Retroperitoneal primitive neuroectodermal tumor (PNET): case report and review of literature.

Primitive Neuroectodermal tumor belongs to the family of Ewing's tumor and is characterized by at (11;22) (q24;ql2) or at (21;22) (q22;ql2) translocation. Retroperitoneal primitive neuroectodermal tumor (PNET) are rare, usually affect young adults, and are often diagnosed late. There is no specific characteristics for imaging. The diagnosis is made on histological examination of the surgical spec- imen or biopsies. Radiotherapy and chemotherapy complete the treatment. The authors report the case of a 26-year-old patient who only had pelvic discomfort. Diagnostic laparoscopy showed a retroperitoneal and retrovesical mass of five centimeters. The patient benefited from adjuvant chemotherapy and radiotherapy. She is free of disease 30 months after treatment.

Gestational choriocarcinoma transmission following multiorgan donation.

An accidental transmission of placental choriocarcinoma (CC) from a multiorgan donor to four recipients is reported. The donor was a 26-year-old pregnant woman, died from a cerebral hemorrhage. Histological examination demonstrated the presence of a placental CC. Diagnosis of CC transmission was established on the basis of an increase of human chorionic gonadotrophin hormone (hCG) level. The recipient of combined pancreas-kidney is still in complete remission 2 years after the beginning of chemotherapy without removal of the grafted organs which show optimal function. The recipient of a single kidney was rapidly transplantectomized and treated with actinomycin. At 2 years, she remains in remission. Liver recipient showed intestinal metastasis and died from digestive hemorrhage after an initial response to chemotherapy. Heart recipient had an initial remission under EMA-CO, but at the last report, he showed diffuse metastasis. Published reports on CC transmission are rare. The long-lasting remission of our pancreas-kidney recipient and her good outcome after 2 years make our observation original. Moreover, the high rate of transmission demonstrates the high malignant potential of CC in immunosuppressed patients. Chemotherapy combined or not with transplantectomy in case of nonvital organ, should be discussed.

[Late outcome of 89 patients with soft-tissue sarcomas treated by surgery and three different radiotherapy schedules]. / Résultats à long terme d'une série de 89 patients suivis pour un sarcome des tissus mous traités par chirurgie conservatrice et trois modalités d'irradiation postopératoire.

PURPOSE: To evaluate the outcome of patients treated for soft tissue sarcoma using three different post-operative radiotherapy schedules. METHODS AND MATERIALS: Between 1990 and 2003, 89 patients (median age 50.8 years) presenting with soft tissue sarcoma (located to the limbs for 66 of them) underwent post-conservative-surgery radiotherapy. Pathology was liposarcoma in 35 cases and 54 others tumors. Tumors grades (FNCLCC classification) were 1, 2, 3 or unknown in 29, 32, 19 and 9 cases, respectively. Surgery was considered as complete in 68 patients. Irradiation was normofractionated (NF) in 62 cases, hyperfractionated (BF) in 19 cases and hypofractionated (HF) in 8 cases. For all the patients, median delivered dose was 61 Gy [34-76 Gy]. RESULTS: Median follow-up of alive patients was 73,8 months [3-184]. Five-year local control (LC) and overall survival (OS) rates were 85.5 and 71.2% respectively. According to multifactorial analysis, favourable prognostic factors were for local control, complete surgery (P=0.0075) and for overall survival, complete surgery (P=0.0267), grade 1 tumor (P=0.012) and absence of distant recurrence (P=0.0488). There was no statistical evidence of difference for the five-year LC and OS rates between the patients who received NF, BF or HF. There were few complications and there were comparable in the three groups. CONCLUSIONS: This retrospective serie showed similar results for all the schedules. There is no evidence to recommend bifractionation. Hypofractionation should be used only in selected patients with poor performans status.

Effects of cis-dichlorodiammineplatinum(II) on human colon carcinoma cells in vitro.

The lethal effects of cis-dichlorodiammineplatinum(II) were investigated on an established human colon carcinoma cell line. cis-Dichlorodiammineplatinum(II) was one of the most efficient antineoplastic agents tested thus far on this human colon carcinoma cell line. Survival of exponentially growing cells exposed to increasing concentrations of the drug (both in medium or in Hanks' balanced salt solution) was of the threshold exponential type (Dq = 1.2 microgram/ml, 1 hr; Do = 3.5 microgram/ml, 1 hr). Stationary-phase cells were extremely sensitive to the drug, and the survival curve demonstrated a simple exponential pattern (Do = 3.9 microgram/ml, 1 hr). Long-term exposure to low concentrations of cis-dichlorodiammineplatinum induced a high degree of killing, with only 0.5% of the cells surviving after incubation for 24 hr with 2 microgram/ml. Cells were unable to recover from potentially lethal or sublethal damages induced by the drug.

In vitro cytokinetic response of human colon cancer cells to cis-dichlorodiammineplatinum(II).

The cytokinetic response of a human colon carcinoma cell line to cis-dichlorodiammineplatinum(II) was investigated using flow cytometry of DNA content, autoradiography after pulse and continuous tritiated thymidine exposure, and mitotic accumulation after continuous Colcemid treatment. With increasing concentration and exposure time, cis-dichlorodiammineplatinum(II) delayed and then blocked cycle traverse in S and G2 phases. After prolonged treatment with high concentrations of cis-dichlorodiammineplatinum(II), an additional block in G1 or at the G1-S boundary was established. Irreversibility of cell cycle distribution changes after prolonged observation periods suggests cell death in G2, S, and G1 compartments.

Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-beta-D-arabinofuranosylcytosine.

cis-Dichlorodiammineplatinum(II) and 1-beta-D-arabinofuranosylcytosine display a dramatic synergistic effect when tested in simultaneous combination on LoVo cells, a human colon carcinoma cell line. 1-beta-D-Arabinofuranosylcytosine alone does not induce any cytotoxicity on LoVo cells even at high concentrations but is able to increase up to 1000 times the lethal effects of cis-dichlorodiammineplatinum(II). DNA elution experiments show that 1-beta-D-arabinofuranosylcytosine increases the amount of cis-dichlorodiammineplatinum(II)-induced DNA cross-links. The possible mechanisms of this effect are discussed, and some explanations are proposed.

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.

Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape.

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNalpha2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNalpha2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNalpha2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFNalpha2a was administered three times weekly at 18 x 10(6) IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNalpha2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNalpha2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNalpha2a. CONCLUSION: Cross-over after failure of IL-2 or IFNalpha2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.

Long-term hypokalemia in acute myeloid leukemia.

A 48-year-old man suffering from acute myeloid leukemia presented a hypokalemia that persisted almost constantly during 18 months despite total hematological remission. The renal investigation demonstrated a hypokalemic nephropathy with an impairment of urinary concentrating function. Light and electron microscopy showed renal lesions related to potassium depletion. We did not observe specific lesions explaining the renal potassium wasting. Metabolic studies showed persistent hyperkaluresis, which appeared to be the main kaliopenic factor. We also found hypomagnesemia and changes of the renin-aldosterone system. We observed a hyperreninism, probably due to hypokalemia and a slight hyperaldosteronism, which could have been one of the kaluretic agents.

Liver abscess due to clostridium septicum. A case report and review of the literature.

The onset of liver abscess due to Clostridium septicum -an anaerobic gram-positive bacillus- is a rare condition, generally arising in cancer patients. The radiological picture is that of gas-containing pyogenic abscess, that predominates within preexisting liver metastases. We report a case of a 50-year-old patient with metastatic colon cancer who was referred with multiple Clostridium septicum liver abscesses. The patient underwent parenteral antibiotherapy as well as transcutaneous drainage of the largest liver abscess. However the outcome was unfavorable in a clinical picture of liver failure that was likely due to disease progression rather than sepsis. Clostridium septicum liver abscess is a life-threatening condition that occurs in fragile patients, mostly with metastatic cancers. A review of the reported cases is presented and treatment options are discussed.

Human blood-derived macrophages: differentiation in vitro of a large quantity of cells in serum-free medium.

Large quantities of human blood-derived monocytes have been cultured in suspension in nonadherent cell culture bags and maintained for up to 3 weeks in a serum-free medium. This serum-free medium contained Iscove's modified Dulbecco's medium (IMDM) supplemented with human albumin, alpha-phosphatidylcholine, transferrin, and insulin. Morphology, cell surface antigens, and functional properties of these in vitro maturing macrophages were studied in comparison with macrophages cultured in a standard medium containing 10% fetal calf serum. In this report we demonstrate that this serum-free medium allows a better yield of cell survival than the standard medium; it also allows the differentiation of blood monocytes into fully functional macrophagic cells that express the different antigens found in mature macrophages. The results indicate that the use of serum-free defined medium offers good conditions in which to culture large numbers of human monocytes and allows an accurate analysis of the effect of supplementation with growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on the differentiation and survival of monocytes and macrophages. Serum-free cultures could also be helpful for the precise analysis of the cell secretion activity and for determining the factors that are responsible for monocyte maturation into macrophages.

CD44 exon 6 expression as a possible early prognostic factor in primary node negative breast carcinoma.

Breast cancer is the most common female malignancy affecting approximately one woman in eight. Many attempts have been made to define markers which may have potential clinical applications in diagnosis as well as therapy. New isoforms of CD44 with alternative spliced exons have recently been described. We studied the expression of CD44 exon 6 using a semi-quantitative RT-PCR reaction on a panel of 25 normal breast specimens, 10 mammary fibroadenomas, eight cystic samples and 52 primary breast tumors. Significant correlation was found between CD44 exon 6 expression and the overall survival of the N-M-population, P = 0.032, (logrank test by Mantel's method). The same result was also observed for the disease-free survival, P = 0.000002 (logrank test by Mantel's method). CD44 exon 6 expression, as detected by our RT-PCR-based method, might be a useful prognostic indicator of metastasis in breast cancer. However, these preliminary results need to be confirmed by later retrospective and prospective studies on a larger number of patients.

Efficacy and safety of docetaxel (Taxotere) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience.

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received > 1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m2/cycle (75 mg/m2 in case of liver function impairment: transaminases > 1.5 x upper limit of normal (ULN), alkaline phosphatases > 3 x ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS > or = 2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received > 2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2-26.2%). Median time to treatment failure was 4 months (95% CI: 3.6-4.3) and median survival was 9.8 months (95% CI: 8.8-10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

Long term cultures of human monocytes in vitro. Impact of GM-CSF on survival and differentiation.

In vitro differentiation of human monocytes (Mo) provides large amounts of mature and functionally competent macrophages (M phi) which may be used as potentially powerful anticancer agents for adoptive immunotherapy. Granulocyte macrophage-colony stimulating factor (GM-CSF) was evaluated for its ability to influence long term cultures of Mo-derived M phi. Large quantities of Mo isolated by leukapheresis and elutriation were cultured in non-adherent cell culture bags or in plastic flasks with or without GM-CSF. At various stages of differentiation, GM-CSF treated M phi were recovered and assayed for survival, morphology, surface antigens, functional properties and proliferation in comparison with control M phi. In the present paper, we demonstrate that GM-CSF at a concentration of 50 U/ml (5 ng/ml) promotes better cell survival and the differentiation of Mo into M phi displaying certain morphological differences as compared to control M phi such as an increased expression of Max-1 antigen, CR3 and Fc gamma II receptors, higher phagocytic properties and increased capacities of cytotoxicity and TNF secretion when the cells are further activated by IFN-gamma. Furthermore, GM-CSF treated cells exhibit a low-grade proliferation although the nature of the proliferating cells has not been entirely elucidated. We conclude that the GM-CSF treated M phi would be particularly suitable for adoptive immunotherapy.

Large scale isolation of human blood monocytes by continuous flow centrifugation leukapheresis and counterflow centrifugation elutriation for adoptive cellular immunotherapy in cancer patients.

The increasing interest in mononuclear phagocytes for adoptive cellular immunotherapy (ACI) trials in cancer patients led us to define a procedural approach to harvest reproducibly highly purified single-cell suspensions of large numbers of functional human circulating blood monocytes (Mo). A semiclosed counterflow centrifugal elutriation (CCE) system has been developed, using a new large capacity Beckman JE 5.0 rotor with one interchangeable 40 ml or 5 ml separation chamber, to purify Mo from mononuclear cell (MNC) concentrates of healthy donors and cancer patients obtained by continuous flow centrifugation leukapheresis (CFCL). This method does not require a Ficoll density gradient centrifugation step. A total of 115 leukapheresis procedures were carried out in 35 patients and in 30 healthy donors by either Cobe 2997 or Cobe Spectra, with a similar efficiency in MNC apheresis. The average yield per leukapheresis procedure was 5.6 x 10(9) MNC of purity 90-100% (25-45% Mo, 40-65% lymphocytes). The average yields per elutriation procedure (R/O fraction) were 1.1 x 10(9) cells (purity 93% Mo) using the 5 ml separation chamber, and 1.5 x 10(9) cells (purity 91%) using the 40 ml separation chamber, with a respective recovery of 82 +/- 7% and 78 +/- 8% Mo. In vitro analysis of the viability and function of the purified Mo shows that neither morphological integrity nor physiological activity was compromised by this two-step isolation procedure, which additionally provides highly purified human Mo suspensions, in a quantity suitable for ACl of cancer patients.

Etoposide, ifosfamide, and methotrexate combination chemotherapy for aggressive non-Hodgkin's lymphomas after failure of the LNH 84 regimen.

We assessed the efficacy and tolerability of VIM (etoposide/ifosfamide/methotrexate) combination therapy in 24 patients who were failing the treatment protocol of the Lymphomes Non Hodgkiniens (LNH) 84 study. Eight patients were refractory to the LNH 84 induction cycles, but ten achieved a partial response (PR). The six remaining patients attained complete response (CR) after LNH 84 induction, but relapsed either during consolidation therapy or after completing the whole program. Twenty-three patients are evaluable for response. The VIM regimen provided a CR rate of 43% and a PR rate of 17%. Treatment failed in nine cases (39%). The CR rate was particularly high (67%) in the group of patients who had PR with LNH 84 induction treatment. Of the ten who had attained CR, five relapsed after 4 to 42 months and five are still alive with no evidence of disease after 29 to 62 months. VIM therapy was well tolerated. A total of 101 VIM courses were given. Myelotoxicity was the most common side effect. Grade 3 or 4 cytopenia was recorded after 11% of the cycles. Among eight infectious episodes recorded, one was fatal. This study demonstrates that CR and long disease-free survival are obtainable with the VIM regimen in a small number of patients failing a high-dose doxorubicin-containing first-line treatment.

Membrane markers, karyotypic abnormalities, ultrastructure and functional properties of lymphocytes in a case of 'D-cell' chronic lymphatic leukemia.

D cells are lymphocytes bearing both receptors for the third complement component and the ability to form spontaneous rosettes with SRBC. We report the case of a patient with a D-cell chronic lymphatic leukemia who presented a long evolution without treatment and whose leukemic cell characteristics have been extensively studied. Cytogenetic analysis showed numerous karyotypic abnormalities among leukemic cells; all metaphases were hypodiploid and arranged in four different clones; seven marker chromosomes were present. The cells were found to bear human T-cell specific antigen, the T helper/inducer phenotype, HLA-A and HLA-B determinants, but no HLA-DR antigens. They displayed a high proliferative response to PHA and Con A, no response to PWM stimulation, and possibly the capacity of allogeneic stimulation in the mixed lymphocyte culture system. Assays for cell-mediated cytotoxicity in the CML system, and for K and NK activities were negative.

Expression of CD44 spliced variants with both exons v9 and v10 in primary N(-)M(-) breast carcinomas correlates with metastasis.

We analyzed the representation of CD44 isoforms with both exons v9 and v10 among CD44 total amount and also examined correlation between their expression, clinical parameters and survival. We used a semi-quantitative RT-PCR reaction and a panel of 25 normal breast specimens, 10 mammary fibroadenomas, 8 cystic samples and 52 primary breast tumors. CD44 expression level was statistically higher in malignant tumors than in normal breast tissues (p = 0.038) or in fibroadenomas (p = 0.047) and correlated with histological grading, p = 0.047. Ratios CD44 variants with both exons v9 and v10/ total CD44 were similar in normal breast tissues and fibroadenomas but lower in the cystic samples. In primary N(-)M(-) breast tumors, unfavourable outcome and relapse were correlated with low ratios.

Disseminated Trichosporon capitatum infection in a patient with acute leukemia undergoing bone marrow transplantation.

A case of disseminated infection with Trichosporon capitatum is reported in a 23-year-old patient with acute myeloid leukemia undergoing HLA-mismatched bone marrow transplantation. He was receiving immunosuppressive therapy with cyclosporine and corticosteroids for acute graft-versus-host disease and he was severely neutropenic. While being treated with fluconazole for 28 days for an oropharyngeal candidiasis the patient developed a T. capitatum septicemia. He died despite receiving amphotericin B therapy. Autopsy revealed widespread infection with T. capitatum. The portal of entry was probably the digestive tract in this patient as T. capitatum had been first isolated in the stools.

The TAM regimen prior to allogeneic and autologous bone marrow transplantation for high-risk acute lymphoblastic leukemias: a cooperative study of 62 patients.

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.