Complex filter removal using forceps from combined transfemoral and transjugular approach unhooking the filter apex using forceps and dual access: Two case reports.

Modern inferior vena cava filters (IVCFs) are intended to be retrieved once a thrombotic process or risk of pulmonary embolism has resolved independent of administration of anticoagulation. IVCF removal can be challenging with the risk of complications including venous perforation, filter migration, and device fracture. IVCF removal has been described using the nomenclature of routine versus advanced retrieval. Routine retrieval is defined as accessing the filter hook with a loop snare device before advancing a sheath over the filter. Advanced retrieval techniques are employed when routine retrieval fails and can refer to a variety of approaches, including filter realignment with loop snare, stiff wire-displacement, use of a wire and snare with dual access, angioplasty balloon advanced over a guidewire, single access sling approach, the sandwich technique, the endobronchial forceps dissection and removal, photothermic ablation with excimer laser, and the filter eversion technique among others. Successful routine retrieval of IVCF has been reported at 74% and IVCF retrieval with advanced techniques has a success rate of nearly 95%. The complication rate with advanced techniques is higher when compared with routine techniques (5.3% vs. 0.4%; p < .05) and, as expected, requires fluoroscopic time. We report two cases of advanced filter retrieval using endobronchial forceps simultaneously or sequentially through the transfemoral and trans-jugular approach.

Congenital hepatic hemangiomas: Clinical, histologic, and genetic correlation.

BACKGROUND: The guide for monitoring and treatment of congenital hepatic hemangiomas (CHH) will depend on the subtype and the postnatal clinical behavior. Our aim is to present a series of CHH and characterize its clinical, histologic and genetic correlation, compared to cutaneous congenital hemangiomas (CCH). MATERIAL AND METHODS: A retrospective review of CHH patients diagnosed between 1991 and 2018 was performed. Clinical, morphological and histological data were analyzed and deep high-throughput sequencing was performed. MAIN RESULTS: Sixteen patients with CHH were included. Five patients were followed up with serial ultrasounds while pharmacological treatment (corticosteroids and propranolol) was decided in five. Surgical resection was performed in five owing to hemorrhage and suspicion of malignancy, and the last patient underwent embolization. Histologic analysis was available in 7 patients and confirmed CHH, showing two different histological patterns that could be associated with the presence of somatic pathogenic variants in GNAQ and/or PIK3CA detected in the genetic testing. Review of 7 samples of CCH revealed some histologic differences compared to CHH. CONCLUSION: CHH resemble its cutaneous homonym with similar clinical behavior. Histologic analysis can differentiate two subgroups while genetic testing can confirm mutations in GNAQ and in PIK3CA in a subset of CHH. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV.

Verteporfin-Loaded Polymeric Microparticles for Intratumoral Treatment of Brain Cancer.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 µm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

Constitutional mosaicism in RASA1-related capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM-AVM. High-throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM-AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21.5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM-AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk and helps to explain the great phenotypic variability in CM-AVM.

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly.

Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K-AKT-mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure.

BACKGROUND: GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. METHODS: In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined. RESULTS: Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. CONCLUSION: Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer.

Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors.

Robotic Roux-en-Y Gastric Bypass, is it Safer than Laparoscopic Bypass?

BACKGROUND: Along with the development of technology, robotic approach is being performed for laparoscopic Roux-en-Y gastric bypass (LRYGB). Some literatures reported same or better peri-operative outcomes with the robotic procedure. The aim of this study is to compare our experience in robot-assisted LRYGB (RA-LRYGB) with LRYGB in terms of peri-operative outcomes. METHODS: From January 1, 2012 to April 30, 2014, a total of 270 patients underwent LRYGB by one surgeon at a single institution. Of these, 64 cases were done robotically. A retrospective review was performed for these patients, noting the outcomes and complications of the procedure. RESULTS: The 64 RA-LRYGB patients had a mean age of 45.9 ± 10.0 years (range, 23-67) and a mean preoperative body mass index (BMI) of 48.4 ± 7.9 kg/m(2) (range, 33.8-76.4). The 207 LRYGB patients had a mean age of 45.0 ± 10.7 years (range, 21-67) and a mean preoperative BMI of 48.4 ± 8.1 kg/m(2) (range, 34.0-80.4). These two groups were clinically comparable. Mean length of hospital stay was 3.0 ± 4.1 days (range, 1-19) in RA-LRYGB patients, significantly longer than 1.6 ± 1.7 days (range, 1-17) in LRYGB patients (p < 0.01). Thirty-day readmission rate was 9.3% (n = 6) in the RA-LRYGB group and 6.8% (n = 14) in the LRYGB group. Higher leak rate was noticed in RA-LRYGB patients at 7.8% (n = 5), compared to 0.5% (n = 1) in LRYGB patients (p < 0.01). All the leaks occurred at the pouch level in the RA-LRYGB group, while one leak from the LRYGB group occurred at the gastrojejunal anastomosis site. CONCLUSIONS: Robot-assisted Roux-en-Y gastric bypass may result in higher leak rate at the pouch level, when compared to that of laparoscopic procedures.

Current Management of Vascular Tumors in the Neonate.

Neonatal vascular tumours present particular difficulties in their diagnosis and treatment. The special behaviour of neonatal hemangioma and the aggressive but benign nature of kaposiform hemangioendothelioma provide examples of a modern need for a conservative approach. Recent advances in their pharmacological management have dramatically changed the therapeutical scope of this group of tumors with surgery playing a minor role in their treatment. Multidisciplinary teams management involving neonatology, pediatric surgery, dermatology, pathology, genetics and radiology specialists among others remains the best option for an optimal outcome.

Chylothorax and chylous ascites: management and pitfalls.

Leakage of lymph from the lymphatic ducts causes chylothorax (CT) or chylous ascitis (CA). This may happen for unknown reasons during fetal life or after birth and may also be caused by trauma after thoracic surgery or by other conditions. Fetal CT and CA may be lethal particularly in cases with fetal hydrops that sometimes benefit of intra-uterine instrumentation. After birth, symptoms are related to the amount of accumulated fluid. Sometimes, severe cardio-respiratory compromise prompts active therapy. Most patients with CT or CA benefit from observation, rest, and supportive measures alone. Drainage of the fluid may be necessary, but then loss of protein, fat, and lymphoid cells introduce new risks and require careful replacement. Low-fat diets with MCT and parenteral nutrition decrease fluid production while allowing adequate nutritional input. If lymph leakage does not stop, secretion inhibitors like somatostatin or octreotide are prescribed, although there is only weak evidence of their benefits. Imaging of the lymphatic system is indicated when the leaks persist, but this is technically demanding in children. Shunting of the lymph from one body space to another by means of valved catheters, embolization of the thoracic duct, and/or ligation of the major lymphatics may occasionally be indicated in cases refractory to all other treatments.

Invasive lymphatic malformation (gorham-stout) of the pelvis with prominent skin involvement.

Gorham-Stout syndrome is a rare disease characterized by progressive osteolysis leading to disappearance of the bone. Vascular proliferations have been implicated in the pathogenesis of this syndrome. The case of a 7-year-old girl with a prominent invasive lymphatic malformation on the lumbosacral area and massive osteolysis of the pelvic girdle is reported.

Osteolysis and lymphatic anomalies: a review of 54 consecutive cases.

BACKGROUND: Progressive osteolysis caused by lympathic malformations is a rare condition that should be known by specialists involved in the study of lymphatic disorders because they are necessarily involved in the treatment. The purpose of the present study is to report on a large series of patients to illustrate the multiple clinical pictures and the wide range of therapeutic measures necessary for arresting bone destruction and lymphatic leak. METHODS AND RESULTS: Inclusion criteria were osteolysis associated with lymphatic malformation that required treatment. Diagnosis was based on history, plain X-rays, MRI, and demonstration of the lymphatic nature of the lesions with D2-40 immunohistochemistry. Treatment was based on resection of the bone lytic lesion or soft tissue lymphatic masses, control of chylothorax or chyloperitoneum, interferon, zoledronic acid, and radiotherapy. The study included 54 patients (25 females and 29 males) with a median age of 9 years (range 2 to 65). Eight patients had focal osteolysis without soft tissue lymphatic anomaly, 15 multifocal osteolysis without soft tissue lymphatic anomaly, 7 focal osteolysis associated with soft tissue lymphatic anomaly, and 24 multifocal osteolysis with soft tissue lymphatic anomaly. Among the wide variety of pharmacological therapies provided, only one protocol showed a consistent positive effect (end of ostelytic progression) in 17 patients who received a course of 6 to 15 months of interferon alpha-2B at 1.5 million units/m(2) body surface area/day in association with zoledronic acid at 0.05 mg/kg/month. Thirty-two patients underwent multiple surgical procedures in order to remove the soft tissue involved, correct orthopedic problems, or improve chylothorax, and three were treated with radiotherapy which was successful in one case. CONCLUSIONS: Osteolysis from lymphatic origin is a devastating surgical condition. Therapeutic options have to be considered separately if the disease is active or inactive and according to the targeted organ (skin, bone, or viscera). Total removal of the lymphatic anomaly is rarely possible, but its subtotal excision together with pharmacological antiangiogenic therapy in selected patients under surveillance of a multidisciplinary group familiarized with the disease, minimize the progression of both, lymphatic invasion, osteolysis, and their serious complications.

Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia.

BACKGROUND: Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking. METHODS: Young adult (12-16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and muscle weights, and muscle fiber diameters were measured. Body composition was determined by Piximus. Plasma analyte levels were determined by bead array assay. RESULTS: Survival and weight loss were dependent upon burn size. The body weight nadir in burned mice was 14 days, at which time we observed reductions in total body mass, lean carcass mass, individual muscle weights, and muscle fiber cross-sectional area. Muscle loss was associated with increased expression of the muscle ubiquitin ligase, MuRF1. Burned mice also exhibited reduced fat mass and bone mineral density, concomitant with increased liver, spleen, and heart mass. Recovery of initial body weight occurred at 35 days; however, burned mice exhibited hyperphagia and polydipsia out to 80 days. Burned mice had significant increases in serum cytokine, chemokine, and acute phase proteins, consistent with findings in human burn subjects. CONCLUSIONS: This study describes a mouse model that largely mimics human pathophysiology following severe burn injury. These baseline data provide a framework for mouse-based pharmacological and genetic investigation of burn-injury-associated cachexia.

Ciliate metallothioneins: unique microbial eukaryotic heavy-metal-binder molecules.

This article represents an updated review of ciliate metallothioneins (Tetrahymena species) including a comparative analysis with regard to well-known metallothioneins (MTs) from other organisms and discussion of their exclusive features. It opens with an introduction to ciliates, summarizing the main characteristics of these eukaryotic microorganisms and their use as cellular models to study metallothioneins and metal-eukaryotic cell interactions. It has been experimentally proved that at least three different metal resistance mechanisms exist in ciliates, of which bioaccumulation is the most studied. Structural comparative analysis reveals that Tetrahymena MTs have unique characteristics, such as longer length, a considerably higher cysteine content, different metal-MT stoichiometry values, the presence of new cysteine clusters, and a strictly conserved modular-submodular structure. Gene expression analysis reveals a multistress and differential response to diverse metals and other environmental stressors, which corroborates the classification of these MTs. An in silico analysis of the promoter sequences of some MT genes reveals the presence of conserved motifs that are probably involved in gene expression regulation. We also discuss the great advantages of the first ciliate whole-cell biosensors based on MT promoters from Tetrahymena thermophila to detect heavy metal ions in environmental samples.

Macrocephaly-capillary malformation: Analysis of 13 patients and review of the diagnostic criteria.

Macrocephaly-capillary malformation (M-CM) is a genetic syndrome of unknown etiology characterized by an enlarged head circumference and patchy, reticular capillary malformation. We describe the clinical features of 13 cases, report on the genome-wide Copy Number Variation characterization of these patients, analyze the main clinical features of this syndrome and propose a modification of the current diagnostic criteria: the inclusion of both overgrowth/asymmetry and neuroimaging alterations as major criteria.

Does Children's Oncology Group hospital membership improve survival for patients with neuroblastoma or Wilms tumor?

PURPOSE: To determine prognostic significance of hospital surgical volume and Children's Oncology Group (COG) membership on neuroblastoma (NBL) and Wilms tumor (WT) survival. METHODS: The Florida Cancer Data System was queried from 1981 to 2004. RESULTS: Of 869 NBL patients, 463 were treated at COG/HVC, 246 at COG/LVC, and 160 at non-COG/LVC. COG hospitals treated a larger proportion of patients <1 year of age (P = 0.002) and relatively more patients with adrenal and mediastinal tumors (P = 0.005). COG centers more frequently administered chemotherapy (72% vs. 51%, P < 0.001). Five- and 10-year survival rates were higher at COG/HVC (70.6%, 67.7%) and COG/LVC (75.8%, 72.6%) than non-COG/LVC (59.5%, 54.4%, P < 0.05). Of 790 WT patients, 395 were treated at COG/HVC, 210 at COG/LVC, and 185 at non-COG/LVC. COG hospitals treated younger patients and lower staged tumors (P < 0.05). COG centers more frequently administered chemotherapy (88% vs. 59%, P < 0.001). Five- and 10-year survival rates were higher at COG/HVC (91.3%, 89.9%) and COG/LVC (96.7%, 94.7%) than non-COG/LVC (82.4%, 81.7%, P < 0.05). Multivariate analysis demonstrated WT patients treated at non-COG hospitals, but not NBL patients, had worse survival (HR 3.107, P = 0.01). CONCLUSION: Children treated at COG hospitals had higher overall use of chemotherapy. This translated into a significantly improved survival benefit for WT.

Loss of GDF-15 abolishes sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer.

BACKGROUND: Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti-tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer. METHODS: GDF-15 null (Gdf15 (-/-)) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc ( min/+ ) were bred. Gdf15 ( -/- ), Apc ( min/+ ) and Gdf15 ( +/+ ), Apc ( min/+ ) mice were generated. RESULTS: In Gdf15 ( -/- ), Apc ( min/+ ) mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15 ( +/+ ), Apc ( min/+ ) mice. Sulindac chemoprotection activity although potent in Gdf15 ( +/+ ), Apc ( min/+ ) mice was abolished in Gdf15 ( -/- ), Apc ( min/+ ) mice. CONCLUSIONS: These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer.

Major and minor arterial malformations in patients with cutaneous vascular abnormalities.

The association of persistent embryonic arteries and the absence of 1 carotid or vertebral arteries with facial or neck hemangioma or vascular malformation have been frequently described. The abnormalities can involve major or minor vessels. Of 22 patients of our series with this neurocutaneous syndrome, 20 had the origin of both anterior cerebral arteries from the same internal carotid artery. Thirteen patients showed absence or hypoplasia of 1 carotid artery and 10 of 1 vertebral artery; 10 showed persistence of the trigeminal artery; 3 had persistent proatlantal artery; 6 showed the absence of the posterior communicating artery; and 4 had hypoplastic posterior cerebral artery. Other less frequent abnormalities were found in 7 patients. Intellectual level of most patients was either borderline or below normal. Abnormalities in the vascularization and perfusion of the frontal lobes may contribute to the borderline or lower mental level of these patients.