 125 is a valuable tool in the follow-up management of ovarian cancer. As a teaching exercise we present the analysis of three clinical cases, in which CA 125 was determined. Two of these patients did not have an ovarian cancer. It appears that this tumour marker very often is not only used in the follow-up of ovarian cancer, but also as a screening test and as a diagnostic tool. This inappropriate use (due to the lack of specificity and therefore many false positive results) can be avoided by considering it's limits.

[Secondary prevention of cancer]. / Sekundäre Prävention von Krebskrankheiten.

Annual screening for cervical cancer is recommended from the onset of sexual maturity onward. Mammography has been recommended after the age of 50 to 70. Colorectal cancer should be looked for by hemoccult-test after 40 to 50 years of age. The negative consequences of false positive test results are in general considered acceptable. They seem unacceptable at the time being for cancer of the breast between 40 and 50 years of age and for cancer of the prostate.

Cisplatin, doxorubicin and etoposide (PAV) in advanced gastric carcinoma: the SAKK experience. Swiss Group for Clinical Cancer Research (SAKK).

EAP (etoposide, doxorubicin, cisplatin), a chemotherapeutic combination given over 8 days, proposed by German investigators in cancer of the stomach, has been considered to be too toxic by others. A positive experience with a similar regimen (PAV) developed by the SAKK given over 3 days in small cell lung cancer led us to test it in gastric adenocarcinoma. 41 patients with metastatic gastric cancer were enrolled in the study and 38 were evaluable for response and toxicity. One complete response and 12 partial responses were recorded, giving a response rate of 34% (95% confidence interval (CI) 20-51%). Median progression-free and overall survival were 3.4 and 6.3 months, respectively. Haematotoxicity was the leading toxicity with 34 (90%) and 17 (45%) grade III-IV neutropenia and thrombocytopenia, respectively. Despite this high rate of granulocytopenia, only six episodes of non-fatal febrile neutropenia were observed. Other toxicities were relatively easy to manage with infrequent grade III-IV occurrences. We conclude that PAV is active in gastric cancer and seems to be better tolerated than EAP.

Epoetin alfa facilitates presurgical autologous blood donation in non-anaemic patients scheduled for orthopaedic or cardiovascular surgery.

Patients expected to need at least three units of blood for their elective cardiovascular or orthopaedic surgery, were allocated randomly to receive intravenous (i.v.) Epoetin alfa 600 IU kg-1 (n = 27), 300 IU kg-1 (n = 30) or placebo (n = 23), on days 1, 4 and 7. Provided haemoglobin > or = 11 g dL-1, one unit of blood was collected on days 1, 4, 7, 11 and 14. Iron supplementation was given throughout the study. Surgery was scheduled between days 18 and 21. Significantly more patients treated with Epoetin alfa (100% for 600 IU kg-1; 97% for 300 IU kg-1) were able to donate > or = 4 units of blood compared with placebo (78%) (P = 0.011 and P = 0.032). No significant differences were seen in total patient exposure to homologous blood (7.4%, 3.3% and 17.4%, respectively). Mean red cell volume donated (P = 0.005 for 600 IU kg-1; P = 0.158 for 300 IU kg-1 both vs. placebo) and production (P < 0.001 and P = 0.012, respectively) were dose related. Twenty-four patients became iron deficient. No differences in the incidence of adverse events were seen between the groups.

[Ovarian cancer: the symptoms and pathology. The cases of the Cantonal Cancer Registry (1989-1995)]. / Cancer de l'ovaire: symptômes et pathologie. Cas d'un Registre cantonal des tumeurs (1989-1995).

BACKGROUND: Ovarian cancer is most frequently discovered at an advanced stage. The absence of symptoms in the early stages is thought to be the main reason for this late discovery. We tried to determine whether there are any specific signs or symptoms for early or late stages. METHODS: From 1989 to 1995, the Cantonal Cancer Registry recorded 124 patients with ovarian cancer; 119 (96%) cases were evaluated. We defined signs and symptoms which led to the diagnosis, their histopathological properties and the medical specialty of the physician first consulted. The data were then analyzed for early stages (IA to IB) (n = 27) and advanced stages (IC to IV) (n = 92). RESULTS: In the early as well as late stages, the most common symptoms were abdominal pain (76%) and gastrointestinal problems (45%). Bladder and gynecological symptoms were rare (25% and 7% respectively). In the early stages, however, the ovarian tumor was larger (median size 14 vs 11 cm), there were more well differentiated tumors (48% G1 vs 25%) and the age was lower (median age 55 vs 66 years). The physician first consulted was a general practitioner in 2/3 (68%) of the cases and a gynecologist in 17%. CONCLUSIONS: There are no specific ovarian carcinoma symptoms either in the early or in the late stages. The histology showed that tumors in the early stages were less aggressive and usually occurred in younger patients. The general practitioner was most often the first physician consulted by women suffering from ovarian cancer. General practitioners, therefore, should be specialists in the diagnosis of this disease, paying particular attention to women over 40 presenting with persistent abdominal pain.

Oral ondansetron in the prophylaxis of nausea and vomiting induced by cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in women with breast cancer. Results of a prospective, randomized, double-blind, placebo-controlled study.

BACKGROUND: The combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a widely used chemotherapy regimen in breast cancer patients. However, the control of nausea and vomiting induced by oral CMF is a rarely examined problem. Therefore we felt a randomized, placebo controlled study justified in order to improve currently available antiemetic therapy. SUBJECTS AND METHODS: In a randomised double-blind trial ondansetron given orally, 8 mg three times a day for 15 days, was compared with placebo in 82 breast cancer patients receiving chemotherapy with CMF (cyclophosphamide 100 mg/m2 orally days 1-14, methotrexate 40 mg/m2 i.v. days 1 and 8 and 5-fluorouracil 600 mg/m2 i.v. days 1 and 8). The patients recorded nausea and the number of vomits and retches daily on diary cards. Forty-two patients received ondansetron and 40 received placebo. RESULTS: Significantly more patients who received ondansetron experienced neither vomiting nor retching (emesis) compared to those receiving placebo over a 15 day treatment period (60% vs. 35%, p = 0.027). The difference, with 95% confidence limits, was estimated at 25 (4.45%). Furthermore, there was a trend in favour of ondansetron in the control of nausea. Ondansetron was well tolerated, with 25 patients (59%) reporting at least 1 adverse event compared to 18 patients (45%) receiving placebo (p = 0.191). CONCLUSION: The results indicate that ondansetron given orally for 15 days is safe and effective in the control of emesis induced by CMF. It is however too early to recommend ondansetron as standard antiemetic therapy for oral CMF, as the treatment of nausea and vomiting in this setting has not been studied thoroughly enough.

Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide.

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1 beta and IL-6 production were low in 9 patients (group L, < 15%) and high in 5 patients (group H, > 40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pre-therapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.

Prolonged interferon-gamma application by subcutaneous infusion in cancer patients: differential response of serum CD14, neopterin, and monocyte HLA class I and II antigens.

This study reports on biological response modification induced by prolonged continuous subcutaneous (s.c.) infusion of recombinant interferon-gamma (rIFN-gamma) with particular attention to changes of soluble CD14. This glycoprotein with an unknown function is derived from myeloid cells carrying membrane CD14, which is the receptor for lipopolysaccharide (LPS)-LPS-binding protein (LBP) complexes. Fifteen metastatic cancer patients received weekly escalating doses of rIFN-gamma starting at either 50 or 100 micrograms/24 h and increasing up to 400 micrograms/24 h for a median duration of 6 weeks. The maximum tolerated dose was higher (200 micrograms/24 h) with the lower (50 micrograms/24 h) starting dose. Biological activity of rIFN-gamma was evaluated by weekly measurements of CD14, neopterin, and beta 2-microglobulin concentrations in serum as well as monocyte HLA class I and II antigen expression and tumor cytotoxicity. Serum IFN-gamma concentrations increased 20-fold within 4 weeks of therapy. The levels were correlated to the mean dose (r = 0.95, p less than 0.05). Among the biological markers, two patterns were observed. First, serum CD14 concentration and expression of monocyte HLA class II antigens increased significantly during the first week, and marker expression correlated with serum IFN-gamma levels (p less than 0.05); CD14 and HLA class II antigens thereafter returned to pretreatment levels within 4 weeks of therapy despite persistently elevated serum IFN-gamma concentrations. Second, serum neopterin and beta 2-microglobulin concentrations as well as monocyte HLA class I expression also increased significantly within the first week, but remained elevated thereafter without any further dose relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for linkage between the swine L blood group and the loci specifying the receptors mediating adhesion of K88 Escherichia coli pilus antigens.

Brush borders or enterocytes obtained from the small intestine of 248 pedigreed pigs were tested by adhesion assay in vitro with enterotoxigenic Escherichia (E.) coli strains, each expressing one of the three K88 pilus variants K88ab, K88ac and K88ad. All pigs were classified as belonging to one of the four adhesion phenotypes: I--K88ab(-), ac(-), ad(-); II--K88ab(-), ac(-), ad(+); III--K88ab(+), ac(+), ad(-); and IV--K88ab(+), ac(+), ad(+). Serum or red cells were typed for 15 blood group systems: A-O, B, C, D, E, F, G, H, I, J, K, L, M, N and O; for 11 biochemical polymorphisms: PI1, PI2, PO1A, A1BG, GPI, PGD, TF, HPX, ADA, PGM and AMY; the polymorphism at the IGHG1 locus. Linkage analysis was performed between the alleles at the locus (loci) specifying K88 receptors able to bind one or more different serological types of K88 E. coli and alleles for markers at other loci. Linkage was demonstrated between the locus for the L blood group system and the locus (loci) for K88 E. coli receptors (Z = 3.24), adding one locus (loci) to the previously identified linkage group IV (LGIV) [L-SLB]. The maximum likelihood estimate of the recombination fraction (theta) was 0.23. No evidence was found for linkage between any of the other biochemical and immunogenetic markers and the receptor locus (loci) of K88 E. coli.

Effect of cytokines and lipopolysaccharide on CD14 antigen expression in human monocytes and macrophages.

The 52 kD myeloid membrane glycoprotein CD14 represents the receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein (LBP); it is involved in LPS induced tumor necrosis factor-alpha production. Expression of CD14 increases in monocytes differentiating into macrophages, and it is reduced by rIFNg in monocytes in vitro. In the present study CD14 membrane antigen expression was investigated in cultures of human mononuclear leucocytes (PBL), in elutriated, purified monocytes, and in blood monocyte derived Teflon cultured macrophages. Cells were incubated for 15 or 45 h with rIL-1, rIL-2, rIL-3, rIL-5, rIL-6, rTNFa, rGM-CSF, rM-CSF, rTGFb1, rIFNa, lipopolysaccharide (LPS), and, as a control, rIFNg. The monoclonal antibodies Leu-M3 and MEM 18 were used for labelling of CD14 antigen by indirect immunofluorescence and FACS analysis of scatter gated monocytes or macrophages. IFNg concentrations were determined in PBL culture supernatants by ELISA. rIFNa and rIL-2 reduced CD14 in 15 and 45 h PBL cultures, an effect mediated by endogenous IFNg, since it was abolished by simultaneous addition of an anti-IFNg antibody. rIFNa and rIL-2 were ineffective in purified monocytes or macrophages. rIL-4 strongly reduced CD14 in PBL and purified monocytes after 45 h, whereas in macrophages the decrease was weak, although measurable after 15 h. The other cytokines investigated did not change CD14 antigen expression. Cycloheximide alone reduced CD14, but when added in combination with rIFNg the effect on CD14 downregulation was more pronounced. The effect of rIFNg on CD14 in PBL cultures was dose-dependently inhibited by rIL-4 and this inhibition is probably due to an IL-4 mediated blockade of IFNg secretion. LPS at a low dose increased CD14, at a high dose it produced a variable decrease of CD14 in PBL, which was probably due to LPS induced IFNg secretion. LPS strongly enhanced CD14 in 45 h cultures of purified monocytes. The results, showing that CD14 antigen expression is upregulated by LPS and downregulated by rIFNg and rIL-4, suggest that the LPS-LBP receptor is involved in the feedback response of IFNg and IL-4 to LPS stimulation.

[Emergency therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF)]. / Notfalltherapie mit Granulozyten-Makrophagen-Kolonien stimulierendem Faktor (GM-CSF).

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been tested for tolerability and efficacy on a compassionate need case basis in 17 patients (5 females, 12 males aged 4-72 years, median 35 years). GM-CSF was given at the rate of 3.5-32 micrograms/kg for 2-64 days as a continuous infusion for the following indications: impending rejection following bone marrow transplantation (5 patients), severe neutropenia secondary to chemotherapy in tumor patients (5), severe aplastic anemia (3), immune granulocytopenia (2) and accidental overdose with cytostatic agents (2 patients). Tolerance of GM-CSF was good in regard to doses of up to 16 micrograms/kg. Fever, myalgia and eosinophilia were the most frequent side effects. The patient treated with 32 micrograms/kg developed thrombosis of the vena cava. Efficacy is more difficult to assess in this heterogenous population, but 11 of 17 patients showed increased granulocyte counts and 3 patients clearly recovered from severe neutropenia. The role of GM-CSF in this recovery, however, cannot be proven. The results further indicate that GM-CSF cannot reverse ongoing rejection following allogenic BMT and cannot correct immune neutropenia. The value of GM-CSF therapy in patients with severe aplastic anemia and in the context of chemotherapy still needs to be defined. It is certainly indicated in patients with an accidental overdose of chemotherapeutic agents.

Acute and subacute toxicity of chemotactic conjugates between monoclonal antibody and fMet-Leu-Phe in humans: a phase I clinical trial.

Conjugates of the chemotactic peptide fMet-Leu-Phe (fMLP) to IgG retain chemotactic and antigen recognition function in vitro and enhance intra-tumour macrophage numbers in a guinea pig model. We report a study approved by the ethics committee on the acute toxicity of fMLP conjugates in ten consenting cancer patients with metastasizing melanoma and colon cancer. They were given increasing single doses (1-2500 micrograms) IgG-fMLP made with the anti-melanoma monoclonal antibody (mAb) 9.2.27. Clinical examinations and blood cell counts, urinalysis, electrolytes, and liver and kidney function tests before and after the infusion and weekly thereafter revealed no relevant toxicities. One patient had a herpes zooster exacerbation on day 1, which was judged to be coincidental. Peak post-infusion conjugate serum concentrations fell to unmeasurable levels within a few days. In no case was a human humoral anti-(mouse Ig) immune response detected.

Human B cells express membrane-bound and soluble forms of the CD14 myeloid antigen.

The expression of the myeloid differentiation antigen CD14 on the B lineage was analyzed. A CD14-specific monoclonal antibody was used to isolate the antigen from normal B, B-type chronic lymphocytic leukemia cells, and a representative Epstein-Barr virus-transformed B lymphoblastoid cell line (EBVLCL). A soluble form of this protein was detected in the culture supernatant of all the B cell types tested. The molecule expressed in the normal B and B-type chronic lymphocytic leukemia cells was identical in size to the 52,000 mol. wt monocyte-isolated CD14 glycoprotein. A 64,000 mol. wt antigen was isolated from the lymphoblastoid cell line. Similar 2-D gel electrophoretic patterns to that of the monocyte-derived CD14 were obtained from the normal B and B-type chronic lymphocytic leukemia cell-isolated molecules. These similarities were reflected in minor isoelectric point (pI) differences between the polypeptide spots (pI 4.8), in the first dimension, and identical molecular weight (52,000) in the second dimension. The EBVLCL-isolated polypeptide, when analyzed by 2-D gel electrophoresis, showed a pI identical to that of the myeloid antigen (pI 4.6). The isolated soluble form was of smaller (47,000 mol. wt, normal B and B-type chronic lymphocytic leukemia cells) or similar size (64,000 mol. wt, lymphoblastoid cell line) compared with their corresponding membrane-bound forms. Interestingly, two-colour immunofluorescence analysis showed that only two out of four CD14-specific mAb tested bound to the B cells. We conclude that the CD14 antigen is, in fact, expressed in the B lineage. Its cell surface expression and serum level in the prognosis of B-type chronic lymphocytic leukemia patients needs to be evaluated.