Pediatric Undifferentiated Pleomorphic Sarcoma of the Cecum.

Background: Undifferentiated pleomorphic sarcoma (UPS) is a high-grade neoplasm typically diagnosed in older adults and localized to the extremities or retroperitoneum. Because of poor response to therapy and high rates of recurrence, this neoplasm is associated with a poor prognosis. Case Report: A 12-year-old female presented with weight loss, abdominal pain, fatigue, and diarrhea. She was profoundly anemic with occult blood-positive stools. On endoscopy, a fungating cecal mass was biopsied and diagnosed as malignant sarcomatoid neoplasm. The neoplasm was resected with clear margins during subsequent surgery, and on final pathology was diagnosed as UPS. A suspicious lung nodule was also removed via video-assisted thoracoscopic surgery and found to be a granuloma positive for Histoplasma capsulatum for which the patient received antifungal therapy. The patient did not receive additional chemotherapy or radiotherapy and was doing well without signs of recurrence at 12 months postresection. Conclusion: This report of cecal UPS in a 12-year-old is rare because of the patient's age and tumor location. We have identified only 2 other case reports of pediatric gastrointestinal UPS. This case illustrates the need for a broad differential and prompt workup in pediatric patients presenting with weight loss and abdominal complaints. More information regarding the management and outcomes in cases of gastrointestinal UPS is needed to assist providers in determining the best treatment course and to allow for better prognostication.

Combinatorial suicide gene strategies for the safety of cell therapies.

Gene-modified cellular therapies carry inherent risks of severe and potentially fatal adverse events, including the expansion of alloreactive cells or malignant transformation due to insertional mutagenesis. Strategies to mitigate uncontrolled proliferation of gene-modified cells include co-transfection of a suicide gene, such as the inducible caspase 9 safety switch (ΔiC9). However, the activation of the ΔiC9 fails to completely eliminate all gene-modified cells. Therefore, we tested a two suicide gene system used independently or together, with the goal of complete cell elimination. The first approach combined the ΔiC9 with an inducible caspase 8, ΔiC8, which lacks the endogenous prodomain. The rationale was to use a second caspase with an alternative and complementary mechanism of action. Jurkat cells co-transduced to co-express the ΔiC8, activatable by a BB homodimerizer, and the ΔiC9 activatable by the rapamycin analog sirolimus were used in a model to estimate the degree of inducible cell elimination. We found that both agents could activate each caspase independently, with enhanced elimination with superior reduction in cell regrowth of gene-modified cells when both systems were activated simultaneously. A second approach was employed in parallel, combining the ΔiC9 with the RQR8 compact suicide gene. RQR8 incorporates a CD20 mimotope, targeted by the anti-CD20 monoclonal antibody rituxan, and the QBend10, a ΔCD34 selectable marker. Likewise, enhanced cell elimination with superior reduction in cell regrowth was observed when both systems were activated together. A dose-titration effect was also noted utilizing the BB homodimerizer, whereas sirolimus remained very potent at minimal concentrations. Further in vivo studies are needed to validate these novel combination systems, which may play a role in future cancer therapies or regenerative medicine.

Detection of a Cryptic KMT2A/AFDN Gene Fusion [ins(6;11)(q27;q23q23)] in a Pediatric Patient with Newly Diagnosed Acute Myeloid Leukemia.

KMT2A gene rearrangements are a major oncogenic driver in multiple hematologic neoplasms. Apart from t(9;11)(p21;q23) (KMT2A/MLLT3) in acute myeloid leukemia (AML), KMT2A gene rearrangements are considered to convey high risk and poor overall survival. Herein, we report a case of a 7 year old boy with newly diagnosed AML and a cryptic KMT2A/AFDN gene fusion resulting from a 5'KMT2A insertional event. The results of conventional chromosome studies revealed trisomy 8 in all 20 metaphases, with normal-appearing chromosomes 6 and 11. A KMT2A break-apart FISH probe identified 2 intact copies of the KMT2A gene region and an extra 5'KMT2A signal in 85% of interphase nuclei. Subsequent FISH studies using a KMT2A/AFDN dual-color dual-fusion FISH probe revealed positive results for a single fusion in 82% of interphase nuclei, indicating a KMT2A/AFDN gene fusion. Subsequently, metaphase FISH confirmed the location of the KMT2A/AFDN fusion at 6q27. To our knowledge, this represents only the second time in the literature that a cryptic KMT2A/AFDN gene fusion resulting from a 5'KMT2A insertional event was reported.

Gene therapy for sickle cell disease: where we are now?

The landscape of sickle cell disease (SCD) treatment continues to evolve rapidly, with new disease-modifying therapies in development and potentially curative options on the horizon. Until recently, allogeneic stem cell transplant has been the only proven cure for SCD. Gene therapy is rising to the forefront of the discussion as a potentially curative or highly disease- modifying option for abating the complications of the disease. Understanding the different types of gene therapy in use, the differences in their end points, and their potential risks and benefits will be key to optimizing the long-term use of this therapy.

DCTN1-ALK gene fusion in inflammatory myofibroblastic tumor (IMT) of the CNS.

PURPOSE: Inflammatory myofibroblastic tumor (IMT) is a rare neoplastic tumor type of intermediate biological potential, only recently distinguished from the non-neoplastic category of inflammatory pseudotumor (IP). The literature describes very few cases of IMTs arising in the central nervous system (CNS), and the distinguishing clinical, pathological, and molecular features of IMT-CNS are not well understood. Our purpose is to publish a case of an IMT-CNS with a novel DCTN1-ALK gene fusion, furthering in the literature's characterization of a rare tumor type. METHODS: Review of the literature included a PubMed Database search of articles found by the following searches: "Inflammatory myofibroblastic tumor;" "Inflammatory myofibroblastic tumor central nervous system;" "ALK gene fusion;" and "DCTN1-ALK gene fusion." Inclusion of articles discovered by these search terms was determined through critical appraisal of article relevance, number of citations, cross-citation within articles of interest, and rare findings with conflicting conclusions in an effort to reduce publication bias. RESULTS: We present a case of IMT-CNS with several distinctive molecular features including a DCTN1-ALK gene fusion, the first of its kind described in an intracranial IMT. CONCLUSION: IMT is an infrequent tumor type and its presentation within the CNS is exceedingly rare. The paucity of cases, along with the ambiguity of terminology in the literature, has stunted accurate clinical, pathological, and molecular characterization of IMT-CNS. Our case report improves the characterization of the recently appreciated category of IMT-CNS so that connections between phenotype and prognosis, and between genotype and treatment, can eventually be made.

Novel CUBN Mutation in a Young Child With Megaloblastic Anemia.

Inherited disorders of cobalamin (Cbl, vitamin B12) metabolism are rare causes of megaloblastic anemia and neurologic abnormalities. More prevalent in certain ethnic groups, these disorders occur despite adequate Cbl intake and usually result from abnormal vitamin cell transport or processing. Cubilin (CUBN, intrinsic factor-cobalamin receptor) is the intestinal receptor for the endocytosis of intrinsic factor-vitamin B12. Its gene is localized to chromosome 10p13 and mutations involving CUBN have been described in patients with congenital megaloblastic anemia. In this report, we describe a novel CUBN pathogenic variant in a child with megaloblastic anemia.

Infection prophylaxis patterns following pediatric autologous hematopoietic stem cell transplantation: A survey of Pediatric Transplant and Cell Therapy Consortium centers.

No standardized guidelines exist for infectious prophylaxis following pediatric auto-HSCT. We hypothesized significant variation in clinical practice. Thirty-three Pediatric Transplant and Cell Therapy Consortium centers completed a survey to assess institutional management. The majority utilize viral (91%) and fungal prophylaxis (94%), but duration varies. Bacterial prophylaxis during neutropenia is instituted by 42%. Our study demonstrates marked practice variability in infectious prophylaxis across centers. Additional research is needed to address patterns of infectious complications and to develop meaningful clinical practice guidelines for pediatric auto-HSCT.

Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease.

Hematopoietic stem cell transplantation is a potent form of immunotherapy, potentially life-saving for many malignant hematologic diseases. However, donor lymphocytes infused with the graft while exerting a graft versus malignancy effect can also cause potentially fatal graft versus host disease (GVHD). Our group has previously validated the inducible caspase-9 suicide gene in the haploidentical stem cell transplant setting, which proved successful in reversing signs and symptoms of GVHD within hours, using a non-therapeutic dimerizing agent. Cellular death pathways such as apoptosis and necroptosis are important processes in maintaining healthy cellular homeostasis within the human body. Here, we review two of the most widely investigated cell death pathways active in T-cells (apoptosis and necroptosis), as well as the emerging strategies that can be exploited for the safety of T-cell therapies. Furthermore, such strategies could be exploited for the safety of other cellular therapeutics as well.