Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis.

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell-specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.

Esophageal stenting in children: indications, application, effectiveness, and complications.

BACKGROUND: Use of esophageal stents is uncommon in children, and there are few reports. We report the first experience in predominantly small children and infants with retrievable, flexible stents designed for tracheobronchial use. OBJECTIVE: Evaluation of initial experience with placement of esophageal stents for benign esophageal disorders in children. DESIGN: A retrospective study. SETTING: A pediatric, academic, tertiary-referral center. PATIENTS: This study involved 7 pediatric patients. INTERVENTIONS: Covered tracheobronchial stents were endoscopically placed in pediatric patients with benign esophageal conditions. Removal involved using forceps to pull the purse-string suture into the endoscope channel and collapsing the top of the stent for easy removal. MAIN OUTCOME MEASUREMENTS: To evaluate the safety and feasibility of performing endoscopic stent placement in children and to establish criteria for early stent removal. RESULTS: Six of 7 patients benefitted from stenting. There were no complications of placement. Novel techniques were developed for difficult retrievals. One patient did not benefit from esophageal stent placement, because the stent migrated downward from the uppermost part of the esophagus. One patient had some gagging, which led to early removal of the stent. A stent was removed emergently in 1 patient for respiratory distress. LIMITATION: Small number of patients. CONCLUSIONS: Retrievable, covered stents are easily placed and removed from the esophagus in small children. They should be considered for severe unrelenting strictures, especially when associated with esophageal leaks. A need exists for development of esophageal stents designed for pediatric use.

Protocols for Paget-Schroetter syndrome and late treatment of chronic subclavian vein obstruction.

BACKGROUND: Paget-Schroetter syndrome is a serious condition that if not treated promptly and properly leads to severe sequelae and permanent disability. In its late stage, chronic fibrous obliteration of the vein is rarely amenable to surgical treatment, except in very few select cases. METHODS: We treated 126 Paget-Schroetter syndrome patients (group I) by implementing an emergency protocol of thrombolysis by catheter-directed infusion, followed by immediate surgery through an anterior subclavian approach entailing (1) decompression of the thoracic inlet and (2) repairing the vein with a vein patch to reestablish its normal caliber. In addition, we treated another selective group of 81 patients (group II) for chronic fibrotic obstruction several months after their original event, but only when the inflow was adequate. RESULTS: Our acute emergency care resulted in a 100% long-term patency rate in group I, with no sequelae. The patency rate in group II was 100% as well, but in 74% a long vein patch, endovascular stents, or homograft implants were used. CONCLUSIONS: Implementation of an emergency approach to treat Paget-Schroetter syndrome is highly recommended to prevent the delayed sequelae of permanent subclavian vein obliteration and disability. In chronic obstruction, when feasible, we recommend a long saphenous vein patch, followed by endovascular stent implant.

Paget-Schroetter syndrome treated with thrombolytics and immediate surgery.

INTRODUCTION: Reviewed are the results of the emergent treatment of effort thrombosis of the subclavian vein. The protocol calls for immediate thrombolysis, followed by surgery at the time of the acute event. The one-stage procedure includes decompression of the thoracic inlet by subclavicular removal of the first rib, subclavius muscle, scalenectomy, and vein patch plasty of the stenotic segment of the vein. METHODS: Between July 1985 through June 2006, 114 patients presented with Paget-Schroetter syndrome (effort thrombosis of the subclavian vein), 97 of which (group I) were seen < or =2 weeks of onset of symptoms. They underwent an emergent protocol treatment in which thrombolysis is immediately followed by surgery at the time of the acute event. In addition, another 17 patients (group II) were referred to our institution after being treated elsewhere with initial thrombolysis, but with surgery deferred a mean 34 days (range, 2 weeks to 3 months) after the initial event. All patients underwent the same lytic and surgical protocol. Operability was determined by the findings on the venogram. Routine postoperative anticoagulation for 8 weeks was implemented with warfarin and clopidogrel. RESULTS: There was 100% success in re-establishing the flow and normal caliber of the subclavian vein in the 97 patients in group I. Seven patients showed some residual stenosis that required balloon plasty and implant of a stent. Postoperative duplex ultrasound imaging documented patency in all 97 patients (100%). The 17 patients with delayed surgery (group II) showed progression of the fibrosis, with vein obstruction in 12 (70%). Only five patients (29%) were operable with successful results. The remaining 12 patients were inoperable owing to extensive fibrosis and occlusion of the inflow, and all 12 have remained disabled for the use of their arm. CONCLUSIONS: The emergent approach to treat Paget-Schroetter syndrome seems to render the optimal results, with 100% effectiveness in re-establishing venous flow and normal caliber to the vessel. When properly conducted, this operation avoids the use of stents or balloon plasty with excellent long-term results, leaving the patients unrestricted for physical activities.

Thymic hyperplasia in a child treated with growth hormone.

OBJECTIVE: To report a case of thymic hyperplasia diagnosed three months after initiation of recombinant human growth hormone (GH) for the treatment of GH deficiency. DESIGN: Retrospective chart review was conducted to evaluate the temporal relationship between treatment with GH and thymic enlargement in a 7-year-old girl who had a history of embryonal rhabdomyosarcoma of the nasopharynx diagnosed at the age of 3 years. RESULTS: The diagnosis of GH deficiency was made based on clinical and auxological criteria, an insufficient response to clonidine-arginine stimulation testing (peak GH level of 4.8 microg/L) and low insulin-like growth factor 1 (IGF-1) level (30 ng/mL, -2.7 SD). The patient was started on GH at a dose of 0.3mg/kg/week. At the initiation of treatment with GH, the baseline growth velocity was 0.8 cm/year (-6.0 SD) and height was 112.5 cm (-1.7 SD). After three months of treatment with GH, her height increased by 4.2 cm (from -1.7 to -1.2 SD), and the IGF-1 level from -2.7 SD to -1.1 SD. A chest CT performed at that time for recurrence surveillance showed 89% increase in thymic volume relative to previous scan before treatment with growth hormone. A thoracoscopic biopsy of the thymus was performed and revealed hyperplasia with normal thymic architecture without evidence of malignancy. CONCLUSIONS: The timing of the development of thymic hyperplasia, along with data from in vitro and in vivo animal studies showing that GH and IGF-1 can directly stimulate growth of the thymus, suggests that GH contributed to the development of thymic hyperplasia in this patient.

Occlusion of subclavian-innominate veins: the increasing problem of receiving improper care.

Acute upper vein obstruction necessitates emergency treatment and always requires surgery. However, it is not treated appropriately most of the time. Leaving this condition untreated, or treating it incorrectly, can result in permanent disability of the patient, as well as malpractice and negligence lawsuits against the treating physicians. Thus, all physicians must be familiar with the proper care of acute upper vein obstruction. We provide in this article an easy-to-follow algorithm and an outline of steps for successful treatment. We also discuss two situations that should not be confused: 1) the acute event involving the axillary-subclavian-innominate vein, which is called effort thrombosis or Paget-Schroetter syndrome, and 2) the chronic, more extensive obstruction caused by the intravenous placement of intraluminal devices.

Liver regeneration after adult living donor and deceased donor split-liver transplants.

As the number of living donor (LD) and deceased donor (DD) split-liver transplants (SLTs) have increased over the last 5 years, so too has the interest in liver regeneration after such partial-liver transplants. We looked at liver regeneration, as measured by computed tomography (CT) volumetrics, to see if there were significant differences among LDs, right-lobe LD recipients, and SLT recipients. We measured liver volume at 3 months postoperatively by using CT, and we compared the result to the patient's ideal liver volume (ILV), which was calculated using a standard equation. The study group consisted of 70 adult patients who either had donated their right lobe for LD transplants (n = 24) or had undergone a partial-liver transplant (right-lobe LD transplants, n = 24; right-lobe SLTs, n = 11; left-lobe SLTs, n = 11). DD (vs. LDs) were younger (P < 0.01), were heavier (P = 0.06), and had longer ischemic times (P < 0.01). At 3 months postoperatively, LDs had attained 78.6% of their ILV, less than the percentage for right-lobe LD recipients (103.9%; P = 0.0002), right-lobe SLT recipients (113.6%; P = 0.01), and left-lobe SLT recipients (119.7%; P = 0.0006). When liver size at the third postoperative month was compared with the liver size immediately postoperatively, LDs had a 1.85-fold increase. This was smaller than the increase seen in right-lobe LD recipients (2.08-fold), right-lobe SLT recipients (2.17-fold), and left-lobe SLT recipients (2.52-fold). In conclusion, liver regeneration, as measured by CT volume, seems to be greatest in SLT recipients. LD recipients seem to have greater liver growth than their donors. The reason for this remains unclear.

Fatal hemorrhage from androgen-related hepatic adenoma after hematopoietic cell transplantation.

Fanconi anemia is a rare genetic disorder that leads to bone marrow failure. Hematopoietic cell transplantation (HCT) is currently the only treatment option with curative potential. When a suitable HLA-matched sibling donor is not available, patients are often treated with androgenic steroids before considering HCT. Such androgen treatments can lead to the development of hepatic adenomas, which usually regress upon stopping androgen therapy. A patient with Fanconi anemia is described who underwent an unrelated umbilical cord blood transplant with a history of a hepatic adenoma related to androgen therapy. No adenomas were detected on an ultrasound examination prior to HCT. Soon after HCT, he died due to sudden rupture and hemorrhage of a hepatic adenoma. This case illustrates the need for extra vigilance in the detection and management of hepatic adenomas in patients treated with androgens, especially prior to HCT.

Using a dopamine type 1A receptor agonist in high-risk patients to ameliorate contrast-associated nephropathy.

OBJECTIVE: The objective of our study was to evaluate the effects of fenoldopam mesylate, a dopamine type 1A receptor agonist and a potent renal vasodilator that markedly increases renal blood flow, on kidney function of patients who were receiving iodinated contrast material for an interventional procedure and thought to be at high risk of contrast-associated nephropathy. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients who received fenoldopam mesylate to determine the acute and, when possible, the longer term effects on kidney function. RESULTS: Twenty-nine cases were reviewed. The average serum creatinine value before contrast administration was 2.55 mg/dL (range, 1.3-5.8 mg/dL) [corrected]. Twenty-four hours after contrast administration, serum creatinine was measured in 28 of the 29 patients. The serum creatinine values had decreased in 16 of the 28 patients by an average of 0.55 mg/dL [corrected]. In nine patients, the serum creatinine value had not changed. Two of the three increases in the serum creatinine value appear to have been caused primarily by problems that did not involve the contrast material. CONCLUSION: The use of fenoldopam mesylate at appropriate doses offers patients at high risk for contrast-associated nephropathy a chance to avoid this complication. To learn the extent and true nature of the effect of fenoldopam mesylate in this patient population requires a rigorous scientific trial, which is currently underway.