[Management for 145 cases of Merkel cell carcinoma]. / Prise en charge de 145 cas de carcinomes à cellules de Merkel.

PURPOSE: Merkel cell carcinoma (MCC)/primary cutaneous neuroendocrine carcinoma is a rare and aggressive malignant tumor. Optimal therapeutic strategy has not yet been established. PATIENTS AND METHODS: Management of 145 patients from five centres was analysed. These data included ages, pathological stages, disease sites, histological and treatment details. Cause-specific (CSS) and overall survivals (OS) were analyzed by the Log-rank and Kaplan-Meier methods. RESULTS: Median age was 78 years (47-95.2). We experienced 37 local, 37 regional and 15 distant relapses. In case of relapse, salvage therapy has been proposed whenever the general state of health condition of patient permitted it. CONCLUSION: Our results for the treatment of relapse encourage multidisciplinary approach. Multicenter prospective trials are still needed to clarify and validate the optimal strategy.

Novel enzymatic abnormalities in AML and CML in blast crisis: elevated leucocyte leukotriene C4 synthase activity paralleled by deficient leukotriene biosynthesis from endogenous substrate.

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory effects on human myelopoiesis. We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.

Efficacy and toxicity of radiation in preparative regimens for pediatric stem cell transplantation. II: Deleterious consequences.

There has been a dramatic improvement in the treatment of both allogeneic and autologous stem cell transplants, especially in children and young adults. However, attempts to apply more intensive conditioning treatments to the more refractory pediatric malignancies have also increased the risks of deleterious consequences. This review examines the risks, and reports important variations in the toxic effects of using different conditioning techniques.

Efficacy and toxicity of radiation in preparative regimens for pediatric stem cell transplantation. I: Clinical applications and therapeutic effects.

Here, we review the role of total body irradiation in the treatment of children with bone marrow transplantation, as well as alternative sources of stem cells. We were unable to demonstrate any clear superiority of TBI-containing preparative regimens, but we were able to find a few definitive reports of significantly enhanced toxicity or important variations in control of the underlying primary diseases, in comparing TBI-based regimens, with those containing only chemotherapy.

Allogeneic marrow grafts from donors with congenital chromosomal abnormalities in marrow cells.

To determine whether siblings with chromosomal abnormalities in marrow cells which are associated with cellular defects (e.g. Down syndrome or heterozygosity for Fanconi syndrome) are suitable donors for allogeneic bone marrow transplants, we have reviewed the patient files at the Fred Hutchinson Cancer Research Center (FHCRC) and carried out a survey among member centres of the International Bone Marrow Transplant Registry (IBMTR). The 57 of 253 (23%) member centres which responded to the survey reported seven transplants from donors with the following conditions: Down syndrome (n = 2), suspected heterozygotes for Fanconi syndrome (n = 3), and 47,XXX syndrome (n = 2), among a total of 5,561 allogeneic transplants from HLA-identical siblings. Adding the three cases seen at the Fed Hutchinson Cancer Research Center among 2,927 HLA-identical sibling transplants during 1992 resulted in 10 transplants among 8,488 cases transplanted overall: four with Down syndrome, four suspected of being heterozygous for Fanconi syndrome, and two trisomy X. Three out of four grafts from siblings with Down syndrome had complications, including poor graft function (n = 2) and graft failure (n = 1). Two of four recipients of marrow from presumed Fanconi syndrome heterozygotes presented with poor graft function and a third recipient developed graft failure after initial evidence of engraftment. The two patients given marrow from siblings with 47,XXX syndrome engrafted uneventfully. The experience reported here shows a low frequency of encountering an HLA-identical sibling donor who has chromosomal abnormalities in marrow cells consistent with Down syndrome or heterozygosity for Fanconi syndrome, about one case among 1,000 transplants. The much higher than expected incidence of graft problems with marrow from such a donor would make it reasonable to look either for an alternative marrow donor or consider an autologous transplant, in case a sibling marrow donor with Down syndrome or heterozygosity for Fanconi syndrome is encountered, although a donor with trisomy X seems acceptable.

Neuroblastoma stage IV-S.

A review of stage IV-S neuroblastoma is provided. The possible uses of prognostic features to guide treatment options in this group of infants with neuroblastoma are suggested. The biologic basis for the spontaneous regression of widespread tumor involvement in some infants with stage IV-S neuroblastoma is discussed. The reasons that some infants with IV-S disease progress to a fatal outcome, while most undergo maturation or involution and eventual long term cure are suggested. The influence of such factors as age at diagnosis, clinical staging, and tumor biology on eventual outcome are covered. Biological variables and markers discussed include: genetic (cytogenetics (1p deletions), nuclear genomic content), molecular biologic (N-myc oncogene amplification, mdr-1, ras, and trk, gene expression), immunological (major histocompatibility antigen density, cellular and humoral immunity), and biochemical (creatine kinase isoenzyme profile, neuron specific enolase, ferritin, chromatograffin, lactic acid dehydrogenase and catecholamine levels).

Destructive skeletal lesions as the primary initial manifestation of acute childhood leukemia.

Bony involvement in leukemia has been long recognized in the medical literature. However, severe osseous changes, as the sole initial manifestation of childhood leukemia is a unique feature of the case reported here.

Difficulty in establishing diagnosis from lung biopsies and bronchial washing analysis in children with leukemia following bone marrow transplantation.

Three children developed severe respiratory distress at days +12, +11, and +11 following allogeneic bone marrow transplantation from donors. The first child was a 13-year-old Hispanic boy transplanted in relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). At day -14, a bronchial washing done for a streaky pulmonary infiltrate was negative for acid-fast bacilli. Miliary tuberculosis was discovered at postmortem examination. A second child, transplanted in remission of null-cell ALL, developed severe hypoxia and hypercarbia on day +11 but recovered fully following prolonged mechanical ventilation. An open-lung biopsy showed a pattern of nonspecific, diffuse alveolar damage compatible with respiratory distress syndrome. The third child was transplanted in remission of B-cell ALL and developed fatal fungal and cytomegalovirus pneumonia on day +12. In these latter two cases, it is likely that open-lung biopsy would have missed the diagnosis because of the uneven pulmonary involvement and multiple etiologies observed. All three children received cyclosporine, granulocyte transfusions, and multiple antimicrobials, including amphotericin B. Hyperfractioned total-body irradiation with lung shielding was used in the latter two patients.

Natural killer cell activity and ultrastructure in myeloproliferative reactions in infants with Down's syndrome.

In some infants with Down's syndrome, the circulating mononuclear population, when viewed with conventional and electron microscopy, contains many cells that closely resemble leukemic blast cells. In contrast with true leukemia, however, most of these infants with the "leukemia-like reaction in Down's syndrome" (LLR-DS) enter spontaneous remissions. We therefore investigated the natural resistance of such infants to hematological malignancy in vitro by means of natural killer cell assays. Mean natural killer cell determinations in four infants with LLR-DS were 17.5 +/- 9.2% and 37.6 +/- 18.5% against K-562 and Molt-4 target cells, respectively, at diagnosis. Later, during remission, these values were 34.3 +/- 14.3% against K-562 and 32.2 +/- 15.6% against Molt-4. The mean percentage lysis of Molt-4 both at diagnosis and during remission was greater (p less than 0.05) in LLR-DS than in children with acute lymphocytic leukemia and acute myelogenous leukemia at diagnosis. Natural killer cell activity levels in these LLR-DS patients were similar to levels obtained in other infants with Down's syndrome who were hematologically normal, as well as levels obtained in normal control specimens. Two of these LLR-DS patients progressively developed acute myelogenous leukemia with ultrastructural abnormalities several months later; one of these also developed another karyotype abnormality. Both remain in long-term remission exceeding 48 months.

Retrospective analysis of 58 children with retinoblastoma.

We performed a retrospective analysis of 58 children with retinoblastoma seen at the University of Illinois at Chicago between 1960 and 1982. Our findings showed an almost equal distribution by sex, a predominance (69%) of white patients, and a common presenting symptom (70%) of leukocoria, with (22%) or without (48%) strabismus. Unilateral involvement was noted in 35 patients (60%). Of the 23 (40%) bilaterally affected children, 19 had simultaneous involvement at the time of diagnosis. All bilateral and 90% of the unilateral cases were diagnosed before age five years. Family history was positive for retinoblastoma in five bilateral and one unilateral case. At the time of diagnosis, 35 patients had stage V disease (Reese-Ellsworth classification, Table 1). Depending on the stage of disease treatment included enucleation, radiation, and chemotherapy. Mortality was 25% from 1960 to 1974, and zero thereafter.

Decreased natural killer cell activity in children with untreated acute leukemia.

Natural killer cell activity was evaluated in children with acute lymphocytic and acute myelogenous leukemia. Peripheral blood mononuclear cells isolated at the time of diagnosis and before initiation of therapy were mixed with 51Cr-labeled K562 or MOLT-4 target cells at a ratio of 100:1. In 13 consecutive cases of acute lymphocytic leukemia, the mean percentage of lysis of K562 cells (15.0%) was significantly below that of adult (49.8%) and age-related controls (35.9%). A similar pattern was observed against MOLT-4 targets (acute lymphocytic leukemia, 11.3%; adults, 39.8%; and pediatric controls, 28.4%). The mean activity in 8 cases of acute myelogenous leukemia was also markedly reduced (6.8% versus K562 and 6.0% versus MOLT-4). Linear regression analyses of white blood cell, lymphocyte, and leukemia blast counts failed to demonstrate any correlation between peripheral cell counts and natural killer cell activity. Thus, it would not appear that the observed decrease in lysis was due merely to dilution of effectors with blasts. The lytic activity of cells isolated from patient blood was significantly lower than that from cells isolated from an equal volume of blood from a normal adult. These results suggest that the decreased natural killer cell activity is not explained by simple dilution. Instead, they indicate an absolute decrease in lytic potential. Additional experiments have precluded suppressor cell involvement and competitive inhibition of blasts with target cells as possible causes for depressed lysis.

Hereditary ring sideroblastic anaemia and Christmas disease in a Swedish family.

The association of hereditary ring sideroblastic anaemia with Christmas disease in a Swedish family is described. We have studied the transmission of the sideroblastic trait, in relation to HLA groups and Christmas disease, and also evaluated the erythrocyte morphology, uroporphyrinogen-I-synthetase activity and S-ferritin for the detection of latent cases of ring sideroblastic anaemia. The proband had ring sideroblastic anaemia, Christmas disease and haemochromatosis. 3 cases of ring sideroblastic anaemia were found among the 12 family members studied. Using the factor IX deficiency as a marker of the X chromosome, it appeared that autosomal transmission of the sideroblastic trait was most likely. The sideroblastic trait did not seem to be linked to HLA-A3-alloantigen. Erythrocyte morphology was normal in all non-anaemic subjects. S-ferritin was found to be increased in all 3 cases of sideroblastic anaemia as well as in 1 non-anaemic relative. Erythrocyte uroporphyrinogen-I-synthetase was elevated in 10 of the 12 family members; those with sideroblastic anaemia had the highest values indicating that uroporphyrinogen-I-synthetase is of importance in the disturbed haem-synthesis of ring sideroblastic anaemia. This interpretation is supported by the positive correlation between S-ferritin values and the uroporphyrinogen-I-synthetase activity.

Elevation of natural killer activity and nonspecific immunity following injection of Listeria cell walls.

Mice given a single intraperitoneal injection of cell walls from Listeria monocytogenes (LCW) prior to challenge with Candida albicans or a mammary carcinoma showed significantly increased survival compared to saline injected controls. The cell walls were mitogenic for spleen cells in vitro. Levels of stimulation were lower than for Con A and PHA but comparable to those induced by LPS. Peritoneal exudative cells, but not spleen cells, harvested from mice injected with LCW showed significant elevation of natural killer (NK) cell activity as early as 1 day following injection. NK activity remained elevated for 10 days and then returned to normal levels by day 145. Macrophage phagocytic and tumorcidal activity in vitro did not appear stimulated. In overall comparison to commercial mitogens, LCW had lower levels of activity measured in vitro but equivalent or higher in vivo levels of protection.

Surface Ia-like expression and MLR-stimulating capacity of human leukemic myeloblasts: implications for immunotherapy and prognosis.

Surface Ia-positive cells were found to vary from 0 to 100% in initial blood specimens from 37 adults with acute myelogenous leukemia (AML). When myeloblasts from 19 patients were tested against panels of lymphocytes from 5 to 19 normal donors, mean stimulation indices ranged from 1 to 60. Some leukemic myeloblasts strongly stimulated most allogenic responder lymphocytes whereas others produced almost no stimulation. The addition of antibody against human Ia to 28 mixed leukocyte reaction (MLR) combinations resulted in significant inhibition (p less than 0.001) of 3H-thymidine incorporation. Testing of myeloblastic Ia may have clinical relevance because patients with greater than 50% Ia-positive myeloblasts had a significantly longer survival than patients with fewer Ia-positive myeloblasts (p less than 0.04).