Publications by authors named "Andrew M Davidoff"

249 Publications

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

Cancer 2022 May 13. Epub 2022 May 13.

Division of Pediatric Surgery, Children's Hospital, London Health Sciences Center, London, Ontario, Canada.

Background: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis.

Methods: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse.

Results: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival.

Conclusions: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC.

Lay Summary: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.
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http://dx.doi.org/10.1002/cncr.34256DOI Listing
May 2022

Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC.

Cancers (Basel) 2022 Mar 25;14(7). Epub 2022 Mar 25.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 133, Memphis, TN 38105, USA.

Increased mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased expression by determining the association between and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the promoter. This study identified near ubiquitous hypermethylation of the promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in (7/45, 15.6%) were found to have lower expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher expression and telomerase activity. In vitro shRNA knockdown of resulted in decreased expression of , reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type . CRISPR-Cas9-mediated knockout of resulted in decreased expression of telomere-related gene pathways. However, an inducible -knockout mouse model showed no relationship between knockout and expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased promoter activity and transcription. Thus, multiple mechanisms of activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of activation in Wilms tumor that could be of therapeutic interests.
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http://dx.doi.org/10.3390/cancers14071655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996936PMC
March 2022

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Clin Transl Radiat Oncol 2022 May 10;34:42-50. Epub 2022 Mar 10.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients.

Methods And Materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later.

Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors.

Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.
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http://dx.doi.org/10.1016/j.ctro.2022.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956847PMC
May 2022

White paper: Oncofertility in pediatric patients with Wilms tumor.

Int J Cancer 2022 Mar 28. Epub 2022 Mar 28.

Department of Pediatric Hematology/Oncology, IWK Health Centre and Dalhousie University, Halifax, Canada.

The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.
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http://dx.doi.org/10.1002/ijc.34006DOI Listing
March 2022

Advocating for the surgical needs of children with cancer.

J Pediatr Surg 2022 Feb 23. Epub 2022 Feb 23.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 133, Memphis, TN 38105-3678, USA. Electronic address:

Outcomes have improved significantly over the last 60 years for children with cancer. However, one consequence of improved survival is that many patients are now living with the long-term consequences of therapy. Pediatric surgeons can impact both the oncologic outcomes and morbidities of therapy. Therefore, it is incumbent upon us to be considerate, informed, and introspective about what we do as surgeons.
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http://dx.doi.org/10.1016/j.jpedsurg.2022.01.050DOI Listing
February 2022

Interhospital variability in localization techniques for small pulmonary nodules in children: A pediatric surgical oncology research collaborative study.

J Pediatr Surg 2022 Feb 23. Epub 2022 Feb 23.

Children's Hospital Colorado, Aurora, CO, United States.

Background: Pulmonary nodules that are deep within lung parenchyma and/or small in size can be challenging to localize for biopsy. This study describes current trends in performance of image-guided localization techniques for pulmonary nodules in pediatric patients.

Methods: A retrospective review was performed on patients < 21 years of age undergoing localization of pulmonary nodules at 15 institutions. Localization and resection success, time in interventional radiology (IR), operating room (OR) and total anesthesia time, complications, and technical problems were compared between techniques.

Results: 225 patients were included with an average of 1.3 lesions (range 1-5). Median nodule size and depth were 4 mm (range 0-30) and 5.4 mm (0-61), respectively. The most common localization techniques were: wire + methylene blue dye (MBD) (28%), MBD only (25%), wire only (14%), technetium-99 only (11%), coil + MBD (7%) and coil only (5%). Localization technique was associated with institution (p < 0.01); technique and institution were significantly associated with mean IR, OR, and anesthesia time (all p < 0.05). Comparing techniques, there was no difference in successful IR localization (range 92-100%, p = 0.75), successful resection (94-100%, p = 0.98), IR technical problems (p = 0.22), or operative complications (p = 0.16).

Conclusions: Many IR localization techniques for small pulmonary nodules in children can be successful, but there is wide variability in application by institution and in procedure time.

Level Of Evidence: Retrospective review, Level 3.
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http://dx.doi.org/10.1016/j.jpedsurg.2022.01.061DOI Listing
February 2022

Preventing packaging of translatable P5-associated DNA contaminants in recombinant AAV vector preps.

Mol Ther Methods Clin Dev 2022 Mar 19;24:280-291. Epub 2022 Jan 19.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Recombinant adeno-associated virus (rAAV) vectors are increasingly being used for clinical gene transfer and have shown great potential for the treatment of several monogenic disorders. However, contaminant DNA from producer plasmids can be packaged into rAAV alongside the intended expression cassette-containing vector genome. The consequences of this are unknown. Our analysis of rAAV preps revealed abundant contaminant sequences upstream of the AAV replication (Rep) protein driving promoter, P5, on the Rep-Cap producer plasmid. Characterization of P5-associated contaminants after infection showed transfer, persistence, and transcriptional activity in AAV-transduced murine hepatocytes, in addition to evidence suggestive of integration. These contaminants can also be efficiently translated and immunogenic, revealing previously unrecognized side effects of rAAV-mediated gene transfer. P5-associated contaminant packaging and activity were independent of an inverted terminal repeat (ITR)-flanked vector genome. To prevent incorporation of these potentially harmful sequences, we constructed a modified P5-promoter (P5-HS), inserting a DNA spacer between an Rep binding site and an Rep nicking site in P5. This prevented upstream DNA contamination regardless of transgene or AAV serotype, while maintaining vector yield. Thus, we have constructed an rAAV production plasmid that improves vector purity and can be implemented across clinical rAAV applications. These findings represent new vector safety and production considerations for rAAV gene therapy.
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http://dx.doi.org/10.1016/j.omtm.2022.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829444PMC
March 2022

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma.

Nat Commun 2021 12 10;12(1):7204. Epub 2021 Dec 10.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
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http://dx.doi.org/10.1038/s41467-021-27502-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664842PMC
December 2021

Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models.

Sci Adv 2021 Nov 17;7(47):eabj5405. Epub 2021 Nov 17.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Aberrant alternative pre-mRNA splicing plays a critical role in MYC-driven cancers and therefore may represent a therapeutic vulnerability. Here, we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation and spliceosomal dependency, requires the splicing factor RBM39 for survival. Indisulam, a “molecular glue” that selectively recruits RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase for proteasomal degradation, is highly efficacious against neuroblastoma, leading to significant responses in multiple high-risk disease models, without overt toxicity. Genetic depletion or indisulam-mediated degradation of RBM39 induces significant genome-wide splicing anomalies and cell death. Mechanistically, the dependency on RBM39 and high-level expression of DCAF15 determine the exquisite sensitivity of neuroblastoma to indisulam. Our data indicate that targeting the dysregulated spliceosome by precisely inhibiting RBM39, a vulnerability in neuroblastoma, is a valid therapeutic strategy.
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http://dx.doi.org/10.1126/sciadv.abj5405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598007PMC
November 2021

Validating an opioid prescribing algorithm in post-operative pediatric surgical oncology patients.

J Pediatr Surg 2020 Oct 6. Epub 2020 Oct 6.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN.

Purpose: We developed an algorithm to decrease opioid prescriptions for pediatric oncology patients at discharge following surgery, based on a retrospective analysis to decrease variability and over-prescribing. The aim of this study was to prospectively test the algorithm.

Methods: Opioid-naïve patients undergoing surgery for tumor resection at a single institution were included. A prescribing algorithm was developed based on surgical approach, day of discharge, and inpatient opioid use. Prospectively collected data included outpatient opioid consumption and patient/family satisfaction. Total home dose prescribed was equal to that used in the 8 or 24 h, depending on length of stay and operative approach, prior to discharge, divided into 0.15 mg/kg doses.

Results: The algorithm was used in 121 patients and correctly predicted outpatient opioid requirements for 102 patients (84.3%). For 15 (12.4%) patients, the algorithm over-estimated opioid need by an average of 0.38 OME/kg. Four (3.3%) patients required additional opioids. Using this algorithm, we decreased overall opioid prescriptions from 6.17 to 0.21 OME/kg (p < 0.001), and all but one patient/family reported being satisfied with post-operative pain control.

Conclusion: Using an algorithm based on inpatient opioid use, outpatient opioid needs can be accurately predicted, thereby reducing excess opioid prescriptions without detriment to patient satisfaction.

Type Of Study: Prospective Quality Initiative Study.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.040DOI Listing
October 2020

Indocyanine Green-Guided Pediatric Tumor Resection: Approach, Utility, and Challenges.

Front Pediatr 2021 20;9:689612. Epub 2021 Sep 20.

Department of Surgery, St. Jude Children Research Hospital, Memphis, TN, United States.

Incomplete tumor resection increases the risk of local recurrence. However, the standard of care approach to distinguishing tumor tissue is less than optimal, as it depends on a conglomeration of preoperative imaging and visual and tactile indicators in real time. This approach is associated with a significant risk of inadequate resection; therefore, a novel approach that delineates the accurate intraoperative definition of pediatric tumors is urgently needed. To date, there is no reliable method for the intraoperative assessment of tumor extent and real-time differentiation between tumor- involved tissues and tumor-free tissues. Use of intraoperative frozen sections is challenging, time consuming, and covers a small surface area. Increased vascular permeability and impaired lymphatic drainage in the tumor microenvironment leads to an enhanced permeability and retention effect of small molecules. ICG is a fluorescent dye that when administered intravenously accumulates passively in the tumor because of EPR, thereby providing some tumor contrast for intraoperative real-time tumor recognition. Preclinical and clinical studies suggest that the tumor-to-background fluorescence ratio is optimized when imaging is obtained 24 h after dye injection, and many studies suggest using a high dose of ICG to optimize dye retention in the tumor tissue. However, in childhood cancers, little is known about the ideal dosing, applications, and challenges of ICG-guided tumor resection. This retrospective study examines the feasibility of ICG-guided tumor resection in common childhood solid tumors such as neuroblastoma, sarcomas, hepatic tumors, pulmonary metastases, and other rare tumors. Pediatric dosing and challenges related to the optimization of tumor-to-background ratio are also examined.
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http://dx.doi.org/10.3389/fped.2021.689612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489593PMC
September 2021

Indocyanine green-guided nephron-sparing surgery for pediatric renal tumors.

J Pediatr Surg 2021 Aug 23. Epub 2021 Aug 23.

Department of Surgery, MS 133, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Division of Pediatric Surgery, University of Tennessee Health Science Center, 910 Madison Ave, Memphis, TN 38163, USA.

Background: Indocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children.

Methods: This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors.

Results: We reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor.

Conclusions: Fluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.08.006DOI Listing
August 2021

Why do subcutaneous ports get stuck? A case-control study.

J Pediatr Surg 2021 Aug 8. Epub 2021 Aug 8.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place Mail Stop 133, Memphis, TN 38105, USA; Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, USA. Electronic address:

Purpose: We sought to identify clinical features associated with difficult subcutaneous port removals in children.

Methods: Ports placed between April 2014 and September 2017 at our institution were prospectively tracked for difficult removals. A case-control analysis was performed. Patients with ports that were difficult to remove (stuck; cases) were compared to biological sex and age-matched controls in a ratio of 1:3. Logistic regression determined the association between case/control status and clinical features adjusting for biological sex and age as covariates. A multivariable analysis was performed to identify independent associations.

Results: 57 stuck ports (28 extreme [10 endovascular intervention] and 29 moderate) and 171 controls were analyzed. Stuck ports were associated with a diagnosis of acute lymphoblastic leukemia (86% cases versus 22.2% controls; p < 0.001) and a longer placement duration (median 2.6 years [interquartile range (IQR) 2.5-2.6] versus 0.8 years [IQR 0.5-1.4]; p < 0.001). On univariate analysis, procedural and device features associated with stuck ports included subclavian access (71.9% cases versus 48.5% controls; p = 0.0126), a polyurethane versus silicone catheter (96.5% cases versus 79.9% controls; p = 0.001), and a rough catheter appearance at removal (92.6% cases versus 9.4% controls; p < 0.0001). A diagnosis of ALL and duration of line placement were associated with having a stuck port on multivariate analysis.

Conclusion: Polyurethane central venous catheters placed for the two-year treatment of acute lymphoblastic leukemia may become difficult to remove. This constellation of factors warrants more extensive preoperative discussion of risk, endovascular backup availability, and scheduling for longer operating room time.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.08.003DOI Listing
August 2021

Management of intravascular thrombus in cases of bilateral Wilms tumor or horseshoe kidney.

J Pediatr Surg 2021 Aug 5. Epub 2021 Aug 5.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 133, Memphis, TN 38105, United States; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, United States. Electronic address:

Purpose: To describe the oncologic and surgical management of bilateral Wilms tumor or Wilms tumor arising in a horseshoe kidney with intravenous tumor thrombus to help pediatric surgeons negotiate this rare and difficult anatomic circumstance.

Methods: A single-institution, retrospective medical record review identified 4 cases of bilateral WT and one case of WT arising in a horseshoe kidney with intravenous tumor thrombus between 2009 and 2021. The presentation, imaging, chemotherapy regimen, intraoperative approach, and surgical and oncologic outcomes were reviewed for each of these patients.

Results: All patients received a total of 12 weeks of neoadjuvant chemotherapy. In two patients, a staged approach to the bilateral tumors was undertaken with the first side being operated on after six weeks of therapy and the other side undergoing surgery after an additional six weeks of therapy. Of five patients, four underwent nephron-sparing surgery of all tumors and one underwent unilateral radical nephroureterectomy with contralateral nephron-sparing surgery. Tumor thrombectomy was performed in four of five cases; one patient demonstrated a complete response of the intravenous tumor thrombus to neoadjuvant chemotherapy and did not require thrombectomy. Three patients received adjuvant flank radiotherapy. Three patients developed medically managed stage II or III chronic kidney disease and no patient required renal replacement therapy or kidney transplant to date.

Conclusion: Nephron-sparing surgery is feasible and safe to perform in selected cases of bilateral Wilms tumor with intravascular thrombus by utilizing three-drug neoadjuvant chemotherapy, staged approaches to each kidney when appropriate, and detailed preoperative and/or intraoperative mapping of renal venous anatomy. Successful nephron-sparing surgery with tumor thrombectomy is dependent on a branched renal venous system or the presence of accessory renal veins.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.025DOI Listing
August 2021

The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphology by regulating steady-state H2A.Z binding in neurons.

Cell Rep 2021 08;36(7):109551

Department of Psychology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G3, Canada. Electronic address:

Rapid removal of histone H2A.Z from neuronal chromatin is a key step in learning-induced gene expression and memory formation, but mechanisms underlying learning-induced H2A.Z removal are unclear. Anp32e was recently identified as an H2A.Z-specific histone chaperone that removes H2A.Z from nucleosomes in dividing cells, but its role in non-dividing neurons is unclear. Moreover, prior studies investigated Anp32e function under steady-state rather than stimulus-induced conditions. Here, we show that Anp32e regulates H2A.Z binding in neurons under steady-state conditions, with lesser impact on stimulus-induced H2A.Z removal. Functionally, Anp32e depletion leads to H2A.Z-dependent impairment in transcription and dendritic arborization in cultured hippocampal neurons, as well as impaired recall of contextual fear memory and transcriptional regulation. Together, these data indicate that Anp32e regulates behavioral and morphological outcomes by preventing H2A.Z accumulation in chromatin rather than by regulating activity-mediated H2A.Z dynamics.
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http://dx.doi.org/10.1016/j.celrep.2021.109551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422973PMC
August 2021

A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions.

Cancer 2021 10 6;127(20):3825-3831. Epub 2021 Jul 6.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors.

Methods: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels.

Results: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived.

Conclusions: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.
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http://dx.doi.org/10.1002/cncr.33750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478797PMC
October 2021

Impact of Neoadjuvant Chemotherapy on Image-Defined Risk Factors in High-Risk Neuroblastoma.

Ann Surg Oncol 2022 Jan 2;29(1):661-670. Epub 2021 Jul 2.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma.

Methods: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined.

Results: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5].

Conclusion: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.
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http://dx.doi.org/10.1245/s10434-021-10386-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688258PMC
January 2022

The cost-effectiveness of gene therapy for severe hemophilia B: a microsimulation study from the United States perspective.

Blood 2021 11;138(18):1677-1690

Department of Global Pediatric Medicine.

Adeno-associated virus (AAV)-mediated gene therapy is a novel treatment promising to reduce morbidity associated with hemophilia. Although multiple clinical trials continue to evaluate efficacy and safety, limited cost-effectiveness data have been published. This study compared the potential cost-effectiveness of AAV-mediated factor IX (FIX)-Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX replacement and primary FIX prophylaxis, using either standard or extended half-life FIX products. A microsimulation Markov model was constructed, and transition probabilities between health states and utilities were informed by using published data. Costs were aggregated by using a microcosting approach. A time horizon from 18 years old until death, from the perspective of a third-party payer in the United States, was conducted. Gene therapy was more cost-effective than both alternatives considering a $150 000/quality-adjusted life-year threshold. The price for gene therapy was assumed to be $2 000 000 in the base case scenario; however, one of the 1-way sensitivity analyses was conducted by using observed manufacturing, administration, and 5-year follow-up costs of $87 198 for AAV-mediated gene therapy vector as derived from the manufacturing facility and clinical practice at St Jude Children's Research Hospital. One-way sensitivity analyses revealed 10 of 102 scenarios in which gene therapy was not cost-effective compared with alternative treatments. Notably, gene therapy remained cost-effective in a hypothetical scenario in which we estimated that the discounted factor concentrate price was 20% of the wholesale acquisition cost in the United States. Probabilistic sensitivity analysis estimated gene therapy to be cost-effective at 92% of simulations considering a $150 000/quality-adjusted life-year threshold. In conclusion, based on detailed simulation inputs and assumptions, gene therapy was more cost-effective than on-demand treatment and prophylaxis for patients with severe hemophilia B.
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http://dx.doi.org/10.1182/blood.2021010864DOI Listing
November 2021

Does epidural analgesia really enhance recovery in pediatric surgery patients?

Pediatr Surg Int 2021 Sep 8;37(9):1201-1206. Epub 2021 Apr 8.

Division of Anesthesiology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: We sought to determine the benefits of epidural anesthesia (EA) in pediatric surgical patients.

Methods: This study is a single-institution retrospective review of EA for pediatric patients undergoing thoracotomy or laparotomy from 2015 to 2020. Patients with recent or chronic opioid use were excluded. Urgent or emergent cases, patients with hemodynamic instability, or those with surgical complications that significantly impacted their post-operative course were also excluded. The primary objectives were comparison of pain scores and systemic opioid use between those patients with EA and those without EA.

Results: Epidural anesthesia was used in 151 (81.6%) laparotomies and 58 (77.3%) thoracotomies. EA use was associated with lower mean systemic opioid administration during the early post-operative period for laparotomy (POD#0-0.33 ± 0.3 oral morphine equivalents per kilogram (OME/Kg) with EA vs 0.93 ± 1.53, p < 0.001, POD#1-1.34 ± 1.79 OME/Kg with EA vs 2.61 ± 2.60, p < 0.001) and thoracotomy (POD#0-0.40 ± 0.37 OME/Kg with EA vs 0.68 ± 0.41, p = 0.008, POD#1-0.89 ± 0.86 OME/Kg with EA vs 2.02 ± 1.92, p < 0.001). There were no differences seen by POD#2. Average pain scores were significantly lower in patients with EA following laparotomy (POD#0-1.22 ± 0.99 with EA vs 1.75 ± 1.33, p = 0.008) and thoracotomy (POD#0-1.71 ± 1.13 with EA vs 2.40 ± 1.52, p = 0.04).

Conclusions: The use of EA in pediatric surgery patients was associated with lower pain scores despite lower systemic opioid requirements in the early post-operative period.
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http://dx.doi.org/10.1007/s00383-021-04897-zDOI Listing
September 2021

Risk for deep venous thrombosis in pediatric cancer patients undergoing surgery.

J Pediatr Surg 2021 Dec 13;56(12):2360-2363. Epub 2021 Feb 13.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, United States; Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave, Memphis, TN 38163, United States; Division of Pediatric Surgery, LeBonheur Children's Hospital, 848 Adams Ave, Memphis, TN 38103, United States. Electronic address:

Purpose: Cancer is a well-established risk factor for deep venous thrombosis (DVT). We sought to assess the incidence of DVT in pediatric cancer patients undergoing select surgical procedures at our institution and to identify additional factors associated with DVT development.

Methods: We performed a retrospective review of cancer patients who underwent select surgical procedures and developed a DVT within 30 days of their operation from 2000 to 2018 at our institution. Catheter-associated DVTs were excluded from this analysis. Major oncologic operations were selected.

Results: From 2000 to 2018, 3031 major oncologic operations were performed following which 14 symptomatic DVTs occurred, for an overall incidence of 0.46%. Procedures associated with post-operative DVT included: mass biopsy (7), pulmonary wedge resection (2), inguinal lymph node excision (1), colectomy (1), nephrectomy (1), lower extremity limb-sparing revision (1), and femur resection (1).

Conclusions: Our data suggest that surgery does not put children with cancer at significant risk for DVT. Given the low incidence of perioperative DVT, routine pharmacologic prophylaxis for children with cancer undergoing surgery does not seem warranted.

Level Of Evidence: II.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.01.047DOI Listing
December 2021

Minimally Invasive Techniques in Pediatric Surgical Oncology.

Surg Oncol Clin N Am 2021 04 10;30(2):417-430. Epub 2021 Feb 10.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address:

Minimally invasive approaches to pediatric cancer surgery are increasingly used, not only for the benefits of smaller incisions, but also for better field visualization and precise dissection. Advances in technology and surgeon experience have facilitated this trend. However, the appropriate indications for its use remain to be determined, and oncologic principles should not be compromised. We discuss the current and potential future uses, and new technologies that are being developed and introduced to assist with and enhance the role of minimally invasive surgery in the management of children with cancer.
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http://dx.doi.org/10.1016/j.soc.2020.11.008DOI Listing
April 2021

Kidney Function after Treatment for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study.

J Am Soc Nephrol 2021 Mar 2. Epub 2021 Mar 2.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Survivors of childhood cancer may be at increased risk for treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust.

Methods: To define the prevalence of and risk factors for impaired kidney function among adult survivors of childhood cancer who had been diagnosed ≥10 years earlier, we evaluated kidney function (eGFR and proteinuria). We abstracted information from medical records about exposure to chemotherapeutic agents, surgery, and radiation treatment and evaluated the latter as the percentage of the total kidney volume treated with ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). We also used multivariable logistic regression models to assess demographic and clinical factors associated with impaired kidney function and Elastic Net to perform model selection for outcomes of kidney function.

Results: Of the 2753 survivors, 51.3% were men, and 82.5% were non-Hispanic White. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3-13.2), and mean age was 31.4 years (IQR, 25.8-37.8) at evaluation. Time from diagnosis was 23.2 years (IQR, 17.6-29.7). Approximately 2.1% had stages 3-5 CKD. Older age at evaluation; grade ≥2 hypertension; increasing cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and volume of kidney irradiated to ≥5 or ≥10 Gy increased the odds for stages 3-5 CKD. Nephrectomy was significantly associated with stages 3-5 CKD in models for V15 or V20.

Conclusions: We found that 2.1% of our cohort of childhood cancer survivors had stages 3-5 CKD. These data may inform screening guidelines and new protocol development.
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http://dx.doi.org/10.1681/ASN.2020060849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017532PMC
March 2021

Improving Exposure Using Thoracoscopy for Apical Thoracic Neuroblastoma Encasing the Subclavian Vessels.

J Laparoendosc Adv Surg Tech A 2021 May 16;31(5):589-593. Epub 2021 Feb 16.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, USA.

Posterolateral thoracotomy provides limited access to the thoracic apex that can result in poor visualization of subclavian vessels, their branches, and the brachial plexus. A thoracoscopic approach may overcome these limitations. We report a thoracoscopic approach and associated technical challenges in resecting apical thoracic neuroblastoma encasing the subclavian artery. A single-institution retrospective chart review was performed (2018-2020) for patients undergoing thoracoscopic resection of apical neuroblastoma encasing the subclavian artery. Patient demographics, imaging, and hospital course were reviewed. Operative video recordings were assessed for exposure quality, technical challenges, and percentage of tumor resection. Patients were placed laterally, with three 5-mm ports triangulated to the apex. Dissection started at the tumor edge and followed along the vessel and branches. Four patients (median age 2.7 years) underwent thoracoscopic apical neuroblastoma resection. Median length of stay was 2.5 days. One low-risk patient underwent resection for tumor growth during observation. One intermediate and 2 high-risk patients received neoadjuvant chemotherapy. Two patients continued having persistent vascular encasement, whereas in 1 patient the mass decreased in size and only abutted the subclavian and vertebral arteries. In 1 patient, tumor involved the brachial plexus, which was freed and preserved thoracoscopically. All cases had substantial tumor-feeding vessels branching from the subclavian artery. There was one conversion to open thoracotomy due to dense tumor adherence to the subclavian artery and vein. More than 95% resection was achieved in all cases. All patients had baseline Horner syndrome. No complications were reported. The thoracoscopic approach for resecting apical neuroblastoma provides optimal exposure and safe access in selected patients.
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http://dx.doi.org/10.1089/lap.2020.0850DOI Listing
May 2021

Neonatal Neuroblastoma.

Clin Perinatol 2021 03 12;48(1):101-115. Epub 2021 Jan 12.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA. Electronic address:

Neuroblastoma accounts for approximately 8% of all pediatric cancers, with 5% diagnosed during the neonatal period. Despite the disproportionate contribution of neuroblastoma to childhood cancer deaths, neonatal neuroblastoma has a favorable prognosis, often with little or no therapy required. Therefore, minimizing therapy and mitigating complications/toxicities are emphasized, including using a watch-and-wait approach for patients at low risk for disease progression/relapse. However, stage MS neuroblastoma exhibits a unique pattern of disseminated disease, can be challenging to manage, and may require early intervention with systemic chemotherapy. In this review, the epidemiology, treatment options, and anticipated outcomes for neonatal neuroblastoma are discussed.
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http://dx.doi.org/10.1016/j.clp.2020.11.006DOI Listing
March 2021

17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.

iScience 2021 Jan 28;24(1):101996. Epub 2020 Dec 28.

Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA.

Histone lysine demethylases (KDMs) play critical roles in oncogenesis and therefore may be effective targets for anticancer therapy. Using a time-resolved fluorescence resonance energy transfer demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as KDM inhibitors. In addition, we found that these Hsp90 inhibitors increase degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the repressive epigenetic mark H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM in combination with chemotherapy may serve as a therapeutic approach to PAX3-FOXO1-positive aRMS.
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http://dx.doi.org/10.1016/j.isci.2020.101996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811140PMC
January 2021

The use of computed tomography versus clinical acumen in diagnosing appendicitis in children: A two-institution international study.

J Pediatr Surg 2021 Aug 4;56(8):1356-1361. Epub 2020 Nov 4.

Division of Pediatric Surgery, Department of Surgery, Le Bonheur Children's Hospital, University of Tennessee Health Sciences Center, Memphis, TN 38105, USA.. Electronic address:

Background: Appendicitis in children can be diagnosed utilizing clinical and laboratory findings, with the assistance of ultrasound (US) and/or computed tomography (CT). However, repeated exposure to ionizing radiation increases the lifetime risk of cancer. We compared the work-up of suspected appendicitis between a children's hospital in the United States (USA) and one in Spain to identify differences in imaging use and associated outcomes.

Methods: A two-institution retrospective review was performed for surgical consultations of suspected appendicitis from 2015-2017. We compared imaging use, the utilization of overnight observation, and diagnostic accuracy rates between the two centers.

Results: A total of 1,952 children were evaluated. Among the 1,288 in the USA center, 754(58.5%) underwent CT during their evaluation. The most common imaging modality was US only (39.9%), then CT only (39.3%), CT+US (19.3%), and no imaging (i.e. only clinical acumen) (1.6%). In Spain, only 19 (2.9%) of 664 children underwent CT compared to the USA (p < 0.0001). Only clinical acumen was the most common modality employed (48.6%), followed by US only (48.5%), US+CT (2.4%), and CT only (0.5%). In the USA, 16.8% were observed overnight, 2.3% of whom received no imaging. In Spain, 33.4% were observed overnight, 32.4% of whom had no imaging (p < 0.0001). The accuracy rates for diagnosing appendicitis in the USA and Spain centers were 94.7% and 95.1%, respectively.

Conclusion: Use of clinical acumen and/or US have similar clinical outcomes and similar accuracy rates compared to heavy reliance on CT imaging for diagnosing appendicitis, with associated decrease in radiation exposure. The disparate diagnostic approach of the two centers may reflect that physical examination is a dying art in North America.

Level Of Evidence: III.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.061DOI Listing
August 2021

Self-complementarity in adeno-associated virus enhances transduction and gene expression in mouse cochlear tissues.

PLoS One 2020 23;15(11):e0242599. Epub 2020 Nov 23.

Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States of America.

Sensorineural hearing loss is one of the most common disabilities worldwide. Such prevalence necessitates effective tools for studying the molecular workings of cochlear cells. One prominent and effective vector for expressing genes of interest in research models is adeno-associated virus (AAV). However, AAV efficacy in transducing cochlear cells can vary for a number of reasons including serotype, species, and methodology, and oftentimes requires high multiplicity of infection which can damage the sensory cells. Reports in other systems suggest multiple approaches can be used to enhance AAV transduction including self-complementary vector design and pharmacological inhibition of degradation. Here we produced AAV to drive green fluorescent protein (GFP) expression in explanted neonatal mouse cochleae. Treatment with eeyarestatin I, tyrphostin 23, or lipofectamine 2000 did not result in increased transduction, however, self-complementary vector design resulted in significantly more GFP positive cells when compared to single-stranded controls. Similarly, self-complementary AAV2 vectors demonstrated enhanced transduction efficiency compared to single stranded AAV2 when injected via the posterior semicircular canal, in vivo. Self-complementary vectors for AAV1, 8, and 9 serotypes also demonstrated robust GFP transduction in cochlear cells in vivo, though these were not directly compared to single stranded vectors. These findings suggest that second-strand synthesis may be a rate limiting step in AAV transduction of cochlear tissues and that self-complementary AAV can be used to effectively target large numbers of cochlear cells in vitro and in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242599PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682903PMC
January 2021

Evolving applications of fluorescence guided surgery in pediatric surgical oncology: A practical guide for surgeons.

J Pediatr Surg 2021 Feb 19;56(2):215-223. Epub 2020 Oct 19.

Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Northwestern University Feinberg School of Medicine, Chicago, IL. Electronic address:

Fluorescence-guided surgery (FGS) is an increasingly available and popular method of visual field augmentation. The basic premise of FGS entails injection of fluorescent indocyanine green (ICG) and subsequent detection with a near-infrared (NIR) camera. For pediatric surgical oncologists, FGS remains experimental but is a promising modality for identifying tumor margins, locating metastases, performing sentinel lymph node biopsies, protecting peritumoral structures of interest, and facilitating reconstruction. Familiarity with basic ICG pharmacokinetics and NIR detection optics is critical for surgeons wishing to judiciously use FGS, as its success is firmly grounded in a thorough understanding of its capabilities and limitations. In this practical guide, we outline several well-described and innovative FGS applications by disease type, including their methods of administration, modes of detection, and typical ICG dosing paradigms. LEVEL OF EVIDENCE: V.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.10.013DOI Listing
February 2021

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Int J Cancer 2021 03 31;148(5):1164-1171. Epub 2020 Aug 31.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.
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http://dx.doi.org/10.1002/ijc.33264DOI Listing
March 2021

Long-term renal function after treatment for unilateral, nonsyndromic Wilms tumor. A report from the St. Jude Lifetime Cohort Study.

Pediatr Blood Cancer 2020 10 24;67(10):e28271. Epub 2020 Jul 24.

Department of Epidemiology and Cancer Control, and Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, and the Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee.

Background: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well documented.

Methods: Among 40 WT survivors and 35 noncancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and nonnephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median -16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t tests.

Results: Twenty-six (65%) WT survivors were female, and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared with controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 mL/min/1.73 m . The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared with controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls.

Conclusions: Chronic kidney disease was infrequent in long-term survivors of unilateral nonsyndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared with controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.
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http://dx.doi.org/10.1002/pbc.28271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735383PMC
October 2020
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