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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M-HLH with optimal combinations of T-lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M-HLH. Cancer 2017;123:3229-40. © 2017 American Cancer Society.

We demonstrated previously that inflammatory cy-tokines TNF, IL-1, IL-6 and IL-8 are signifi-cantly expressed in meconium-instilled lungs. Capto-pril was a strong inhibitor of meconium-induced lung injury, inflammation and apoptosis and reduces lung alveolar and airway epithelial cell damage. Presently we demonstrate that IL-13 expression in the me-conium aspiration syndrome (MAS). IL-13 was maximally expressed 8 hrs after meconium instilla-tion. It was previously described that IL-13 plays a major role in degradation of airway epithelial cells and inducing of lung fibrosis by activating collagen production that is a major point in identification of lung fibrosis. We also showed that Captopril treat-ment significantly inhibits IL-13 expression in the lungs. We believe it reduces meconium-induced lung injury and has a therapeutic effect on histological and biochemical functions of the lungs and possibly pulmonary fibrosis. Captopril treatment significantly reduced the number of neuprophils and macrophages which express IL13 and levels of other inflammatory cytokines after meconium instillation. Selective neu-tralization of IL-13 ameliorated lung injury, airway hyper responsiveness, eosinophil recruitment and mucus overproduction.

Langerhans cell histiocytosis (LCH) is an enigmatic histiocytic proliferative disorder of unknown etiology that affects children primarily. We have investigated the possibility that viruses are etiological or that they have a "triggering effect" in LCH. Sensitive in situ hybridization and polymerase chain reaction (PCR) techniques were used in 56 cases of LCH. We sought and failed to find evidence of genomes for adenovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, human herpesvirus type 6, human immunodeficiency virus, human T-cell leukemia virus types I and II, and parvovirus. Although some probes hybridized to tissues from several cases, PCR failed to confirm the presence of viral genome in any. We conclude that there is no evidence that these viruses are associated with LCH.

We report a case of a child with precursor-B acute lymphoblastic leukemia (ALL) who experienced refractory thrombocytopenia and massive splenomegaly during standard induction chemotherapy. He was diagnosed with hemophatocytic lymphohistiocytosis (HLH) during induction. Clinical and laboratory evaluation showed no evidence of infectious cause to HLH. Pancytopenia and HLH persisted after consolidation therapy even with remission from leukemia. After failure to control HLH with ALL-directed therapy and HLH-directed therapy, the patient underwent unrelated donor hematopoietic stem cell transplantation 8 months after diagnosis. He is 34 months post-transplant and in remission from leukemia and HLH.

To determine the feasibility and results of treating children with non-Hodgkin's lymphomas (NHL) according to very intensive protocols based on the German Berlin Frankfurt Münster NHL 90 study.From 1991 until 1995 eighty two patients less than 18 years of age with NHL were admitted to our department. Sixty three of them were eligible for the study. The entire group consisted of 43 males and 20 females (ratio 2.1:1). Median age was 10 2/12 years. Eleven had stage I disease, 4 stage II, 29 stage III and 19 stage IV disease. Histologies represented were: large cell lymphoma 22, lymphoblastic lymphoma 19, and Burkitt lymphoma 10 patients. In 12 cases the immunophenotype was not further classified as to B-cell or T-cell subtype. Patients were stratified into the therapy groups "B" or "non B" according to histopathology, clinical stage and LDH level. Therapy for the B group consisted of 2, 4 or 6 courses of intensive 5 day pulses of 6 drugs. Patients in the non B group received the protocol for acute lymphoblastic leukemia including reinduction and CNS irradiation for advanced stages. At a median follow-up of 35 months the probability of event free survival (pEFS) at 5 years 70% and overall survival 73% for entire group. For therapy group B pEFS was 76%. The non B therapy group had a pEFS 60% (p = 0.22). There was a significantly better outcome for children classified as stage I and II. There was no statistical difference between stage III and IV. Treatment results were comparable between NHL subtypes, except for large cell lymphomas, which did significantly better (pEFS 90%).The use of protocols based on BFM 90 study in the Czech Republic was feasible. The pEFS are approximately 10% lower than the German study but comparable to some other studies. Outcome for large cell lymphomas was excellent. Reduction of treatment related complication and mortality rate as well as more precise classification are required.

Congenital parvovirus infection was diagnosed in two liveborn premature infants born at 24 and 35 weeks of gestational age. The illnesses were associated with placentomegaly, petechial rash, edema, hepatomegaly, anemia and thrombocytopenia, respiratory insufficiency, and death at 5 and 6 days of age. The syndromes exhibited by these cases shared common but nonspecific features with other life-threatening congenital infections. Serological studies in one case supported the diagnosis of parvoviral infection. Postmortem examination of both revealed nuclear inclusions in erythroid precursor cells characteristic of parvovirus infection. Use of the polymerase chain reaction confirmed the presence of parvovirus DNA in one of the cases. Intrauterine parvovirus B19 infection is most commonly associated with hydrops fetalis, "transient" hydrops, or a favorable outcome in infants found to be viremic after birth. These and previously reported examples of congenital B19 disease exemplify an exceptional form of human parvovirus infection.

Infection with human parvovirus B19 is the most common cause of transient aplastic crisis in patients with chronic hemolytic anemia. Multiple reports of children with simultaneous B19 infection and thrombocytopenia as well as the known association between experimental B19 infection and thrombocytopenia prompted us to hypothesize that B19 may be associated with childhood idiopathic, or immune, thrombocytopenic purpura (ITP). Because there is a paucity of evidence regarding a viral etiology for ITP, we performed a comprehensive study to explore its possible relationship to B19 infection.Thirty-five previously healthy children with ITP were studied prospectively. Bone marrow and peripheral blood were analyzed for B19 DNA using the polymerase chain reaction (PCR). Serum was analyzed for anti-B19 immunoglobulin (Ig) M and IgG antibodies using a B19 VP1 antigen-based enzyme-linked immunosorbent assay. Fourteen healthy children served as controls for peripheral blood PCR and serologic analyses.The presenting clinical and laboratory features of the study population were typical of classic ITP. Seventeen of the 35 patients (49%) had evidence of B19 DNA in the peripheral blood, bone marrow, or both. Six of 35 (17%) had anti-B19 IgM antibodies. Eight of 35 (23%) were anti-B19 IgG seropositive. The control group had no positive PCR or anti-B19 IgM specimens.Our results suggest that infection with human parvovirus B19 may be associated with childhood ITP. More investigation is warranted regarding the role of PCR methodology and serologic detection methods in defining B19 pathobiology as it relates to ITP.

No effective therapy is available for the majority of the 30-40% of children with acute lymphoblastic leukemia (ALL) who relapse. Since the morphologically undetectable, or occult, leukemia cells that persist during remission originate from the clone present at diagnosis, may also have both the capability to sustain the disease and to give rise to relapse, we are evaluating a method of identifying them. We have combined, for the first time, an ALL blast colony assay (BCA) and the polymerase chain reaction (PCR) to isolate residual leukemia cells in remission bone marrow aspirate specimens from eight patients with B-precursor ALL during early continuation therapy. We found colony-forming leukemia cells with in vitro self-renewal capability that survived chemotherapy for 15 months after diagnosis in all sequential specimens from these patients. To verify the leukemic nature of these cells their DNA was amplified by PCR and the product directly sequenced. In every case, the VHDJH sequence observed at diagnosis was found. None of the patients relapsed during this early phase of their treatment, consistent with the observation that patients with B-precursor ALL experience recurrence late in their course. Since it is possible that some of these persistent leukemia cells belong to the leukemia progenitor cell population that sustains the disease, the study of them could provide the means to determine the mechanisms of relapse.

The cases of 63 children treated for Hodgkin's disease were retrospectively evaluated according to clinical and laboratory characteristics at initial appearance, clinical and pathologic staging, and treatment for their effects on survival and disease-free survival. An initial erythrocyte sedimentation rate over 50 mm/h was common in patients who ultimately had a relapse. There was no correlation between the size of the mediastinal mass at diagnosis and occurrence of relapse. A residual mediastinal mass was found in 22% of patients after 1 year of treatment regardless of its size at initial appearance. With a median follow-up time of 10.5 years, the overall survival rate is 89%, and disease-free survival rate is 71%. The disease-free survival rates for patients with stages I-IV disease are 92, 81, 78, and 40%, respectively. Relapses occurred in 7 of 22 (36%) patients with positive staging laparotomy despite radiotherapy for three with stage IA and IIA disease, chemotherapy alone for two with stage IIIB disease, or chemotherapy for one with stage IIIB and one with stage IVB disease. Of patients who had no evidence of abdominal Hodgkin's disease at a staging laparotomy, 6 of 34 (19%) had a relapse. These included one with stage IA and five stage IIA disease, all treated with radiotherapy alone. Treatment of stage III and IV disease with regimens including CCNU (lomustine) or cyclophosphamide, plus vinblastine sulfate or vincristine sulfate, prednisone, and procarbazine hydrochloride with or without radiation therapy yielded poor results, with 6/7 having a relapse.

B cell lymphoproliferative disorders (BLPD) developed in eight patients following bone marrow transplantation (BMT) for leukemia (five patients) or immunodeficiency (three patients). Recipients of T depleted marrow from a mismatched donor were at particularly high risk of this complication. Six of 25 (24%) recipients of mismatched T depleted bone marrow developed BLPD. In contrast, none of 47 matched T depleted transplants, one of ten (10%) who received non-depleted marrow from an unrelated donor, and only one of 424 matched non-depleted transplants were associated with BLPD. Epstein-Barr virus (EBV) specific serology and DNA hybridization studies demonstrating five to 50 copies of EBV genome/cell in involved tissues implicate this virus as an associated etiologic agent. Restriction fragment length polymorphism (RFLP) and cytogenetic analysis of involved tissue demonstrated donor origin (five of seven) or host origin (two of seven). Histologic appearance was similar to EBV-induced polymorphic B cell proliferations described following solid organ transplantation, or which occur de novo in primary immunodeficiency. Six of seven patients with adequate tissue available for study were found to have monoclonal proliferations by: in situ immunofluorescence (six of seven), and/or immunoglobulin gene rearrangement, (four of six). Cytogenetic analysis of involved tissues from four patients showed a normal karyotype, whereas two had multiple clonal chromosomal abnormalities. Seven patients died despite aggressive attempts at therapy with combinations of antiviral, immunologic, and chemotherapeutic agents.

A case of therapy-related myelodysplasia followed by acute nonlymphocytic leukemia in a 5-year-old child successfully treated for diffuse Langerhans cell histiocytosis is described. A syndrome of severe cell-mediated immune deficiency and persistent Epstein-Barr virus (EBV) infection coincided with the evolution of myelodysplasia. Specific abnormalities of chromosomes number 7 and 3 were associated with the onset of myelodysplasia and acute nonlymphocytic leukemia and are believed to be linked to the patient's immune dysfunction and compromised ability to contain viral infection.

We describe the development of Epstein-Barr-virus (EBV)-related lymphoproliferative disease (LPD) in the recipient of a histocompatible bone marrow transplant (BMT). Although this rare complication is more common in recipients of mismatched bone marrow, several distinguishing features of our case may have contributed to the development of LPD in the recipient of a matched bone marrow transplant. The patient had received marrow from a sibling with Trisomy 21, a syndrome associated with variable cellular and humoral immune defects. Our patient also was infected with cytomegalovirus and was treated with immunosuppressant therapy for graft versus host disease. Although development of LPD in transplant recipients is a multifactorial process, either acquired or congenital immunosuppression/dysregulation is a common prerequisite for the process. Our case suggests that subtle immune defects in individuals with Down syndrome may contribute to the immunosuppressed setting in which EBV-related LPD can develop.

A 12-year-old white female with recurrent Burkitt's lymphoma had a spontaneous remission associated with a localized herpes zoster infection. The remission lasted nearly 2 months before the tumor recurred in the central nervous system. LDH isoenzyme determinations done on an earlier ovarian tumor and serum at time of bone marrow relapse showed different predominant LDH isoenzyme patterns. These data might be interpreted as showing that different malignant cell clones were responsible for ovarian and bone marrow relapses. Studies to elucidate the mechanism of spontaneous remission at the time of zoster infection demonstrated serum factor(s) which stimulated normal B lymphocytes.

The virus-associated hemophagocytic syndrome (VAHS) is a histiocytic proliferative disorder with bone marrow and liver failure for which the connection with a specific virus is often tenuous. Epstein-Barr virus (EBV) is one candidate for the association, but serologic or culture confirmation may be lacking in a particular case. As a means of directly identifying the presence of EBV in patients' cells, molecular hybridization studies were carried out using a radioactively labeled viral DNA segment. DNA from mononuclear cells of two children with VAHS had specific hybridization to the EBV DNA probe. One of the patients had serologic evidence for EBV infection. Several immunologic deficiencies were found. VAHS may represent one of several hematologic and/or immunologic dysfunctions caused by EBV.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine lymphosarcoma. Much speculation continues to be directed at the role of BLV in human leukemia. To test this hypothesis rigorously, a case-control study of childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma was conducted between December 1983 and February 1986. Cases (less than or equal to 16 years at diagnosis) derived from patients diagnosed at the primary institutions and affiliated hospitals were matched (age, sex, and race) with regional population controls. DNA samples from bone marrow or peripheral blood from 157 cases (131 acute lymphoblastic leukemia, 26 non-Hodgkin's lymphoma) and peripheral blood from 136 controls were analyzed by Southern blot technique, under highly stringent conditions, using cloned BLV DNA as a probe. None of the 157 case or 136 control DNA samples hybridized with the probe. The high statistical power and specificity of this study provide the best evidence to date that genomic integration of BLV is not a factor in childhood acute lymphoblastic leukemia/non-Hodgkin's lymphoma.

Human B19 parvovirus infection may cause severe erythroid hypoplasia in patients with an underlying hemolytic anemia. We report a case of severe parvovirus-induced anemia with initial marrow erythroid hyperplasia in a child with no underlying hematologic disorder.The patient's rapid hemoglobin recovery after treatment with i.v. immunoglobulin further supports this form of therapy for children with parvovirus-induced anemia.

Nineteen children who presented with fever, hepato-splenomegaly, bone marrow and/or hepatic failure, and biopsy evidence of histiocytic proliferations were evaluated for lymphocyte dysfunction and evidence of prior viral infection. Seventeen of the children had erythrophagocytosis consistent with the previously described virus-associated hemophagocytosis syndrome (VAHS) or Familial erythrophagocytic lymphohistiocytosis (FEL). The other two had benign histiocytic proliferations in the central nervous system (CNS) with liver and bone marrow dysfunction. There were two sibling pairs and six patients with known disorders of immune deficiency. The remaining nine cases appeared to be sporadic and idiopathic. Epstein-Barr Virus (EBV) was identified in patients by serologic or DNA hybridization studies (15), EBV and cytomegalovirus (CMV) (1), adenovirus plus EBV and CMV (1), or adenovirus and EBV (1). Herpes zoster was associated with reactivation of symptoms in one patient. Immunologic impairment was evidenced by lymphopenia in 10 of 19 patients. More extensive evaluations could be done at diagnosis on only some of the children because the histiocytic proliferative syndrome was not recognized or because there were insufficient numbers of lymphocytes in samples obtained. For those who could be evaluated, the following immune deficiencies were found: decreased lymphocyte proliferation to mitogens (4 of 9), absent or markedly decreased natural killer function (5 of 5), and decreased cytotoxic lymphocyte reactivity to allogenic EBV-infected target cells (3 of 3). A new finding reported here is a higher than expected prevalence of HLA types A30, B8, and A1/B8 among the patients tested.

Population-based data from the Texas Cancer Registry were used to describe the incidence of cancer in 1990 among Texas residents younger than 20 years. A total of 788 primary malignant neoplasms were diagnosed. Higher incidence of all cancers was observed among Texas Anglo children compared with Hispanics or African-Americans, and lower rates of central nervous system (CNS) neoplasms were seen among Hispanics. Compared with national data, significantly fewer cases of all cancers combined, non-Hodgkin's lymphoma, neuroblastoma, and CNS neoplasms were seen in Texas Hispanics. The overall incidence of leukemia and acute nonlymphocytic leukemia (ANLL) was highest in Hispanics compared with other Texas children, and a three-fold statistically significant excess of ANLL was evident in Hispanic females compared with national whites. In summary, the incidence of cancer in Texas Hispanic children and adolescents differs from that seen in other racial and ethnic groups. Incidence data for Texas provide additional insight into the descriptive nature of childhood and adolescent cancers.

The molecular hallmark of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) is the expression of 1 of 2 alternate forms of the aberrant BCR-ABL protein-p210BCR-ABL or p190BCR-ABL. The presence of BCR-ABL message provides a target for analyzing the lineage derivation of this disease. We, therefore, studied myeloid and erythroid progenitor involvement in Philadelphia chromosome-positive ALL. Bone marrow low-density cells from Philadelphia chromosome-positive ALL patients (5 with the p190BCR-ABL and 2 with the p210BCR-ABL anomaly) were cultured in the mixed colony culture assay. cDNA from individually plucked colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies was then analyzed using the hybridization protection assay in conjunction with the polymerase chain reaction to detect BCR-ABL molecular aberrations. Colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from 1 of 5 p190BCR-ABL-positive patients and 1 of 2 p210BCR-ABL-positive patients expressed BCR-ABL transcripts, whereas colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from the other patients did not. Our study suggests that the origin of both p190BCR-ABL- and p210BCR-ABL-positive ALL is heterogenous with involvement of either a pluripotent precursor or a lymphoid lineage-committed hematopoietic progenitor.

An 8-year-old maternally related relative of three boys who had developed agammaglobulinemia associated with Epstein-Barr virus (EBV)-induced infectious mononucleosis was studied for X-linked lymphoproliferative syndrome (XLP) in 1979. At that time, he demonstrated no striking immunologic aberrations and was seronegative for EBV. Subsequently, immunologic abnormalities including failure to switch from IgM to IgG antibody synthesis after secondary immunization with bacteriophage phi X174 were detected. In 1983, he experienced episodic intracerebral hemorrhages, with the second being fatal. At autopsy, necrotizing vasculitis and aneurysms involving arteries of the central nervous system were observed. Studies of blood obtained immediately before and after death failed to show antibodies to EBV. However, EBV genome was demonstrated in tissues obtained at autopsy by DNA hybridization studies. Fatal lymphoid vasculitis in this patient is unique among boys with XLP in the registry. These findings probably extend the phenotypic expressions of XLP.

Giant hemangiomas occurring in the neonatal period often present a therapeutic challenge, especially when confounded by consumptive coagulopathy (Kasabach-Merritt syndrome). We treated three infants with tranexamic acid after therapy with corticosteroids was ineffective. One patient had a partial response. The remaining two developed progressive disease.