Institutional Management of Abdominal Lymphatic Malformations: Evolution of Treatment Over a Decade.

INTRODUCTION: Abdominal lymphatic malformations (LM) have been historically managed with surgical resection; however, sclerotherapy and sirolimus have emerged as effective therapies. The purpose of our study is to evaluate our institutional change in management and outcomes for abdominal LM over the past decade. METHODS: A retrospective cohort study was performed for all children with an abdominal LM managed at our multidisciplinary Vascular Anomalies Center from 2011 to 2020. Patient demographics, symptoms, treatment, treatment response, and complications were analyzed with descriptive statistics. RESULTS: Twenty-nine patients with abdominal LM were identified with a median age at treatment of 6 y (interquartile range 3-14). A majority of lesions were identified as macrocystic (n = 18, 62%). The most common intervention was surgery alone (n = 14, 48%) followed by sirolimus alone (n = 4, 14%), and sclerotherapy + sirolimus (n = 4, 14%). Five patients were observed due to lack of symptoms at presentation. Prior to 2017, 91% (10/11) of LM were treated with surgery alone. Following 2017, only 31% (4/13) were treated with surgery alone. Sixty-seven percent (16/24) of treated patients had >95% reduction in LM maximum diameter. A majority of patients (23/24) who received treatment had improvement or resolution of symptoms at median 9-mo follow-up. Only three patients had post-treatment complications, including a drain site infection, small bowel obstruction, and an aspiration event. Complications only occurred after sclerotherapy sessions. CONCLUSIONS: Over the study period, our institution has transitioned to initial management of symptomatic abdominal LM with sclerotherapy and/or sirolimus with almost all treated patients having excellent or satisfactory treatment response. Post-treatment complications were rare.

Sirolimus efficacy in the treatment of critically ill infants with congenital primary chylous effusions.

BACKGROUND: Chylothorax can be a presenting symptom of complex lymphatic anomaly in children and is associated with significant respiratory morbidity. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus; however, data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in infantile primary chylous effusions warrants further investigation. METHODS: In this retrospective study at Texas Children's Hospital, data were extracted for all infants with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, comorbidities, and number of days from sirolimus initiation to resolution of effusion were collected. RESULTS: Initially a total of 12 infants were identified. Among them, seven patients had complete data and were included in the study. Reasons for chylous effusions include presumed complex lymphatic anomaly, generalized lymphatic anomaly, and complex congenital lymphatic anomaly. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7-22 days. No patients had progression of effusions while on sirolimus. CONCLUSION: With close monitoring, sirolimus appears to be an effective therapy for pediatric lymphatic effusions even in critically ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Larger multi-institutional studies are needed to further support our findings.

Secretory Carcinoma of the Salivary Gland: A Rarity in Children.

Originally described as mammary analog secretory carcinoma (SC), SC of the salivary gland is a rare malignancy with morphologic and molecular similarities to SC of the breast. We present 2 children with salivary gland SC with the classic ETV6-NTRK3 gene fusion, including 1 with lymph node metastases. Both patients underwent surgical resection and were in remission 24 months postsurgery. One patient was additionally found to have synchronous papillary thyroid carcinoma with a TFG-MET fusion. A review of published cases highlights the expanding molecular profile and confirms the favorable course of salivary gland SC after surgical resection.

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children.

Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.

An evidence-based, risk-adapted algorithm for antifungal prophylaxis reduces risk for invasive mold infections in children with hematologic malignancies.

BACKGROUND: Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of antifungal prophylaxis with antimold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence-based recommendations are lacking. PROCEDURE: We conducted a 15-year, single-institution retrospective review in a diverse cohort of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020. Multivariable logistic regression was used to identify host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence-based, risk-adapted antifungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI. RESULTS: We identified 61 cases of proven or probable IMI in 1456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an antifungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. Both Hispanic ethnicity and cancer diagnosis prior to 2016 were associated with risk for IMI. CONCLUSION: An evidence-based, risk-adapted approach to antifungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma.

BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. METHODS: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. RESULTS: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. CONCLUSIONS: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.

Sclerosing Encapsulating Peritonitis in a Pediatric Patient Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Sclerosing encapsulating peritonitis (SEP) is a rare chronic inflammatory condition characterized by small bowel encapsulation by a thick fibrocollagenous membrane. Patients with SEP often present with nonspecific symptoms, such as abdominal pain and distension, however some patients may present with symptoms suggestive of intestinal obstruction. Secondary SEP has been reported in patients undergoing peritoneal dialysis and has been recently described in adults following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). OBSERVATIONS: We report a clinical case of a 13-year-old female who presented with worsening abdominal pain and distension and persistent emesis who was found to have SEP 13 months following CRS and HIPEC for management of desmoplastic small round cell tumor and subsequently required operative intervention. CONCLUSION: Although there have been published reports of adult patients experiencing cases of SEP following CRS/HIPEC, this is the first published case of secondary SEP occurring in a pediatric oncology patient.

Clinical variability in multifocal lymphangioendotheliomatosis with thrombocytopenia: a review of the literature.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently recognized disorder characterized by vascular lesions marked by distinct endothelial proliferation. Lesions affect multiple tissues, and MLT can be associated with refractory thrombocytopenia resulting in life-threatening bleeding. Diagnosing MLT may be challenging given its rarity and phenotypic variability. There is no consensus on the optimal management or treatment duration. We report a 4-month-old male who presented with multiple vascular malformations involving the gastrointestinal tract, lung, bones, choroid plexus, and spleen, with minimal cutaneous involvement and no thrombocytopenia. Wedge resection of a pulmonary nodule was strongly positive for lymphatic vessel endothelial hyaluronan receptor 1 favoring MLT despite the lack of thrombocytopenia. The patient's clinical symptoms and vascular lesions improved on sirolimus therapy. We review the literature to highlight the clinical variability of MLT and discuss the diagnostic and therapeutic options for MLT.

Contemporary management of ovarian germ cell tumors and remaining controversies.

Ovarian germ cell tumors (GCTs) are rare in adults, but are more common in adolescents and young adults. Contemporary management of ovarian GCTs is evolving as collaboration among pediatric, medical, and gynecologic oncologists increases, and studies increasingly incorporate female adult patients. Despite an improved understanding of ovarian GCT, many questions remain. Areas of continued controversy include which stage I ovarian GCTs and immature teratomas can be observed without adjuvant therapy, appropriate risk classification for ovarian GCT, surveillance strategies, and optimal therapy for recurrence. These topics as well as active areas of clinical investigation are discussed.

Management of pediatric differentiated thyroid cancer: An overview for the pediatric oncologist.

Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.

Mediastinal Germ Cell Tumor and Acute Megakaryoblastic Leukemia With Co-occurring KRAS Mutation and Complex Cytogenetics.

Young males have a unique but rare predilection to develop mediastinal nonseminomatous germ cell tumors (NSGCTs) and concomitant acute megakaryoblastic leukemia (AMKL). Common cytogenetic and molecular abnormalities such as isochromosome 12p and somatic Tumor Protein P53(TP53) and Phosphatase And Tensin Homolog (PTEN) mutations have been reported in the presumed mutual neoplastic clones of origin. We report the case of a 17-year-old male who presented with a mediastinal NSGCT with high-grade sarcomatous transformation and a diagnosis of AMKL approximately 4 months later. Next-generation sequencing revealed identical KRAS Proto-Oncogene, GTPase (KRAS) p.Ala146Thr, TP53 p.Leu257Pro, and PTEN p.Leu181Pro missense mutations at similar variant allele frequencies in both the NSGCT and AMKL samples. Cytogenetic and microarray analyses detected shared copy gains in all chromosomes except chromosomes 9, 13, and Y. Multiple additional clonal chromosomal alterations were detected in the AMKL sample when compared with the NSGCT. This case emphasizes the shared clonal origins of these malignancies and identifies KRAS and other copy number alterations as potential molecular drivers in a subset of these combined diseases.

Combining ligand- and structure-based in silico methods for the identification of natural product-based inhibitors of Akt1.

The traditional method of drug discovery process has been surpassed by a rational approach where computer-aided drug designing plays a vital role in the identification of leads from large compound databases. Further, natural products have an important role in drug discovery as these have been the source of most active ingredients of medicines. Herein, in silico structure- and ligand-based approaches have been applied to screen in-house IIIM natural product repository for Akt1 (serine/threonine protein kinases) which is a well-known therapeutic target for cancer due to its overexpression and preventing the cells from undergoing apoptosis. Combined ligand-based and structure-based strategies were applied on to the existing library comprising of about 700 pure natural products, and the compounds identified from screening were biologically evaluated for Akt1 inhibition using Akt1 kinase activity assay. Fourteen promising compounds showed significant inhibition at 500 nM through in vitro screening, and from them, eight were new for Akt1 inhibition. Through the MD studies of Akt1 with the most active compound IN00145, it was inferred that Lys179, Glu191, Glu228, Ala230, Glu234 and Asp292 are the important amino acid residues which provide stability to the Akt1-IN00145 complex. Lead optimization studies were also performed around the actives to design better and selective inhibitors for Akt1. The results emphasized the successful application of virtual screening to identify new Akt1 inhibitor scaffolds that can be developed into a drug candidate in drug discovery programme.

Design, synthesis and biological evaluation of pyrazolopyrimidinone based potent and selective PDE5 inhibitors for treatment of erectile dysfunction.

Our previous discovery of series of pyrazolopyrimidinone based PDE5 inhibitors led to find potent leads but with low aqueous solubility and poor bioavailability, and low selectivity. Now, a new series of same pyrazolopyrimidinone scaffold is designed, synthesized and evaluated for its PDE5 inhibitory potential. In this study, some of the molecules are found more potent and selective PDE5 inhibitors in vitro than sildenafil. The studies revealed that compound 5 is 20 fold selective to PDE5 against PDE6. As PDE6 enzyme is involved in the phototransduction pathway in the retina and creates distortion problem, the selectivity for PDE5 specifically against PDE6 enzyme is preferred for any development candidate and in present study, compound 5 has been found to be devoid of this liability of selectivity issue. Moreover, compound 5 has shown excellent in vivo efficacy in conscious rabbit model, it's almost comparable to sildenafil. The preclinical pharmacology including pharmacokinetic and physicochemical parameter studies were also performed for compound 5, it was found to have good PK properties and other physicochemical parameters. The development of these selective PDE5 inhibitors can further lead to draw strategies for the novel preclinical and/or clinical candidates based on pyrazolopyrimidinone scaffold.

Design and synthesis of 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones by Huisgen 1,3-dipolar cycloaddition with PI3Kγ isoform selective activity.

A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ. This repositioning of scaffold from PI3Kδ to PI3Kγ isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways.

Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors.

Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication. Thus, to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X-ray crystal structures and known inhibitors of CDK2 provides a gateway to perform efficient computational studies on this target. With the aim to identify new chemical entities from commercial libraries, with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A druglike library of 50,000 compounds from ChemDiv and ChemBridge databases was screened against CDK2, and 110 compounds were identified using the parallel application of these models. On in vitro evaluation of 40 compounds, seven compounds were found to have more than 50% inhibition at 10 µM. MD studies of the hits revealed the stability of these inhibitors and pivotal role of Glu81 and Leu83 for binding with CDK2. The overall study resulted in the identification of four new chemical entities possessing CDK2 inhibitory activity.

Myofibroma in Infancy and Childhood.

Myofibromas are rare fibroblastic-myofibroblastic tumors in children. Their biological behavior is unpredictable and spontaneous regressions have been described. This is a retrospective review of clinical characteristics, treatment, and outcome of children diagnosed with myofibroma between 1999 and 2013 at Texas Children's Hospital. The median age at diagnosis of 42 patients was 37 months. Approximately two thirds of the patients were male. The median length of follow-up was 50.5 months (range, 0 to 165 mo). Thirty-eight patients (90%) had solitary lesions; 19 (50%) in the head and neck, 10 (26%) in the limbs, and 9 (24%) in the trunk. Twelve patients underwent a complete surgical resection. Of the 30 patients with positive margins, only 1 had tumor progression. Two patients had multicentric involvement, and 2 patients had generalized disease with visceral involvement. One patient with generalized disease and a progressive maxillary sinus mass was treated with vinblastine and methotrexate chemotherapy followed by complete surgical resection. All patients were alive at last follow-up. Myofibromas of childhood demonstrate clinical variability, and may spontaneously regress. Positive surgical margins do not adversely affect outcome. The rare patient with progressive unresectable disease may benefit from chemotherapy.

4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines as inhibitors of mammalian target of rapamycin.

A series of 4-(N-phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines was designed, synthesized and evaluated for their biological potential as anticancer agents by screening the molecules against panel of five human cancer cell lines viz. HL-60, MiaPaCa-2, HCT116, PC-3 and HEP-G2. The series has shown good mTOR inhibitory activity at 0.5 µM concentration. The representative compound 7h was found to be most active with the IC50 of 613 nM against mTOR. In supportive evidence, the western blotting experiment revealed that compound 7h is more potent in inhibiting p-mTOR (S2448) activity in 2-4h at 5 and 10 µM concentrations and was selective and specific towards mTORC1 versus mTORC2. Towards understanding the mechanistic aspects we studied cell cycle analysis, mitochondrial membrane potential loss in MiaPaca-2 cells for compound 7h. The docking study for this series was performed to understand the binding mode of the compounds and its consequent effect in biological activity, the initial interaction studies were found to be useful in design of molecules, where compound 7h has shown additional H-bond interaction with Lys2171 apart from Val2240 and also a small hydrophobic cleft was observed with Leu2185, Met2345 and Ile2356.

Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.

Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC50 value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.