Fecal Microbiota Transplantation for Treatment of Severe Clostridioides difficile Colitis in a Pediatric Patient With Non-Hodgkin Lymphoma.

BACKGROUND: Patients with malignant diseases are at high risk for refractory Clostridioides difficile infections (CDI). Fecal microbiota transplantation (FMT) restores the gastrointestinal microbiome and may be an effective treatment for patients who fail pharmacotherapy. However, FMT is not commonly used in the oncology population because of risk for donor-derived infection. OBSERVATIONS: The authors report successful use of FMT in a pediatric patient with refractory CDI actively receiving chemotherapy. The patient's symptoms improved 1 day following FMT. He did not experience infectious complications or other adverse effects. CONCLUSIONS: FMT may be a feasible option for treatment of refractory CDI in pediatric oncology patients.

Pulmonary toxicity in paediatric patients with relapsed or refractory Hodgkin lymphoma receiving brentuximab vedotin.

Brentuximab vedotin (Bv) is becoming increasingly important in the treatment of Hodgkin lymphoma (HL), with improved outcomes and an overall favourable toxicity profile. However, Bv is associated with severe pulmonary toxicity when combined with bleomycin, suggesting that additive toxicity may be an important consideration. Furthermore, little has been published on tolerability in paediatric patients. We retrospectively evaluated the occurrence of pulmonary toxicity of Bv in 19 paediatric and young adult patients with relapsed or refractory HL. Patient characteristics, baseline health status, treatment regimens including cumulative doses of Bv, bleomycin, gemcitabine, radiation and carmustine, and the occurrence of pulmonary toxicity were collected. Seven (36·8%) of the 19 patients were treated with Bv. The odds of pulmonary toxicity were 4·0-fold higher (95% confidence interval 0·55-29·18) in patients exposed to Bv compared to unexposed patients in univariate analysis (P = 0·17). Similar results were found in multivariable analysis. Pulmonary toxicity occurred frequently in our cohort and was more common in patients who received Bv than in patients who did not receive Bv, although this was not statistically significant. Because patients with HL are exposed to a myriad of therapies with potential for pulmonary toxicity, continuing to evaluate the risk associated with Bv is critical.

Outcomes of children, adolescents, and young adults following allogeneic stem cell transplantation for secondary acute myeloid leukemia and myelodysplastic syndromes-The MD Anderson Cancer Center experience.

We conducted a retrospective analysis of outcomes for children and young adults with sAML/sMDS who underwent HSCT at our institution. Thirty-two patients (median age 20 years) with sAML (n=24) and sMDS (n=8) received HSCT between 1990 and 2013. The median time from sAML/sMDS diagnosis to HSCT was 4.1 months (range: 1.2-27.2 months). The transplant regimens were primarily busulfan based (n=19). BM was the primary donor source (n=15). Eleven recipients were transplanted with residual disease. At a median follow-up of 62.3 months (range: 0.4-250.9 months), 14 patients had disease recurrence. Acute GVHD, grade III/IV, occurred in three patients. Causes of death were as follows: disease relapse (n=12), infection (n=2), pneumonia (n=1), pulmonary hemorrhage (n=1), acute GVHD (n=1), and graft failure (n=1). A PS of ≥90% at the time of HSCT had a significant impact on PFS (P=.02). Patients achieving pretransplant primary CR (n=8) and those with sMDS and RA (n=6) had prolonged PFS (P=.04). On multivariate analysis, shorter time to transplantation (≤6 months from diagnosis of sAML/sMDS) was associated with superior OS (P=.0018) and PFS (P=.0005).

Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen.

Several studies reported improved outcomes of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric-based ALL regimens. This prompted the prospective investigation of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen, and its comparison with hyper-fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone (hyper-CVAD) in AYA patients. One hundred and six AYA patients (median age 22 years) with Philadelphia chromosome- (Ph) negative ALL received ABFM from October 2006 through March 2014. Their outcome was compared to 102 AYA patients (median age 27 years), treated with hyper-CVAD at our institution. The complete remission (CR) rate was 93% with ABFM and 98% with hyper-CVAD. The 5-year complete remission duration (CRD) were 53 and 55%, respectively (P = 0.98). The 5-year overall survival (OS) rates were 60 and 60%, respectively. The MRD status on Day 29 and Day 84 of therapy was predictive of long-term outcomes on both ABFM and hyper-CVAD. Severe regimen toxicities with ABFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD. In summary, ABFM and hyper-CVAD resulted in similar efficacy outcomes, but were associated with different toxicity profiles, asparaginase-related with ABFM and myelosuppression-related with hyper-CVAD. Am. J. Hematol. 91:819-823, 2016. © 2016 Wiley Periodicals, Inc.

Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

BACKGROUND: Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen. METHODS: Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes. RESULTS: The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively. CONCLUSIONS: ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.

Safety and clinical activity of 5-aza-2'-deoxycytidine (decitabine) with or without Hyper-CVAD in relapsed/refractory acute lymphocytic leukaemia.

To test the safety and activity of 5-aza-2'-deoxycytidine (decitabine) in patients with relapsed/refractory acute lymphocytic leukaemia (ALL), we conducted a phase 1 study with two parts: administering decitabine alone or in combination with Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine). Patients participated in either part of the study or in both parts sequentially. In the initial part, decitabine was administered intravenously at doses of 10-120 mg/m(2) per d for 5 d every other week in cycles of 28 d. In the combination part, patients were treated on the first 5 d of Hyper-CVAD with intravenous decitabine at 5-60 mg/m(2) per d. A total of 39 patients received treatment in the study: 14 in the first part only, 16 sequentially in both parts and 9 in the second part only. Decitabine was tolerated at all doses administered, and grade 3 or 4 toxic effects included non-life-threatening hepatotoxicity and hyperglycaemia. Induction of DNA hypomethylation was observed at doses of decitabine up to 80 mg/m(2) . Some patients who had previously progressed on Hyper-CVAD alone achieved a complete response when decitabine was added. Decitabine alone or given with Hyper-CVAD is safe and has clinical activity in patients with advanced ALL.

Hematopoietic stem cell transplantation in adolescents and young adults.

BACKGROUND: Adolescents and young adults (AYAs) are a very unique subset of our population journeying through a dynamic stage of their lives. This age group often remains understudied as a separate entity because they are commonly lumped into either pediatric or adult subgroups. METHODS: Here we review acute and chronic issues surrounding hematopoietic stem cell transplantation (HSCT) with a focus on the AYA age group. RESULTS: HSCT is a commonly used treatment modality for patients with certain types of cancers. AYA patients undergoing HSCT present a very unique perspective, circumstances, medical, psychological and social issues requiring a diligent workup, care and follow-up. CONCLUSION: The medical care of these patients should be approached in a multidisciplinary method involving the patient, caregivers, physicians, psychologists and social workers.

Outcome of adolescents and young adults with acute myeloid leukemia treated on COG trials compared to CALGB and SWOG trials.

BACKGROUND: A retrospective meta-analysis of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) was performed to determine if differences in outcome exist following treatment on pediatric versus adult oncology treatment regimens. METHODS: Outcomes were compared of 517 AYAs with AML aged 16 to 21 years who were treated on Children's Oncology Group (COG), Cancer and Leukemia Group B (CALGB), and Southwest Oncology Group (SWOG) frontline AML trials from 1986 to 2008. RESULTS: There was a significant age difference between AYA cohorts in the COG, CALGB, and SWOG trials (median, 17.2 versus 20.1 versus 19.8 years, P < .001). The 10-year event-free survival of the COG cohort was superior to the combined adult cohorts (38% ± 6% versus 23% ± 6%, log-rank P = .006) as was overall survival (45% ± 6% versus 34% ± 7%), with a 10-year estimate comparison of P = .026. However, the younger age of the COG cohort is confounding, with all patients aged 16 to 18 years doing better than those aged 19 to 21 years. Although the 10-year relapse rate was lower for the COG patients (29% ± 6% versus 57% ± 8%, Gray's P < .001), this was offset by a higher postremission treatment-related mortality of 26% ± 6% versus 12% ± 6% (Gray's P < .001). Significant improvements in 10-year event-free survival and overall survival were observed for the entire cohort in later studies. CONCLUSIONS: Patients treated on pediatric trials had better outcomes than those treated on adult trials, but age is a major confounding variable, making it difficult to compare outcomes by cooperative group.

Therapy Selection for Hodgkin Lymphoma in Sickle Cell Disease: balancing risks and benefits.

Advances in treatment have reduced mortality from Hodgkin lymphoma; therefore, greater attention should be focused on minimizing the late effects. A variety of risk-adapted treatment regimens exist that prioritize disease presentation but not patient-specific comorbidities. Herein, we describe a patient with sickle cell disease diagnosed with Hodgkin lymphoma and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient's preexisting sickle cell disease complications.

The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model systems. Neuroblastoma tumor cell lines demonstrated high rates of lactate accumulation and low rates of oxygen consumption, suggesting a potential susceptibility to inhibitors of glycolysis. In all ten human tested neuroblastoma tumor cell lines, 3-BrOP induced cell death via apoptosis in a dose and time dependent manner. Furthermore, 3-BrOP-induced depletion of ATP levels correlated with decreased neuroblastoma cell viability. In a mouse neuroblastoma xenograft model, glycolysis inhibition with 3-BrOP demonstrated significantly reduced final tumor weight. In neuroblastoma tumor cells, treatment with 3-BrOP induced mTOR activation, and the combination of 3-BrOP and mTOR inhibition with rapamycin demonstrated synergistic efficacy. Based on these results, neuroblastoma tumor cells are sensitive to treatment with inhibitors of glycolysis, and the demonstrated synergy with rapamycin suggests that the combination of glycolysis and mTOR inhibitors represents a novel therapeutic approach for neuroblastoma that warrants further investigation.

Restlessness in Generalized Anxiety Disorder: Using Actigraphy to Measure Physiological Reactions to Threat.

Generalized anxiety disorder (GAD) is characterized by excessive, uncontrollable worry accompanied by symptoms of physiological arousal. Although individuals with GAD report greater subjective arousal than healthy individuals, they show equivalent or even attenuated physiological reactions to threat. This may result from using physiological measures better suited to fear than anxiety. To test this possibility, 102 adults with and without GAD were assessed for restlessness, a core physiological symptom of GAD. They were exposed to an in vivo threat task designed to elicit anxiety in the laboratory. Throughout the task, restlessness was measured physiologically with actigraphy sensors on both ankles and both wrists, and subjectively with self-report ratings. The GAD group reported higher subjective restlessness than the no-GAD group, and in the subset of cases who had restlessness as a clinically significant symptom, actigraphy scores were reliably elevated as well. However, although actigraphy scores increased with proximity to the threat, the increases did not differ by group. These findings provide initial validation for actigraphy as a novel measure of motor restlessness in GAD. In addition, they underscore the value of measuring restlessness using multiple assessment methods. These methods suggest that, in GAD, restlessness reflects a chronic state of arousal rather than a heightened physiological reaction to threat.

Can't get it out of my mind: A systematic review of predictors of intrusive memories of distressing events.

Intrusive memories, when persistent and distressing, are theorized to underlie a range of transdiagnostic psychological symptoms and associated impairment. However, little is known about factors predicting the development and persistence of intrusive memories. The aim of this systematic review is to evaluate the literature on pre-event, event-based, and post-event predictors of intrusive memories. A systematic review was conducted, searching for studies that examined intrusive, event-based memories. One hundred and six articles were identified from PsycInfo, PubMed, and Medline databases. Experimental and prospective studies with clinical (N = 14) and nonclinical (N = 92) samples were critically reviewed, provided the inclusion of an analogue stressor with nonclinical samples, and that intrusive memories frequency and/or distress were assessed as primary dependent variables. Pre-existing psychopathology and pre-event appraisal style appear to predict intrusive memories (small to medium effects), whereas trait dissociation did not predict intrusive memories. Of studies examining event-based predictors, higher data-driven processing appears to predict intrusive memories with generally large effects. Post-event negative appraisals consistently predicted intrusive memories (medium to large effects), and preliminary evidence suggests higher post-event conceptual processing predicting fewer intrusive memories. This review synthesizes findings regarding a broad range of pre-event, event-based, and post-event factors that may influence the development of intrusive memories. Methodological issues of current paradigms and the lack of emphasis on memory retrieval processes limit our understanding of what predicts intrusive memory persistence. These limitations are particularly important given that individuals typically seek treatment for distressing intrusive memories once a memory has been fully consolidated, where retrieval processes are of utmost importance. (PsycINFO Database Record

A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies.

PURPOSE: The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies. EXPERIMENTAL DESIGN: In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles. RESULTS: The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study. CONCLUSIONS: Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.

Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin.

Rapidly proliferating solid tumor cells are often dependent on glycolysis for ATP production even in normoxia (the Warburg effect), however it is not yet clear whether acute leukemias have a similarly increased dependence on aerobic glycolysis. We report that all acute leukemia subtypes (pre-B ALL, T-ALL and AML) demonstrated growth arrest and cell death when treated the novel glycolysis inhibitor 3-BrOP. Potentiated ATP depletion and pro-apoptotic effects were seen for 3-BrOP combinations with the cytochrome-c-reductase inhibitor antimycin A and the mTOR inhibitor rapamycin. These results reveal a potential role for glycolysis inhibition in acute leukemia subtypes and suggest potential combinations.

Starting an adolescent and young adult program: some success stories and some obstacles to overcome.

Adolescent and young adult (AYA) patients seem to be in a sort of no-man's land, halfway between the two different worlds of pediatric and adult medical oncology and bearing the brunt, in terms of inclusion in clinical trials and quality of professional care, of the lack of integration between these two worlds. This article discusses the different organization models of care used in pediatric oncology (mainly family-focused) and in adult medical oncology (disease-focused). There is a growing awareness that these models are not ideally suited to the complex needs of AYA patients, which require a different, new, patient-focused multidisciplinary approach. A comprehensive, multipronged effort is required to bridge the gap in the care of AYA patients, with the ultimate challenge of creating a new discipline, AYA oncology. In this article, we review the experiences of AYA oncology programs in Europe, North America, and Australia, focusing on similarities and differences in strategy, as well as the major challenges and opportunities faced by these programs. Among the most important factors for the successful establishment of an AYA oncology service are the degree of engagement of both pediatric and adult medical oncologists, the philanthropic support of powerful charities, and the role of dedicated professionals across a range of disciplines in driving the development of services for AYA patients.

Long-term follow-up of patients with primary immunodeficiencies.

As an example of the need for long-term follow-up by specialty health care to adequately manage immunodeficient patients, we report the case of a patient with Wiskott-Aldrich syndrome who was lost to follow-up for 4 years to the immunology clinic and came back with a neck mass that was diagnosed as B-cell lymphoma. Patients with immunodeficiency are at high risk for the development of malignancy and autoimmune diseases and should be evaluated by a trained specialist with a frequency of not less than every 6 months.

Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity.

Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.