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Surgery is a crucial component of pediatric cancer treatment, but conventional methods may lack precision. Image-guided surgery, including fluorescent and radioguided techniques, offers promise for enhancing tumor localization and facilitating precise resection. Intraoperative molecular imaging utilizes agents like indocyanine green to direct surgeons to occult deposits of tumor and to delineate tumor margins. Next-generation agents target tumors directly to improve specificity. Radioguided surgery, employing tracers like metaiodobenzylguanidine (MIBG), complements fluorescent techniques by allowing for detection of tumors at a greater depth. Dual-labeled agents combining both modalities are under development. Three-dimensional modeling and virtual/augmented reality aid in preoperative planning and intraoperative guidance. The above techniques show great promise to benefit patients with pediatric tumors, and their continued development will almost certainly improve surgical outcomes.

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BACKGROUND AND OBJECTIVES: In the field of surgical oncology, there has been a desire for innovative techniques to improve tumor visualization, resection, and patient outcomes. Augmented reality (AR) technology superimposes digital content onto the real-world environment, enhancing the user's experience by blending digital and physical elements. A thorough examination of AR technology in surgical oncology has yet to be performed. METHODS: A scoping review of intraoperative AR in surgical oncology was conducted according to the guidelines and recommendations of The Preferred Reporting Items for Systematic Review and Meta-analyzes Extension for Scoping Reviews (PRISMA-ScR) framework. All original articles examining the use of intraoperative AR during surgical management of cancer were included. Exclusion criteria included virtual reality applications only, preoperative use only, fluorescence, AR not specific to surgical oncology, and study design (reviews, commentaries, abstracts). RESULTS: A total of 2735 articles were identified of which 83 were included. Most studies (52) were performed on animals or phantom models, while the remaining included patients. A total of 1112 intraoperative AR surgical cases were performed across the studies. The most common anatomic site was brain (20 articles), followed by liver (16), renal (9), and head and neck (8). AR was most often used for intraoperative navigation or anatomic visualization of tumors or critical structures but was also used to identify osteotomy or craniotomy planes. CONCLUSIONS: AR technology has been applied across the field of surgical oncology to aid in localization and resection of tumors.

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Synoptic operative notes for pediatric surgical oncology provide standardized and structured documentation of surgical procedures performed on pediatric patients with cancer. These reports capture essential details such as preoperative diagnosis, intraoperative findings, surgical technique, and tumor characteristics in a concise and uniform format. By promoting consistency, accuracy, and completeness in reporting, synoptic operative notes facilitate effective communication among multidisciplinary healthcare teams, enhance quality assurance efforts, and streamline data extraction for research purposes. The integration of synoptic reporting within electronic medical record systems further enhances accessibility and usability, ensuring efficient documentation practices and improved patient care outcomes in pediatric surgical oncology.

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Chronic pancreatitis is a debilitating disease affecting millions worldwide. These patients suffer from bouts of severe pain that are minimally relieved by pain medications and may necessitate major surgeries with high morbidity and mortality. Previously, we demonstrated that "chemical pancreatectomy," a pancreatic intraductal infusion of dilute acetic acid solution, ablated the exocrine pancreas while preserving the endocrine pancreas. Notably, chemical pancreatectomy resolved chronic inflammation, alleviated allodynia in the cerulein pancreatitis model, and improved glucose homeostasis. Herein, we extensively tested the feasibility of a chemical pancreatectomy in NHPs and validated our previously published pilot study. We did serial computed tomography (CT) scans of the abdomen and pelvis, analyzed dorsal root ganglia, measured serum enzymes, and performed histological and ultrastructural assessments and pancreatic endocrine function assays. Based on serial CT scans, chemical pancreatectomy led to the loss of pancreatic volume. Immunohistochemistry and transmission electron microscopy demonstrated exocrine pancreatic ablation with endocrine islet preservation. Importantly, chemical pancreatectomy did not increase pro-nociceptive markers in harvested dorsal root ganglia. Also, chemical pancreatectomy improved insulin secretion to supranormal levels in vivo and in vitro. Thus, this study may provide a foundation for translating this procedure to patients with chronic pancreatitis or other conditions requiring a pancreatectomy.

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Currently, guidelines recommend ticagrelor over clopidogrel as part of dual antiplatelet therapy with aspirin in treating individuals with acute coronary syndrome. As there is an increased usage of ticagrelor, it is important to keep in mind uncommon adverse events, including hypersensitivity skin reactions. To date, only a few studies have been published regarding ticagrelor-induced skin eruptions. Additionally, there is no consensus on antiplatelet therapy management after a hypersensitivity reaction to antiplatelet agents. Hereinafter, we describe a case of an 81-year-old female who presents with a diffuse erythematous hypersensitivity eruption, including palms and soles, secondary to ticagrelor use. Ticagrelor transitioned to clopidogrel, and the patient was started on steroid taper with an antihistamine. The patient's rash progressively improved after the treatment. Our case demonstrates a rare adverse effect of ticagrelor, which needs prompt diagnosis and switching to one of the thienopyridines to prevent thrombosis.

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Pediatric surgeons have been pursuing high quality, affordable care or value-based care for over 50 years. One approach to streamlining the clinical care for a complex problem was the development of a center of excellence (COE). The concept of COE focuses on a shared vision of providing high quality care through a multidisciplinary approach. The goal is to improve diagnostic accuracy as well as therapeutic outcomes using focused expertise within a group. COEs are often resource intensive before becoming fiscally viable and therefore require initial support from hospital leadership. This review discusses the key steps to consider before building a COE, strategies to help build one, and how to keep one successful as defined by quality, accessibility, equity, training, and maintaining teams within the group.

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Chronic pancreatitis is a debilitating disease affecting millions worldwide. These patients suffer from bouts of severe pain that are minimally relieved by pain medications and may necessitate major surgeries with high morbidity and mortality. Previously, we demonstrated that "chemical pancreatectomy," a pancreatic intraductal infusion of dilute acetic acid solution, ablated the exocrine pancreas while preserving the endocrine pancreas. Notably, chemical pancreatectomy resolved chronic inflammation, alleviated allodynia in the cerulein pancreatitis model, and improved glucose homeostasis. Herein, we extensively tested the feasibility of a chemical pancreatectomy in NHPs and validated our previously published pilot study. We did serial computed tomography (CT) scans of the abdomen and pelvis, analyzed dorsal root ganglia, measured serum enzymes, and performed histological and ultrastructural assessments and pancreatic endocrine function assays.  Based on serial CT scans, chemical pancreatectomy led to the loss of pancreatic volume. Immunohistochemistry and transmission electron microscopy demonstrated exocrine pancreatic ablation with endocrine islet preservation. Importantly, chemical pancreatectomy did not increase pro-nociceptive markers in harvested dorsal root ganglia. Also, chemical pancreatectomy improved insulin secretion to supranormal levels in vivo and in vitro. Thus, this study may provide a foundation for translating this procedure to patients with chronic pancreatitis or other conditions requiring a pancreatectomy.

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The pancreas is a bifunctional organ with both endocrine and exocrine components. A number of pathologies can afflict the pancreas, including diabetes, pancreatitis, and pancreatic cancer. All three of these diseases mark active areas of study, not only to develop immediate therapy, but also to better understand their pathophysiology. There are few tools to further these areas of study. Pancreatic duct infusion is an important technique that can allow for lineage tracing, gene introduction, and cell line-specific targeting. The technique requires the intricate dissection of the second portion of the duodenum and ampulla, followed by the occlusion of the bile duct and the cannulation of the pancreatic duct. Although the technique is technically challenging at first, the applications are myriad. Ambiguity in the specifics of the procedure between groups highlighted the need for a standard protocol. This work describes the expression of a green fluorescent protein (GFP) within the pancreas after the pancreatic duct infusion of a viral vector expressing GFP versus a sham surgery. The infusion and therefore expression is specific to the pancreas, without expression present in any other tissue type.

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Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%-2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid-treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.

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BACKGROUND/AIMS: Infectious and genetic factors are invoked, respectively in isolated biliary atresia (BA), or syndromic BA, with major extrahepatic anomalies. However, isolated BA is also associated with minor extrahepatic gut and cardiovascular anomalies and multiple susceptibility genes, suggesting common origins. METHODS: We investigated novel susceptibility genes with genome-wide association, targeted sequencing and tissue staining in BA requiring liver transplantation, independent of BA subtype. Candidate gene effects on morphogenesis, developmental pathways, and ciliogenesis, which regulates left-right patterning were investigated with zebrafish knockdown and mouse knockout models, mouse airway cell cultures, and liver transcriptome analysis. RESULTS: Single nucleotide polymorphisms in Mannosidase-1-α-2 (MAN1A2) were significantly associated with BA and with other polymorphisms known to affect MAN1A2 expression but were not differentially enriched in either BA subtype. In zebrafish embryos, man1a2 knockdown caused poor biliary network formation, ciliary dysgenesis in Kupffer's vesicle, cardiac and liver heterotaxy, and dysregulated egfra and other developmental genes. Suboptimal man1a2 knockdown synergized with suboptimal EGFR signaling or suboptimal knockdown of the EGFR pathway gene, adenosine-ribosylation-factor-6, which had minimal effects individually, to reproduce biliary defects but not heterotaxy. In cultured mouse airway epithelium, Man1a2 knockdown arrested ciliary development and motility. Man1a2 -/- mice, which experience respiratory failure, also demonstrated portal and bile ductular inflammation. Human BA liver and Man1a2 -/- liver exhibited reduced Man1a2 expression and dysregulated ciliary genes, known to cause multisystem human laterality defects. CONCLUSION: BA requiring transplantation associates with sequence variants in MAN1A2. man1a2 regulates laterality, in addition to hepatobiliary morphogenesis, by regulating ciliogenesis in zebrafish and mice, providing a novel developmental basis for multisystem defects in BA.

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Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin+ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

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Autophagy is a major regulator of pancreatic beta cell homeostasis. Altered autophagic activity has been implicated in the beta cells of patients with type 2 diabetes, and in the beta cells of obese diabetic rodents. Here, we show that autophagy was induced in beta cells by either a high-fat diet or a combined high-fat and high-glucose diet, but not by high-glucose alone. However, a high-glucose intake alone did increase beta cell mass and insulin secretion moderately. Depletion of Atg7, a necessary component of the autophagy pathway, in beta cells by pancreatic intra-ductal AAV8-shAtg7 infusion in C57BL/6 mice, resulted in decreased beta cell mass, impaired glucose tolerance, defective insulin secretion, and increased apoptosis when a combined high-fat and high-glucose diet was given, seemingly due to suppression of autophagy. Taken together, our findings suggest that the autophagy pathway may act as a protective mechanism in pancreatic beta cells during a high-calorie diet.

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INTRODUCTION: Transanastomatic feeding tube (TAT) use in the repair of tracheoesophageal fistulas (TEF) with or without esophageal atresia (EA) and EA with or without TEF allows for earlier enteral feedings, however, may predispose to esophageal stricture. METHODS: We review our institutional experience with esophageal atresia repair over a 15-year period from 2000 to 2015 and report on our observed complication rate with emphasis on the surgical approach and use of TATs. RESULTS: We identified 110 TEF repairs. Ninety-six were Type C, 7 were Type A, 4 were Type D, and 3 were Type E (H-Type). TATs were used in 74% of patients. The stricture rate with the TAT approached 56% versus 17% without a TAT (p<0.0005). There was no difference in leak rate (p=0.27). Ninety-four TEF repairs were performed via open thoracotomy, and 16 were initially approached thoracoscopically. Six out of 16 that were started thoracoscopically were completed with the minimally invasive approach. Whether the case was started thoracoscopically, completed thoracoscopically, or performed open made no difference in the rate of stricture or anastomotic leak, but we did observe an increase in musculoskeletal complications in the open thoracotomy group (28% vs. 0). CONCLUSION: Our data suggests that the use of TATs does not protect against anastomotic leak, but may increase stricture rate. Further, the thoracoscopic group showed no difference in the leak or stricture rate and demonstrated less musculoskeletal complications. Confirmation of these findings will require a prospective study. LEVEL OF EVIDENCE: III.

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BACKGROUND: Lymphatic mapping to guide sentinel lymph node biopsy (SLNB) typically requires lymphoscintigraphy prior to surgery. In young pediatric patients, this process often requires intubation in the nuclear medicine suite followed by transport to the operating room (OR). METHODS: We reviewed 14 pediatric cases in which a portable nuclear imaging camera was utilized to perform the entirety of the SLNB in the OR. RESULTS AND CONCLUSION: This method, utilizing intraoperative nuclear imaging, helped to confirm removal of the sentinel lymph node in real time, decreased anesthesia time, and avoided transport of a sedated or intubated child. LEVEL OF EVIDENCE: III.

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AIMS/HYPOTHESIS: The Cre/loxP system, which enables tissue-specific manipulation of genes, is widely used in mice for diabetes research. Our aim was to develop a new Cre-driver mouse line for the specific and efficient manipulation of genes in pancreatic alpha cells. METHODS: A Gcg CreERT2 knockin mouse, which expresses a tamoxifen-inducible form of Cre from the endogenous preproglucagon (Gcg) gene locus, was generated by homologous recombination. The new Gcg CreERT2 mouse line was crossed to the Rosa26 tdTomato (R26 tdTomato ) Cre reporter mouse line in order to evaluate the tissue specificity, efficiency and tamoxifen dependency of Gcg CreERT2 -mediated recombination. Cell types of pancreatic islets were identified using immunohistochemistry. Biochemical and physiological data, including blood glucose levels, plasma glucagon and glucagon-like peptide (GLP)-1 levels, and pancreatic glucagon content, were collected and used to assess the overall effect of Gcg gene targeting on Gcg CreERT2/w heterozygous mice. RESULTS: Tamoxifen-treated Gcg CreERT2/w ;R26 tdTomato/w mice displayed Cre reporter activity, i.e. expression of tdTomato red fluorescent protein (RFP) in all known cells that produce proglucagon-derived peptides. In the adult pancreas, RFP was detected in 94-97% of alpha cells, whereas it was detected in a negligible (~ 0.2%) proportion of beta cells. While more than 98% of cells labelled with tamoxifen-induced RFP were glucagon-positive cells, 14-25% of pancreatic polypeptide (PP)-positive cells were also positive for RFP, indicating the presence of glucagon/PP bihormonal cell population. Tamoxifen-independent expression of RFP occurred in approximately 6% of alpha cells. In contrast to alpha cells and GLP-1-producing neurons, in which RFP expression persisted for at least 5 months after tamoxifen administration (presumably due to rare neogenesis in these cell types in adulthood), nearly half of RFP-positive intestinal L cells were replaced with RFP-negative L cells over the first 2 weeks after tamoxifen administration. Heterozygous Gcg CreERT2/w mice showed reduced Gcg mRNA levels in islets, but maintained normal levels of pancreatic and plasma glucagon. The mice did not exhibit any detectable baseline physiological abnormalities, at least in young adulthood. CONCLUSIONS/INTERPRETATION: The newly developed Gcg CreERT2 knockin mouse shows faithful expression of CreERT2 in pancreatic alpha cells, intestinal L cells and GLP-1-producing neurons. This mouse line will be particularly useful for manipulating genes in alpha cells, due to highly specific and efficient CreERT2-mediated recombination in this cell type in the pancreas.

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Exendin-4 is a long acting glucagon-like peptide 1 (GLP-1) analogue that is an agonist for the GLP-1 receptor, a G-protein coupled receptor (GPCR). Exendin-4 is used to clinically improve glucose tolerance in diabetic patients due to its ability to enhance insulin secretion. In rodents, and possibly in humans, exendin-4 can stimulate ß-cell proliferation. The exact mechanism of action to induce ß-cell proliferation is not well understood. Here, using a ß-cell specific epidermal growth factor receptor (EGFR) null mouse, we show that exendin-4 induced an increase in proliferation and ß-cell mass through EGFR. Thus, our study sheds light on the role of EGFR signaling in the effects of exendin-4 on the control of blood glucose metabolism and ß-cell mass.

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Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis-related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant ß-cell dedifferentiation, followed by a time-dependent decrease in functional ß-cell mass-all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor ß1 (TGFß1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of ß-cell mass was then found to result from TGFß1-triggered epithelial-mesenchymal transition (EMT) by ß-cells, rather than resulting directly from ß-cell apoptosis. Mechanistically, TGFß1-treated ß-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in ß-cells ameliorated ß-cell EMT and ß-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFß1-mediated ß-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in ß-cells.

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The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in ß cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated ß cell dysfunction and loss of proliferation capacity, two features of ß cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in ß cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in ß cells prevented ß cell dysfunction and loss in this model. Thus, we present a model of accelerated ß cell aging that may be useful for studying the mechanisms underlying ß cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining ß cell identity in the context of SMAD7 failure.

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A thorough understanding of the signaling pathways involved in the regulation of ß cell proliferation is an important initial step in restoring ß cell mass in the diabetic patient. Here, we show that epidermal growth factor receptor 1 (EGFR) was significantly up-regulated in the islets of C57BL/6 mice after 50% partial pancreatectomy (PPx), a model for workload-induced ß cell proliferation. Specific deletion of EGFR in the ß cells of adult mice impaired ß cell proliferation at baseline and after 50% PPx, suggesting that the EGFR signaling pathway plays an essential role in adult ß cell proliferation. Further analyses showed that ß cell-specific depletion of EGFR resulted in impaired expression of cyclin D1 and impaired suppression of p27 after PPx, both of which enhance ß cell proliferation. These data highlight the importance of EGFR signaling and its downstream signaling cascade in postnatal ß cell growth.

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