Survival following salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL).

Optimal salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL) and the role of hematopoietic stem cell transplant (SCT) remain poorly defined. We conducted a retrospective review of clinical outcomes and prognostic factors in a single-center cohort of 93 patients with primary refractory PTCL, defined as progression during first-line therapy or relapse within 6 months of its completion. Clinical outcomes were poor in this population, with median event-free survival (EFS) of 3.5 months, median overall survival (OS) of 9.1 months, and 34% 3-year survival. Outcomes were comparable in patients who progressed through first-line therapy and patients who achieved CR/PR and subsequently relapsed within 6 months. A majority exhibited high-risk features and had intermediate to high risk IPI, which correlated with inferior outcomes. There was no difference in outcomes between patients who received single-agent salvage regimens and patients who underwent traditional, multi-agent salvage regimens. Thus, participation in well-designed clinical trials should be encouraged in this population. Additionally, there may be a trend toward improved EFS and OS in patients who underwent autologous or allogeneic SCT compared to patients who achieved CR or PR but were not transplanted.

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

Purpose: O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.

Making Sense of a Complex Disease: A Practical Approach to Managing Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are a heterogeneous clinical entity with a broad range of grade, pace of disease, functional status, and primary sites. Pathologic classification, diagnostic modalities, and therapeutic options for NETs have evolved considerably in the past decade. In part driven by these advances, incidence and prevalence of NETs are rising in the United States and the practicing oncologist is likely to encounter these in the clinic. However, there are no clear lines of therapy for unresectable or metastatic NETs, and sequencing of systemic therapies depends on consideration of patient and tumor characteristics including extent of disease, grade, pace of growth, functional status, primary site, somatostatin receptor status, performance status, and comorbidities. Familiarity with ongoing clinical trials will guide therapeutic decision making as well. In this review, we seek to provide a framework to formulate and tailor an individualized treatment plan for each patient with a NET.

Research Resource: The Dexamethasone Transcriptome in Hypothalamic Embryonic Neural Stem Cells.

Exposure to excess glucocorticoids during fetal development has long-lasting physiological and behavioral consequences, although the mechanisms are poorly understood. The impact of prenatal glucocorticoids exposure on stress responses in juvenile and adult offspring implicates the developing hypothalamus as a target of adverse prenatal glucocorticoid action. Therefore, primary cultures of hypothalamic neural-progenitor/stem cells (NPSCs) derived from mouse embryos (embryonic day 14.5) were used to identify the glucocorticoid transcriptome in both males and females. NPSCs were treated with vehicle or the synthetic glucocorticoid dexamethasone (dex; 100nM) for 4 hours and total RNA analyzed using RNA-Sequencing. Bioinformatic analysis demonstrated that primary hypothalamic NPSC cultures expressed relatively high levels of a number of genes regulating stem cell proliferation and hypothalamic progenitor function. Interesting, although these cells express glucocorticoid receptors (GRs), only low levels of sex-steroid receptors are expressed, which suggested that sex-specific differentially regulated genes identified are mediated by genetic and not hormonal influences. We also identified known or novel GR-target coding and noncoding genes that are either regulated equivalently in male and female NPSCs or differential responsiveness in one sex. Using gene ontology analysis, the top functional network identified was cell proliferation and using bromodeoxyuridine (BrdU) incorporation observed a reduction in proliferation of hypothalamic NPSCs after dexamethasone treatment. Our studies provide the first characterization and description of glucocorticoid-regulated pathways in male and female embryonically derived hypothalamic NPSCs and identified GR-target genes during hypothalamic development. These findings may provide insight into potential mechanisms responsible for the long-term consequences of fetal glucocorticoid exposure in adulthood.

Minireview: the impact of antenatal therapeutic synthetic glucocorticoids on the developing fetal brain.

The life-threatening, emotional, and economic burdens of premature birth have been greatly alleviated by antenatal glucocorticoid (GC) treatment. Antenatal GCs accelerate tissue development reducing respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, they can also alter developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. This review summarizes animal model and clinical studies that examined the impact of antenatal GCs on the developing brain. In addition, we describe studies that assess glucocorticoid receptor (GR) action in neural stem/progenitor cells (NSPCs) in vivo and in vitro. We highlight recent work from our group on two GR pathways that impact NSPC proliferation, ie, a nongenomic GR pathway that regulates gap junction intercellular communication between coupled NSPCs through site-specific phosphorylation of connexin 43 and a genomic pathway driven by differential promoter recruitment of a specific GR phosphoisoform.