Preserving Fertility in Children and Adolescents with Cancer

In the face of excellent survival rates for pediatric and adolescent cancer, preserving the opportunity to have biological children is an important component of long term quality of life. Yet, modern chemotherapeutic regimens continue to pose a threat to fertility. The only fertility preservation methods available to pre-pubertal children of both genders is cryopreservation of gonadal tissue, a highly experimental intervention, or shielding/re-location of reproductive tissue in the setting of radiation. These techniques are available in the post pubertal population as well, but post pubertal patients also have the option for cryopreservation of gametes, a process that is much simpler in males than females. For this reason, prior to the initiation of therapy, sperm banking should be considered standard of care for males, while consideration of embryo or oocyte cryopreservation should be limited to those females at risk of developing ovarian failure. Attention to reproductive health and fertility preservation should continue after the completion of therapy. Establishing programs that streamline access to current fertility preservation techniques will assist in ensuring that all eligible patients can avail themselves of current options

Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

Relationships between cerebrospinal fluid characteristics, injury severity, and functional outcome in dogs with and without intervertebral disk herniation

BACKGROUND : Cerebrospinal fluid (CSF) is commonly acquired in dogs with intervertebral disk herniation (IVDH) and is a common method to assess inflammatory responses following spinal cord injury (SCI). OBJECTIVES : The purpose of the study was to describe relationships between cisternal CSF characteristics, behavioral measures of SCI, T2 weighted (T2W) hyperintensity on magnetic resonance imaging (MRI), and long-term outcome in dogs with IVDH. Diagnostic accuracy of CSF for differentiating IVDH from other myelopathies was also assessed. METHODS : The retrospective case series included 727 dogs, 443 with thoracolumbar IVDH, 103 with cervical IVDH, and 181 with other spinal cord diseases. Signalment, initial neurologic function, ambulatory function at long-term follow-up, T2W MRI, and CSF variables were recorded for dogs with IVDH. Signalment, etiology, and CSF data were retrieved for dogs with other myelopathies. Associations between CSF predictors, diagnosis, and outcomes were assessed. RESULTS : CSF total nucleated cell count (TNCC) increased with SCI severity (rho -0.256, P<.001) in dogs with IVDH, TNCC was significantly higher in the presence of T2W hyperintensity (P = .001) in dogs with thoracolumbar IVDH, but TNCC, RBC count, microprotein, and percent neutrophils decreased with increasing injury duration (rho -0.253, P<.001; rho -0.269, P<.001; rho -0.141, P=.004, and rho -0.356, P <.001, respectively). CSF characteristics were not accurate for differentiating IVDH from other spinal cord diseases.CONCLUSIONS : In dogs with IVDH, CSF TNCC, RBC count, microprotein, and percent neutrophils are correlated to clinical aspects of SCI such as injury severity and duration, but cannot differentiate IVDH from other etiologies.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1939-165X2015-09-30hb201

Effects of divided attention on episodic memory in chronic traumatic brain injury: A function of severity and strategy

Abstract Eleven patients with mild traumatic brain injury (MTBI) and 13 patients with moderate-to-severe TBI (STBI) were compared to 10 matched controls on episodic memory for pictorial scene-object associations (e.g. kitchen-bread) and a range of standardized neuropsychological tests of memory and frontal-lobe functions. We tested the hypothesis that deficits in episodic memory result from impaired attentional resources and/or strategic control by manipulating attentional load at encoding (focused versus divided attention) and environmental support at retrieval (free recall and recalled cued by scene versus recognition of object and scene). Patients with TBI were disproportionately affected by the divided attention manipulation, but this effect was modulated by injury severity and encoding strategy. Overall, MTBI patients were impaired only when items were encoded under divided attention, indicating memory deficits that were secondary to deficits in the executive control. STBI patients could be differentiated into two distinct functional subgroups based on whether they favored a strategy of attending to the encoding or digit-monitoring task. The subgroup favoring the digit-monitoring task demonstrated deficits in the focused attention condition, and disproportionate memory deficits in the divided attention condition. In contrast, the subgroup favoring the encoding task demonstrated intact performance across all memory measures, regardless of attentional load, and despite remarkable similarity to the other STBI subgroup on demographic, neuropsychological, and acute injury severity measures. We discuss these outcome differences in terms of the relationship between strategy and executive control and highlight the need for more sensitive anatomical and behavioral measurement at both acute and chronic stages of injury

Effects of divided attention on episodic memory in chronic traumatic brain injury: A function of severity and strategy

Abstract Eleven patients with mild traumatic brain injury (MTBI) and 13 patients with moderate-to-severe TBI (STBI) were compared to 10 matched controls on episodic memory for pictorial scene-object associations (e.g. kitchen-bread) and a range of standardized neuropsychological tests of memory and frontal-lobe functions. We tested the hypothesis that deficits in episodic memory result from impaired attentional resources and/or strategic control by manipulating attentional load at encoding (focused versus divided attention) and environmental support at retrieval (free recall and recalled cued by scene versus recognition of object and scene). Patients with TBI were disproportionately affected by the divided attention manipulation, but this effect was modulated by injury severity and encoding strategy. Overall, MTBI patients were impaired only when items were encoded under divided attention, indicating memory deficits that were secondary to deficits in the executive control. STBI patients could be differentiated into two distinct functional subgroups based on whether they favored a strategy of attending to the encoding or digit-monitoring task. The subgroup favoring the digit-monitoring task demonstrated deficits in the focused attention condition, and disproportionate memory deficits in the divided attention condition. In contrast, the subgroup favoring the encoding task demonstrated intact performance across all memory measures, regardless of attentional load, and despite remarkable similarity to the other STBI subgroup on demographic, neuropsychological, and acute injury severity measures. We discuss these outcome differences in terms of the relationship between strategy and executive control and highlight the need for more sensitive anatomical and behavioral measurement at both acute and chronic stages of injury

Reproductive function and outcomes in female survivors of childhood, adolescent and young adult cancer: a review

Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring