COMPLETE (Communication Plan Early Through End of Life): Development of a Research Program to Diminish Suffering for Children at End of Life.

While overall survival has improved significantly for children with cancer over the past 75 years, cancer remains the leading cause of death from disease among children and adolescents. Further, despite the many advances in medical and nursing care, children with cancer still experience significant physical and emotional suffering over the course of their illness, especially at the end of life (EOL). Children endure significant rates of high-intensity medical interventions (e.g., intubation, intensive care unit admission) at the EOL despite many parents, adolescents, and young adult patients identifying home as their preferred location of death. Hospice care has the potential to ease suffering at the EOL and facilitate home deaths, and yet, most children still die in acute care settings without hospice care. Numerous barriers prevent timely enrollment in hospice among children with cancer who are in the EOL period. This report describes the development and testing of a palliative care/EOL communication intervention designed to overcome some of these barriers and improve EOL outcomes (i.e., earlier hospice enrollment, less use of high-intensity medical interventions, reduced pain and suffering) among children with cancer and their parents (i.e., less emotional distress and uncertainty, improved hope and healthcare satisfaction).

Association of Posttraumatic Growth and Illness-Related Burden With Psychosocial Factors of Patient, Family, and Provider in Pediatric Cancer Survivors.

Research has indicated that childhood cancer may lead to posttraumatic growth (PTG), given cancer's association with posttraumatic stress. PTG may be associated with family/home and health care dynamics, as well as parental resilience, distress, and coping. This cross-sectional study investigated the associations of psychosocial factors of the patient, family, and health care team with PTG and illness-related burden (IRB) in childhood cancer survivors. The sample comprised 61 children and adolescents (7-18 years of age), their parents, and their nurses. Respondents completed their assessment an average of 1.73 years after the end of treatment for the child's disease, which was either leukemia, a solid tumor, or lymphoma. Regression analyses showed that PTG was positively associated with the patients' posttraumatic stress symptoms. It was also positively associated with the parents' religious coping, and with measures of stronger family and oncologist relationships (R2 = .32). IRB was positively associated with patient-reported posttraumatic stress symptoms, negatively associated with the nurse's trust in the family, and positively associated with parent-reported mental distress, lower family socioeconomic status, and female gender (R2 = .53). There was no significant association with parenting style or parent-reported posttraumatic stress symptoms in the child. The findings suggested that the young cancer patient's psychosocial and resource milieu (e.g., financial) may be instrumental in PTG and IRB. Psychosocial interventions with high-risk families and their health care teams could increase growth and reduce burden.

Post-transplant lymphoproliferative disease and other malignancies after pediatric cardiac transplantation: an evolving landscape.

PURPOSE OF REVIEW: Post-transplant lymphoproliferative disorders (PTLDs) remain a significant cause of morbidity and mortality after pediatric solid organ transplantation (SOT). PTLD treatment outcomes have improved steadily over the past decade, in large part due to an enhanced understanding of the disease process, newer immunosuppression regimens, and implementation of evolving chemotherapeutic treatment protocols. RECENT FINDINGS: New therapies continue to be employed to treat PTLDs while maintaining normal allograft function in SOT recipients. These include use of immunosuppressant medications with antitumor activity (mammalian target of rapamycin inhibitors), monoclonal antibody therapies, and the advent of cytotoxic T-cell therapy. Treatment methods to render latent Epstein-Barr virus (EBV)-infected tumor cells more susceptible to antiviral agents continue to be investigated. SUMMARY: PTLD remains a significant potential complication after SOT, particularly in pediatric patients who are more likely to be EBV-negative at the time of transplant and subsequently undergo EBV seroconversion. Risk for PTLD may be reduced by employing strategies such as EBV prophylaxis in seronegative patients, minimizing overall intensity of immunosuppression, and utilizing newer agents that have both immunosuppressive and antiproliferative properties. Treatment outcomes for PTLD have steadily improved over the past decade, related in part to the availability of monoclonal antibody therapies and refined chemotherapeutic regimens.

Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers.

Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.

Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events.

Bevacizumab is well suited for use in combination with first- or second-line chemotherapy in the treatment of metastatic colorectal cancer because its side effects are predictable and appear not to add to the incidence or severity of the side effects of chemotherapy. Clinical trials of bevacizumab in combination with oxaliplatin-containing and 5-fluorouracil-based regimens have shown that combination therapy is well tolerated and its toxicity is not substantially greater than that of the chemotherapy alone. Preliminary data from community-based and observational studies show that the incidence and severity of adverse events with combinations of bevacizumab and newer chemotherapy regimens are similar to those in the pivotal phase III trial with irinotecan, 5-fluorouracil, and leucovorin plus bevacizumab. Across trials, these side effects include a greater risk of grade 3 hypertension and grade 1 or 2 proteinuria, a slight increase (<2 percentage points) in grade 3 or 4 bleeding, and impaired surgical wound healing in patients who undergo surgery during treatment with bevacizumab. Potentially life-threatening events (arterial thrombotic events and gastrointestinal perforation) have occurred in a small number of patients. Close patient monitoring, especially in patients who are at greater risk of adverse events, is important.

Phase I trial of pazopanib in patients with advanced cancer.

PURPOSE: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. EXPERIMENTAL DESIGN: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. RESULTS: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily. CONCLUSION: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.