Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 80%. However, additional changes using available drugs are unlikely to provide significant improvement in survival. New therapies are warranted given the risk of severe therapy-associated toxicities including infertility, organ damage, and secondary malignancy. Here, we report ectopic expression of the receptor tyrosine kinase Mer in pediatric B-cell ALL. Inhibition of Mer prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, we discovered cross-talk between the Mer and mammalian target of rapamycin (mTOR) signaling pathways. Our results identify Mer as a novel therapeutic target in ALL and suggest that inhibitors of Mer will interact synergistically with currently used therapies. This strategy may allow for dose reduction resulting in decreased toxicity and increased survival rates. Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

Pediatric developmental therapies: interesting new drugs now in early-stage clinical trials.

The current high cure rates for children diagnosed with cancer can be attributed in part to emphasis on large cooperative group clinical trials. The significant improvement in pediatric cancer survival over the past few decades is the result of optimized chemotherapy drug dosing, timing, and intensity; however, further alterations in traditional chemotherapy agents are unlikely to produce substantially better outcomes. Furthermore, there remains a subset of patients who have a very poor prognosis due to tumor type or stage at presentation, or who have a dismal prognosis with relapse or recurrence. As such, innovative approaches to therapy and new drugs are clearly needed for introduction into the current pediatric oncology arsenal. A variety of biologically targeted therapies that have shown promise in preclinical studies and early-phase adult clinical trials are now being explored in pediatric clinical trials. These novel agents hold the promise for continuing to drive forward improvements in patient survival, with potentially less toxicity than exists with traditional chemotherapy drugs.

Salivary Adenoid Cystic Carcinoma with Contralateral Cavernous Sinus Metastasis: A Rare Adult Tumor in an Adolescent Patient.

Adenoid cystic carcinoma (ACC) accounts for only 1% of all malignant head and neck tumors, and rarely affects children or adolescents. We present a 16-year-old female patient who was diagnosed with ACC at 12 years of age. The primary tumor was located in the left parotid gland. Initial treatment consisted of surgical resection and radiation therapy. Less than two years later, she developed recurrent disease in the right cavernous sinus with pulmonary metastases. At the time of this report, she is alive with disease. Both the patient's age and pattern of metastasis are rarely reported in the literature.

The need for reproductive and sexual health discussions with adolescent and young adult cancer patients.

Reproductive health consistently ranks as one of the most important issues cited by adolescent and young adult (AYA) cancer survivors. Most literature on AYA cancer populations neglects broader reproductive health issues such as unintended pregnancies, contraception use and sexually transmitted infections, which, for cancer patients and survivors with compromised immune systems, can facilitate a multitude of future health problems. Lack of attention coupled with traditional risk-taking behaviors of AYAs poses a significant health risk to patients and survivors, particularly if fertility status is unknown or inaccurately assessed. AYA oncology patients and survivors are vulnerable to reproductive health complications that should be addressed prior to, during and after treatment; however, there are currently no tracking systems or evidence-based guidelines to discuss this subject with patients and survivors. Further research is needed to identify physician practices, AYA preferences and strategies for communication that can pave the way to establishing guidelines to discuss in oncology settings.

Having cancer does not change wanting a baby: healthy adolescent girls' perceptions of cancer-related infertility.

PURPOSE: The goal of this study was to determine healthy adolescents' perceptions of cancer and fertility. A secondary goal of the study was to test items related to the development of a health-related quality-of-life tool with healthy control subjects to determine whether the participants shared a common understanding of the items and response options and to confirm face and content validity. METHODS: Four focus groups of two age-groups were held with healthy female adolescents: 12-14 years (N = 11) and 15-18 years (N = 14). RESULTS: Adolescents in both age-groups expressed significant concerns regarding potential infertility from cancer treatment, hereditary transmission, and the impact it would have on their future. Differences emerged in language preferences among older adolescents who preferred more open-ended statements. CONCLUSIONS: Fertility concerns and desires for future motherhood can be accurately assessed using the 10 statements tested, and clinicians should be made aware of the differences between younger and older adolescents to facilitate effective communication. This research suggests adolescents have predetermined expectations for becoming future parents, and their concerns about fertility and childbearing are present before becoming a patient.

Using a patient-centered approach to develop a fertility preservation brochure for pediatric oncology patients: a pilot study.

STUDY OBJECTIVES: Most pediatric education materials are designed for a parent audience. Social marketing techniques rely on the principles called the "4 P's": product, price, place, and promotion. The objective of this study was to test the design, readability, likelihood to read, and overall opinion of a pediatric fertility preservation brochure with patients, parents, and providers. DESIGN: Qualitative face-to-face interviews. SETTING: The Children's Cancer Center in Tampa, FL, and All Children's Hospital in St. Petersburg, FL. PARTICIPANTS: Male and female cancer patients and survivors aged 12-21 (N = 7), their parents (N = 11), and healthcare providers (N = 6). INTERVENTIONS: Patients, survivors, parents, and healthcare providers were given two versions of gender concordant brochures on fertility preservation designed for both pediatric oncology patients and their parents. OUTCOME MEASURES: Design, readability, likelihood to read, and overall opinion from interviews in order to identify facilitators of involving patients in fertility preservation discussions. RESULTS: Parents and teens differed on the design, readability, and likelihood to read, the highest discord being preferences for medical terminology used in the brochures. While parents remarked that much of the language was 'too advanced,' the majority of teens explained that they understood the terminology and preferred it remained on the brochure. Overall feedback from all three groups was utilized to revise the brochures into final versions to increase the likelihood of reading. CONCLUSION: Information about the development of the 4 P's of social marketing highlights needs from the intended audience. Barriers to patient education in pediatrics can be ameliorated when using the social marketing approach.

Congruence of reproductive concerns among adolescents with cancer and parents: pilot testing an adapted instrument.

OBJECTIVE: To identify whether a health-related quality of life (HRQoL) instrument intended to capture reproductive concerns is sensitive and appropriate for adolescent patients with cancer. METHODS: Pilot testing was completed by administering a 10-item instrument designed to identify reproductive concerns of female adolescent patients with cancer aged 12-18. Parents were also asked to predict their daughters' responses. Fourteen patients and parents participated. The main outcome measures were language, relevance, accuracy, sensitivity, and missing content regarding the HRQoL instrument. Two pediatric hospitals and 1 local support group for patients and survivors served as the setting for this study. RESULTS: The majority of parents provided inaccurate predictions of their daughters' responses regarding their reproductive concerns. Overall, parents underestimated their daughters' concerns because the majority of adolescents reported a strong desire for future parenthood whereas parents expected their daughters to be satisfied with survivorship. CONCLUSIONS: Adolescent patients with cancer have strong reproductive concerns; however, this may not be captured on current HRQoL instruments and may be further neglected due to parents' unawareness. Discussions should be encouraged with adolescent patients before beginning treatment regarding their concerns and values about parenting in the future and cannot rely on parent-proxy reports.

Rhabdomyomatous differentiation in Wilms tumor pulmonary metastases: a case report and literature review.

While sparsely reported in the literature, Wilms tumor may differentiate into more mature mesenchymal tissue types, such as skeletal muscle, following chemotherapy. The frequency of this event is unknown. Chemotherapy and radiation may induce cytodifferentiation of Wilms tumor cells or select for the survival of less mitotically active cells. In follow-up biopsies, the presence of rhabdomyomatous differentiation can confound the histologic diagnosis. Furthermore, these differentiated tumors appear to be more resistant to chemotherapy, thus biopsy and positron emission tomography scans following chemotherapy and radiation may prevent unnecessary treatment. We report an unusual case of Wilms tumor in a 21- year-old man with rhabdomyomatous differentiation of pulmonary metastases after chemotherapy, which presented a challenge during frozen section diagnosis.

Who decides? Decision making and fertility preservation in teens with cancer: a review of the literature.

PURPOSE: The knowledge that cancer treatment may impair fertility in pediatric populations is an emerging aspect of quality of life in this population. However, decision making and use of fertility preservation (FP) among adolescent cancer patients and their families has not been well studied. This review summarizes the available published data on aspects of decision making and FP in adolescent cancer patients. METHODS: An electronic search was performed to identify peer-reviewed studies published between 1999 and 2009 using key Medical Subject Heading terms and inclusion criteria. Inclusion criteria limited eligible studies to those that focused on adolescent decision making in cancer treatment or FP, fertility concerns in pediatric oncology, capacity for decision making, and health decision making in pediatrics. Studies that did not meet at least one of these criteria were excluded. RESULTS: A total of 29 articles were reviewed and summarized. Three categories of results were seen: a focus on adolescent decision making in oncology, decision making in chronic illness, and decision making in cancer-related infertility and preservation. CONCLUSION: Most of the studies showed that adolescents have a strong desire to participate in decisions related to their cancer treatment and many have concerns regarding their future fertility, although barriers often prevented these discussions. More research is needed to explore the role of teenagers and parents in decisions about fertility in relation to cancer treatment.

Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress.

The MerTK plays several important roles in normal macrophage physiology, including regulation of cytokine secretion and clearance of apoptotic cells. Mer signaling in other cell types, including malignant cells that ectopically overexpress the RTK, leads to downstream prosurvival pathway activation. We explored the hypothesis that Mer has a prosurvival role in macrophages exposed to oxidative stress. H(2)O(2) treatment of peritoneal exudate murine macrophages and J774 cells rapidly stimulated Mer phosphorylation in a concentration-dependent manner. Mer phosphorylation was dependent on the ligand Gas6, as treatment with warfarin or MerFc (a fusion protein of the extracellular domain of Mer and the Fc portion of human Ig), inhibitors of Gas6 activity, blocked H(2)O(2)-mediated activation of Mer. Antiapoptotic signals including pAkt and pErk 1/2 were increased dramatically (threefold and 4.5-fold, respectively) in WT Mer-positive macrophages compared with Mer KO macrophages stimulated with H(2)O(2). In a consistent manner, Mer expression led to decreased cleavage of proapoptotic indicators PARP and Caspase-3. Furthermore, Mer provided up to twofold enhanced cellular survival to primary macrophages exposed to H(2)O(2). These data represent the first report of Mer activation in response to oxidative stress and demonstrate the ability of Mer RTK to promote macrophage survival in disease states that involve an oxidative stress environment.

Cord blood transplant in childhood ALL.

BACKGROUND: Optimal therapy for high risk and relapsed acute lymphoblastic leukemia (ALL) remains uncertain. Wider availability of cord blood from related and unrelated donors has prompted studies of its use for hematopoietic stem cell transplant (HSCT). PROCEDURE: We evaluated 26 consecutive cord blood transplants (CBT) for ALL performed at our center from 1996 to 2002 on studies using consistent conditioning therapy and graft-versus-host disease (GVHD) prophylaxis. Median patient age was 8.5 years (range, 0.5-24 year). Cord blood (CB) was from unrelated donors in 25/26 cases. Median CB nucleated cell dose was 3.26e7/kg (range, 0.8-12.9). RESULTS: With median follow-up of 548 days, 16/26 patients (62%) are event-free survivors. Acute GVHD developed in 14/24 evaluable patients, reaching grade III-IV in 7 patients. Chronic GVHD occurred in 10/22 evaluable patients. Multivariate analysis showed higher total nucleated cell dose per kilogram to be the strongest predictor of event-free survival. CONCLUSIONS: We conclude that CBT can effectively treat ALL in children with high risk features and following relapse.