HSV-1 thymidine kinase gene therapy for peritoneal carcinomatosis.
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Adenocarcinoma↗
Biomedical subjects
G Fillet
Publications and source records attributed to G Fillet.
Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation.
A 37-year-old man with acute myeloblastic leukemia in first remission developed ulcerative colitis and bronchiolitis obliterans organizing pneumonia (BOOP) 7 months after bone marrow transplantation (BMT) from an HLA-matched brother who suffered from severe Crohn's disease. BOOP occurred 20 days after idiopathic interstitial pneumonia, in the context of severe ulcerative colitis. Lung and colon biopsies showed no signs of CMV infection or GVHD. The patient was treated with oral methylprednisolone 1 mg/kg/day and his clinical status and chest X-ray improved slowly. Remarkably, the symptoms of colitis also resolved with prednisone therapy and he is now symptom-free. We hypothesize that ulcerative colitis may have been transmitted from donor to recipient (adoptive autoimmunity) and that it was complicated by BOOP. However, other factors such as CMV may have contributed to the occurrence of BOOP.
Adoptive Transfer↗
Repeated cycles of retrovirus-mediated HSVtk gene transfer plus ganciclovir increase survival of rats with peritoneal carcinomatosis.
Peritoneal carcinomatosis is a common clinical situation that requires novel therapeutic approaches. We investigated the efficiency of an HSVtk gene therapy for the treatment of peritoneal carcinomatosis induced in syngeneic rats by DHD/K12 colon carcinoma cells. In this setting, the efficiency of two different retrovirus producing cell lines (GP+AmEnv12 and FLYA13) was compared. Rats treated with a single injection of retrovirus producing cells followed by a 5-day course of ganciclovir treatment showed an increased survival as compared with control animals. Animals treated with three injections of producing cells, each followed by a 4-5-day course of ganciclovir treatment, showed an increased survival as compared with control rats and with those treated with a single cycle of retrovirus producing cells plus ganciclovir. However, only a few animals remained tumor-free after day 180. There was no difference between the two producing cell lines in any of the experiments. RT-PCR demonstrated a faint expression of the tk transgene in the liver, spleen, epiploon, bowels and the lung of the animals injected with the HSVtk producing cells, reflecting most likely the transduction of only a limited number of cells.
Animals↗
Hematopoietic recovery in cancer patients after transplantation of autologous peripheral blood CD34+ cells or unmanipulated peripheral blood stem and progenitor cells.
BACKGROUND: A study of CD34+ cell selection and transplantation was carried out with particular emphasis on characteristics of short- and long-term hematopoietic recovery. STUDY DESIGN AND METHODS: Peripheral blood stem and progenitor cells (PBPCs) were collected from 32 patients, and 17 CD34+ cell-selection procedures were carried out in 15 of the 32. One patient in whom two procedures failed to provide 1 x 10(6) CD34+ cells per kg was excluded from further analysis. After conditioning, patients received CD34+ cells (n = 10, CD34 group) or unmanipulated (n = 17, PBPC group) PBPCs containing equivalent amounts of CD34+ cells or progenitors. RESULTS: The yield of CD34+ cells was 53 percent (18-100) with a purity of 63 percent (49-82). The CD34+ fraction contained 66 percent of colony-forming units--granulocyte-macrophage (CFU-GM) and 58 percent of CFU of mixed lineages, but only 33 percent of burst-forming units-erythroid (BFU-E) (p < 0.05). Early recovery of neutrophils and reticulocytes was identical in the two groups, although a slight delay in platelet recovery may be seen with CD34+ cell selection. Late hematopoietic reconstitution, up to 1.5 years after transplant, was also similar. The two groups were thus combined for analyses of dose effects. A dose of 40 x 10(4) CFU-GM per kg ensured recovery of neutrophils to a level of 1 x 10(9) per L within 11 days, 15 x 10(4) CFU of mixed lineages per kg was associated with platelet independence within 11 days, and 100 x 10(4) BFU-E per kg predicted red cell independence within 13 days. However, a continuous effect of cell dose well beyond these thresholds was apparent, at least for neutrophil recovery. CONCLUSION: CD34+ cell selection, despite lower efficiency in collecting BFU-E, provides a suitable graft with hematopoietic capacity comparable to that of unmanipulated PBPCs. In both groups, all patients will eventually show hematopoietic recovery of all three lineages with 1 x 10(6) CD34+ cells per kg or 5 x 10(4) CFU-GM per kg, but a dose of 5 x 10(6) CD34+ cells or 40 x 10(4) CFU-GM per kg is critical to ensure rapid recovery.
Antigens, CD34↗
Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group.
PURPOSE AND METHODS: Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS: A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION: In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.
Acute Disease↗
[How I treat colorectal cancer. I. Prevention and adjuvant treatment].
Colorectal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Belgium and in other western countries. Prevention implies a modification of alimentation and maybe a chronic uptake of acetylsalicylic acid. Treatment of colorectal cancers is based on surgery and the prognosis is determined by the locoregional or metastatic tumor spread. Complete resection of any Astler Coller stage C colorectal malignant tumor has to be followed by a 5-fluorouracil-based adjuvant chemotherapy. In these protocols, 5-fluorouracil is administered together with folinic acid or levamisole. The administration of an adjuvant chemotherapy could also be considered for stage BII diseases. As rectal cancers are characterized by high local relapse rates, their treatment should associate radiotherapy, given either post-surgery or preferentially pre-surgery, with resection and chemotherapy. Appropriate treatment of colorectal cancers thus requires a concerted multidisciplinary approach.
Adenocarcinoma↗
[Treatment of colorectal cancer. Pharmaco-economic aspects].
Cancer patients care is mainly based on scientific studies, but sometimes approaches are empiric. Rapid growth of health care expenses force the physician to take pharmacoeconomic aspects into consideration. New clinical studies have to analyse clinical benefits but also cost-effectiveness. We will review the various aspects of colorectal cancer from primary prevention to post-treatment follow-up. Scientific data are integrated in a pharmacoeconomic analysis.
Antineoplastic Agents↗
[Drug clinics. How I treat. II. Therapeutic approaches to metastatic colorectal cancer].
Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the therapeutic efficacy of this agent. Quality of life is limited by the toxicity of these regimens as well as by the frequent visits to the hospital during each cycle. Raltitrexed, a thymidylate synthase inhibitor, offers similar antitumoral activity together with a tolerability in comparison to standard 5-fluorouracil based chemotherapy and its simple dosage schedule also contributes to better quality of life. New chemotherapeutic agents are currently in development for the treatment of patients refractory to 5-fluorouracil. Irinotecan and oxaliplatin demonstrate promising activity.
Antidotes↗
[Myelodysplastic syndromes: preleukemic syndromes].
The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by peripheral blood cytopenias with a hypercellular bone marrow exhibiting dyspoiesis. The predominant in elderly patients are associated with a high risk of progression to acute myelogenous leukemia. The etiology of MDS is unknown in most cases. About 10% of MDSs are secondary. MDS are classified by the French American British (FAB) classification into five subgroups. The incidence of the disorders is difficult to estimate but it seems to be increasing. Clonal cytogenetic aberrations are found in 30 to 50% of de novo MDS. The only currative treatment for MDS is allogeneic bone marrow transplantation.
Aged↗
Circadian and seasonal variations of hematopoiesis in cord blood.
Cord blood hematopoietic progenitors undergo circadian and seasonal variations. The lowest values are obtained between 4:00 and 12:00, as well as between May and August. This represents the first observation of such rhythms before birth.
Blood Banks↗
[Clinical case of the month. The association of Hodgkin's disease and nephrotic syndrome].
The nephrotic syndrome is a rare complication of Hodgkin's disease. The majority of the cases do not respond to corticosteroids but are cured by the treatment of the lymphoma. We describe a patient with a nephrotic syndrome at the time of diagnosis of mixed cellularity Hodgkin's disease and the resolution of this nephrotic syndrome by MOPP-ABV chemotherapy.
Adult↗
Influence of marrow erythropoietic activity on serum erythropoietin levels after autologous hematopoietic stem cell transplantation.
BACKGROUND AND OBJECTIVE: Serum erythropoietin (sEpo) concentration depends primarily on the rate of renal production in response to hypoxia. However, sEpo levels increase inappropriately after conditioning for autologous stem cell transplantation (ASCT) before progressively returning to adequate levels. We investigated the possible influence of erythropoietic activity on these observations. DESIGN AND METHODS: Forty patients undergoing an ASCT, 8 with bone marrow (BMT) and 32 with peripheral blood stem cells (PBSC), were separated into 3 groups. Group 1 was formed of the 8 BMT patients (median time to 1% reticulocytes: 39 days), group 2 of 16 PBSC patients with relatively slow erythroid engraftment (> or = 15 days to 1% reticulocytes, median 19 days) and group 3 of 16 PBSC patients with prompt erythroid recovery (< 15 days to 1% reticulocytes, median 13 days). Marrow erythroid activity was assessed by serum transferrin receptor levels (sTfR). Serum Epo (sEpo) levels were expressed in relation to the degree of anemia as observed/predicted (O/P) ratios of (O/P) log (sEpo). RESULTS: Serum sTfR levels decreased by more than 50% in all 3 groups after conditioning, reaching their nadir on day 7. Nadir values doubled by day 28 in group 3, day 60 in group 2, but not within 100 days in group 1. O/P sEpo ratios increased inappropriately in all 3 groups after conditioning but then declined at very differing speeds in the 3 groups. In group 1, ratios remained above 1.10 through to day 28 and above 1.00 through to day 42, before leveling off at around 1.00 thereafter. In group 2, ratios remained above 1.00 through to day 14, than decreased to a minimum of 0.89 by day 42 before returning to 1.00 by day 100. In group 3, ratios decreased to 0.84 by day 21 and remained below 0.90 thereafter. INTERPRETATION AND CONCLUSIONS: We conclude that sEpo levels are not only influenced by tissue oxygenation but also depend on the mass of erythroid precursors in the bone marrow. This may be the main explanation for the observed changes in sEpo levels during ASCT.
Adolescent↗
Long term follow-up of patients with acute myelogenous leukemia who received the daunorubicin, vincristine, and cytosine arabinoside regimen.
BACKGROUND: In 1985, the authors published a study of acute myelogenous leukemia (AML) patients treated with a chemotherapeutic regimen that was then considered intensive. Ten years later, the authors reanalyzed the same cohort to determine whether the very promising actuarial results observed at 5 years held after longer follow-up. METHODS: Between 1977 and 1982, 61 patients with AML were treated with a protocol consisting of daunorubicin, vincristine, and cytosine arabinoside induction followed by consolidation and maintenance for a total of 2 years. The complete remission (CR) rate was 66%, 84% in males versus 47% in females (P < 0.005). At the time of the first analysis in 1984, the overall survival (OS) was 17%, the projected 5-year continuous CR rate (CCR) 32%, and the disease free survival (DFS) rate 29%, with the best results observed for males and for patients ages 40-60 years (P < 0.05). RESULTS: When the data were reanalyzed 11 years later in 1995, the results were 14% OS, 23% CCR, and 16% DFS at 5 years. However, these figures dropped to 8%, 18%, and 11% at 10 years and to 8%, 12%, and 7% at 15 years, respectively. Among the 40 CR patients, 31 relapsed (up to 13 years after CR), and all died within 1.6 years after relapse. Nine patients were in CCR: 4 died of unrelated causes (suicide, alcoholic cirrhosis, acute peritonitis, or bladder carcinoma), 1 was lost to follow-up after 11 years, 2 were alive and well at 17 years at last follow-up, and 2 were transplanted in first CR and were doing well at 13 and 14 years at last follow-up. The survival advantage for males over females persisted (P = 0.0197), but the advantage for patients age 40-60 years did not hold. CONCLUSIONS: These long term data indicate that actuarial analysis at 5 years may overestimate the cure rate of AML patients because a number of late relapses do occur. However, the picture is blurred by the incidence of death not related to leukemia or its treatment; and when these patients were censored at the time of death, 17% of CR patients were still projected to be alive and free of leukemia after 17 years.
Adolescent↗
Soluble and cell-associated transferrin receptor in lung cancer.
The expression of transferrin receptor (TfR) has been identified in many malignant tumours. In lung cancer, lymphoma and breast cancer, it has been shown that the expression of TfR correlates with tumour differentiation, probably implying some prognostic value. A soluble form of TfR (sTfR) in human serum has been shown to be proportional to the number of cellular TfRs. Based on these data we examined the utility of measuring sTfR in the serum and bronchoalveolar lavage (BAL) fluid of patients with lung cancer (n = 32) and patients with chronic obstructive pulmonary disease (n = 22). BAL fluid was centrifuged to separate the supernatant from the cellular component. Cells were lysed in a detergent and cell-associated TfR was measured by enzyme-linked immunosorbent assay (ELISA) and expressed as ng 10(-6) cells in this cellular component. There was no difference in serum sTfR between the cancer and chronic obstructive pulmonary disease (COPD) groups. A higher level of cell-associated TfR was found in BAL of non-small-cell lung cancer patients than in COPD patients (P = 0.01). The calculated number of TfR molecules per cell in BAL correlated positively with the percentage of macrophages in BAL (P < 0.0001), suggesting that cell-associated TfR in BAL originates primarily from macrophages in this fluid. No correlation existed between BAL cell-associated TfR and tumour size, nodal status, the presence of metastases and serum sTfR. BAL cell-associated TfR was negatively correlated with BAL supernatant neuron-specific enolase (NSE) (P = 0.01). A combination of BAL supernatant NSE and cell-associated TfR detected lung cancer with a sensitivity of 91%, a specificity of 59% and positive and negative predictive values of 81% and 71% respectively. In conclusion, BAL cell-associated TfR may help in the differential diagnosis of lung cancer vs pneumonia.
Aged↗
HSV-1 thymidine kinase gene therapy for colorectal adenocarcinoma-derived peritoneal carcinomatosis.
Peritoneal carcinomatosis is a common clinical situation which, in most cases, cannot be eradicated by surgery or chemotherapy. The feasibility of an HSV-TK-based suicide gene therapy for peritoneal carcinomatosis induced by DHD/K12 colon carcinoma cells was investigated. DHD/K12 cells stably expressing the tk gene were killed in vitro in the presence of low concentrations of ganciclovir, they exhibited a 'bystander effect' when mixed with TK-negative cells. BD-IX rats injected intraperitoneally, either directly or after surgical peritoneal irritations, with DHD/K12 cells developed peritoneal carcinomatosis within 2 weeks. Ganciclovir treatment of animals injected with DHD/K12-TK cells allowed a significant reduction of the tumor volume as well as a prolonged survival. Of these animals 35-40% showed a long-term disease-free survival after ganciclovir therapy. Residual or relapsing tumors could be explained by a low expression of the transgene as demonstrated by RT-PCR.
Adenocarcinoma↗
Anaemia of lung cancer is due to impaired erythroid marrow response to erythropoietin stimulation as well as relative inadequacy of erythropoietin production.
Many studies have been done in order to elucidate the pathogenesis of the anaemia of chronic disorders accompanying cancer, with conflicting results. This is probably due to the heterogeneity of the patient population selected for these studies (many patients treated by chemotherapy). To avoid this pitfall, in this study a very homogenous group of chemotherapy and radiotherapy-naive patients with lung cancer were selected. Serum erythropoietin and soluble transferrin receptor measurements suggested that the anaemia of non-treated lung cancer is mainly due to an impaired erythroid marrow response to erythropoietin stimulation. However, a relative inadequacy of erythropoietin production may also contribute.
Anemia↗
Acute functional iron deficiency in obese subjects during a very-low-energy all-protein diet.
We examined whether a very-low-energy all-protein diet (VLED) would produce detectable changes in iron as well as in other trace elements. Twenty-five obese patients consumed for 2 wk a VLED containing 70 g protein after a 1-wk period during which total daily energy intake was progressively reduced to 1.26 MJ. Serum iron fell sharply by approximately equal to 50% (P < 0.0001), and despite a small decrease in total-iron-binding capacity, transferrin saturation decreased from 30 +/- 11% to 18 +/- 5% (P < 0.0001). Serum ferritin did not change significantly but serum soluble transferrin receptor (sTfR), an indicator of iron deficiency, increased progressively from 4630 +/- 1110 to 6070 +/- 1390 micrograms/L (P < 0.0001). Changes in sTfR correlated inversely with prior changes in serum iron. Changes in iron metabolism did not translate into changes in erythropoiesis or red cell indexes, but the white blood cell count decreased from 7.3 +/- 1.6 to 6.2 +/- 1.9 x 10(9)/L (P < 0.002). There was no evidence of deficiency for the other trace elements and minerals tested. Daily supplementation with 200 mg Fe in 18 other subjects only partially corrected these observations despite some increase in iron stores. These results indicate that during a 2-wk VLED serum iron is significantly depressed, inducing functional tissue iron deficiency too short in duration to produce alterations in red blood cell indexes. These changes are not mediated by absolute iron deficiency, inflammation, or protein malnutrition but could be related to alterations in the iron storage and release behavior of the reticuloendothelial cell during energy deprivation alone.
Adolescent↗
Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood.
Cord blood transplantations successfully reconstituted hemopoiesis in patients treated with myeloablative therapies. These transplantations were associated with a low rate of acute graft-versus-host disease (aGVHD), a major life-threatening complication of allo-transplantation. The physiopathology of aGVHD implies the recognition of host alloantigens by donor T cells but also involves a cytokine cascade. In this cascade, interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) produced by donor T cells and monocytes/macrophages play a major effector role. Therefore, we investigated whether the lower percentage of aGVHD in cord blood transplants could be related to a lower ability to produce these cytokines in vitro compared with adult blood. Mononucleated cells (MNCs) isolated from term cord blood and adult peripheral blood were stimulated with a combination of lipopolysaccharide and phytohemaglutinin and incubated for 96 hours. Levels of IL-1beta, IL-2, IL-3, IL-4, IL-6, TNF-alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in the supernatants after various times of incubation. The productions of IL-1beta, IL-6, and GM-CSF were similar in stimulated cord and adult blood and IL-3 levels, though lower and delayed in cord blood, were not statistically different. On the other hand, we found markedly lower levels of IFN-gamma, TNF-alpha, and IL-4 in cord blood throughout the incubation period. The stimulated levels of IL-2 were similar in cord and adult samples throughout the first 48 hours of incubation but became significantly lower in cord blood after 72 and 96 hours. We suggest that the cytokine production pattern that characterizes cord blood could provide an explanation for the lower occurence of aGVHD following cord blood transplants.
Adult↗