Detection of colorectal carcinoma by emission-computerized tomography after injection of 123I-labeled Fab or F(ab')2 fragments from monoclonal anti-carcinoembryonic antigen antibodies.

This clinical study was based on experimental results obtained in nude mice grafted with human colon carcinoma, showing that injected 131I-labeled F(ab')2 and Fab fragments from high affinity anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAb) gave markedly higher ratios of tumor to normal tissue localization than intact MAb. 31 patients with known colorectal carcinoma, including 10 primary tumors, 13 local tumor recurrences, and 21 metastatic involvements, were injected with 123I-labeled F(ab')2 (n = 14) or Fab (n = 17) fragments from MAb anti-CEA. The patients were examined by emission-computerized tomography (ECT) at 6, 24, and sometimes 48 h after injection using a rotating dual head scintillation camera. All 23 primary tumors and local recurrences except one were clearly visualized on at least two sections of different tomographic planes. Interestingly, nine of these patients had almost normal circulating CEA levels, and three of the visualized tumors weighed only 3-5 g. Among 19 known metastatic tumor involvements, 14 were correctly localized by ECT. Two additional liver and several bone metastases were discovered by immunoscintigraphy. Altogether, 86% of the tumor sites were detected, 82% with F(ab')2 and 89% with Fab fragments. The contrast of the tumor images obtained with Fab fragments suggests that this improved method of immunoscintigraphy has the potential to detect early tumor recurrences and thus to increase the survival of patients. The results of this retrospective study, however, should be confirmed in a prospective study before this method can be recommended for the routine diagnosis of cancer.

Plasminogen activator inhibitor-2 in patients with monocytic leukemia.

Plasma and tumor cells from 103 patients with leukemia or lymphoma at initial presentation were investigated for the presence of plasminogen activator inhibitor-2 (PAI-2) antigen, a potent inhibitor of urokinase. PAI-2 was detected in plasma and leukemic cells of the 21 patients with leukemia having a monocytic component [acute myelomonocytic (M4), acute monoblastic (M5), and chronic myelomonocytic leukemias], and in the three patients with acute undifferentiated myeloblastic leukemia (M0). In contrast, this serine protease inhibitor was undetectable in 79 patients with other subtypes of acute myeloid leukemia or other hematological malignancies. Serial serum PAI-2 determinations in 16 patients with acute leukemia at presentation, during therapy, remission, and relapse revealed that in the five patients with M4-M5, elevated PAI-2 levels rapidly normalized under therapy and during remission, but increased again in the patients with a relapse associated with an M4-M5 phenotype. Thus, PAI-2 seems to be a marker highly specific for the active stages of monocytic leukemia, i.e. presentation and relapse. The presence of PAI-2 in the plasma and cells of patients with M0 may give a clue to a monocytic origin of these cells.

Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia.

Fifty-four patients with acute lymphoblastic leukemia (ALL: 1 relapse, 21 high risk first complete remission (CR 1), 29 second CR (CR 2), and 3 third CR (CR 3) were treated by autologous bone marrow transplantation at three centers. Before storage, the marrows were purged ex vivo with appropriate MAbs RFAL3 (CD10), SB4 (CD19), and RFT2 (CD7), with rabbit serum as the source of complement. All patients received total body irradiation either 750 cGy (middose 15 cGy/min) as a single fraction or 6 x 200 cGy over 3 days (midline dose 16 cGy/min) with lung shielding from 1,100 cGy. The patients who received 750 cGy also received cyclophosphamide or the same drug combined with ara-C or prednisone, teniposide, vincristine, ara-C, and dauno-rubicin. Patients receiving 200 cGy x 6 also received either cyclophosphamide, melphalan, or ara-C and cyclophosphamide. Three patients died of post transplantation complications (interstitial pneumonia, hepatitis B liver necrosis, or encephalitis). This gives a procedure related mortality of 5%. Nonfatal complications were 10 cases of septicemia, 4 interstitial pneumonia, 2 interstitial nephritis, 1 veno-occlusive disease (VOD), and 1 case of hemolytic uremic syndrome. The patient autografted in relapse died of relapse within 2 months. In CR 1 6 or 21 patients have had a relapse, and the actuarial leukemia free survival from CR is 65% (median follow-up 16 months). In CR 2-3 18 of 32 patients have relapsed, and the actuarial leukemia free survival is 31% (median follow-up 18.5 months) from CR. Twelve patients have achieved an inversion, (i.e., present CR longer than previous CR), with a further seven with the potential to achieve inversion. We conclude that ABMT in high risk ALL has a low procedure related mortality (5%), and there are few other complications. The in vitro purging with MAbs had no adverse effect on bone marrow reconstitution, but this study was not designed to demonstrate its antileukemic efficacy. The actuarial leukemia free survival time in the present study for patients with high risk CR 1 and the inversions in CF 2-3 are promising and indicate a potential beneficial effect of ABMT.

Campylobacter fetus subspecies fetus bacteremia.

Eight patients with Campylobacter fetus bacteremia, six of them with serious underlying diseases, were seen in a two-year period. Besides fever, which was observed in all cases, the most frequent clinical manifestation was lower extremity phlebitis and cellulitis (four patients). In one of these patients, it had the peculiar aspect of bilateral pretibial cellulitis. One patient had vertebral osteomyelitis, a complication, to our knowledge, not yet described. Two patients, both with advanced underlying diseases, died. The five patients who completed a two- to three-week course of erythromycin gluceptate, all had initial clinical improvement. However, one patient suffered a relapse at the end of treatment, and progression of vertebral osteomyelitis while on erythromycin therapy was observed in another patient. These clinical and bacteriologic failures occurred despite the in vitro sensitivity to erythromycin of the two strains. This suggests that erythromycin might not be adequate therapy for C fetus septicemia.

The contribution of large granular lymphocytes to B cell activation and differentiation after T-cell-depleted allogeneic bone marrow transplantation.

Immunoglobulin and specific antibody levels are well maintained in the recipients of T-cell-depleted allogeneic bone marrow transplants (BMT), even though up to 99% of mature T cells are removed from the donor graft. For 3-8 weeks after the procedure, natural killer (NK) cells with an activated pattern of target cell killing have been shown to circulate in the recipient. This study investigates whether these recipient NK cells spontaneously secrete lymphokines that modulate B cell function in a way analogous to that of in-vitro-activated NK cells from normal individuals. Large granular lymphocytes (LGLs) (which contain a high proportion of NK cells) have been prepared from the peripheral blood of 11 recipients of T-cell-depleted major-histocompatibility-complex-matched allografts. In the first 4-6 weeks after BMT these LGLs were found spontaneously to secrete interleukin 2, interferon gamma and B cell differentiation factor. While secretion of these factors declines by 20-24 weeks after BMT, the quantities are still greater than those seen from control donors. Patient LGLs are also able to activate autologous (donor) B cells, rendering them potentially responsive to the secreted factors. It appears likely that activated NK cells (or LGL) play a significant role in maintaining B cell function in vivo after T-cell-depleted BMT.

Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome.

Defects of 3q in bands q21 and q26 have been reported in more than 70 cases of acute nonlymphocytic leukemia (ANLL), myelodysplastic syndrome (MDS), and myeloproliferative disorder (MPD) in blast crisis. In this paper three additional patients are described: patient 1 with refractory anemia with excess of blasts in transformation (RAEB-T) and inv(3)(q21q26), patient 2 with RAEB-T and t(3;3)(q21;q26), and patient 3 with myelofibrosis with myeloid metaplasia (MMM) in blast crisis and inv(3)(q21q26). In addition to 3q rearrangements, monosomy 7 and del(7)(q22q36) were observed in patients 1 and 2, respectively. In the three patients, the most characteristic clinical features were elevated platelet counts, marked hyperplasia with dysplasia of the megakaryocytes, and poor prognosis. Although disturbance of thrombopoiesis was not systematically observed in all patients with t(3;3)(q21;q26), inv(3)(q21q26), and ins or dup(3)(q21----q26), study of the 77 cases reported and of the three cases presented here brings further evidence to the existence of a cytogenetic syndrome involving bands q21 and q26 simultaneously, which represents a subtype of ANLL, MDS, and MPD, characterized by normal or elevated platelet counts, hyperplasia with dysplasia of megakaryocytes, multilineage involvement, young median age of patients with MDS, preferential involvement of women in t(3;3), high incidence of chromosome 7 defects in MDS and ANLL, short duration of the MDS phase, no response to chemotherapy, short survival, and por prognosis.

Dysmegakaryopoiesis predicting response to therapy in acute myeloid leukaemia. A histologic and clinical study.

With standard induction therapy between 50 to 85% of patients with Acute Myeloid Leukaemia (AML) achieve Complete Remission (CR). We investigated whether any morphological feature of bone marrow (BM) plastic embedded biopsies could predict failure of therapy. We reviewed BM plastic embedded biopsies from 54 adult patients presenting with untreated AML. The main histologic parameters analysed were cellularity, dysmegakaryopoiesis (DysM), percentage of marrow blasts and fibrosis. CR was obtained in 34 of 49 treated patients (69%). The rate of CR was significantly lower in the group of patients presenting with DysM: CR was achieved in 54% of the 28 treated patients with DysM and in 90% of the 21 treated patients without DysM (p less than 0.02). Patients with DysM had a significantly lower blood count and bone marrow blasts at presentation. Median age was not significantly different in the 2 groups. Cellularity and fibrosis were not predictive. DysM may be the hallmark of an AML subgroup with distinct clinical behaviour and lower rate of CR with conventional therapy. DysM should be carefully looked for on BM marrow biopsies and aspirate from AML patients at diagnosis.

Enzymes transducing extracellular signals in acute myeloid human leukemias.

The ectoenzymes gamma-glutamyltransferase (gamma-GT) and the PIP2 phospholipid phospholipase-C (PLC), a second messenger generating enzyme active on the cytoplasmic membrane bilayer, were biochemically investigated in leukemic cells isolated from 67 patients with acute leukemia. Six groups were distinguished on the basis of morphology, cytochemistry and immunophenotyping according to the FAB classification: M0, M1-M2, M3, M4, M5 and CML blast crisis (CML-BC). The activity of PLC ranged from 0.6 to 14.5 nmol/min/mg without a significant difference among groups, whereas the gamma-GT activity varied significantly from 0 to 31.6 nmol/min/mg. The highest mean activity was measured in monoblastic leukemia (M5), followed by groups M4, CML-BC and M0 (undifferentiated) while the lowest activity was found in M1-M2 and M3 groups. Within each group, activity distribution profiles of both enzymes never correlated with each other, suggesting that in leukemic cells functional-structural constituents of both membrane leaflets were independently affected by the neoplastic process.

[Acute myeloid leukemia with poor prognosis: treatment with oral 4-demethoxydaunorubicin (idarubicin) and low-dose cytarabine via subcutaneous route]. / Leucémies myéloïdes aiguës de mauvais pronostic: traitement par 4-démethoxydaunorubicine (idarubicine) per os et cytarabine à doses réduites par voie sous-cutanée.

26 patients with poor risk acute myelogenous leukemia (elderly, in relapse or resistant) were treated with a combination of oral idarubicin (30 mg/m2/d for 3 days) and low dose subcutaneous cytarabine (10 mg/m2 twice a day for 10 days). Of 26 patients, 14 achieved complete remission, 2 partial remission, and 5 died in aplasia (3 without evidence of response, 2 inevaluable); 5 further patients were non-responders. All responses but two occurred among patients treated for AML at presentation or in relapse. Side effects consisted mainly of severe hematologic and moderate gastrointestinal toxicities. The main interest of this regimen is adaptability to outpatient conditions and rapid cytoreduction in patients with hyperleukocytic presentation.

[Clinical characteristics and evaluation of risk in the graft versus host reaction following transfusion]. / Charactéristiques cliniques et évaluation du risque de la réaction "graft versus host" après transfusion.

Graft versus host disease (GVHD) is a well recognized entity following bone marrow transplantation. Similar syndromes have been described after blood product transfusions, notably in patients with primary immunodeficiency syndromes and in patients with malignancies associated with immune deficiency or under immunosuppressive treatment. Review of the literature shows that posttransfusion GVHD is characterized by maculopapular skin rash, gastro-intestinal symptoms, liver disease, severe pancytopenia and, in some cases, hepatosplenomegaly and lymphadenopathy. The time to onset and the duration of the disease are short (10 days) and the mortality approaches 90%. The clinical features of this rare disorder are presented in the hope that, with increased awareness of this complication, clinicians will take preventive measures in patients at risk because no satisfactory therapy yet exists.

The use of monoclonal antibodies in graft versus host disease prevention.

One of the most important causes of procedure related death after bone marrow transplantation (BMT) is graft versus host disease (GvHD) in which donor T-lymphocytes recognise alloantigens in the recipient and attack and damage the cells bearing them. Even when donor and recipient are matched at all loci of the major histocompatibility complex (MHC) 40%-70% of recipients develop severe graft versus host disease after conventional BMT: in a third of those affected the outcome is fatal. When donor and recipient are less than identical at the MHC the incidence and severity of acute graft versus host disease are correspondingly higher. The morbidity and mortality associated with acute GvHD has limited the application of bone marrow transplantation in two ways: first by restricting the procedure to patients with serious haematological disease and second by excluding individuals who might benefit from BMT but who lack an MHC identical sibling. In this review we discuss briefly the theoretical work that led us to our protocol for T-cell depletion for GvHD prevention and then describe the results of our own and other groups undertaking T-cell depleted bone marrow transplants. Finally, we discuss some of the new problems--and benefits--associated with T-cell depletion and outline the improvements in techniques now taking place.

Low morbidity and mortality from infection in neutropenic patients, a possible result of multiple measures of infection prevention.

138 patients with neutropenia (PMN's less than 1000), 66 of them with acute myelocytic leukaemia (AML), were hospitalised over a 6-year-period in reverse-barrier isolation. All had skin, orifices and gut decontamination. Fever occurred in 78% of the 216 neutropenic episodes. Overall, the incidence of septicemia during febrile episodes was 10% and the mortality from infection 7%; both figures were identical in the patients with AML and are lower than those normally found in this type of patients. Various factors that might be responsible for this low incidence of severe infections in neutropenic patients have been examined. The microbiological methods used to document infection were identical to those currently used. The severity of the underlying diseases and of neutropenia in the patients with AML was similar to that reported in other series. The measures taken for infection prevention, i.e. reverse-barrier isolation plus skin, orifices and gut decontamination, were not different than those used in many other centers, although their strict application in a small specialized unit might partially explain these favourable results. In addition the outcome of infection was analysed in relation to the response to treatment of the underlying disease. The mortality due to infection in patients with a tumor responding to chemotherapy was only 4% but was 45% in patients with end-stage malignant diseases. These results suggest therefore that infection in patients whose malignancy respond to treatment can be efficiently controlled by prompt empiric broad spectrum antibiotic therapy, and failures of antiinfectious treatment are mostly observed in patients with advanced cancer.

[Biliopancreatic bypass and disorders of iron absorption]. / Courts-circuits bilio-pancréatiques et troubles de l'absorption du fer.

Sideropenic anemia is a common long-term complication of surgical bilio-pancreatic bypass for morbid obesity, and is frequently resistant to oral iron therapy. To study the pathogenesis of this phenomenon we investigated 7 such patients clinically and biologically, with special emphasis on iron absorption. Our results show that sideropenia, consistently present and frequently complicated by anemia, is due to deficient iron absorption and that this malabsorption is non-selective. Replacement therapy, when indicated, should therefore use the parenteral route.

[Should patients over 65 years old with acute myeloid leukemia be treated with myelosuppressive chemotherapy?]. / Faut-il traiter avec une chimiothérapie aplasiante des patients de plus de 65 ans souffrant d'une leucémie myéloïde aiguë?

Acute myeloid leukemia (AML) is frequently encountered in elderly patients (> 65) whereas most myelosuppressive chemotherapy protocols are restricted to younger patients. We retrospectively reviewed the 21 patients older than 65 (median age: 70, range: 66-86) hospitalized in our leukemia unit for recently diagnosed AML between 1. 1. 1988 and 31. 3. 1993. 16 had de novo AML (n-AML) and 5 had AML secondary to myelodysplastic syndromes (s-AML). Induction therapy consisted of cytarabine and either daunorubicine or mitoxantrone at conventional dosage in 18/21 patients. Early consolidation therapy was given to 14/21 patients and consisted of m-AMSA and VP-16 in 11 of them. The response to, and toxicity from, myelosuppressive chemotherapy was different according to the type of AML. In patients with n-AML a complete remission (CR) was obtained in 63% (10/16) and only 19% (3/16) died of MCT-related toxicity. In contrast, only 1/5 patients with s-AML achieved CR while 4/5 died of toxicity. The median duration of CR was 40 weeks (range: 5-147+) and median overall survival 23 weeks (range: 1-211+), with an estimated 3-year overall survival rate of 9.5% (2/21). Overall survival of patients with n-AML was significantly longer than that of patients with s-AML (p < 0.05). Hospital stay in relation to survival time was 100% for patients with s-AML, 49% for patients with n-AML not achieving CR and 25% for patients with n-AML with CR. In conclusion, elderly patients with AML can benefit from myelosuppressive chemotherapy providing they present with de novo AML.

[The treatment of acute lymphatic leukemia in adults: pilot project with intensive early therapy without a maintenance phase]. / Behandlung der akuten lymphatischen Leukämie beim Erwachsenen: Pilotversuch mit intensiver Frühtherapie und ohne Erhaltungsphase.

Acute lymphoblastic leukemia (ALL) is conventionally treated in three phases: remission induction, consolidation and maintenance. In adults initial remission rates of nearly 80% can be achieved. The 3 to 5 year leukemia free survival is 20 to 40%. Most relapses occur during maintenance, despite continuous therapy for 2 to 3 years. The value of maintenance therapy following intensive induction in adults is not documented. In this pilot study we treated 34 patients with ALL in five Swiss centers between 1986 and 1989 with intensive induction/consolidation therapy alone. Three induction/consolidation courses were applied: course I, 43 days, consisting of daunomycin, vincristine, prednisone, methotrexate, L-asparaginase and intrathecal CNS prophylaxis; course II, 6 days, consisting of high dose cytosine arabinoside and VP-16; course III, three non randomized arms, either allogeneic or autologous bone marrow transplantation (BMT) or high dose cyclophosphamide and repeated intrathecal therapy alone. 32 patients (94%) reached complete remission (CR): 24 after course I (71%), 7 after course II (cumulative 91%) and one after course III only (cumulative 94%). 3 patients had early, relapses before course III, 3 died of infection, and 2 of graft-versus-host disease. One patient had refractory leukemia in all three courses. 26 patients (76%) were in CR after completion of therapy. 16 relapsed within 1 to 17 months (median 5). 10 patients are free of disease after 10 to 44 months (median 24): 5 had had allogeneic BMT, 3 autologous BMT and 2 cyclophosphamide in course III.(ABSTRACT TRUNCATED AT 250 WORDS)

Intensive induction/consolidation therapy without maintenance in adult acute lymphoblastic leukaemia: a pilot assessment. Working Party on Leukaemia of the Swiss Group for Epidemiologic and Clinical Cancer Research (SAKK).

Maintenance chemotherapy for up to 3 years is traditionally given to patients with acute lymphoblastic leukaemia (ALL) achieving complete remission. We questioned the value of such maintenance therapy in adult patients treated with intensive induction/consolidation. In a phase II study (SAKK 33/86) 63 patients between 17 and 72 years of age (median 27 years) with newly diagnosed ALL were treated with three intensive cycles of marrow-ablative chemotherapy. All subtypes were included. No maintenance phase was added. 53 patients (84%) entered a complete remission (CR) and 21 (33%) continue to be in unmaintained remission for 11-69 months (median 21 months). The disease-free survival of patients achieving CR and completing all three cycles is 40% at 3 years, with a 95% confidence interval of +/- 19%. These findings are comparable to the results of conventional studies. We conclude that maintenance therapy might not be needed in all adult ALL patients. Its value should be tested in a randomized trial. For patients failing, novel approaches are needed to improve outcome in adult ALL.

[Clinical characteristics of immature T-type (negative E-rosette) acute lymphoblastic leukemia detected by LAU-A1 monoclonal antibody]. / Caractéristiques cliniques des leucémies lymphoblastiques aiguës de type T immature (E-rosette négatif) détecté par l'anticorps monoclonal LAU-A1.

Immature T-ALL is a newly defined subgroup of ALL in which the blasts lack the receptor for sheep erythrocytes (ER) and the usual T-cell markers, but express the 40 kDa pan-T surface antigen recognized by our monoclonal antibody LAU-A1. Patients with immature T-ALL represent 10% of all cases of adult ALL. Leukocyte counts are lower and spleen, liver and lymph node enlargement is less prominent, but mediastinal enlargement is more frequent than in mature (ER-positive) T-ALL. 7 patients with immature T-ALL (median age 42 years, range 13-73) were treated with intensified chemotherapy regimens, and only one 47-year-old female entered a short-lived complete remission. The overall survival of our patients was poor (median 7.5 months, with only one patient surviving at 15 months) and seemed not to be influenced by age. Our study indicates that immature T-ALL can only be accurately identified by the use of monoclonal antibodies recognizing the 40 kDa pan-T antigen, and that immature T-ALL is a separate disease entity typified by a poor prognosis.