Utilization of Photobiomodulation for the Prevention and Treatment of Oral Mucositis.

Background: Oral mucositis is a significant and common toxicity experienced by patients who receive high-dose chemotherapy as a preparatory regimen for a hematopoietic cell transplant (HCT). Photobiomodulation (PBM) has been found to be feasible with significant efficacy in preventing the progression of oral mucositis in adult patients undergoing HCT. The purpose of this study was to determine the feasibility and efficacy of PBM in pediatric oncology patients undergoing HCT. Method: Forty children and adolescents admitted to the transplant unit for an allogeneic HCT for acute lymphoblastic leukemia or acute myeloid leukemia were treated daily at six sites until day + 20 or engraftment. Results: There were 1,035 patient encounters, with successful treatment of four or more sites during 979 patient encounters for a feasibility 93.3% CI [0.926, 0.039]. We had estimated a meaningful effect size of 20% for PBM and estimated 51% of patients treated with PBM would have at least one day or more of Grade 3 mucositis. The rate of patients who received PBM and developed Grade 3 mucositis was 20% CI [0.091, 0.356]. Patients treated with PBM had fewer days of hospitalization (p = .009) and less severe mucositis in comparison to the matched control group (p = .03). Conclusion: PBM is feasible and effective in preventing and treating oral mucositis and is now supported by the Children's Oncology Group for prevention and treatment of oral mucositis in patients undergoing an allogeneic HCT or receiving head/neck radiation.

Integration of Palliative Care in Hematopoietic Cell Transplant: Pediatric Patient and Parent Needs and Attitudes.

CONTEXT: Early integration of palliative care (PC) in hematopoietic cell transplantation (HCT) has demonstrated benefits, yet barriers remain, including perceived lack of patient/caregiver receptivity despite no data on attitudes toward PC and limited patient/caregiver reported outcomes in pediatric HCT. OBJECTIVES: This study aimed to evaluate perceived symptom burden and patient/parent attitudes toward early PC integration in pediatric HCT. METHODS: Following IRB approval, consent/assent, eligible participants were surveyed at St. Jude Children's Research Hospital including English-speaking patients aged 10-17, 1-month to 1-year from HCT, and their parents/primary-caregivers, as well as parent/primary-caregivers of living HCT recipients

Global Transcriptomics of Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease using PCK rats.

Congenital hepatic fibrosis / Autosomal recessive polycystic kidney disease (CHF/ARPKD) is an inherited neonatal disease induced by mutations in the PKHD1 gene and characterized by cysts, and robust pericystic fibrosis in liver and kidney. The PCK rat is an excellent animal model which carries a Pkhd1 mutation and exhibits similar pathophysiology. We performed RNA-Seq analysis on liver samples from PCK rats over a time course of postnatal day (PND) 15, 20, 30, and 90 using age-matched Sprague-Dawley (SD) rats as controls to characterize molecular mechanisms of CHF/ARPKD pathogenesis. A comprehensive differential gene expression (DEG) analysis identified 1298 DEGs between PCK and SD rats. The genes overexpressed in the PCK rats at PND 30 and 90 were involved cell migration (e.g. Lamc2, Tgfb2 , and Plet1 ), cell adhesion (e.g. Spp1, Adgrg1 , and Cd44 ), and wound healing (e.g. Plat, Celsr1, Tpm1 ). Connective tissue growth factor ( Ctgf ) and platelet-derived growth factor ( Pdgfb ), two genes associated with fibrosis, were upregulated in PCK rats at all time-points. Genes associated with MHC class I molecules (e.g. RT1-A2 ) or involved in ribosome assembly (e.g. Pes1 ) were significantly downregulated in PCK rats. Upstream regulator analysis showed activation of proteins involved tissue growth (MTPN) and inflammation (STAT family members) and chromatin remodeling (BRG1), and inhibition of proteins involved in hepatic differentiation (HNF4α) and reduction of fibrosis (SMAD7). The increase in mRNAs of four top upregulated genes including Reg3b, Aoc1, Tm4sf20 , and Cdx2 was confirmed at the protein level using immunohistochemistry. In conclusion, these studies indicate that a combination of increased inflammation, cell migration and wound healing, and inhibition of hepatic function, decreased antifibrotic gene expression are the major underlying pathogenic mechanisms in CHF/ARPKD.

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner.

Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, we investigate the role of global deletion of an IFT-A gene, Ttc21b, in juvenile and adult mouse models of ADPKD. Both juvenile (postnatal day 21) and adult (six months of age) ADPKD mice exhibited kidney cysts, increased kidney weight/body weight ratios, lengthened kidney cilia, inflammation, and increased levels of the nutrient sensor, O-linked ß-N-acetylglucosamine (O-GlcNAc). Deletion of Ttc21b in juvenile ADPKD mice reduced cortical collecting duct cystogenesis and kidney weight/body weight ratios, increased proximal tubular and glomerular dilations, but did not reduce cilia length, inflammation, nor O-GlcNAc levels. In contrast, Ttc21b deletion in adult ADPKD mice markedly attenuated kidney cystogenesis and reduced cilia length, inflammation, and O-GlcNAc levels. Thus, unlike IFT-B, the effect of Ttc21b deletion in mouse models of ADPKD is development-specific. Unlike an IFT-A adaptor, deleting Ttc21b in juvenile ADPKD mice is partially ameliorative. Thus, our studies suggest that different microenvironmental factors, found in distinct nephron segments and in developing versus mature stages, modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a pathological feature of ADPKD.

Managing Pandora's Box: Familial Expectations around the Return of (Future) Germline Results.

BACKGROUND: Pediatric oncology patients are increasingly being offered germline testing to diagnose underlying cancer predispositions. Meanwhile, as understanding of variant pathogenicity evolves, planned reanalysis of genomic results has been suggested. Little is known regarding the types of genomic information that parents and their adolescent children with cancer prefer to receive at the time of testing or their expectations around the future return of genomic results. METHODS: Parents and adolescent children with cancer eligible for genomic testing for cancer predisposition were surveyed regarding their attitudes and expectations for receiving current and future germline results (ClinicalTrials.gov Identifier: NCT02530658). RESULTS: All parents (100%) desired to learn about results for treatable or preventable conditions, with 92.4% wanting results even when there is no treatment or prevention. Parents expressed less interest in receiving uncertain results for themselves (88.3%) than for their children (95.3%). Most parents (95.9%) and adolescents (87.9%) believed that providers have a responsibility to share new or updated germline results indefinitely or at any point during follow-up care. Fewer parents (67.5%) indicated that they would want results if their child was deceased: 10.3% would not want to be contacted, 19.3% were uncertain. CONCLUSIONS: Expectations for return of new or updated genomic results are high among pediatric oncology families, although up to one third of parents have reservations about receiving such information in the event of their child's death. These results underscore the importance of high-quality pre-and post-test counseling, conducted by individuals trained in consenting around genomic testing to elicit family preferences and align expectations around the return of germline results.

Knowledge Is Power: Benefits, Risks, Hopes, and Decision-Making Reported by Parents Consenting to Next-Generation Sequencing for Children and Adolescents with Cancer.

OBJECTIVES: To qualitatively describe parent perspectives of next-generation genomic sequencing (NGS) for their children with cancer, including perceived benefits, risks, hopes/expectations, and decision-making process when consenting or not consenting to NGS and prior to result disclosure. DATA SOURCES: Qualitative interviews were used. CONCLUSION: Altruism is an important factor in parents consenting to NGS testing, as well as making sense of their child's cancer and legacy building. Parents described realistic hopes and expectations associated with NGS participation. Although parents endorsed the likelihood of no medical benefit, those consenting to NGS felt there was no reason not to participate. Parents declining participation expressed avoidance of worry and parent guilt if a germline variant were to be disclosed. IMPLICATIONS FOR NURSING PRACTICE: As NGS evolves into a component of the routine diagnostic workup for pediatric cancer patients, genetic nurses play a role in conducting informed consent conversations and ensuring that patients and families have realistic hopes and expectations associated with NGS.

IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease.

Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2- and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst-lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT-B and -A. Notably, increased Notch signaling in cyst-lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Sphingosine-1-phosphate and its mimetic FTY720 do not protect against radiation-induced ovarian fibrosis in the nonhuman primate†.

Oocytes are highly radiosensitive, so agents that prevent radiation-induced ovarian follicle destruction are important fertility preservation strategies. A previous study in rhesus macaques demonstrated that ovarian treatment with antiapoptotic agents, sphingosine-1-phosphate (S1P) and FTY720, its long-acting mimetic, preserved follicles following a single dose of 15 Gy X-ray radiation, and live offspring were obtained from FTY720-treated animals. However, it is unknown whether these antiapoptotic agents also protected the ovarian stroma from late effects of radiation, including vascular damage and fibrosis. Using ovarian histological sections from this study, we evaluated the vasculature and extracellular matrix in the following cohorts: vehicle + sham irradiation, vehicle + irradiation (OXI), S1P + irradiation (S1P), and FTY720 + irradiation (FTY720). One ovary from each animal was harvested prior to radiation whereas the contralateral ovary was harvested 10 months post-treatment. We assessed vasculature by immunohistochemistry with a PECAM1 antibody, hyaluronan by a hyaluronan binding protein assay, and collagen by picrosirius red and Masson's trichrome staining. Disorganized vessels were observed in the medulla in the OXI and S1P cohorts relative to the sham, but the vasculature in the FTY720 cohort appeared intact, which may partially explain fertoprotection. There were no differences in the hyaluronan matrix among the cohorts, but there was thickening of the tunica albuginea and fibrosis in the OXI cohort relative to the sham, which was not mitigated by either S1P or FTY720 treatment. Thus, the fertoprotective properties of S1P and FTY720 may be limited given their inability to protect the ovarian stroma against the late effects of radiation-induced fibrosis.

Macrophage-derived multinucleated giant cells: hallmarks of the aging ovary.

Inflammaging is a state of chronic, low-grade inflammation associated with aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.

Low Molecular Weight Hyaluronan Induces an Inflammatory Response in Ovarian Stromal Cells and Impairs Gamete Development In Vitro.

The ovarian stroma, the microenvironment in which female gametes grow and mature, becomes inflamed and fibrotic with age. Hyaluronan is a major component of the ovarian extracellular matrix (ECM), and in other aging tissues, accumulation of low molecular weight (LMW) hyaluronan fragments can drive inflammation. Thus, we hypothesized that LMW hyaluronan fragments contribute to female reproductive aging by stimulating an inflammatory response in the ovarian stroma and impairing gamete quality. To test this hypothesis, isolated mouse ovarian stromal cells or secondary stage ovarian follicles were treated with physiologically relevant (10 or 100 µg/mL) concentrations of 200 kDa LMW hyaluronan. In ovarian stromal cells, acute LMW hyaluronan exposure, at both doses, resulted in the secretion of a predominantly type 2 (Th2) inflammatory cytokine profile as revealed by a cytokine antibody array of conditioned media. Additional qPCR analyses of ovarian stromal cells demonstrated a notable up-regulation of the eotaxin receptor Ccr3 and activation of genes involved in eosinophil recruitment through the IL5-CCR3 signaling pathway. These findings were consistent with an age-dependent increase in ovarian stromal expression of Ccl11, a major CCR3 ligand. When ovarian follicles were cultured in 10 or 100 µg/mL LMW hyaluronan for 12 days, gametes with compromised morphology and impaired meiotic competence were produced. In the 100 µg/mL condition, LMW hyaluronan induced premature meiotic resumption, ultimately leading to in vitro aging of the resulting eggs. Further, follicles cultured in this LMW hyaluronan concentration produced significantly less estradiol, suggesting compromised granulosa cell function. Taken together, these data demonstrate that bioactive LMW hyaluronan fragments may contribute to reproductive aging by driving an inflammatory stromal milieu, potentially through eosinophils, and by directly compromising gamete quality through impaired granulosa cell function.

Speaking genomics to parents offered germline testing for cancer predisposition: Use of a 2-visit consent model.

BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.

Are we meeting the informational needs of cancer patients and families? Perception of physician communication in pediatric oncology.

BACKGROUND: High-quality oncology care is marked by skillful communication, yet little is known about patient and family communication perceptions or content preferences. Our study sought to elicit pediatric oncology patient and parent perceptions of early cancer communication to establish whether informational needs were met and identify opportunities for enhanced communication throughout cancer care. METHOD: An original survey instrument was developed, pretested, and administered to 129 patients, age 10-18 years, and their parents at 3 cancer centers between 2011 and 2015. Statistical analysis of survey items about perceived communication, related associations, and patient/parent concordance was performed. RESULTS: A greater percentage of participants reported "a lot" of discussion about the physical impact of cancer (patients, 58.1% [n = 75]; parents, 69.8% [n = 90]) compared with impact on quality of life (QOL) (patients, 44.2% [n = 57]; parents, 55.8% [n = 72]) or emotional impact (patients, 31.8% [n = 41]; parents, 43.4% [n = 56]). One fifth of patients (20.9% [n = 27]) reported they had no up-front discussion about the emotional impact of cancer treatment. Parents indicated a desire for increased discussion regarding impact on family life (27.9% [n = 36]), long-term QOL (27.9% [n = 36]), and daily activities (20.2% [n = 26]). Patients more frequently than parents indicated a desire for increased physician/patient discussion around the impact on daily activities (patients, 40.3% [n = 52]; parents, 21.7% [n = 28]; P < .001), long-term QOL (patients, 34.9% [n = 45]; parents, 16.3% [n = 21]; P < .001), pain management (patients, 23.3% [n = 30]; parents, 7% [n = 9]; P < .001), physical symptom management (patients, 24% [n = 31]; parents, 7.8% [n = 10]; P < .001), short-term QOL (patients, 23.3% [n = 30]; parents, 9.3% [n = 12]; P = .001), and curative potential (patients, 21.7% [n = 28]; parents, 8.5% [n = 11]; P = .002, P values calculated using McNemar's test). CONCLUSION: Oncologists may not be meeting the informational needs of many patients and some parents/caregivers. Communication could be enhanced through increased direct physician-patient communication, as well as proactive discussion of emotional symptoms and impact of cancer on QOL.

Inhibition of Mast Cell Degranulation With Cromolyn Sodium Exhibits Organ-Specific Effects in Polycystic Kidney (PCK) Rats.

Autosomal recessive polycystic kidney disease (ARPKD) is a monogenic disease characterized by development of hepatorenal cysts, pericystic fibrosis, and inflammation. Previous studies show that mast cell (MC) mediators such as histamine induce proliferation of cholangiocytes. We observed robust MC accumulation around liver cysts, but not kidney cysts, in polycystic kidney (PCK) rats (an animal model of ARPKD). Therefore, we hypothesized that MCs contribute to hepatic cyst growth in ARPKD. To test this hypothesis, we treated PCK rats with 1 of 2 different MC stabilizers, cromolyn sodium (CS) or ketotifen, or saline. The CS treatment decreased MC degranulation in the liver and reduced serum tryptase (an MC granule component). Interestingly, we observed an increase in liver to body weight ratio after CS treatment paralleled by a significant increase in individual cyst size. Hepatic fibrosis was not affected by CS treatment. The CS treatment increased hepatic cyst wall epithelial cell (CWEC) proliferation and decreased cell death. Ketotifen treatment also increased hepatic cyst size. In vitro, CS treatment did not affect proliferation of isolated hepatic CWECs from PCK rats. In contrast, CS decreased kidney to body weight ratio paralleled by a significant decrease in individual cyst size. The percentage of kidney to body weight ratio was strongly correlated with serum renin (an MC granule component). Ketotifen did not affect kidney cyst growth. Collectively, these data suggest that CS affects hepatic and renal cyst growth differently in PCK rats. Moreover, CS may be beneficial to renal cystic disease but may exacerbate hepatic cyst growth in ARPKD.

Sleep and mood during hospitalization for high-dose chemotherapy and hematopoietic rescue in pediatric medulloblastoma.

OBJECTIVE: Disrupted sleep is common in pediatric cancer, which is associated with psychological distress and may impact neural recovery. Information regarding sleep during pediatric brain tumor treatment is limited. This study aimed to describe objective sleep-wake patterns and examine the sleep-mood relation in youth hospitalized for intensive chemotherapy and stem cell rescue. METHODS: Participants included 37 patients (M age = 9.6 ± 4.2 years) enrolled on a medulloblastoma protocol (SJMB03) and their parents. Respondents completed a mood disturbance measure on 3 days, and patients wore an actigraph for 5 days as an objective estimate of sleep-wake patterns. General linear mixed models examined the relation between nocturnal sleep and next-day mood, as well as mood and that night's sleep. RESULTS: Sleep duration was deficient, sleep efficiency was poor, and daytime napping was common, with large between-subjects variability. There were minimal mood concerns across all days. The sleep and next-day mood relationship was nonsignificant (P > .05). Greater parent-reported child mood disturbance on day 2 was associated with decreased same-night sleep (P < .001) and greater patient-reported mood disturbance was associated with greater same-night sleep latency (P = .036). CONCLUSIONS: Patients with medulloblastoma are vulnerable to disturbed sleep during hospitalization, and mood may be an important correlate to consider. Sleep and mood are modifiable factors that may be targeted to maximize daytime functioning.

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF.

Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes-associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in ARPKD/CHF is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Ccnd1 (cyclin D1) and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.

Patients' and Parents' Needs, Attitudes, and Perceptions About Early Palliative Care Integration in Pediatric Oncology.

IMPORTANCE: Early palliative care integration for cancer patients is now touted as the optimal care model, yet significant barriers often prevent its implementation. A perceived barrier, especially for pediatric oncology patients, is the notion that patients and their families may not need or want palliative care involvement early in the disease trajectory. OBJECTIVE: To determine the perception of symptom burden early in treatment and assess attitudes toward early integration of palliative care in pediatric oncology patient-parent pairs. DESIGN, SETTING, AND PARTICIPANTS: Novel but pretested survey tools were administered to 129 patient-parent dyads of hospital-based pediatric oncology ambulatory clinics and inpatient units between September 2011 and January 2015. All patient participants were aged between 10 and 17 years and were diagnosed as having an oncologic condition 1 month to 1 year before enrollment. Both the patient and the parent in the dyad spoke English, and all participating parents provided written informed consent. A convenience sample was used for selection, with participants screened when otherwise presenting at a participating site. A total of 280 eligible participants were approached for study inclusion, 258 of whom were enrolled in the study (92.1% positive response-rate). MAIN OUTCOMES AND MEASURES: Degree of perceived suffering from early symptom-related causes, attitudes toward early palliative care integration, and patient-parent concordance. Statistical analysis included descriptive statistics, calculation of concordance, McNemar test results, and Cochran-Armitage trend test results. RESULTS: Of the 129 patients in the dyads, 68 were boys, and 61 girls; of the 129 parents, 15 were men, and 114 women. Patients reported the following symptoms in the first month of cancer therapy: nausea (n = 109; 84.5%), loss of appetite (n = 97; 75.2%), pain (n = 96; 74.4%), anxiety (n = 77; 59.7%), constipation (n = 69; 53.5%), depression (n = 64; 49.6%), and diarrhea (n = 52; 40.3%). A large proportion of those reporting suffering indicated substantial suffering severity from specific symptoms (ie, a great deal or a lot) including nausea, 52.3% (57 of 109), loss of appetite, 50.5% (49 of 97), constipation 30.4% (21 of 69), pain 30.2% (29 of 96), anxiety 28.6% (22 of 77), depression 28.1% (18 of 64), and diarrhea 23.1% (12 of 52). Few children and parents expressed opposition to early palliative care involvement (2 [1.6%] and 8 [6.2%]) or perceived any detrimental effects on their relationship with their oncologist (6 [4.7%] and 5 [3.9%]), loss of hope (3 [2.3%] and 10 [7.8%]), or therapy interference (3 [2.3%] and 2 [1.6%], respectively). Intradyad concordance was low overall: 26% to 29% for exact concordance and 40% to 69% for agreement within 1 response category. Significant differences in patient-parent attitudes toward aspects of early palliative care included child participants being more likely than their parents (40.3% [n = 52] vs 17.8% [n = 23]) to indicate that palliative care would have been helpful for treating their symptoms (P < .001). CONCLUSIONS AND RELEVANCE: Pediatric oncology patients experience a high degree of symptom-related suffering early in cancer therapy, and very few patients or parents in this study expressed negative attitudes toward early palliative care. Our findings suggest that pediatric oncology patients and families might benefit from, and are not a barrier to, early palliative care integration in oncology.

C57BL/6 Substrains Exhibit Different Responses to Acute Carbon Tetrachloride Exposure: Implications for Work Involving Transgenic Mice.

Biological differences exist between strains of laboratory mice, and it is becoming increasingly evident that there are differences between substrains. In the C57BL/6 mouse, the primary substrains are called 6J and 6N. Previous studies have demonstrated that 6J and 6N mice differ in response to many experimental models of human disease. The aim of our study was to determine if differences exist between 6J and 6N mice in terms of their response to acute carbon tetrachloride (CCl4) exposure. Mice were given CCl4 once and were euthanized 12 to 96 h later. Relative to 6J mice, we found that 6N mice had increased liver injury but more rapid repair. This was because of the increased speed with which necrotic hepatocytes were removed in 6N mice and was directly related to increased recruitment of macrophages to the liver. In parallel, enhanced liver regeneration was observed in 6N relative to 6J mice. Hepatic stellate cell activation occurred earlier in 6N mice, but there was no difference in matrix metabolism between substrains. Taken together, these data demonstrate specific and significant differences in how the C57BL/6 substrains respond to acute CCl4, which has important implications for all mouse studies utilizing this model.

Evidence for a "Pathogenic Triumvirate" in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe monogenic disorder that occurs due to mutations in the PKHD1 gene. Congenital hepatic fibrosis (CHF) associated with ARPKD is characterized by the presence of hepatic cysts derived from dilated bile ducts and a robust, pericystic fibrosis. Cyst growth, due to cyst wall epithelial cell hyperproliferation and fluid secretion, is thought to be the driving force behind disease progression. Liver fibrosis is a wound healing response in which collagen accumulates in the liver due to an imbalance between extracellular matrix synthesis and degradation. Whereas both hyperproliferation and pericystic fibrosis are hallmarks of CHF/ARPKD, whether or not these two processes influence one another remains unclear. Additionally, recent studies demonstrate that inflammation is a common feature of CHF/ARPKD. Therefore, we propose a "pathogenic triumvirate" consisting of hyperproliferation of cyst wall growth, pericystic fibrosis, and inflammation which drives CHF/ARPKD progression. This review will summarize what is known regarding the mechanisms of cyst growth, fibrosis, and inflammation in CHF/ARPKD. Further, we will discuss the potential advantage of identifying a core pathogenic feature in CHF/ARPKD to aid in the development of novel therapeutic approaches. If a core pathogenic feature does not exist, then developing multimodality therapeutic approaches to target each member of the "pathogenic triumvirate" individually may be a better strategy to manage this debilitating disease.

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice.

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24-96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure.

Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?

The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.