Purpose Thousands of children are living with advanced cancer; yet patient-reported outcomes (PROs) have rarely been used to describe their experiences. We aimed to describe symptom distress in 104 children age 2 years or older with advanced cancer enrolled onto the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) Study (multisite clinical trial evaluating an electronic PRO system). Methods Symptom data were collected using age- and respondent-adapted versions of the PediQUEST Memorial Symptom Assessment Scale (PQ-MSAS) at most once per week. Clinical and treatment data were obtained from medical records. Individual symptom scores were dichotomized into high/low distress. Determinants of PQ-MSAS scores were explored using linear mixed-effects models. Results During 9 months of follow-up, PQ-MSAS was administered 920 times: 459 times in teens (99% self-report), 249 times in children ages 7 to 12 years (96% child/parent report), and 212 times in those ages 2 to 6 years (parent reports). Common symptoms included pain (48%), fatigue (46%), drowsiness (39%), and irritability (37%); most scores indicated high distress. Among the 73 PQ-MSAS surveys administered in the last 12 weeks of life, pain was highly prevalent (62%; 58% with high distress). Being female, having a brain tumor, experiencing recent disease progression, and receiving moderate- or high-intensity cancer-directed therapy in the prior 10 days were associated with worse PQ-MSAS scores. In the final 12 weeks of life, receiving mild cancer-directed therapy was associated with improved psychological PQ-MSAS scores. Conclusion Children with advanced cancer experience high symptom distress. Strategies to promote intensive symptom management are indicated, especially with disease progression or administration of intensive treatments.

The AMP-activated protein kinase (AMPK) consists of catalytic ␣ and noncatalytic ␤ and ␥ subunits and is responsible for acting as a metabolic sensor for AMP levels. There are multiple genes for each subunit and the rat liver AMPK ␣ 1 and ␣ 2 catalytic subunits are associated with ␤ 1 and ␥ 1 noncatalytic subunits. We find that the isolated ␥ 1 subunit is N-terminally acetylated with no other posttranslational modification. The 5Ј-AMP-activated protein kinase (AMPK) 1 isolated from liver consists of three subunits, the catalytic ␣ subunit (548 residues, M r 62,497 ϳ63 kDa) and two noncatalytic subunits, ␤ (M r 30,378 ϳ40 kDa) and ␥ (M r 37,429 ϳ38 kDa) (1-3). The AMPK phosphorylates a number of protein substrates including key enzymes involved in the control of lipid metabolism, acetyl-CoA carboxylase, HMG-CoA reductase and hormonesensitive lipase (reviewed in Ref. 4). It has been proposed that the AMPK functions in stress responses since it is activated by increasing intracellular AMP resulting from a variety of treatments including arsenite, heat shock (5-7), ischaemia (8), exercise (9), and electrical stimulation of skeletal muscle (10).There are multiple isoforms of the AMPK subunits present in rat liver (2, 11). The AMPK ␣ 1 isoform (2) is encoded by a gene localized to chromosome 5p11 (12), whereas the AMPK ␣ 2 isoform gene is localized to chromosome 1p31 (13). The ␤ 1 and ␥ 1 subunits genes are located on chromosome 12 (12) The AMPK ␣ 1 and ␣ 2 isoforms are 90% identical in their catalytic cores but only 60% identical in their COOH-terminal tails. Previously, we found that the ␤ 1 subunit of the AMPK was multiply phosphorylated in an intramolecular autophosphorylation reaction (14). The ␤ 1 subunit of the AMPK contains an N-terminal consensus sequence for myristoylation with glycine at position 1 and serine (a small uncharged residue) at position 5 (15).In view of the potential importance of posttranslational modifications of the AMPK subunits in its physiological function, we have characterized the native state of the ␤ subunit. We find that the ␤ subunit purified from rat liver is fully myristoylated and present as a mixture of di-and triphosphorylated species with small amounts of monophospho-␤ subunit. Autophosphorylation of the AMPK in vitro results in up to 6 or more moles of phosphate incorporated per mole of ␤ subunit. The mass of the isolated N-terminally acetylated ␥ subunit is identical to the mass inferred from the cDNA sequence and is not phosphorylated. EXPERIMENTAL PROCEDURESAMPK Purification and Assay-The AMPK was purified from rat liver (14) and assayed (16) as described previously using the SAMS peptide substrate and 200 M 5Ј-AMP. The enzyme was diluted in 50 mM Tris⅐HCl, pH 7.5, 0.05% (v/v) Triton X-100, and the reactions were initiated by adding enzyme. The reactions were stopped by withdrawing 30-l aliquots for liquid scintillation counting as described (17). Protein concentration was assayed by the method of Lowry (18).AMPK Autophosphorylation-Purified AMPK was desalted into assay bu...

A B S T R A C T PurposeThis study aimed to determine whether feeding back patient-reported outcomes (PROs) to providers and families of children with advanced cancer improves symptom distress and health-related quality of life (HRQoL). Patients and MethodsThis study was a parallel, multicentered pilot randomized controlled trial. At most once per week, children age Ն 2 years old with advanced cancer or their parent completed the computer-based Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) survey consisting of age-and respondent-adapted versions of the Memorial Symptom Assessment Scale (MSAS), Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL4.0), and an overall Sickness question. In the intervention group (n ϭ 51), oncologists and families received printed reports summarizing PROs; e-mails were sent to oncologists and subspecialists when predetermined scores were exceeded. No feedback was provided in the control group (n ϭ 53). Primary outcomes included linear trends of MSAS, PedsQL4.0 total and subscale scores, and Sickness scores during 20 weeks of follow-up, along with child, parent, and provider satisfaction with PediQUEST feedback. ResultsFeedback did not significantly affect average MSAS, PedsQL4.0, or Sickness score trends. Post hoc subgroup analyses among children age Ն 8 years who survived 20 weeks showed that feedback improved PedsQL4.0 emotional (ϩ8.1; 95% CI, 1.8 to 14.4) and Sickness (Ϫ8.2; 95% CI, Ϫ14.2 to Ϫ2.2) scores. PediQUEST reports were valued by children, parents, and providers and contributed at least sometimes to physician initiation of a psychosocial consult (56%). ConclusionAlthough routine feedback of PROs did not significantly affect the child's symptoms or HRQoL, changes were in expected directions and improvements observed in emotional HRQoL through exploratory analyses were encouraging. Importantly, children, parents, and providers value PRO feedback.

A CHr of less than 27.5 pg is a more accurate hematological indicator of iron deficiency compared with hemoglobin of less than 11 g/dL in these healthy 9- to 12-month-old infants. Further studies are warranted to determine whether CHr should be the preferred screening tool in the early detection of iron deficiency in infants.

Context Modifiable factors of health-related quality of life (HRQOL) are poorly described among children with advanced cancer. Symptom-distress may be an important factor for intervention. Objectives We aimed to describe patient-reported HRQOL and its relationship to symptom distress. Methods Prospective, longitudinal data from the multicenter Pediatric Quality of Life and Symptoms Technology (PediQUEST) study included primarily patient-reported symptom-distress and HRQOL, measured at most weekly with the Memorial Symptoms Assessment Scale and Pediatric Quality of Life [PedsQL] inventory, respectively. Associations were evaluated using linear mixed-effects models adjusting for sex, age, cancer type, intervention arm, treatment intensity, and time since disease progression. Results Of 104 enrolled patients, 49% were female, 89% were white, and median age was 12.6 years. Nine hundred and twenty surveys were completed over nine months of follow-up (84% by patients). The median total PedsQL score was 74 (IQR 63–87) and was “poor/fair” (e.g., <70) 38% of the time. “Poor/fair” categories were highest in physical (53%) and school (48%) compared to emotional (24%) and social (16%) subscores. Thirteen of 24 symptoms were independently associated with reductions in overall or domain-specific HRQOL. Patients commonly reported distress from two or more symptoms, corresponding to larger HRQOL score reductions. Neither cancer type, time since progression, treatment intensity, sex, nor age was associated with HRQOL scores in multivariable models. Among 25 children completing surveys during the last 12 weeks of life, 11 distressing symptoms were associated with reductions in HRQOL. Conclusion Symptom-distress is strongly associated with HRQOL. Future research should determine whether alleviating distressing symptoms improves HRQOL in children with advanced cancer.

Background Stem cell transplantation (SCT) is an intensive therapy offering the possibility of cure for life-threatening conditions although with risk of serious complications and death. Outcomes associated with pediatric palliative care (PPC) for children who undergo SCT are unknown. Objective To evaluate whether PPC consultation is associated with differences in end-of-life (EOL) care patterns for children who underwent SCT and did not survive Methods Medical records of children who underwent SCT at Boston Children’s Hospital/Dana-Farber Cancer Institute for any indication from September 2004-December 2012 and did not survive were reviewed. Child demographic and clinical characteristics and PPC consultation and EOL care patterns were abstracted. Children who received PPC (PPC group) were compared with those who did not (non-PPC group). Results Children who received PPC consultation (n=37) did not differ from the non-PPC group (n=110) with respect to demographic or clinical characteristics, except they were more likely to have undergone unrelated allogeneic SCT (PPC=68%, non-PPC=39%, p=0.02) or to have died from treatment-related toxicity (PPC=76%, non-PPC=54%, p=0.03). PPC consultation occurred at a median of 0.7 (interquartile range [IQR] 0.4–4.2) months before death. PPC consultations most commonly addressed goals of care/decision-making (92%), psychosocial support (84%), pain management (65%), and non-pain symptom management (70%). Prognosis discussions (i.e., the likelihood of survival) occurred more commonly in the PPC group (PPC=97%, non-PPC=83%, p=0.04), as did resuscitation status discussions (PPC=88%, non-PPC=58%, p=0.002). These discussions also occurred earlier in the PPC group, for prognosis a median of 8 (IQR 4–26) days prior to death compared to 2 (IQR 1–13) days in the non-PPC group and for resuscitation status a median of 7 (IQR 3–18) days compared to 2 (IQR 1–5) in the non-PPC group (p<0.001 for both of the timing of prognosis and resuscitation status discussions). The PPC group was also was more likely to have resuscitation status documented, (PPC=97%, non-PPC=68%, p=0.002). With respect to patterns of care, compared to non-PPC, the PPC group was as likely to die in a medicalized setting (i.e. the hospital) (PPC=84%, non-PPC=77%, p=0.06) or have hospice (PPC=22%, non-PPC=18%, p=0.6). However, among children who died in the hospital, those who received PPC were more likely to die outside the ICU (PPC=80%, non-PPC=58%, p=0.03). In addition, the PPC group was less likely to receive intervention-focused care such as intubation in the 24 hours prior to death (PPC=42%, non-PPC=66%, p=0.02) or cardiopulmonary resuscitation (CPR) (PPC=3%, non-PPC=20%, p=0.03) at EOL. Children who received PPC for at least a month were more likely to receive hospice (PPC=41%, non-PPC=5%, p=0.01). Conclusion Children who underwent SCT and do not survive were likely to die in a medicalized setting, irrespective of PPC. However, PPC was associated with less intervention-focused care and greater opportunity for E...

The end-of-life (EOL) experience of children who undergo stem cell transplantation (SCT) may differ from that of other children with cancer. To evaluate perspectives and patterns of EOL care after SCT, we surveyed 141 parents of children who died of cancer (response rate, 64%) and their physicians. Chart review provided additional information. Children for whom SCT was the last cancer therapy (n ‫؍‬ 31) were compared with those for whom it was not (n ‫؍‬ 110). SCT parents and physicians recognized no realistic chance for cure later than non-SCT peers (both P < .001) and were more likely to have a primary goal of cure at death (parents, P < .001; physicians, P ‫؍‬ .02). SCT children were more likely to suffer highly from their last cancer therapy and die in the intensive care unit (both P < .001), with less opportunity for EOL preparation. SCT parents who recognized no realistic chance for cure more than 7 days before death along with the physician were more likely to prepare for EOL, and if their primary goal was to reduce suffering, to achieve this (P < .001). SCT is associated with significant suffering and less opportunity to prepare for EOL. Children and families undergoing SCT may benefit from ongoing discussions regarding prognosis, goals, and opportunities to maximize quality of life. (Blood.

HIV-1 Tat, in addition to its critical role in viral transcription, is secreted from infected cells and can act as a proto-cytokine. We studied the effects of HIV-1 Tat in primary human microvascular endothelial cells of lung origin and found that it caused apoptosis. This apoptosis occurred without induction of either Fas or TNF, known mediators of programmed cell death. Tat, like Fas ligand, induced cleavage of chromatin structure, as evidenced by changes in DNA laddering, incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay), and mono- or oligonucleosomes. Furthermore, Tat treatment caused cleavage of poly(A/DP)-ribose polymerase, a substrate of caspases. Caspase-3, but not caspase-9, was activated following treatment of primary human microvascular endothelial cells of lung origin with either Tat or anti-Fas agonist Ab (anti-Fas). Inhibition of caspase-3 activity markedly reduced apoptosis. Although Fas-mediated apoptosis involved changes in Bcl-2, Bax, and Bad regulatory proteins, such alterations were not observed with Tat. Taken together, these data demonstrate that HIV-1 Tat is able to activate apoptosis in microvascular endothelium by a mechanism distinct from TNF secretion or the Fas pathway.