Correction: Porphyrin overdrive rewires cancer cell metabolism.

Cancer cells exhibit a metabolic phenotype termed “porphyrin overdrive,” characterized by dysregulated heme metabolic pathways for intermediate accumulation. This rewiring is cancer-essential and cancer-specific. Targeting this vulnerability with a “bait-and-kill” strategy shows promise in eradicating malignant cells.

Porphyrin overdrive rewires cancer cell metabolism.

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific.

Review and Updates on Systemic Mastocytosis and Related Entities.

Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia.

Dual JAK2/Aurora kinase A inhibition prevents human skin graft rejection by allo-inactivation and ILC2-mediated tissue repair.

Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation.

Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results.

Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation.

Patients And Methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD.

Utility of flow cytometry and gene rearrangement analysis in tissue and blood of patients with suspected cutaneous T‑cell lymphoma.

Cutaneous T‑cell lymphoma (CTCL) is difficult to diagnose at an early stage. Current diagnostic tools include clinical examination, histomorphologic analysis, immunohistochemistry, flow cytometry of peripheral blood and/or lesional tissue, and evaluation of T‑cell receptor (TCR) clonality by gene rearrangement analysis (TCRGR). Advances in genomic sequencing, including high‑throughput sequencing (HTS), can be used to identify specific clones of rearranged TCR genes.

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease.

Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what we believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention.

Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity.

Immunosuppressive donor Tregs can prevent graft-versus-host disease (GVHD) or solid-organ allograft rejection. We previously demonstrated that inhibiting STAT3 phosphorylation (pSTAT3) augments FOXP3 expression, stabilizing induced Tregs (iTregs). Here we report that human pSTAT3-inhibited iTregs prevent human skin graft rejection and xenogeneic GVHD yet spare donor antileukemia immunity.

Partial Splenic Artery Embolization in 35 Cancer Patients: Results of a Single Institution Retrospective Study.

Purpose: To evaluate the safety and efficacy of partial splenic embolization (PSE) in cancer patients with different etiologies of splenomegaly/hypersplenism.

Materials And Methods: The medical records of 35 cancer patients who underwent 39 PSE procedures were analyzed. The splenomegaly/hypersplenism was due to chemotherapy (n = 17), portal hypertension (n = 10), or hematologic malignancy (n = 8).

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity.

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.

Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation.

Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2 donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia.

IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation.

T-helper 1 and T-helper 17 lymphocytes mediate acute graft--host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40).

CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response.

Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4(+) T cells among human recipients of allogeneic HCT before the onset of Grade II-IV acute GVHD.

Rosai-Dorfman disease: tumor biology, clinical features, pathology, and treatment.

Background: Rosai-Dorfman disease (RDD) is a rare, nonmalignant clinical entity characterized by a group of clinical symptoms and characteristic pathological features.

Methods: Articles that reviewed tumor biology, clinical features, pathology, and treatment for RDD were identified in a search of the literature for the years 1990 to 2014. The results from this body of literature were reviewed and summarized.

Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.

Background: Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms.

Follicular lymphoma with progression to diffuse large B-cell lymphoma and concurrent CD5-negative mantle cell lymphoma-3 entities in a lymph node.

A 68-year-old woman with a history of follicular lymphoma had pathological findings of grade 3B follicular lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) identified in 1 lymph node. The DLBCL appeared to be a transformation of the follicular lymphoma. The nodules were diffusely and strongly positive for CD20, BCL6, and BCL2.

Therapy-related B lymphoblastic leukemia with t(4;11)(q21;q23)/AF4-MLL in a patient with mantle cell lymphoma after recent aggressive chemotherapy: a unique case report.

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma associated with the hallmark translocation t(11;14)(q13;32), which involves the cyclin D1 (CCND1) and immunoglobin heavy chain (IgH) genes. It may transform to a more aggressive blastoid or pleomorphic variant, with or without acquisition of chromosomal abnormalities. MCL could also present with a leukemic phase with marked lymphocytosis.

Current pathology practices in and barriers to MDS diagnosis.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell malignancies that represent a diagnostic challenge for pathologists. Accurate classification and prognostic scoring are essential to treating MDS. To understand factors that affect MDS management, a case-based survey was distributed to hematopathologists (n=53) and general pathologists (n=72) to identify perceived barriers, attitudes, and practices in MDS diagnosis.

Double-hit mantle cell lymphoma with MYC gene rearrangement or amplification: a report of four cases and review of the literature.

Mature B-cell lymphomas with both BCL2 and MYC translocations are known as "double hit" lymphomas. These lymphomas are aggressive and show high proliferation rate due to the growth advantages provided by MYC and BCL2 translocation and overexpression. Mantle cell lymphoma (MCL) is a neoplasm of mature B-lymphocytes with characteristic t(11;14) and subsequent Cyclin D1 overexpression.

Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia.

Background: The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. The Rai and Binet clinical staging systems are used to define disease extent and predict survival. The pathology laboratory also provides important prognostic information.

Primary cutaneous B-cell lymphoma in a child.

Primary cutaneous B-cell lymphoma is a B-cell lymphoma of the skin with no evidence of extracutaneous involvement at the time of diagnosis. In this report, we describe an 8-year-old boy who presented with a firm, alopecic, skin-colored, smooth nodule over the right frontal scalp. Histological examination revealed a mid-to deep-dermal mononuclear lesion.

Activation of the serine/threonine protein kinase Akt during the progression of Barrett neoplasia.

Esophageal adenocarcinoma has demonstrated a rapid increase in incidence over the last 10 years. This increase mirrors a dramatic rise in that of Barrett esophagus, which is associated with esophageal adenocarcinoma in at least 95% of cases. In an attempt to understand the pathogenesis of esophageal adenocarcinoma, attention has turned to the antiapoptotic and oncogenic pathways.

Acral keratosis with eosinophilic dermal deposits: a distinctive clinicopatholgic entity or colloid milium redux?

Aims: The differential diagnosis of acral keratoses is broad. Encompassing a variety of infectious, heritable and degenerative disorders, emphasis upon the clinical setting and histologic subtlety are often required to arrive at the correct diagnosis. Herein, we report on a series of adult patients who presented with agminated or solitary papules of the distal finger found on histologic examination to contain amorphous eosinophilic deposits.