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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3SH2 domain mutations is a recurrent event in LV-HES.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Genetics has played an important role in risk stratification for plasma cell myeloma patients, providing therapeutic guidance. In this study, we investigated the correlation of bone marrow morphologic features and genetic aberrations, including gene expression profiles, translocations, and gene mutations. For the first time we show that high plasma cell volume, diffuse sheet growth pattern, immature cell morphology, high mitotic index, and increased reticulin fibrosis, significantly correlates with high risk disease determined by MyPRS gene expression profiles. Furthermore, we show the association between MyPRS risk stratification and chromosomal alterations and specific gene mutations. We also demonstrate the combinational effect of TP53mutation and 17p loss on the histological changes in bone marrow.

Genetics has played an important role in risk stratification for plasma cell myeloma patients, providing therapeutic guidance. In this study, we investigated the correlation of bone marrow morphologic features and genetic aberrations, including gene expression profiles, translocations, and gene mutations. For the first time we show that high plasma cell volume, diffuse sheet growth pattern, immature cell morphology, high mitotic index, and increased reticulin fibrosis, significantly correlates with high risk disease determined by MyPRS gene expression profiles. Furthermore, we show the association between MyPRS risk stratification and chromosomal alterations and specific gene mutations. We also demonstrate the combinational effect of TP53mutation and 17p loss on the histological changes in bone marrow.

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-a2a (IFN-a2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-a2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2V617F+PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.govas #NCT02407080.

Clinical trials of imetelstat therapy have indicated that this telomerase inhibitor might have disease-modifying effects in a subset of patients with myelofibrosis (MF). The mechanism by which imetelstat induces such clinical responses has not been clearly elucidated. Using in vitro hematopoietic progenitor cell (HPC) assays and in vivo hematopoietic stem cell (HSC) assays, we examined the effects of imetelstat on primary normal and MF HSCs/HPCs. Treatment of CD34+ cells with imetelstat reduced the numbers of MF but not cord blood HPCs (colony-forming unit–granulocyte/macrophage, burst-forming unit–erythroid, and colony-forming unit–granulocyte/erythroid/macrophage/megakaryocyte) as well as MF but not normal CD34+ALDH+ cells irrespective of the patient’s mutational status. Moreover, imetelstat treatment resulted in depletion of mutated HPCs from JAK2V617F+ MF patients. Furthermore, treatment of immunodeficient mice that had been previously transplanted with MF splenic CD34+ cells with imetelstat at a dose of 15 mg/kg, 3 times per week for 4 weeks had a limited effect on the degree of chimerism achieved by normal severe combined immunodeficiency repopulating cells but resulted in a significant reduction in the degree of human MF cell chimerism as well as the proportion of mutated donor cells. These effects were sustained for at least 3 months after drug treatment was discontinued. These actions of imetelstat on MF HSCs/HPCs were associated with inhibition of telomerase activity and the induction of apoptosis. Our findings indicate that the effects of imetelstat therapy observed in MF patients are likely attributable to the greater sensitivity of imetelstat against MF as compared with normal HSCs/HPCs as well as the intensity of the imetelstat dose schedule.

TET2 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies including MDS, CMML, MPN, and AML. However, little is known regarding the biological function of TET2 and its role in the pathogenesis of myeloid malignancies. To study the function of TET2 in vivo, we generated a Tet2 knock out mouse model. Deletion of Tet2 in mice led to dramatic reduction in the 5-hydroxymethylcytosine levels and concomitant increase in the 5-methylcytosine levels in the genomic DNA of BM cells. The Tet2−/− mice contained an increased Lin−Sca-1+c-Kit+ (LSK) cell pool before the development of myeloid malignancies. A competitive reconstitution assay revealed that Tet2−/− LSK cells had an increased hematopoietic repopulating capacity with an altered cell differentiation skewing toward monocytic/granulocytic lineages. Approximately 1/3 of Tet2−/− and 8% of Tet2+/− mice died within 1 year of age because of the development of myeloid malignancies resembling characteristics of CMML, MPD-like myeloid leukemia, and MDS. Furthermore, transplantation of Tet2−/−, but not wild-type (WT) or Tet2+/− BM cells, led to increased WBC counts, monocytosis, and splenomegaly in WT recipient mice. These data indicate that Tet2-deficient mice recapitulate patients with myeloid malignancies, implying that Tet2 functions as a tumor suppressor to maintain hematopoietic cell homeostasis.

BACKGROUND

No relevant conflicts of interest to declare.

The mechanism of the dehydrobromination of two isomeric dibromo-cis-4a-methyldecalin-2,5-diones and tribromo-cis-4a-methyldecalin-2,5-dione is described. Treatment of dione (2), with 2 equiv of bromine gave a mixture of dibromides (3) and (4) in a 1:1 ratio. Treatment of (2) with 3.2 equiv of bromine gave tribromide (5) as the major product. Dehydrobromination of (3) and (4), independently with DBU in THF, resulted in the loss of HBr and the exclusive formation of two isomeric tricyclic compounds (6) and (7) respectively. Dehydrobromination of tribromide (5) with DBU gave a mixture of two tricyclic compounds (6) and (8) in an approximate ratio of 1:1. The mechanisms of the formation of the isomeric tricyclic bromoketones (6) and (7) from compounds (3) and (4), and that of (6) and (8) from the tribromide (5) are discussed. Both tricyclic compounds (6) and (8), readily available in good yields from Wieland Miescher ketone (1), have the same carbon skeleton as the sesquiterpene hydrocarbon sativene.

Laticifers were identified in frozen sections of embryoids from callus and suspension cultures of Asclepias syriaca(common milkweed) by an indirect fluorescent antibody technique. Sections were treated with the IgG fraction of rabbit anti‐latex antiserum, produced with field‐collected A. syriacalatex as a source of antigens, and with fluorescein‐conjugated IgG fraction goat anti‐rabbit IgG. Laticifers were identified by their fluorescence in embryoids dissected from 3–4‐month‐old callus cultures and in embryoids from 2‐month‐old suspension cultures. Laticifers are not present in early globular embryoids of A. syriacabut embryoids similar in shape to late globular stage zygotic embryos possess branching laticifers typical of zygotic material. Sections on control slides, treated with whole serum or IgG fraction from whole serum, both from an uninjected rabbit, contained no fluorescent cells. No laticifers were detected with the fluorescent antibody assay in A. tuberosaembryoids.

The potential impact of local intracoronary infusion of streptokinase (SK) on vascular prostaglandin synthetic pathways was studied in a canine model. Control animals (n = 10) underwent left coronary artery (LCA) infusion of 50,000 units SK for 90 minutes; experimental animals (n = 10) underwent LCA infusion of normal saline. Plasma samples for radioimmunoassay (RIA) of prostacyclin (PGI-2) and thromboxane (TXA-2) were obtained from the coronary sinus (C5) as follows: one sample preinfusion, six samples during infusion, and three samples postinfusion in each animal. Comparisons between control and experimental plasma levels of PGI-2 and TXA-2 were made for each sampling time. The PGI-2 levels remained at or below the lower limits of detectability by RIA (the most sensitive assay available) in both control and experimental animals. TXA-2 levels were higher in experimental than in control animals at all sampling times, with the most significant differences occurring in samples 3 (after 30 minutes of infusion, 001 < P.01), 4 (after 45 minutes of infusion, .05 < P< .10), and 5 (after 60 minutes of infusion, .02 < P< .05).

Mass spectrometric sensitivity data for the compounds cholesterol, cholestane, DDT, decafluorotriphenyl-phosphine, morphine, LSD and methyl stearate have been developed over a period of time and under a variety of conditions. This information is presented on both a relative and an absolute basis. With the exception of morphine, relative sensitivities were repoducible to within a factor of three over a six month period. This reproducibility facilitates quantitation and a single standard can be used for calibration of organic compounds from various classes. Detection limits of 50 femtograms for LSD are realized for samples introduced via the direct inlet probe.

Separation of 2 grams of the methylene chloride extract of NIST SRM 1649 (Washington, D.C. urban air particulate matter) into six compound class fractions by acid-base partitioning and silica gel column chromatography is demonstrated here. Recoveries of organic mass and Salmonella typhimurium TA98 mutagenic activity were greater than 80%. The fractionation method showed reproducible distribution of both mass and mutagenic activity; the compound class mass distribution results were similar to those obtained for more typical analytical fractionation of a milligram quantity of the extract mass. The most polar compound class fractions contained the greatest proportions of mutagenic activity.

Malnutrition produces a pronounced effect on the complement system of man and animals. There is little information, however, to indicate whether individual complement components are affected at different stages of age. In the following studies, we have demonstrated that in guinea pigs and in both conventional and germ-free rats, protein malnutrition adversely affects the complement system. The levels of complement components C2 and C3 are suppressed by protein malnutrition at an early stage while C4 and C8 are less affected by malnutrition. Experiments in germ-free animals demonstrated that decreased complement component levels can be directly associated with decreased synthesis and/or secretion of components. In conventional animls, further reductions in complement levels could occur as a result of infection associated with malnutrition.

Estradiol has been reported to suppress numerous cellular immune response. What is not known is how estradiol exerts this effect. In vivo administration of estradiol to male rats caused time-related immunomodulatory effects leading to enhancement of lymphocyte transformation while suppressing a mixed lymphocyte reaction (MLR) response. The suppression of the MLR response was not due to alterations in the ratio of helper and suppressor T cells, nor was it due to alterations in either cell viability or the number of cells in culture. Lymphocytes cultured in vitro with estradiol, however, fail to show any alteration in the resposiveness in either MLR or lymphocyte transformation assays. The suppressive effects of estradiol cannot be transfered from a primary MLR culture to a second MLR culture using the supernatants from the primary MLR culture. Lymphocytes from animals given estradiol in vivo show no alteration in the production of interleukin 2: added in vitro to primary MLR cultures, Interleukin 2 failed to restore full responsiveness to lymphocytes from animals treated in vivo with estradiol. These results suggest that estradiol acts indirectly to cause an alteration in the responsiveness of the regulatory cells of the cellular immune system.

The pharmacokinetics of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) was investigated in 13 patients with adenocarcinomas who received single intravenous doses ranging from 40 to 250 mg/m2and in three patients who were administered 1.5 mg/kg every 48 to 72 hours for up to 15 doses. Five patients in the single-dose study also received 100 μCi of [3H]-KS1/4-DAVLB. Overall mean values for the pharmacokinetic variables were as follows: elimination half-life, 31.5 hours; distribution volume, 4.43 L; and clearance, 0.09 L/hr. KS1/4-DAVLB demonstrated linear elimination kinetics in both the single- and multiple-dose studies. Significant concentrations of KS1/4-DAVLB were noted in a pleural effusion. Ten percent of the radioactive dose was recovered in the urine and 20% in the feces over a 5-day period. Small molecular weight vinca species were detected in the feces but not in the serum.Clinical Pharmacology and Therapeutics (1990) 47, 36–41; doi:10.1038/clpt.1990.5

Significant polymorphism of serum complement components Bf, C2, C3, C6, and C8 in the chimpanzee has been demonstrated. The data are consistent with the hypothesis thatC2 andBf are closely linked toChLA and argue against close linkage ofChLA toC3 or toC8, as in man. In addition, a blank allele for C6 and C6 deficiency was detected in several chimps.

• Rapid whitening of scalp hair developed during a three-month period along with a diffuse, subtotal alopecia in a patient. Immunofluorescence microscopy of biopsy material showed prominent deposits of IgG and IgM in a granular pattern in the epithelium of the lower portions of hair follicles. Some return of the color and amount of scalp hair occurred within a year, but occasional bouts of hair loss continued to occur. It is theorized that the rapid graying was caused by a selective loss of pigmented hair, which was perhaps caused by an immunologic mechanism. Some of the findings suggest that the cause of this patient's loss of hair color may be different from those of patients who have been previously described as having rapid whitening of scalp hair because of alopecia areata or vitiligo.(Arch Dermatol 1981;117:576-578)

Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL, current recommendations include dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), with or without bortezomib. We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.

Rampal: Jazz: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Stemline: Research Funding; Constellation: Research Funding; Celgene: Honoraria. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; Janssen: Research Funding. Hoffman:Formation Biologics: Research Funding; Summer Road: Research Funding; Merus: Research Funding; Incyte: Research Funding; Janssen: Research Funding.

Myeloproliferative neoplasm-blast phase (MPN-BP) and de novoacute myeloid leukemia (AML) each have distinct mutational patterns and clinical courses. MPN-BP patients have a particularly dismal prognosis with a median survival of less than 6 months with currently available therapies. So far, the cellular hierarchy that characterizes MPN-BP and the evolution of various leukemia-initiating clones (LIC) in MPN-BP have not been well delineated. We therefore established an in vivoMPN-BP xenograft model to address these questions.

Myeloproliferative neoplasms (MPN) are chronic hematopoietic malignancies characterized by the clonal proliferation of mature myeloid elements (Campbell PJ, Green AR. N Engl J Med. 2006; 355:2452). A subset of MPNs progress to MPN-blast phase (BP). The cells that are responsible for the progression to BP and the mechanisms and pathways that underlie this progression have not been well delineated. We therefore established an in vivo MPN-BP xenograft mouse model to address these questions.

Background:Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with an increased risk of thrombosis, progression to myelofibrosis (MF) and significant symptom burden. While hydroxyurea, interferon, and JAK2 inhibitors are used to treat these myeloproliferative neoplasms (MPNs), hematopoietic stem cell-depleting therapies may result in an alternative mechanism to alter disease course and improve outcome. MDM2, a negative regulator of P53, is overexpressed in CD34+ MPN cells harboring wild type P53. It is the target of idasanutlin (IDA), an oral MDM2 antagonist that results in up-regulation of P53 and down-stream activators of apoptosis. Preclinical data from our laboratory group supports the clinical evaluation of IDA in patients (pts) with ET/PV (Lu et al Blood. 2014;124(5):771-9). We evaluated the safety and tolerability of IDA in a phase I dose escalation trial of pts with JAK2V617F-positive ET or PV [NCT02407080].

Nocardiaspp. can cause pulmonary infection, usually in the setting of immunosuppression or underlying lung disease. There have been a few reports of these organisms isolated from cystic fibrosis patients and, when recovered, the isolates were almost always Nocardia asteroides. We present the first reported case of a child with cystic fibrosis harboring Nocardia farcinica.

Donor cell leukemia (DCL) represents a rare complication of allogeneic transplantation. The precise incidence remains unclear, though it may be higher following umbilical cord blood transplants. Here, we present an unusual case of a patient with B-ALL who presented with a donor derived myeloid sarcoma of the heart following a double cord blood transplant. To our knowledge, it is the first case of sarcomatous or chloromatous presentation of DCL following a UCBT.

Off Label Use: Oral histone deacetylase inhibitor that targets epigenetic changes in malignant myelofibrosis cells with an goal to modify the disease process.

Abstract 794FN2This icon denotes a clinically relevant abstract

Introduction: Among patients with diffuse large B-cell lymphoma (DLBCL), it is well documented that for unknown reasons men have shorter progression-free and overall survival than women. Recently, a specialized subset of CD4+ T-cells, called regulatory T-cells (T-regs), which can suppress the effector functions of cytotoxic CD8+ T-cells, has been proposed to have a role in controlling tumor progression. While elevated T-regs in animal models of cancer can block anti-tumor responses and thereby enhance tumor growth, paradoxically, high T-regs are associated with improved survival in humans with DLBCL. To our knowledge, the relationship between T-regs and gender has not been investigated. Since T-regs constitutively express FoxP3, a transcription factor of the forkhead family, we used this marker to retrospectively study the number and density of FoxP3+ T-regs in tissue sections from both male and female patients with DLBCL, and to compare their effects on survival. Methods: Tumor microarrays of DLBCL containing three 1 mm diameter cores per patient were immunohistochemically stained for FoxP3 and CD4. We enumerated tumor infiltrating FoxP3+ lymphocytes by counting positive nuclei that crossed the lines of a 1 mm2 10×10 grid in a 10× ocular that was combined with a 40× objective in a BX41 Olympus microscope. The mean FoxP3 T-regs per field and the ratio of FoxP3 T-regs to total CD4+ T-cells were compared between 34 men and 48 women with de novo, non-AIDS related DLBCL. The median values were used as cut-offs for total FoxP3 counts and for FoxP3/CD4 ratios. We analyzed survival differences between “high” and “low” groups by using Kaplan-Meier curves and Logrank tests. Cox regression analyses were used to compare mortality after adjusting for age and staging. Results: Men had lower values than women both for mean total FoxP3 counts (7.05 vs 8.15, p=0.636) and for mean FoxP3/CD4 ratios (0.31 vs 0.51, p=0.183). Differences between genders in the proportion above the overall median (“high” group) were statistically significant when comparing total FoxP3 counts (32.4% in men vs. 60.4% in women, p=0.012) and FoxP3/CD4 ratios (35.3% vs. 58.3%, p=0.040). Using gender-specific cut-offs, higher FoxP3/CD4 ratios were associated with worse overall survival in men (Figure 1, p=0.052), but improved overall survival in women (Figure 2, p=0.047). The crude hazard ratio comparing groups with gender-specific “high” vs. “low” FoxP3/CD4 ratios was 3.99 (p=0.077) in men and 0.33 (p=0.061) in women. Adjusting for age did not result in significant changes, but adjusting for stage at diagnosis shifted the hazard ratios toward the null (1.06, p=0.947 in men and 0.45, p=0.218 in women). In men, those in the “high” FOXP3/CD4 ratio group appeared more likely to have stage 3 or 4 disease at diagnosis compared to the “low” group (66.7% vs 36.8%, p=0.139). This was not seen in women (33.3% vs 38.9%, p=0.718). Conclusions: More T-regs infiltrated DLBCL in women than in men. This is difficult to explain, but could be a clue to the relationship between survival and gender in DLBCL. Paradoxically, high T-regs predicted worse overall survival in men, but better overall survival in women. Also, stage 3 or 4 disease at diagnosis was associated with high T-regs in men but not in women. To confirm the significance of these findings, a larger sample size and prospective study design will be needed. Figure 1 Survival in Men with DLBCL by FoxP3/CD4
 p=0.052 Figure 1. Survival in Men with DLBCL by FoxP3/CD4
 p=0.052 Figure 2 Survival in Women with DLBCL by FoxP3/CD4
 p=0.048 Figure 2. Survival in Women with DLBCL by FoxP3/CD4
 p=0.048

Introduction: Among patients with diffuse large B-cell lymphoma (DLBCL), it is well documented that for unknown reasons men have shorter progression-free and overall survival than women. Recently, a specialized subset of CD4+ T-cells, called regulatory T-cells (T-regs), which can suppress the effector functions of cytotoxic CD8+ T-cells, has been proposed to have a role in controlling tumor progression. While elevated T-regs in animal models of cancer can block anti-tumor responses and thereby enhance tumor growth, paradoxically, high T-regs are associated with improved survival in humans with DLBCL. To our knowledge, the relationship between T-regs and gender has not been investigated. Since T-regs constitutively express FoxP3, a transcription factor of the forkhead family, we used this marker to retrospectively study the number and density of FoxP3+ T-regs in tissue sections from both male and female patients with DLBCL, and to compare their effects on survival.

Bactericidal and opsonic actrvttres in convalescent-phase sera from patients with disseminated gonococcal infection (DCI) were analyzed with use of the patients' infecting strains and other strains of Neisseria gonorrhoeae. Serum from a patient with C8 deficiency was opsonic for her first DCI isolate grown on solid medium or in chick embryos; with added complement the serum was bactericidal (at a dilution of 1:320). Her serum was not bactericidal for nine other isolates from patients with DCI. Only one of the other patients with DCI had detectable serum bactericidal activity (dilution, I :2.5) against her own isolate; this patient's serum was also active against one other DCI isolate. Opsonization was detectable only in sera that were potentially bactericidal and could be distinguished from bactericidal activity only with C8-deficient serum. The isolates from patients with DCI were of an auxotype different from that of most other gonococci, and most of the isolates tested were not killed by sera from patients with uncomplicated gonorrhea, even though these sera killed other gonococci. Thus, isolates from patients with DCI appeared to be significantly different from other gonococcal isolates.

We have previously reported transient depression of % B cells, Phytohemagglutinin (PHA) responsiveness and T Helper/Suppressor cell (T H/S) ratios in GH-deficient children during treatment (Tx) with pituitary derived human growth hormone (PHGH) (J Pediatr 109:434, 1986). In vitro, incubation of peripheral blood lymphocytes. (PBL) with GH resulted in decreased % B cells. The PBL of children undergoing GH Tx had increased baseline and GH stimulated proliferation.In the current study, we evaluated IF during Tx with BMHGH (kindly provided by Eli Lilly & Co.) in 7 children, ages 4-15, 2 female. Four pts. had been part of the previously cited report. Cell surface markers (SM) and interleukin-2 receptors (IL-2r) were measured by flow cytometry. All pts. had normal baseline IF. Data obtained during 6 months of Tx were analyzed.% B cells decreased significantly at 1 month of Tx (mean change vs baseline -3.9 ± 3.2, p<.05 by two-tailed paired T test) and remained below baseline in most pts. at 3 and 6 months, confirming our in vitro and in vivo findings with PHGH. % T total cells increased (mean change +3.5 ± 3.4, p<.05) at 1 month. There were no other statistically significant changes in SM. Mitogen responses to PHA and concanavalin-A (Con-A) increased in 5/7 and 6/7 pts. at 1 day-1 month of Tx, in agreement with our in vitro data. At 3 months of Tx PHA and Con-A responses decreased in 2/7 and 6/7 children respectively. IL-2r expression was diminished at 1 day-1 month in 6/7 pts. Most of these changes were transient and none was clinically evident.We provide first evidence that BMHGH treatment does affect IF in children. The effects of BMHGH on IF appear to be similar to those of PHGH. These data further support our concept of the presence of a GH-immune network that needs to be considered when treating children with human growth hormone.