Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee.

BACKGROUND: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB. PROCEDURES: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. RESULTS: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%). CONCLUSION: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Successful use of transarterial radioembolization with yttrium-90 (TARE-Y90) in two children with hepatoblastoma.

Primary malignant liver tumors are rare but all require surgical resection as part of therapy with curative intent. A minority of patients have resectable tumors at diagnosis. Chemotherapy has a therapeutic role in hepatoblastoma but only one-third of patients have resectable disease at diagnosis. Two children with hepatoblastoma and suboptimal responses to initial chemotherapy received therapy with transarterial radioembolization utilizing yttrium-90 (TARE-Y90) and had significant response leading to resection and remission. The role of TARE-Y90 needs to be studied further to define its use in primary pediatric liver neoplasms.

Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial.

BACKGROUND: Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. METHODS: In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children <10 kg) intravenously over 6 h on day 1; fluorouracil (600 mg/m2 per dose or 20 mg/kg per dose for children <10 kg) intravenous push on day 2; and vincristine (1·5 mg/m2 per day to a maximum dose of 2 mg, or 0·05 mg/kg per day for children <10 kg) intravenous push on days 2, 9, and 16. The primary outcome was investigator-assessed event-free survival. As prespecified by protocol, we analysed the primary endpoint 6 years after enrolment (cutoff date June 30, 2017). This trial is registered with ClinicalTrials.gov, number NCT00980460, and is now permanently closed to accrual. FINDINGS: Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36-62). 4-year event-free survival was 92% (95% CI 79-97) and 5-year event-free survival was 88% (72-95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3-4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. INTERPRETATION: Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. FUNDING: National Institutes of Health.

Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee.

BACKGROUND: The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma. METHODS: Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level <100 ng/mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m2 /day intravenously on days 1 and 8 and I at a dose of 50 mg/m2 /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% (>1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS: A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS: The VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.

Investigating the role of Clinical Nurse Consultants in one health district from multiple stakeholder perspectives: a cooperative inquiry.

BACKGROUND: The impetus for this research came from a group of 11 Clinical Nurse Consultants (CNCs) within a health service in NSW, Australia, who wanted to investigate the CNC role from multiple stakeholder perspectives. With support from academic researchers, the CNCs designed and implemented the study. OBJECTIVES: The aim of this research project was to investigate the role of the CNC from the multiple perspectives of CNCs and other stakeholders who work with CNCs in the Health District. DESIGN: This was a co-operative inquiry that utilised qualitative descriptive research approach. METHODS: Co-operative inquiry methods enabled 11 CNCs to work as co-researchers and to conduct the investigation. The co-researchers implemented a qualitative descriptive design for the research and used interviews (7) and focus groups (16) with CNC stakeholders (n = 103) to gather sufficient data to investigate the role of the CNC in the organisation. Thematic analysis was undertaken to obtain the results. FINDINGS: The CNC role is invaluable to all stakeholders and it was seen as the "glue" which holds teams together. Stakeholder expectations of the CNC role were multiple and generally agreed. Five themes derived from the data are reported as "clinical leadership as core", "making a direct difference to patient care", "service development as an outcome", "role breadth or narrowness and boundaries", and "career development". There was clear appreciation of the work that CNCs do in their roles, and the part that the CNC role plays in achieving quality health outcomes. CONCLUSION: The role of the CNC is complex and the CNCs themselves often negotiate these complexities to ensure beneficial outcomes for the patient and organisation. For the wider audience this study has given further insights into the role of these nurses and the perspectives of those with whom they work.

Acquired discrete subaortic stenosis in solid organ transplant recipients.

DSS is a rare acquired abnormality of the LV outflow tract in children and adults. DSS can be seen with or without associated congenital heart disease, but the mechanism of its emergence has been poorly understood. Here, we report two cases of DSS that developed after solid organ transplant in childhood. One patient underwent liver and kidney transplant at three yr of age for hereditary polycystic disease, and the other had liver transplant at three months of age due to uncontrollable high-output failure secondary to a large hepatic hemangioma. Both patients developed mild dynamic LV outflow tract obstruction and systemic hypertension soon after transplant, both of which resolved by the time of discharge. Transient LV hypertrophy was observed in both cases. Corticosteroids, cyclosporine A, and tacrolimus were used as initial immunosuppressants. Both patients developed DSS long after the regression of the initial dynamic LV outflow tract obstruction. Herein, we report DSS as an atypical late cardiovascular complication after solid organ transplant and postulate that transient post-transplant hyperdynamic LV outflow tract obstruction and chronic immunosuppressive treatment may lead to subendocardial remodeling resulting in a fibromuscular membranous ridge in susceptible subjects.

ParkinSong Online: Feasibility of Telehealth Delivery and Remote Data Collection for a Therapeutic Group Singing Study in Parkinson's.

BACKGROUND: Parkinson's disease can negatively affect vocal functioning and social wellbeing, particularly in the latter stages of disease progression. Face-to-face group singing interventions can improve communication and wellbeing outcomes, yet not all people can access in-person sessions. To help overcome barriers to participation, exploration of the feasibility and utility of online therapeutic singing programs is needed. OBJECTIVES: To evaluate the feasibility, acceptability, and preliminary efficacy of a 12-week ParkinSong Online intervention on speech and wellbeing for people with Parkinson's disease. METHODS: A total of 28 participants with idiopathic Parkinson's disease were recruited to a single-arm feasibility study. Weekly 90-minute online sessions were co-facilitated by a music therapist and speech pathologist. Speech and wellbeing assessments were conducted pre and post intervention. Participant and facilitator surveys were administered after each session, with focus group interviews at the end of the program. RESULTS: The recruitment rate was high (90%) with no attrition, adverse events, or safety issues. There was good intervention fidelity, attendance (average 89%), and positive participant experience. Feasibility was good, with technology reported as the main challenge (connecting and navigating Zoom). No improvements were seen in voice measures or wellbeing outcomes in this small trial. The online format used in this study did not provide the same benefits as in-person ParkinSong sessions. CONCLUSIONS: ParkinSong Online is feasible for recreational purposes and social engagement provided that people have adequate technological knowledge or support. The optimal online delivery format to achieve communication improvements in Parkinson's awaits confirmation.

Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience.

UNLABELLED: Posttransplant lymphoproliferative disorder (PTLD) causes significant morbidity and mortality in pediatric recipients of liver transplantation (LT). OBJECTIVE: Describe the incidence of PTLD and symptomatic Epstein-Barr virus (SEBV) disease in a large multicenter cohort of children who underwent LT with a focus on the risk factors and changes in incidence over time. SEBV and PTLD were prospectively determined in 2283 subjects who had undergone LT for the first time with at least 1 year of follow-up in the Studies of Pediatric Liver Transplantation database. SEBV was defined with specific criteria, and PTLD required tissue confirmation. The incidence of SEBV and PTLD was determined with a Kaplan-Meier analysis. Univariate and multivariate modeling of risk factors was performed with standard methods. SEBV occurred in 199 patients; 174 (87.4%) were EBV-negative at LT. Seventy-five patients developed PTLD, and 64 (85.3%) of these patients were EBV-negative at LT. Among the 2048 patients with at least 2 years of follow-up, 8.3% developed SEBV by the second year after LT, and 2.8% developed PTLD. There were lower rates of SEBV (5.9% versus 11.3%, P < 0.001) and PTLD (1.7% versus 4.2%, P = 0.001) in 2002-2007 versus 1995-2001. In 2002-2007, tacrolimus and cyclosporine trough blood levels in the first year after LT were significantly lower, and fewer children were receiving steroids. Biliary atresia, and recipient EBV status were correlated. In a multivariate analysis, era of LT, recipient EBV status, and frequent rejection episodes were associated with SEBV and PTLD. The incidence of SEBV and PTLD is decreasing in pediatric LT recipients concomitantly with a reduction in immunosuppression. Younger recipients and those with multiple rejections remain at higher risk for SEBV and PTLD.

The Wolfson Prize: designing the hospital of the future.

Background: The 2021 Wolfson Economics Prize asked how new hospitals should be designed to radically improve patient experiences, clinical outcomes, staff wellbeing and integration with wider health and social care. With a major programme to rebuild and renew hospitals in England underway, the Prize offered an opportunity to understand current thinking about hospitals and their future place. Methods: The 41 submissions that were identified as 'most promising' were reviewed and subjected to framework analysis. Emerging themes were identified and discussed iteratively. Results: Five dominant themes were identified: a calming environment; systems of care; distribution of services; use of technology; and going green. Several tensions and trade-offs were evident across the submissions and a number of gaps were identified in the knowledge base that need to be remedied to ensure that new hospitals are safe and efficient. Conclusion: The previous approach to building new hospitals, with its over-riding drive to reduce costs, has not served the UK well. New ways of thinking about hospital building and design are urgently needed, especially the funding of research and the creation of a national repository devoted to design solutions and post-build evaluations of new hospitals.

Critical elements of pediatric liver cancer surgery.

The appropriate management of pediatric liver malignancies, primarily hepatoblastoma and hepatocellular carcinoma, requires an in depth understanding of contemporary preoperative risk stratification, experience with advanced hepatobiliary surgery, and a good relationship with one's local or regional liver transplant center. While chemotherapy regimens have become more effective, operative indications more well-defined, and overall survival improved, the complexity of liver surgery in small children provides ample opportunity for protocol violation, inadequate resection, and iatrogenic morbidity. These guidelines represent the distillation of contemporary literature and expert opinion as a means to provide a framework for preoperative planning and intraoperative decision-making for the pediatric surgeon.

Pirfenidone for diabetic nephropathy.

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

Employment search, initial employment experience, and career preferences of recent pediatric surgical fellowship graduates: An APSA survey, part of the right child/right surgeon initiative.

BACKGROUND: APSA's Right Child/Right Surgeon Initiative addresses issues concerning patient access to appropriate pediatric surgical care and workforce distribution. The APSA Workforce Committee sought to understand the experiences and motivations of recent graduates of Pediatric Surgery Training Programs entering the workforce. METHODS: Using APSA membership databases, we identified members who completed fellowship training from 2010 to 2019. An online survey was created using Survey Monkey, and invitations to participate were sent via email. RESULTS: 144 of 447 invited participants responded (32% response rate). 91% of respondents participated in dedicated research prior to fellowship, but only 64% perform research during their employment. 23% completed an additional clinical fellowship, but only 54% currently practice within the second field. When asked to identify the top three factors used to choose a position, the most common responses were "location or geography" (71%), "available mentorship" (53%), and "compensation and benefits" (37%). Describing their first position, 77% reported working in an academic institution, 78% reported working in a metropolitan/urban area, and 55% reported working in a free-standing children's hospital. 94% participate in General Surgery resident education, and 49% are faculty within a Pediatric Surgery fellowship. Overall, 92% of respondents were able to find the type of employment position that they had wanted. CONCLUSION: In our survey the overwhelming majority of young pediatric surgeons found the type of job they desired. Most report beginning their practice in more populated, urban areas within academic institutions. Geographic location and work environment played heavily into their employment decisions. These preferences could contribute to continued disparity in access to pediatric surgeons between urban and rural America and to dilution of experience for urban surgeons. Possible solutions include alternative incentive programs for employment in less populated areas or new training models for general surgeons in rural areas to train in fundamentals of Pediatric Surgery.

Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

Outcomes of children with well-differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731.

BACKGROUND: Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone. PATIENTS AND METHODS: Patients on the Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's stage, tumor histology, and serum alpha-fetoprotein level at diagnosis. Patients were eligible for the very low risk stratum of surgery and observation if they had a complete resection at diagnosis and rapid central histologic review demonstrated HB with 100% WDF histology. RESULTS: A total of 8 eligible patients were enrolled on study between September 14, 2009 and May 28, 2014. Outcome current to 06/30/2020 was used in this analysis. The median age at enrollment was 22.5 months (range: 8-84 months) and the median AFP at enrollment was 714 ng/ml (range: 18-77,747 ng/mL). With a median follow-up of 6.6 years (range: 3.6-9.8 years), the 5-year event-free (EFS) and overall survival (OS) were both 100%. CONCLUSION: This report supports that HB with 100% WDF histology completely resected at diagnosis is curable with surgery only. The development of evidence-based surgical guidelines utilizing criteria based on PRETEXT group, vascular involvement (annotation factors), tumor-specific histology and corresponding biology will be crucial for optimizing which patients are candidates for resection at diagnosis followed by observation. LEVEL OF EVIDENCE: Prognosis study, Level I evidence.

Adiponectin regulates albuminuria and podocyte function in mice.

Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad(-/-)) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad(-/-) mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad(-/-) mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.

Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant.

A 6-week-old boy presented with fever, pallor, and hepatomegaly. Ultrasound showed a huge midline abdominal mass. ß-human chorionic gonadotropin was markedly elevated, suggesting a diagnosis of infantile choriocarcinoma of the liver. A biopsy confirmed the diagnosis. The patient received 6 cycles of bleomycin, cisplatin, and etoposide with significant decrease in tumor size. However, the tumor remained unresectable. A donor liver became available, and the infant underwent successful liver transplantation. He received 2 posttransplant cycles of moderate dose of methotrexate. This case shows the use of liver transplantation in cases of infantile choriocarcinoma of the liver where the tumor remains unresectable despite chemotherapy.

ParkinSong Online: protocol for a telehealth feasibility study of therapeutic group singing for people with Parkinson's disease.

INTRODUCTION: Parkinson's disease can be associated with speech deterioration and low communication confidence which in turn compromises social interaction. Therapeutic singing is an engaging method for combatting speech decline; however, face-to-face delivery can limit access to group singing. The aim of this study is to test the feasibility and acceptability of an online mode of delivery for a Parkinson's singing intervention (ParkinSong) as well as remote data collection procedures. METHODS AND ANALYSIS: This ParkinSong Online feasibility trial is a single-arm, pre-post study of online singing delivery and remote data collection for 30 people living with Parkinson's. The primary outcome measure is feasibility: recruitment, retention, attendance, safety, intervention fidelity, acceptability and associated costs. Secondary outcomes are speech (loudness, intelligibility, quality, communication-related quality of life) and wellbeing (apathy, depression, anxiety, stress, health-related quality of life). This mode of delivery aims to increase the accessibility of singing interventions. ETHICS AND DISSEMINATION: Ethics approval was obtained from The University of Melbourne Human Research Ethics Committee (2021-14465-16053-3) and the trial has been prospectively registered. Results will be presented at national and international conferences, published in a peer-reviewed journal, and disseminated to the Parkinson's community, researchers and policymakers. TRIAL REGISTRATION NUMBER: ACTRN12621000940875.

Regulation of transforming growth factor-beta1 by insulin in prediabetic African Americans.

Insulin resistance has been associated with kidney disease even in the absence of diabetes; however, pathways linking insulin resistance to kidney disease are unclear. The purpose of this study was to determine if transforming growth factor (TGF)-beta1, a key cytokine associated with kidney disease, responds to circulating levels of glucose and/or insulin. Urinary TGF-beta1 levels were measured in 249 young adult African Americans (mean age 40) at baseline, after an oral glucose tolerance test and after a euglycemic hyperinsulinemic clamp procedure. Baseline urinary geometric mean TGF-beta1 levels were somewhat lower in those with normal compared with the impaired glucose tolerance. The urinary TGF-beta1 level increased by 56% followed by a 23% decrease in the normal glucose tolerance group, changes that were significant and corresponded to the changes in the plasma glucose and insulin concentrations. The impaired tolerance group showed little change in the urinary TGF-beta1 level following glucose ingestion. All participants had a significant increase in urinary TGF-beta1 level after steady-state hyperinsulinemia, with sustained euglycemia during the clamp procedure in both of the groups. At baseline, there was a significant correlation between the urinary TGF-beta1 level and urinary albumin excretion. Thus our results suggest that insulin contributes to increased TGF-beta1 production and possible early renal injury in prediabetic young African Americans.