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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The results of the multimodality management of 145 cases of cutaneous Merkel cell carcinoma (MCC) are reported herein. Patient information was obtained from medical records of four Canadian institutions and one French institution. These data included ages, pathological stages, disease sites, histological and treatment details. Cause-specific survival (CSS), overall survival (OS) and disease-free survival (DFS) rates were analyzed by the log-rank and Kaplan-Meier methods. From 1988 to 2007, 145 cases were analyzed. There were 74 men and 71 women. Median age was 78 years (range 47-95.2). Median follow-up was 21.5 months (range 0.5-169.1). During the follow-up period, 37 local, 37 regional nodal and 15 distant recurrences were determined to be either solitary or multifocal sites of treatment failure. Relapsing patients were treated with multimodal treatments provided that their general state of health did not preclude this approach. Either initially and/or at relapse, 30 patients were treated with either multiagent (mostly etoposide with cisplatin or carboplatin) or single-agent chemotherapy, including irinotecan, taxotere and topotecan. In conclusion, recurrence should be treated with multimodalities. Our experience of long-term survivors after treatment of recurrence is encouraging.

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.

The focus of this review is on the relationships between autoimmune diseases and cancer from two closely related perspectives: 1.Those autoimmune diseases which are often associated with malignancies. 2.Those prevalent cancers which may increase the risks of developing autoimmune disorders. The review concludes with a brief discussion of some selected innovative approaches to cancer immunotherapy.

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.

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.

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).

Currently at the University of Florida, 22/45 children and adolescents are long-term survivors in complete sustained remission of standard chemotherapy regimens and central nervous system prophylaxis. All such therapy was discontinued in these survivors at 36 months after diagnosis and they were given monthly inoculations of BCG of the Tice strain by tine technique. 19/22 of BCG-treated patients remain in remission for 12 to 44 + months after cessation of chemotherapy. 1/22 has suffered relapse. Immunological function tests have shown statistically significant increased lymphocyte responses to PPD in contrast to age-matched controls and normal siblings. A trend to earlier than expected return to normal in other immunological parameters, including absolute lymphocyte counts, intradermal skin tests, phagocytosis indices, PHA transformation, and E-rosette forming cells was also observed, coincident with the BCG treatment. Further study of the role of BCG in acute lymphoblastic leukemia patients after cessation of chemotherapy is encouraged.

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.

The early detection and treatment of two cases of acute monocytic leukemia (AMoL) was hampered by the presence of positive slide tests for infectious mononucleosis (IM). This assumes great importance with the recent development of specific therapy, effective for certain subtypes of nonlymphocytic leukemia.

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.

The prognosis for children with cancer has changed significantly over the past 10 years. Currently, it is anticipated that cure can be achieved in approximately 50% of newly diagnosed cases of childhood cancer. The quality of life for these children depends not only on their medical treatment but also on the successful management of the psychological problems related to their diagnosis. A summer camp was established in Florida as a part of our psychosocial rehabilitation program for pediatric cancer patients. Participating in the day-to-day camp life were 26 children with various forms of cancer. Each child not only had the opportunity to enjoy a normal out-of-door life style, away from their overprotective parents, but experienced daily contact with other children who shared a similarly stressful existence. It is felt the awareness gained through the realization that they were not along in their plight and the independence instilled through separation from parents was beneficial to each child. It is anticipated that future camps with the inclusion of psychological testing will provide us with the opportunity to further assess the need for psychosocial rehabilitation for the child with cancer.

Thirty-seven children and adolescents with acute leukemia in relapse were treated with cyclocytidine in a cooperative group setting. Only one of the 27 evaluable patients achieved complete remission. A significant decrease (greater than or equal to 20%) in circulating and/or bone marrow leukemia cells occurred in an additional five patients. Drug toxicity was evaluated in 35 patients and included ten cases of jaw pain, two cases of hypotension, one case of fever, and one case of severe vomiting.

The overall 38% response rate in histiocytosis X for cyclophosphamide, vincristine (Oncovin), prednisone, and procarbazine was not superior to responses that can be achieved with the component single agents. This is in contrast to the higher response rates that can be achieved by the combination of these agents in Hodgkin's disease. This is the second study of combination chemotherapy with individually effective agents that has failed to improve the response rates in histiocytosis patients with poor prognostic indicators.

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.

The "late" relapse patterns of childhood acute leukemia were studied in 83 children in their first continuous complete remission for more than three years prior to randomization for stopping therapy (40 patients) or continuing therapy (43 patients) for a total of six years. Twenty of 83 (22.9%) have relapsed: Ten in the bone marrow, one in the central nervous system, and nine in the testes. The testes relapse rate of 41.1% (7/17) in males discontinuing therapy at three years was much higher than that of 8.7% (2/23) in males continuing therapy. This difference is significant at P = 0.01 (Wilcoxon test).

Computerized, semiquantitative image analysis of 2913 erythrocytes from 29 young patients with sickle cell anemia and its variants was conducted utilizing a modified method for determination of fetal hemoglobin distribution by an acid elution procedure. Histograms of eight arbitrary levels of staining intensity, proportional to fetal hemoglobin levels, were analyzed in relationship to both computer-generated, mathematical parameters of erythrocytic shape abnormalities and clinical parameters of disease severity. Shifts in fetal hemoglobin distribution were observed in analysis of sequential specimens. An inverse correlation was observed between angularity of erythrocytes and their individual fetal hemoglobin content (p less than or equal to 0.05). A positive correlation was noted between growth percentiles and percentage erythrocyte ghosts by acid elution (p less than or equal to 0.01).

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).

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.

Measurements of polyamines have potential practicality as biochemical markers of disease activity in adult cancer patients. On this basis, similar measurements were made in children with leukemia and solid tumors. Fluctuations in blood polyamine concentration were studied in relationship to chemotherapy schematics, cellularity and composition of blood and bone marrow specimens, and remission status of patients. Our results indicate that each of these factors may influence these determinations and consequently their clinical usefulness.

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.

This report updates experience with the CONPADRI-I, COMPADRI-II, and COMPADRI-III adjuvant chemotherapy programs for the treatment of nonmetastatic osteosarcoma. A total of 200 patients received one of the three regimens. The analysis of response to treatment is based on disease-free survival time (DFS time). The effect of treatment, age, sex, site of disease involvement, and race on DFS time were investigated. Cox's life-table regression analysis found only sex to have a significant effect on DFS time with males having 1.8 times the risk of recurrence or death per unit time as female patients (P = 0.004). An analysis of the 81 patients still alive and disease-free 18 months after the start of treatment shows significantly longer DFS time for CONPADRI-I than COMPADRI-II patients (P = 0.01). This trend is true for both male (P = 0.12) and female (P = 0.08) patients.

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.

A retrospective study was undertaken comparing the frequency and severity of anaphylactic reactions to E. coli-derived and Erwinia-derived asparaginase given intravenously on a weekly dosage schedule. Both drugs were found to produce life-threatening hypersensivity reactions with the chance of reaction per dose administered being almost identical--8% for each dose administered. Eleven of 31 patients (35%) experienced anaphylactic reactions, 9/27 (33%) with E. coli and 3/10 (30%) with Erwinia asparaginase, with one patient suffering anaphylaxis to both preparations. A marked increase in the percentage of patients having reactions occurred after the fourth dose of either preparation, with the incidence per dose increasing from 3.3% with the first dose to 32% on the fifth and subsequent doses. Rationale for an antibody-mediated allergic reaction is presented to explain the data.

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.

Lymphocyte proliferation, as measured by incorporation of tritiated thymidine (3H-TdR), was significantly enhanced (p less than 0.01) when macrophages sensitized by target myeloblasts were added to monocyte-depleted lymphocyte fractions in the mixed leukocyte reaction (MLR) with human leukemic myeloblasts as stimulators and panels of normal lymphocytes as responders. Monocyte addition in the same concentration range to unfractionated lymphocytes resulted in highly significant facilitation (p less than 0.0001) of MLR response patterns to myeloblastic stimulation. However, with substitution of a different myeloblastic stimulator, this facilitation was not observed. At higher monocyte-lymphocyte ratios (1:15) the monocytes appeared to be capable of strongly inhibiting the MLR. Monocyte capacity to engulf and kill Candida albicans organisms was normal in acute myeloid leukemia (AML) patients given "immunotherapy" with BCG and leukemic cells.