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Intravenous immunoglobulin (IVIg) is increasingly used across multiple specialties for the treatment of inflammatory and autoimmune diseases. Cutaneous reactions to IVIg are generally minor. Pompholyx is a common eruption of small vesicles on the palms, soles, and/or lateral aspects of the fingers. It has a multifactorial aetiology but is rarely attributed to being a drug-related side effect. We describe a 43-year-old woman presenting with peripheral sensory neuropathy who developed pompholyx eczema on both palms following treatment with IVIg.

Myeloid sarcoma is an uncommon pathological diagnosis of proliferation of blasts of one or more of the myeloid lineages in regions other than the blood and bone marrow. Myeloid sarcoma of the testis after allogeneic bone marrow stem cell transplantation is very rare and only few cases are reported in the literature. It is usually misdiagnosed as malignant lymphoma, particularly with large cell lymphoma, due to similar histological morphology. Due to difficulty in diagnosis, it is suggested that an appropriate panel of immunohistochemical marker studies be performed in conjunction with clinical correlation to avoid misleading diagnosis and improper treatment of patients. We report an interesting case of a 49-year-old man with a diagnosis of acute myelogenous leukaemia. He had undergone allogeneic peripheral blood stem cell transplantation, achieved complete molecular remission and later relapsed with myeloid sarcoma of the testis.

A case of mass-forming breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) with onset a short time after explanation of the cosmetic prosthesis is reported. The cause of implant removal was carcinoma diagnosed in the ipsilateral breast. The rarity of an almost synchronous manifestation of BIA-ALCL and breast carcinoma and the diagnostic challenges of mass-forming BIA-ALCL in a previously operated breast substantiate this report. The clinical course, diagnostic workup and therapeutic considerations are presented and discussed in detail. This case shows that a diagnosis of BIA-ALCL must always be considered even without a prosthesis in place in patients with a long history of textured implants.

Anaplastic large cell lymphoma (ALCL) is a subtype of T cell non-Hodgkin’s lymphoma and can present as an extranodal disease. Primary ALCL of skeletal muscle is rare. We report a case of ALK-positive ALCL involving the left thigh and anterior chest wall in a 12-year-old male child. The fine needle aspiration cytology from the lesion showed cellular smears with singly scattered and occasional clusters of large pleomorphic atypical cells. A diagnosis of poorly differentiated malignant neoplasm was rendered. On core biopsy, the histomorphological features posed a diagnostic challenge with a myriad of morphological mimickers. The diagnosis was established by excluding specific entities by relevant immunostains and confirming the diagnosis by strong expression of CD30 and ALK on immunohistochemistry. Fluorescence in-situ hybridisation confirmed the characteristic t(2:5) translocation. Presentation of ALCL with skeletal muscle involvement is uncommon, and the diagnosis relies on broadening the diagnostic possibilities and judicious use of immunohistochemical markers.

Primary splenic diffuse large B-cell lymphoma (PS-DLBCL) is a relatively rare malignancy, and there are no optimal approaches for diagnosis and management. There are less invasive splenic biopsies that effectively obviate diagnostic and elective splenectomies. We report a man in his 50s with 2-day history of pain in the abdomen and who was found to have a splenic mass on PET-CT. A CT-guided core needle splenic biopsy confirmed the diagnosis of PS-DLBCL. He was managed with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alone, without splenectomy. The patient attained complete remission, and he is disease free at 6 years of follow-up.

Backgrounds: Imatinib is one of the tyrosine kinase inhibitors used for the treatment of chronic myeloid leukemia (CML) patients. The exact association of imatinib with anemia in CML patients is still unclear. Aim: The current study aimed to find the prevalence of anemia in chronic myeloid leukemia patients treated with imatinib. Methods: The relevant articles were searched in PubMed, Google scholar, and Clinical trials registries till 31st July, 2021. The quality of the articles was assessed using the Newcastle-Ottawa Scale. The prevalence rate with 95% CI was calculated using StatsDirect Statistical analysis software V.3. Results: A total of 18 studies containing 3537 patients were found relevant for the analysis. The pooled prevalence of anemia in CML was found to be 34% (95% CI: 23%-46%). However, the heterogeneity among studies was found to be high. Conclusion: The monitoring of hemoglobin levels and identifying the cause of anemia are major concerns for the CML patients treated with Imatinib.

Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers.A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program.A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

Objective: Although peer difficulties and sluggish cognitive tempo (SCT) are related, studies have yet to examine environmental factors that may advance further understanding of this association. The current study tested whether peer difficulties, specifically social competence and peer victimization, interacted with school support, a component of school climate, in relation to adolescents' SCT symptoms. Further, we explored whether these relations would be differentially associated with SCT in adolescents with and without attention-deficit/hyperactivity disorder (ADHD).Method: Adolescents (N = 288; Mage = 14.08, 45% female, 82.6% White; 52% with ADHD) completed measures of social competence, peer victimization, school climate support, and SCT and ADHD inattentive (IN) symptoms. Parents also reported on adolescents' social competence, SCT, and ADHD-IN symptoms.Results: Results indicated that adolescent and parent ratings of lower social competence were both associated with higher adolescent-reported SCT symptoms in the context of low, but not high, school support. Relational and nonphysical victimization were associated with higher self-reported SCT symptoms in the context of low school support. Lower adolescent- and parent-reported social competence were also related to higher parent-reported SCT symptoms, with these associations not moderated by school support. These results remained after controlling for demographics and ADHD-IN symptoms and were similar across adolescents with and without ADHD.Conclusions: Findings from the current study are the first to provide evidence that peer difficulties and school climate are jointly related to adolescents' self-reported SCT and underscore the importance of continued research investigating social adversity and environmental factors in relation to SCT.

A 25-year-old woman with a history of immune thrombocytopaenia (ITP) in childhood was referred to haematology clinic for review with a platelet count of 50 μ/L at 9 weeks gestation, gravida 2, para 0. She developed progressive severe thrombocytopaenia as the pregnancy progressed, with associated bleeding complications. The thrombocytopaenia was refractory to standard therapies. This led to a need for a planned delivery, which was performed via caesarean section under general anaesthetic with platelet transfusion support, Intravenous Immune Globulin (IVIG), high-dose corticosteroid and the thrombopoietin (TPO) mimetic romiplostim. Both the mother and the neonate survived; however, the neonate required treatment for severe prolonged neonatal thrombocytopaenia. The patient subsequently re-presented 15 months later with recurrent ITP complicating another pregnancy, refractory to rituximab but responsive to romiplostim. She had a successful elective caesarean section under epidural anaesthesia, but the neonate once again suffered severe thrombocytopaenia, which was responsive to IVIG.

Pericardial effusion secondary to isolated severe iron-deficiency anaemia is an extremely rare condition. We present a case with severe anaemia presented with moderate pericardial effusion. Pericardial effusion completely resolved with correction of anaemia.

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are conditions related to renal failure that can rarely occur in association as a contiguous gene syndrome. Angiomyolipomas (AMLs) are renal tumors strongly related to TSC that may rupture and cause life-threatening bleedings. We present a patient with TSC, ADPKD, and renal AMLs with persistent hematuria requiring blood transfusion. The persistent hematuria was successfully treated through endovascular embolization, a minimally invasive nephron sparing technique. Keywords: Tuberous Sclerosis; Polycystic [...]

Anaemia is a common complication of chronic kidney disease. The most important contributory factor is an abnormally low circulating concentration of erythropoietin, which is produced by the kidney peritubular cells. Anaemia of kidney disease is likely to develop once the glomerular filtration rate (GFR) is

Purpose To report the case of a patient presenting with newly diagnosed atypical hemolytic uremic syndrome (aHUS) and Purtscher-like retinopathy. Methods Observational case report and review of literature. Patient A 38-year-old female presented with 3 months of rashes, fevers, arthralgias, and abdominal pain. Initial workup was suggestive of hypereosinophilic syndrome or adult-onset Still's disease. The patient developed acute renal failure and progressively blurry vision bilaterally over the course of 5 days. Funduscopic exam was notable for numerous Purtscher flecken and cotton-wool spots, with rare intraretinal hemorrhages at the posterior pole. The constellation of renal failure, hemolytic anemia, and thrombocytopenia prompted a work-up for thrombotic microangiopathy that was remarkable for a mutation in the gene coding for complement protein C9. Results The patient was diagnosed with aHUS. The patient was treated with intravenous pulse dose steroids for 3 days and an extended course of eculizumab. The patient's renal failure resolved, and her visual acuity improved, though she had residual visual field constriction and developed bilateral optic atrophy. Outcomes of other cases of Purtscher-like retinopathy related to aHUS are reviewed. Conclusion Purtscher-like retinopathy is a rare, but severe ophthalmic complication of aHUS. Eculizumab is an effective treatment for the systemic illness caused by aHUS, and anatomic resolution of Purtscher-like retinopathy may follow, although visual prognosis remains guarded. Recovery of visual acuity may lag behind resolution of macular edema in these patients.

Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML). The prognostic impact of the presence of IDH mutations may be influenced by the comutational status, the specific location of the mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172) at diagnosis, and the dynamics of the mutation burden during disease course. Even though many patients with IDH-mutated AML are consolidated by hematopoietic stem cell transplantation (HSCT), the underlying biology and prognostic consequences remain largely unknown. Here, we present a large analysis of 292 patients with AML who received HSCT in complete remission (CR) or CR with incomplete peripheral recovery (CRi), in which we assessed the IDH mutation status at diagnosis and HSCT as a potential marker for measurable residual disease (MRD). About a quarter of all patients were IDH-mutated at diagnosis. The diagnostic presence of IDH mutations in AML did not have a significant prognostic impact when consolidated with HSCT. However, IDH1 R132 and IDH2 R172 MRD positivity in remission at HSCT associated with an increased risk of relapse, while IDH2 R140 mutations did not. The IDH2 R140 variant allele frequency (VAF) at diagnosis was higher, clustering around 50%, and the mutation clearance at HSCT in morphologic remission was much lower compared with IDH1 R132 and IDH2 R172. In our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberration, while IDH1 R132 and IDH2 R172 harbored AML disease-specific features.

NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle–associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wild-type in the nucleus and nucleolus, caused by the loss of one wild-type allele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice that transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1-binding occupancies such that it binds the promoter of the oncogene structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild-type–harboring Hoxa9/Meis1-transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c+ AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared with AML cells with nonmutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.

This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

PURPOSE Patients with non-Hodgkin lymphoma including chronic lymphocytic leukemia (NHL/CLL) are at higher risk of severe SARS-CoV-2 infection. We investigated vaccine-induced antibody responses in patients with NHL/CLL against the original SARS-CoV-2 strain and variants of concern including B.1.167.2 (Delta) and B.1.1.529 (Omicron). MATERIALS AND METHODS Blood from 121 patients with NHL/CLL receiving two doses of vaccine were collected longitudinally. Antibody binding against the full-length spike protein, the receptor-binding, and N-terminal domains of the original strain and of variants was measured using a multiplex assay. Live-virus neutralization against Delta, Omicron, and the early WA1/2020 strains was measured using a focus reduction neutralization test. B cells were measured by flow cytometry. Correlation between vaccine response and clinical factors was determined. RESULTS Mean anti-SARS-CoV-2 spike immunoglobulin G–binding titers were 85-fold lower in patients with NHL/CLL compared with healthy controls, with seroconversion occurring in only 67% of patients. Neutralization titers were also lower and correlated with binding titers ( P < .0001). Treatment with anti-CD20-directed therapies within 1 year resulted in 136-fold lower binding titers. Peripheral blood B-cell count also correlated with vaccine response. At 3 months from last anti-CD20-directed therapy, B-cell count ≥ 4.31/μL blood around the time of vaccination predicted response (OR 7.46, P = .04). Antibody responses also correlated with age. Importantly, neutralization titers against Delta and Omicron were reduced six- and 42-fold, respectively, with 67% of patients seropositive for WA1/2020 exhibiting seronegativity for Omicron. CONCLUSION Antibody binding and live-virus neutralization against SARS-CoV-2 and its variants of concern including Delta and Omicron were substantially lower in patients with NHL/CLL compared with healthy vaccinees. Anti-CD20-directed therapy < 1 year before vaccination and number of circulating B cells strongly predict vaccine response.

Nilotinib is used as standard treatment in managing chronic myeloid leukaemia (CML). A 23-year-old man with CML and on nilotinib was admitted to the intensive care unit due to respiratory failure. Three years prior, he developed pleural effusion from dasatinib therapy thus, his CML regimen was changed to nilotinib. Although the pleural effusion had once improved, the chest imaging revealed left-dominant bilateral pleural effusion. Endotracheal intubation and left thoracic drainage were performed. Nilotinib treatment was discontinued, and approximately 60 hours later, nilotinib concentrations of 927 and 2092 ng/mL were determined in his blood and pleural effusion, respectively. Severe pleural effusion may be induced in patients administering nilotinib, and nilotinib concentrations in blood and pleural effusion can be elevated in patients with nilotinib-related pleural effusion. Cross-occurrence of pleural effusions needs to be monitored precisely, especially in patients who are switched to other tyrosine kinase inhibitors after dasatinib treatment.

Sweet syndrome (SS), also referred as acute febrile neutrophilic dermatosis, is an inflammatory process characterised by the abrupt appearance of erythematous papules or nodules with predominant neutrophilic infiltration in the dermis. Fever and neutrophilia are common presenting features. However, extracellular manifestations, including ocular and musculoskeletal, may occur. SS is divided into three subtypes: classical (or idiopathic), malignancy associated and drug induced. Medication-induced subtype accounts for up to 26% of cases. In recent years, emerging evidence has showed that SS may also occur in neutropenic patients who underwent induction for acute myeloid leukemia (AML). The identification of FMS-like tyrosine kinase 3 (FLT3) gene mutation in approximately 30% of patients with AML has promoted the targeted therapy with FLT3-internal tandem duplication (ITD) inhibitors. Midostaurin, a recently Food and Drug Administration-approved medication for FLT3-ITD-positive AML, was reported once as cause for SS. We report a midostaurin-induced SS with neutropenia in a patient following induction chemotherapy of AML

Central nervous system lymphoproliferative disorder (CNS-PTLD) after organ transplant is a unique clinicopathological entity and is associated with poor survival rates. When the CNS is involved, intravenous rituximab might not be the treatment of choice, due to its poor CNS penetration. However, intrathecal (IT) administration of rituximab has shown to be safe and efficient in small studies and in case series. We report here the case of a patient with late development of CNS-PTLD after kidney-pancreas transplantation who achieved complete remission after surgical resection and four cycles of IT rituximab and we provide a review of the literature for this treatment option.

A 37-year-old woman presented with a few days’ history of lower abdominal pain and an incidental finding of hypercalcaemia. A thorough workup ensued, and the cause was found to be an exceptionally rare ovarian tumour—ovarian small cell carcinoma of the hypercalcaemic type. Acute treatment of hypercalcaemia consisted of aggressive intravenous fluids and bisphosphonates. She underwent surgery to remove the tumour and is currently receiving systemic platinum/etoposide chemotherapy combination to be followed by pelvic radiotherapy. This case highlights the wide range of differential diagnosis for hypercalcaemia and the importance of a stepwise and thorough approach during investigations. We discuss the pathophysiology of malignancy-related hypercalcaemia, focusing especially on parathyroid hormone-related peptide-associated hypercalcaemia.

Primary lymphoma of the visual pathway is rare, especially at the chiasm. Very few cases have been reported. The lesion is frequently confused with an optic–hypothalamic glioma. A 55-year-old man was found disoriented at his home by a friend and evaluated with a brain MRI which demonstrated an expansile mass located at the optic chiasm and hypothalamus level. The principal differential was a high-grade hypothalamic glioma due to the contrast enhancement. A biopsy of the chiasmal lesion was performed. Histological diagnosis of the lesion was compatible with a diffuse large B cell lymphoma. He was started on methotrexate and rituximab; however, his clinical course kept deteriorating, and he died 64 days after his presentation. All prior cases of primary lymphoma of the chiasm are reviewed.

Non-Hodgkin’s lymphoma (NHL) presenting as a soft tissue sarcoma is rare, occurring at a rate of 0.11%. Peripheral T-cell lymphomas comprise 4% of all NHLs. We report the case of a 49-year-old Caucasian man who presented with a mass in the medial aspect of the thigh. Ultrasound showed a complex subcutaneous mass. MRI demonstrated a superficial complex skeletal mass affecting the sartorius muscle with other lesions involving the femur and the gluteus maximus. Positron emission tomography-computed tomography (PET-CT) showed diffuse pulmonary metastases with no involvement of nodes, liver, spleen with high suspicion of advanced sarcoma. Core biopsy revealed a T-cell NHL, and staining was positive for anaplastic lymphoma kinase. The patient received six cycles of cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone. Repeat PET-CT showed reduction in the mass, with no fluorodeoxyglucose-avid uptake. Latest MRI showed near-normal intensity. Further PET-CTs determine disease remission or progression.

Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition.

Primary cardiac lymphoma is a rare entity of extranodal lymphoma and is observed with increasing frequency in immunocompromised hosts. However, a considerable proportion of cardiac lymphomas still occur in immunocompetent patients. We report the case of a 55-year-old immunocompetent Japanese man with a large amount of pericardial fluid and the presentation of heart failure secondary to primary cardiac B cell lymphoma, which was diagnosed by cytological examination of pericardial fluid and imaging. The right atrium, right ventricle and pericardium were affected by the tumour, which encased the mid/distal portion of the right coronary artery (RCA). Pretreatment optical coherence tomography of the RCA demonstrated no tumour extension into the vascular structure but a focal mural thrombus. We initiated chemotherapy (steroid therapy then COP at half dose/R-CHOP/R-CHASE) [COP (C: Cyclophosphamide, O: Oncovin, P: Prednisolone) R-CHOP (R: Rituximab, C: Cyclophosphamide, H: Doxorubicin Hydrochloride, O: Oncovin, P: Prednisolone) R-CHASE (R: Rituximab, C: Cyclophosphamide, HA: high dose Cytarabine, S: Steroid, E: Etoposide)]with administration of low-dose aspirin to prevent possible ischaemic events. The patient had a good clinical course without adverse events except for transient pericarditis.

Methotrexate is a versatile antineoplastic and immunosuppressive agent. We report a case of a young adult on the Cancer and Leukaemia Group B 10403 treatment protocol for B-cell acute lymphoblastic leukaemia. She has previously completed the induction and consolidation phases with good tolerance then started on Capizzi methotrexate during the interim maintenance phase. Few days after receiving one intermediate dose of methotrexate, she developed severe multiorgan toxicities including pancytopaenia and several dermatologic toxicities. The patient underwent extensive diagnostic workup, with all results negative, pointing eventually towards severe methotrexate toxicity. This case highlights the broad spectrum of toxicities that can occur even with low doses of methotrexate. Capizzi methotrexate therapy implies no leucovorin therapy, hence putting patients at risk for multiorgan toxicity. Our experience reinforces the importance of close monitoring for patients receiving methotrexate, regardless of dose, and the prompt administration of high-dose leucovorin once toxicity suspected.

Abstract: Although metabolic tumor volume (MTV) assessed with pretreatment 18F-FDG PET/CT has shown significant prognostic value across many lymphoma types, it is still not used in clinical practice due to technical concerns and the lack of standardisation. Numerous studies on the prognostic value of MTV in lymphomas have been published in recent years, but there is still no full agreement on the best methodology for MTV calculation. In this paper, we reviewed the methodological aspects of MTV assessment and reported recent works about its impact on outcome in lymphomas, with a focus on Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL).

Objectives With large patient population and complement inhibitors naïve background, the characteristics patients with paroxysmal nocturnal hemoglobinuria (PNH) in China have not been well studied, especially for different subtypes. Methods We retrospectively reviewed patients with complete data who visited Peking Union Medical College Hospital (PUMCH) from 2009 to 2019 and had been followed up for more than 2 years. Results Five hundred and twelve patients were enrolled including 56.3% males and 43.7% females. The median age at disease onset was 33 (9∼80) years. Most were aged 21∼40 years (50.6%). 52.1%, 46.3% and 1.6% of the patients had classic PNH, bone marrow failure (BMF)/PNH and subclinical PNH, respectively. Symptoms of classic PNH were associated with hemolysis, whereas bleeding was more common in BMF/PNH patients. Classic PNH had higher survival rate, larger PNH clone size, higher lactate dehydrogenase (LDH) level and lower ferritin level than BMF/PNH. Although the rate of thrombosis was similar in the classic PNH and BMF/PNH (P = 0.66), those with BMF/PNH had higher chance of renal impairment (P

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Endogenous BFL1 expression renders diffuse large B-cell lymphoma (DLBCL) cells insensitive to B-cell lymphoma 2 (BCL2) and/or MCL1 inhibitors. Considering the difficulties in developing a direct BFL1 inhibitor, we intended to inhibit histone deacetylase (HDAC) to mitigate the biological role of BFL1 by modulating WT1 and NOXA. Cells expressing high BFL1 exhibited enhanced sensitivity to pan-HDAC inhibitor compared to low BFL1 expressing cells, mainly attributable to the difference in the amount of apoptosis. HDAC inhibitors decreased BFL1 and WT1 expressions while increasing NOXA levels. The BFL1 knockdown experiment demonstrated that HDAC inhibitor's sensitivity depends on the BFL1 expression in DLBCL cells. Furthermore, we found that the specific HDAC class was expected to play a critical role in BFL1 inhibition by comparing the effects of several HDAC inhibitors. Thus, our study provides a rationale for using HDAC inhibitors to induce apoptosis in DLBCL patients using BFL1 as a predictive biomarker.

Patients after heart transplantation are at increased risk for malignancy secondary to immunosuppression and oncogenic viral infections. Most common among children is posttransplant lymphoproliferative disorder (PTLD), occurring in 5% to 10% of patients. We used a national database to examine the incidence and risk factors for posttransplant malignancy.The United Network for Organ Sharing database was queried for pediatric (18 years) heart transplant recipients from October 1987 through November 2019. Freedom from malignancy after transplant was assessed with Kaplan-Meier analysis. Cox regression was performed to generate hazard ratios (HRs) and 95% CIs for risk of malignancy development.Of 8581 pediatric heart transplant recipients, malignancy developed in 8.1% over median follow-up time of 6.3 years, with PTLD compromising 86.4% of the diagnosed cancers. The incidence of PTLD development was 1.3% at 1 year and 4.5% at 5 years. Older age at the time of transplant was protective against the development of malignancy (HR, 0.98; 95% CI, 0.96-0.99; P.001), whereas a history of previous malignancy (HR, 1.9; 95% CI, 1.2-3.0; P = .007) and Ebstein-Barr virus (EBV) recipient-donor mismatch (HR, 1.7; 95% CI, 1.3-2.2; P.001) increased the risk. Induction therapy, used in 78.9% of the cohort, did not increase malignancy risk (P = .355) nor did use of maintenance tacrolimus (P = .912).PTLD occurred after 7% of pediatric heart transplants, with risk increased by younger age and EBV mismatch, highlighting the importance of PTLD monitoring in EBV-seronegative recipients. Induction therapy, used in most of the pediatric heart transplants, does not seem to increase posttransplant malignancy nor does tacrolimus, the most commonly used calcineurin inhibitor.

Although sarcoidosis is an established cause of multiorgan dysfunction, acute presentation with thrombotic microangiopathy resulting in severe renal and hematological sequelae has not been reported. We describe the case of a patient presenting with hypercalcemia, pancreatitis, and acute renal failure, followed by microangiopathic hemolytic anemia. Although there were no significant respiratory symptoms, thoracic radiology and mediastinal lymph node biopsy results were in keeping with sarcoidosis as the underlying cause of this multisystem presentation. Corticosteroids were commenced with clinical and biochemical improvement. This novel case highlights the need to consider sarcoidosis as part of the differential diagnosis for unusual multiorgan presentations and for early multidisciplinary involvement in such cases to permit optimal treatment.

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation.Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21–expanded NK cells. Collectively, these data support development of mbIL-21–expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK− anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK− ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP.

Introduction We have previously shown that some patients present thrombocytopenia (less than 100 × 109/L platelets) in non-alcoholic fatty liver disease (NAFLD). To further explore the nature of this association, we have now analyzed the association of thrombocytopenia with neutropenia (less than 0.5 × 109/L granulocytes) in NAFLD. Material and methods Persons with NAFLD were prospectively accrued in the study after February 2018. The presence of NAFLD was defined by both serologic determinations (Fibromax ®) and liver transient elastography (TE/Fibroscan ®). Results In 123 consecutive patients with NAFLD without cirrhosis, thrombocytopenia was identified in 20 (16%), whereas neutropenia was identified in 9 (7%). In the subset of 20 patients with NAFLD and thrombocytopenia, granulocytopenia was identified in 5 (25%), whereas in the subset of 9 patients with granulocytopenia, thrombocytopenia was identified in 5 (55%). We found a significant association between thrombocytopenia and both leukopenia and granulocytopenia (OR 8.25, 95% CI 1.9–34.2, p = 0.004). Conclusions Both thrombocytopenia and neutropenia were identified in persons with NAFLD and, as there is a significant relationship between these two variables, we speculate that this finding may support the possibility of hypersplenism being involved in the cytopenias found in NAFLD without cirrhosis.

Purpose To describe a patient with a history of pre-B cell acute lymphoblastic leukemia (pre-B ALL) in remission, who developed recurrent alternating intraocular pre-B ALL manifesting with pseudohypopyon, uveal mass, and serous retinal detachment. In multiple instances this constellation of ocular findings preceded systemic leukemia recurrence. Method Case report. Results A 29-year old man with history of pre-B cell acute lymphoblastic leukemia, in remission following a hematopoietic stem cell transplant, presented with pseudo-hypopyon, uveal lesions, and serous retinal detachment of the right eye. Comprehensive workup for infectious and inflammatory etiologies was unremarkable, and a bone marrow biopsy revealed systemic recurrence of leukemia. One year later, while again in remission, the patient developed a pseudo-hypopyon, uveal mass, and serous retinal detachment of the other eye. Repeat bone marrow biopsy showed impending leukemia relapse, which occurred 1 month later. Orbital radiation resulted in complete ocular resolution. Conclusions The constellation of pseudohypopyon, serous retinal detachment, and uveal mass (pseudo-panuveitis) should be recognized as a harbinger for systemic pre-B ALL recurrence.

Follicular lymphoma (FL) is one of the most common types ofNon-Hodgkin Lymphoma (NHL) which originates from B-cells.1Generally it has an indolent clinical course, althoughhistological transformation to aggressive lymphoma mayoccur in 25-35 % of cases, and therafter the prognosis hasbeen reported to be poor. Transformation to histiocytic sar-coma may also be seen but very rarely 2-s2.0-85116800278

IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.

Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space, without evidence of systemic involvement. The diagnosis of PCNSL requires a high level of suspicion because clinical presentation varies depending upon involved structures. Initiation of treatment is time sensitive for optimal neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely as a result of the introduction and widespread use of high-dose methotrexate (MTX) chemotherapy, which is considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required to prolong duration of response. Consolidation can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by autologous stem cell transplant. Unfortunately, even with consolidation, relapse is common, and 5-year survival rates stand at only 30% to 40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis, including activation of the B-cell receptor pathway, immune evasion, and a suppressed tumor immune microenvironment. These insights have led to the identification of novel small molecules targeting these aberrant pathways. The Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising clinical response rates for relapsed/refractory PCNSL and are increasingly used for the treatment of recurrent disease. This review provides a discussion of the clinical presentation of PCNSL, the approach to work-up and staging, and an overview of recent advancements in the understanding of the pathophysiology and current treatment strategies for immunocompetent patients.

Non-Hodgkin lymphomas (NHL) represent the most common hematologic malignancies. Patient-derived xenografts (PDXs) are used for various aspects of translational research including preclinical in vivo validation of experimental treatment approaches. While it was repeatedly demonstrated that PDXs keep majority of somatic mutations with the primary lymphoma samples, from which they were derived, the composition of PDX tumor microenvironment (TME) has not been extensively studied. We carried out a comparative genetic and histopathological study of 15 PDX models derived from patients with various types of NHL including diffuse large B-cell lymphoma (DLBCL; n = 7), Burkitt lymphoma (BL; n = 1), mantle cell lymphoma (MCL; n = 2), and peripheral T-cell lymphomas (PTCL; n = 5). Whole exome sequencing (WES) of the PDXs and primary lymphoma cells was implemented in 13 out of 15 cases with available DNA samples. Standard immunohistochemistry (IHC) was used to analyze the composition of PDX TME. WES data confirmed that PDXs maintained the genetic heterogeneity with the original primary lymphoma cells. In contrast, IHC analysis revealed the following recurrently observed alterations in the composition of PDX tumors: more blastoid lymphoma cell morphology, increased proliferation rate, lack of non-malignant cellular components including T cells and (human or murine) macrophages, and significantly lower intratumoral microvessel density and microvessel area composed of murine vessels. In addition, PDX tumors derived from T-NHL displayed additional differences compared to the primary lymphoma samples including markedly lower desmoplasia (i.e., the extent of both reticular and collagen fibrosis), loss of expression of cytotoxic granules (i.e., perforin, TIA, granzyme B), or loss of expression of T-cell specific antigens (i.e., CD3, CD4, CD8). Our data suggest that despite keeping the same genetic profiles, PDX models of aggressive NHL do not recapitulate the microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

Background: Bladder cancer (BCa) is a common cancer associated with high morbidity and mortality worldwide. Pre-B-cell leukemia transcription factor 1 (PBX1) has been reported to be involved in tumor progression. Objective: The aim of the study was to explore the specific role of PBX1 in BCa and its underlying mechanisms. Methods: The relative expressions of PBX1 in muscle-invasive BCa tissues and cell lines were analyzed through RT-qPCR and western blotting. Kaplan–Meier analysis was used to analyze the relationship between PBX1 levels and survival status. Co-immunoprecipitation (CO-IP) and chromatin immunoprecipitation (ChIP)-qPCR assays were adopted to verify the interaction between PBX1 and Estrogen receptors (ERs) and explore the estrogen receptors (ERs)-dependent genes transcription. Results: PBX1 was upregulated in invasive BCa patients and BCa cells, positively associated with tumor size, lymph node metastasis, distant metastasis and poorer survival status. The overexpression of PBX1 promoted cell growth, invasion, epithelial-mesenchymal transition (EMT) process and cisplatin resistance in BCa cells, while the silence of PBX1 showed opposite effects. Furthermore, PBX1 interacted with ERs and was required for ER function. PBX1 overexpression aggravated the tumorpromoting effect of estrogen on BCa cells, while it partially suppressed the inhibitory effects of ER antagonist AZD9496 on BCa cells. Conclusion: This study revealed that PBX1 participated in estrogen mediated BCa progression and chemo-resistance through binding and activating estrogen receptors. Hence, PBX1 may serve as a potential prognostic and therapeutic target for BCa treatment.

The World Health Organization estimates that approximately a quarter of the world’s population suffers from anemia, including almost half of preschool-age children. Globally, iron deficiency anemia is the most common cause of anemia. Other important causes of anemia in children are hemoglobinopathies, infection, and other chronic diseases. Anemia is associated with increased morbidity, including neurologic complications, increased risk of low birth weight, infection, and heart failure, as well as increased mortality. When approaching a child with anemia, detailed historical information, particularly diet, environmental exposures, and family history, often yield important clues to the diagnosis. Dysmorphic features on physical examination may indicate syndromic causes of anemia. Diagnostic testing involves a stepwise approach utilizing various laboratory techniques. The increasing availability of genetic testing is providing new mechanistic insights into inherited anemias and allowing diagnosis in many previously undiagnosed cases. Population-based approaches are being taken to address nutritional anemias. Novel pharmacologic agents and advances in gene therapy-based therapeutics have the potential to ameliorate anemia-associated disease and provide treatment strategies even in the most difficult and complex cases.

Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.

ALK rearrangement defines a unique non-small cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti-ALK therapies. So far, the outcomes of the canonical EML-ALK patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region (IGR) ALK fusion, as detected by using DNA-based next-generation sequencing (NGS), who experienced a partial response to alectinib treatment. While whole transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasingly application of the ALK-TKIs, it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that non-canonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.