Jonathan E. Wickiser

Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours

Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5′-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours.

A comparison of pediatric, adolescent, and adult testicular germ cell malignancy.

Testicular germ cell tumors (T‐GCTs) occur from infancy to adulthood, and are the most common solid tumor in adolescent and young adult males. Traditionally, pediatric T‐GCTs were perceived as more indolent than adult T‐GCTs. However, there are few studies comparing these groups and none that specifically evaluate adolescents.

Oncologic outcomes of partial versus radical nephrectomy for unilateral Wilms tumor.

Radical nephrectomy (RN) is the recommended surgical management as part of multi‐modality therapy for unilateral Wilms tumor (UWT). Based on recent data demonstrating that renal preserving surgery decreases the likelihood of chronic renal disease and associated co‐morbidities, we analyzed oncologic outcomes of patients after partial nephrectomy (PN) for UWT.

Robot-assisted laparoscopic retroperitoneal lymph node dissection in an adolescent population.

Abstract Laparoscopic retroperitoneal lymph node dissection (RPLND) has been shown to be safe and effective in appropriately selected pediatric and adolescent patients with paratesticular rhabdomyosarcoma (RMS) and testicular germ-cell tumors (T-GCT). While the use of robot-assisted laparoscopy has expanded rapidly in many areas, there are very limited reports of its use with RPLND. We present two cases of adolescents who were treated using robot-assisted laparoscopic RPLND (R-RPLND)-one with paratesticular RMS (PT-RMS) and one with testicular GCT (T-GCT)-with good outcomes and low morbidity.

Extracorporeal membrane oxygenation (ECMO) initiation without intubation in two children with mediastinal malignancy

We report the cases of two children presenting with severe airway compromise secondary to a mediastinal malignancy managed with extracorporeal membrane oxygenation without intubation. Results are presented on the use of ECMO as a primary means of stabilizing a pediatric patient with a critical mediastinal mass, thus providing another management strategy for this difficult situation. Pediatr Blood Cancer 2007;49:751–754.

Pathological Review of Wilms Tumor Nephrectomy Specimens and Potential Implications for Nephron Sparing Surgery in Wilms Tumor

PURPOSE Nephron sparing surgery is accepted as standard of care for children with bilateral Wilms tumor or Wilms tumor in a solitary kidney and some study protocols allow nephron sparing surgery in select cases of unilateral Wilms tumor. With the increasing use of nephron sparing surgery in Wilms tumor, we reviewed pathological features from Wilms tumor radical nephrectomy specimens to determine the potential efficacy of a nephron sparing approach. MATERIALS AND METHODS Medical records of children undergoing pre-chemotherapy radical nephrectomy for unilateral Wilms tumor at our institution were reviewed. Ideal candidates for nephron sparing surgery were defined as those having a unifocal mass outside the renal hilum, sparing a third or more of the kidney, favorable histology, no signs of renal sinus or segmental vascular invasion, no metastatic lymph nodes or gross regional disease, and a distinct interface on pathological review between tumor and remaining parenchyma. RESULTS A total of 78 children at a median age of 3.2 years (range 0.3 to 16.2) underwent pre-chemotherapy radical nephrectomy for unilateral Wilms tumor. Median tumor diameter was 11 cm (range 2.5 to 22). Of these children 36 (46.2%) had tumors sparing a third or more of the kidney and 70 (89.7%) had unifocal tumors. There were 73 specimens (94.6%) that showed favorable histology, and 56 (71.8%) of the specimens had a distinct border between tumor and remaining parenchyma. In total, 19 (24.4%) of the patients reviewed met all of our strict pathological criteria as ideal partial nephrectomy candidates. CONCLUSIONS In a post hoc analysis using strict pathological criteria and accepted surgical oncologic principles, as many as 1 in 4 children undergoing pre-chemotherapy surgery for nonmetastatic, unilateral Wilms tumor have post-resection pathological tumor characteristics favorable for nephron sparing surgery.

HENOCH-SCHONLEIN PURPURA IN A CHILD WITH HYPERIMMUNOGLOBULINEMIA D AND PERIODIC FEVER SYNDROME

Abstract:  This report describes a 3‐year‐old girl with a long history of periodic fever who presented with Henoch‐Schönlein purpura. She was diagnosed with hyperimmunoglobulinemia D and periodic fever syndrome by means of mutation analysis of the mevalonate kinase gene. The serum IgA concentration was markedly elevated, but the serum IgD concentration was normal. This report emphasizes that Henoch‐Schönlein purpura may be an important clinical feature of hyperimmunoglobulinemia D and periodic fever syndrome. In addition, this syndrome should be considered in patients with Henoch‐Schönlein purpura in whom there is a history of recurrent fevers, even when the serum IgD concentration is normal.

Risk stratification of pubertal children and postpubertal adolescents with clinical stage i testicular nonseminomatous germ cell tumors

PURPOSE The COG (Childrens Oncology Group) currently recommends surveillance for all children and adolescents with clinical stage I testicular germ cell tumors. However, up to 30% of adults with clinical stage I testicular germ cell tumors harbor occult metastatic disease. In adults with clinical stage I nonseminoma some groups advocate a risk stratified approach. Occult metastases were noted in 50% of patients with features such as lymphovascular invasion or embryonal carcinoma predominance in the orchiectomy. However, to our knowledge there are no data on the impact of high risk features in such pubertal children and postpubertal adolescents. MATERIALS AND METHODS We reviewed an institutional testis cancer database for pubertal children and postpubertal adolescents younger than 21 years. We tested the hypothesis that lymphovascular invasion, or 40% or greater embryonal carcinoma in the orchiectomy specimen, would increase the risk of occult metastases, ie relapse during surveillance or positive nodes on retroperitoneal lymph node dissection. RESULTS We identified 23 patients with a median age of 18.6 years (range 7.1 to 20.9) at diagnosis. Of these patients 14 (60.9%) were on surveillance, 9 (39.1%) underwent primary retroperitoneal lymph node dissection and none received initial chemotherapy. Seven patients (30.4%) had occult metastatic disease. High risk pathological features were found in the orchiectomy specimen in 12 patients (52.2%), including all 12 (52.2%) with 40% or greater embryonal carcinoma and 3 (13.0%) with lymphovascular invasion. Seven patients (58.3%) with high risk features had occult metastatic disease vs none (0%) without high risk features (log rank p = 0.031). CONCLUSIONS Approximately half of pubertal children and postpubertal adolescents with high risk clinical stage I testicular germ cell tumors harbor occult metastatic disease. These results may be useful when discussing prognosis and treatment with patients and families.

Wilms Tumor: Preoperative Risk Factors Identified for Intraoperative Tumor Spill

PURPOSE We identified preoperative parameters associated with increased risk of intraoperative Wilms tumor spill. MATERIALS AND METHODS We retrospectively reviewed an institutional database of patients diagnosed with Wilms tumor between 2000 and 2008. Inclusion criteria consisted of available abdominal computerized tomogram and pathological stage I to IV disease. Patient characteristics and neoadjuvant chemotherapy use were noted. After blinding, a radiologist reviewed preoperative computerized tomogram parameters, calculating tumor volume and assigning a preoperative radiological stage. RESULTS Of 67 patients diagnosed with Wilms tumor 41 (22 males, 19 females) met inclusion criteria, while 26 had incomplete imaging for analysis. Comparison of patients with and without intraoperative tumor spill demonstrated no significant differences in age (3.8 vs 3.6 years), sex (3 males and 3 females vs 19 males and 16 females), body weight or tumor capsule thickness. Preoperative radiological staging was unable to predict pathological stage I to III disease. Six intraoperative tumor spills (15%) were identified (left in 4, right in 2), of which 3 were stage III disease and 3 stage IV. Without neoadjuvant chemotherapy, patients with tumors greater than 1,000 cc had an increased risk of spill (2 of 2 [100%] vs 4 of 33 [12%], p = 0.03). Of 9 patients with stage IV disease 0% (0 of 4) receiving neoadjuvant chemotherapy experienced tumor spill, while lack of neoadjuvant chemotherapy was associated with a 60% (3 of 5 patients, 1 male and 2 females) risk of stage IV spill (p = 0.17). CONCLUSIONS The sole significant tumor spill risk factor identifiable preoperatively was tumor volume greater than 1,000 cc. However, spill occurred at volumes less than 400 cc. Although not statistically significant, neoadjuvant chemotherapy for stage IV disease trended toward diminishing spill risk. Patients with Wilms tumors greater than 1,000 cc may benefit from neoadjuvant chemotherapy with less tumor spill, while stage IV tumors warrant further study in this regard.

Correlation Between Preoperative Staging Computerized Tomography and Pathological Findings After Nodal Sampling in Children with Wilms Tumor

PURPOSE Guidelines for staging Wilms tumor mandate regional lymph node sampling at nephrectomy. However, the usefulness of preoperative computerized tomography in staging lymph nodes has not been rigorously investigated. Thus, we correlated preoperative computerized tomography and pathological lymph node findings to establish a radiological criterion for pathological lymph node enlargement. MATERIALS AND METHODS We reviewed the medical records of children with Wilms tumor at our institution who underwent pre-chemotherapy surgery with lymph node sampling and had preoperative computerized tomography with contrast medium available for interpretation. Computerized tomography was independently reviewed by 2 radiologists blinded to the pathological findings. We collected data on the diameter of the largest regional lymph node identified and this measurement was correlated with the pathological results. RESULTS A total of 52 children (25 male, 27 female) with a median age of 3.1 years (range 0.4 to 9.6) were identified. The median largest regional lymph node diameter was 6 mm (range 2 to 15). Of the children 10 (19.2%) had metastatic involvement of sampled lymph nodes. A radiological cutoff of 7 mm for lymph node positivity corresponded to a negative predictive value of 89.0%, a sensitivity of 70.0% and a specificity of 57.1%. A ROC curve was constructed with these data describing the prognostic ability of the diameter of the largest regional lymph node on preoperative computerized tomography to determine lymph node positivity in Wilms tumor, which revealed an AUC of 0.67 (95% CI 0.48-0.87, p = 0.09). CONCLUSIONS By defining a radiological size cutoff for suspicious lymph nodes, preoperative computerized tomography for staging lymph nodes in Wilms tumor demonstrates potential clinical usefulness through risk stratification for therapy and future study design.