Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs.

Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.

Mild Acute Graft-Versus-Host Disease Improves Outcomes After HLA-Haploidentical-Related Donor Transplantation Using Posttransplant Cyclophosphamide and Cord Blood Transplantation.

Haploidentical-related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) and cord blood transplantation (CBT) are valid alternatives for patients with hematological malignancies when HLA-matched donor transplantation (MDT) is unavailable. However, the effects of graft-versus-host disease (GVHD) on outcomes after these transplants have not been fully elucidated. Therefore, we evaluated the effects of acute and chronic GVHD on transplant outcomes after PTCy-haplo transplants and compared them with CBT and MDT. We included a total of 914 adult patients with hematological malignancies in the Kyoto Stem Cell Transplantation Group registry who received PTCy-haplo (N = 120), CBT (N = 402), and MDT (N = 392), and achieved neutrophil engraftment. A multivariate analysis revealed that grade I-II acute GVHD improved of overall survival (OS) after PTCy-haplo [hazard ratio (HR) = 0.39, P = 0.018] and CBT (HR = 0.48, P < 0.001), but not after MDT (HR = 0.80, P = 0.267) compared with patients without acute GVHD. Grade I-II acute GVHD had a trend toward reducing the risk of nonrelapse mortality (NRM) after PTCy-haplo (HR = 0.13, P = 0.060) and this positive effect was significant after CBT (HR = 0.39, P = 0.003). A negative impact of grade III-IV acute GVHD on NRM was observed after CBT and MDT, but not after PTCy-haplo. Limited chronic GVHD had a positive impact on OS after CBT and MDT, but not after PTCy-haplo. In conclusion, mild acute GVHD improved outcomes after PTCy-haplo and CBT, and limited chronic GVHD improved outcomes after CBT and MDT. These data indicated that the effects of GVHD on transplant outcomes depended on transplant platforms.

Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy.

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.

[Perforin gene mutation in middle-age onset hemophagocytic lymphohistiocytosis].

A 54-year-old woman was referred to our hospital for pancytopenia and liver dysfunction, and with no personal or family history of hemophagocytic lymphohistiocytosis (HLH). Although the etiology was unknown, she was diagnosed with HLH. She experienced exacerbation of HLH even after initiating systemic chemotherapy with etoposide, dexamethasone, and cyclosporine. Furthermore, flow cytometric analysis of the natural killer cells revealed a reduction in perforin expression, and DNA sequencing of the perforin gene (PRF1) revealed two known mutations, confirming the diagnosis of late-onset familial HLH type 2. She received an allogeneic stem cell transplant from an unrelated human leukocyte antigens identical donor, but developed thrombotic microangiopathy, and succumbed to septic shock shortly after the transplant. Previously, HLH in adults was believed to develop from underlying diseases. However, as in our case, several reports demonstrated that HLH gene mutations could be found even after adolescence. Adult with HLH with no underlying disorders should undergo early HLH-associated gene testing for confirmatory diagnosis.

Single Cord Blood Transplantation Versus HLA-Haploidentical-related Donor Transplantation Using Posttransplant Cyclophosphamide in Patients With Hematological Malignancies.

BACKGROUND: Unrelated cord blood (UCB) and haploidentical related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without a HLA-matched donor. METHODS: We conducted a retrospective study using registry data from the Kyoto Stem Cell Transplantation Group for patients with hematological malignancies who received their first allogeneic hematopoietic cell transplantation using a single UCB unit (n = 460) or PTCy-haplo (N = 57) between 2013 and 2019. RESULTS: We found that overall survival in the UCB group was comparable to that in the PTCy-haplo group (hazard ratio, 1.00; 95% confidence interval, 0.66-1.52), although neutrophil and platelet engraftment were significantly delayed. Nonrelapse mortality risk and the incidence of graft-versus-host disease in the UCB group were also comparable to those in the PTCy-haplo group. Although the relapse risk was similar between the UCB group and the PTCy-haplo group regardless of the disease risk, acute myeloid leukemia patients benefit from UCB transplant with a significantly lower relapse rate (hazard ratio, 0.38; 95% confidence interval, 0.18-0.76). CONCLUSIONS: UCB transplant gives outcomes comparable to PTCy-haplo transplant, and both UCB and PTCy-haplo units are suitable as alternative donor sources for patients without an HLA-matched sibling or unrelated donor.

Next-generation sequencing in two cases of de novo acute basophilic leukaemia.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34+ , CD203c- , CD117+ , CD123dim+ ) and basophils (CD34- , CD203c+ , CD117± , CD123+ ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33+ , CD34+ , CD123- ) and basophils (CD33+ , CD34+ , CD123+ ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis.

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n = 108), HLA-matched sibling donors (MSDs, n = 143), or HLA-matched unrelated donors (MUDs, n = 143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P = .975). However, we found a significant interaction between transplant year and CBT outcomes (P = .010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

Successful treatment with famciclovir for varicella zoster virus infection resistant to acyclovir.

Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo, and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase.

[Small B-cell neoplasm responding to ibrutinib after 17 years of cold agglutinin disease symptom].

In this study, we report a case of a 77-year-old woman who was presented with anemia in the winter of 2002. She was diagnosed with cold agglutinin disease (CAD) and treated with corticosteroids. Further, her hemoglobin levels were maintained between 7.0 g/dl and 8.0 g/dl. In May 2019, mature peripheral blood lymphocytes increased with exacerbation of hemolytic anemia. The lymphocytes were positive for CD19 and CD20, but negative for CD5, CD10, and CD23. Additionally, they were positive for cell surface IgM-κ. The B-cell neoplasm could not be further subclassified due to the lack of BCL2-IgH and BCL1-IgH rearrangement and morphology. The IgM-κ-type M-protein was found in serum, and the direct Coombs test was negative for IgG but positive for C3b/C3d. These findings suggested that small B-cell neoplasm-associated M-protein was involved in the development of CAD through complement activation. Based on the presence of TP53 deletion, the patient was treated with ibrutinib monotherapy. Although hemolysis rapidly improved with a dramatic decrease in lymphocytes, she died from a cerebral hemorrhage. It is assumed that ibrutinib improved CAD through suppression of small B-cell neoplasm-related M-protein. CAD can precede lymphoproliferative disorders; however, the risk of ibrutinib-associated hemorrhage should be noted.

Primary hepatic lymphoma as other iatrogenic immunodeficiency-related lymphoproliferative disorders: a case report and review of the literature.

We report a case of 68-year-old man with stable polymyositis complicated with primary hepatic lymphoma (PHL) as other iatrogenic immunodeficiency-related lymphoproliferative disorders (OIIA-LPD). Multiple liver masses were diagnosed as diffuse large B-cell lymphoma (DLBCL) by biopsy. The LPD was associated with Epstein-Barr virus (EBV) reactivation, because EBV-DNA was detected in peripheral blood, and EBV antigen was detected in the tumour. He presented with high fever, cytopenia and hyperferritinemia, suggesting hemophagocytosis. Only discontinuation of methotrexate and tacrolimus resulted in a dramatic regression of the liver masses and improvement of fever and cytopenia. We review six cases of OIIA-LPD localised in the liver. All cases were DLBCL; 4/6 cases (67%) were positive for EBV staining, and 2/6 cases (33%) were improved after the discontinuation of immunosuppressants. Screening for EBV in blood and liver tumour is important, when a patient in immunosuppressive status presented with liver masses.

GVHD-free, relapse-free survival provides novel clues for optimizing allogeneic-HSCT for adult T-cell leukemia/lymphoma.

The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult T-cell leukemia/lymphoma (ATL) is still unsatisfactory. To illustrate the advantages and disadvantages of each donor source, we performed a nationwide retrospective study of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) of patients with allo-HSCT-treated ATL. One-year GRFS did not significantly differ between patients who received related bone marrow transplantation (R-BMT; 26%, n = 117), related peripheral blood stem cell transplantation (R-PBSCT; 22%, n = 225), unrelated bone marrow transplantation (UR-BMT; 26%, n = 619), and cord blood transplantation (CBT; 21%, n = 359; p = 0.09). This was attributable to a low incidence of systemically-treated chronic GVHD after CBT (9% at 1 year) and reduced non-GVHD/relapse mortality after R-PBSCT (9% at 1 year). Among patients transplanted in complete remission (CR), 1-year overall survival after CBT (52%, n = 132) was not inferior to that after R-BMT (55%, n = 51), R-PBSCT (57%, n = 79), and UR-BMT (58%, n = 280; p = 0.15), and relapse rates were equivalent among the four sources (p = 0.19). Our results suggest that all donor sources are feasible for CR patients and that GRFS provides important clues toward optimizing allo-HSCT for ATL.

Impact of HLA class I allele-level mismatch on viral infection within 100 days after cord blood transplantation.

Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

Secondary failure of platelet recovery in patients treated with high-dose thiotepa and busulfan followed by autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation for Mature T Cell and Natural Killer Cell Neoplasms in the Kyoto Stem Cell Transplantation Group.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the key strategy to cure patients with mature T and natural killer (NK) cell lymphomas/leukemia, especially those with relapsed/refractory diseases, there is no consensus strategy for donor selection. We retrospectively analyzed the outcomes of allo-HSCT in 111 patients in 15 Japanese institutions as a multi-institutional joint research project. Thirty-nine patients received bone marrow or peripheral blood stem cell transplantation from related donors (rBMT/rPBSCT), 37 received BMT/PBSCT from unrelated donors (uBMT/uPBSCT), and 35 received cord blood transplantation (CBT). Overall survival (OS) and progression-free survival (PFS) at 4 years were 42% and 34%, respectively. The cumulative incidences of relapse and nonrelapse mortality were 43% and 25%. In multivariate analysis, CBT showed comparable OS with rBMT/rPBSCT (rBMT/rPBSCT versus CBT: hazard ratio [HR], 1.63; P = .264) and better OS compared with uBMT/uPBSCT (HR, 2.99; P = .010), with a trend toward a lower relapse rate (rBMT/rPBSCT versus CBT: HR, 2.60; P = .010; uBMT/uPBSCT versus CBT: HR, 2.05; P = .082). This superiority of CBT was more definite in on-disease patients (OS: rBMT/rPBSCT versus CBT: HR, 5.52; P = .021; uBMT/uPBSCT versus CBT: HR, 6.80; P = .007). Better disease control was also strongly associated with better OS and PFS with lower relapse rate. In conclusion, allo-HSCT is beneficial for the survival of patients with mature T and NK cell lymphomas/leukemia if performed in a timely fashion. Since CBT showed favorable survival with a lower relapse risk, it could be a preferred alternative, especially in on-disease patients.

High-dose cytarabine chemotherapy (≥4 g/m2/day) before allogeneic hematopoietic stem cell transplantation for non-core-binding-factor AML in the first complete remission.

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data from 79 non-core-binding-factor AML patients who underwent allo-HSCT in their first complete remission (CR1). In univariate analysis, HD-AraC (≥4 g/m2/day) before allo-HSCT improved disease-free survival (DFS) (p = .018), overall survival (OS) (p = .029), and cumulative incidence of relapse (CIR) (p = .033). Four-year DFS, OS, and CIR of patients receiving and not receiving HD-AraC were 79% vs. 49%, 82% vs. 56%, and 18% vs. 42%, respectively. In multivariate analysis, HD-AraC was a positive prognostic factor for DFS (hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14-0.88), OS (HR = 0.37, 95% CI: 0.14-0.99), and CIR (HR = 0.38, 95% CI; 0.14-1.0). Our study demonstrates that HD-AraC before allo-HSCT at a dose ≥4 g/m2/day is effective for treating AML patients in CR1.

Correction to: Histologic transformation of t(11;18)-positive MALT lymphoma presented with aberrant T-cell marker expression.

M. Nishikori receives honoraria from Eisai and funding from Eisai and Sumitomo Dainippon Pharmaceutical.

Lymphopenia at diagnosis predicts survival of patients with immunodeficiency-associated lymphoproliferative disorders.

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n = 26; other iatrogenic immunodeficiency-associated LPD, n = 45) were reviewed and analyzed. The median age at diagnosis was 63 years (range, 3-83). Diffuse large B cell lymphoma was the most common subtype (n = 33), followed by Hodgkin lymphoma (n = 12), B cell monomorphic LPD not specified (n = 11), and polymorphic LPD or early-phase diseases (n = 15). The median follow-up period for survivors was 2.5 years and overall survival (OS) and progression-free survival (PFS) at 2.5 years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/µL) at diagnosis predicted inferior OS (HR, 3.72; P = 0.043) and PFS (HR, 3.82; P = 0.012). Serum albumin values also strongly affected OS (> 3.18 g/dL vs. ≤ 3.18 g/dL; HR, 0.21; P = 0.010) and PFS (HR, 0.26; P = 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds.