Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children With Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall. SUMMARY OF BACKGROUND DATA: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence. METHODS: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys. RESULTS: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection. CONCLUSIONS: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.

Adolescent Vaping-Associated Trauma in the Western United States.

INTRODUCTION: Electronic cigarettes (e-cigarettes) are handheld, battery-powered vaporizing devices. It is estimated that more than 25% of youth have used these devices recreationally. While vaping-associated lung injury is an increasingly recognized risk, little is known about the risk of traumatic injuries associated with e-cigarette malfunction. METHODS: A multi-institutional retrospective study was performed by querying the electronic health records at nine children's hospitals. Patients who sustained traumatic injuries while vaping from January 2016 through December 2019 were identified. Patient demographics, injury characteristics, and the details of trauma management were reviewed. RESULTS: 15 children sustained traumatic injuries due to e-cigarette explosion. The median age was 17 y (range 13-18). The median injury severity score was 2 (range 1-5). Three patients reported that their injury coincided with their first vaping experience. Ten patients required hospital admission, three of whom required intensive care unit admission. Admitted patients had a median length of stay of 3 d (range 1-6). The injuries sustained were: facial burns (6), loss of multiple teeth (5), thigh and groin burns (5), hand burns (4), ocular burns (4), a radial nerve injury, a facial laceration, and a mandible fracture. Six children required operative intervention, one of whom required multiple operations for a severe hand injury. CONCLUSIONS: In addition to vaping-associated lung injury, vaping-associated traumatic injuries are an emerging and worrisome injury pattern sustained by adolescents in the United States. This report highlights another means by which e-cigarettes pose an increasing risk to a vulnerable youth population.

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.

Minimizing Variance in Gastroschisis Management Leads to Earlier Full Feeds in Delayed Closure.

BACKGROUND: Limited guidance exists regarding appropriate timing for feed initiation and advancement in gastroschisis. We hypothesized that implementation of a gastroschisis management protocol would allow for standardization of antibiotic and nutritional treatment for these patients. METHODS: We conducted a retrospective comparison of patients with simple gastroschisis at two pediatric hospitals before and after initiation of our gastroschisis care protocol. Complicated gastroschisis and early mortality were excluded. The control group extended from January 2012 to January 2014 and the protocol group from July 2014 to July 2016. Variables of interest included time to feed initiation, time to goal feeds, length of stay, and National Surgical Quality Improvement Program-defined complications. We performed a subgroup analysis for primary versus delayed gastroschisis closure. Statistical analyses, including F-tests for variance, were conducted in Prism. RESULTS: Forty-seven patients with simple gastroschisis were included (control = 22, protocol = 25). Protocol compliance was 76% with no increase in complication rates. There was no difference in length of stay or time from initiation to full feeds overall between the control and protocol groups. However, neonates who underwent delayed closure reached full feeds significantly earlier, averaging 9 d versus 15 d previously (P = 0.04). CONCLUSIONS: For infants undergoing delayed closure, the time to full feeds in this group now appears to match that of patients undergoing primary closure, indicating that delayed closure should not be a reason for slower advancement. Additional studies are needed to assess the impact of earlier full enteral nutrition on rare complications and rates of necrotizing enterocolitis.

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma.

BACKGROUND: Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. PROCEDURE: A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. RESULTS: A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. CONCLUSIONS: PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.

Critical elements of pediatric neuroblastoma surgery.

Neuroblastoma (NB) is the most common solid extracranial malignancy of childhood with an incidence of 1 per 100,000 in the United States compromising approximately 10 % of childhood cancer. Unfortunately, patients with high-risk NG continue to have long-term survival less than 50 %. Both Children's Oncology Group and the International Society of Paediatric Oncology have demonstrated the important role of surgery in the treatment of high-risk NB. Herein, we compose the results of an extensive literature review as well as expert opinion from leaders in pediatric surgical oncology, to present the critical elements of effective surgery for high-risk neuroblastoma.

Minimizing variance in pediatric surgical care through implementation of a perioperative colon bundle: A multi-institution retrospective cohort study.

BACKGROUND: Employing an institutional initiative to minimize variance in pediatric surgical care, we implemented a set of perioperative bundled interventions for all colorectal procedures to reduce surgical site infections (SSIs). METHODS: Implementation of a standard colon bundle at two children's hospitals began in December 2014. Subjects who underwent a colorectal procedure during the study period were analyzed. Demographics, outcomes, and complications were compared with Wilcoxon Rank-Sum, Chi-square and Fisher exact tests, as appropriate. Multivariable logistic regression was performed to assess the influence of time period (independent of protocol implementation) on the rate of subsequent infection. RESULTS: One hundred and forty-five patients were identified (preprotocol=68, postprotocol= 77). Gender, diagnosis, procedure performed and wound classification were similar between groups. Superficial SSIs (21% vs. 8%, p=0.031) and readmission (16% vs. 4%, p=0.021) were significantly decreased following implementation of a colon bundle. Median hospital days, cost, reoperation, intraabdominal abscess, and anastomotic leak were unchanged before and after protocol implementation (all p > 0.05). Multivariable logistic regression found time period to be independent of SSIs (OR: 0.810, 95% CI: 0.576-1.140). CONCLUSION: Implementation of a standard pediatric perioperative colon bundle can reduce superficial SSIs. Larger prospective studies are needed to evaluate the impact of colon bundles in reducing complications, hospital stay and cost. LEVEL OF EVIDENCE: III - Retrospective cohort study.

"Sideways": results of repair of biliary injuries using a policy of side-to-side hepatico-jejunostomy.

BACKGROUND: The Hepp-Couinaud technique describes side-to-side HJ to the main left hepatic duct but a side-to-side approach is not consistently used when repairing other ducts. Compared with end-to-side repairs, side-to-side anastomoses require less dissection, theoretically preserving blood supply to the bile ducts, and usually permit wider anastomoses. METHODS: We report the treatment results of 113 consecutive biliary injuries, with intention to perform side-to side anastomosis in all. RESULTS: 113 biliary injuries, 109 associated with cholecystectomy, were treated from 1992-2006. Injury types were B (7 patients, 6%); C (11 patients, 10%); E1 (8 patients, 7%); E2 (37 patients, 33%); E3 (20 patients, 18%); E4 (24 patients, 21%); E5 (6 patients, 5%). 19% of repairs were early (within 1 week after cholecystectomy), 58% were delayed (at least 6 weeks after cholecystectomy), and 22% were reoperations for recurrent strictures. In 92% of cases, side-to-side repair was accomplished. 23/113 (20%) developed postoperative complications, with one postoperative death. Mean follow-up was 4.9 years. Excellent anastomotic function was achieved in 107/112 (95%). "Poor" anastomotic results occurred in 5 patients: 2 patients with E4 injuries had postoperative anastomotic stenting >3 months, and 3 developed strictures requiring percutaneous dilation. There have been no reoperations for biliary strictures. CONCLUSIONS: HJ using side-to-side anastomosis has theoretical advantages and is usually possible. In some high right-sided injuries it could not be achieved. 95% excellent anastomotic function without intervention attests to the benefit of the method, especially as postoperative stenting >3 months was considered to be a "poor" result.

Minimizing variance in Care of Pediatric Blunt Solid Organ Injury through Utilization of a hemodynamic-driven protocol: a multi-institution study.

BACKGROUND: An expedited recovery protocol for management of pediatric blunt solid organ injury (spleen, liver, and kidney) was instituted across two Level 1 Trauma Centers, managed by nine pediatric surgeons within three hospital systems. METHODS: Data were collected for 18months on consecutive patients after protocol implementation. Patient demographics (including grade of injury), surgeon compliance, National Surgical Quality Improvement Program (NSQIP) complications, direct hospital cost, length of stay, time in the ICU, phlebotomy, and re-admission were compared to an 18-month control period immediately preceding study initiation. RESULTS: A total of 106 patients were treated (control=55, protocol=51). Demographics were similar among groups, and compliance was 78%. Hospital stay (4.6 vs. 3.5days, p=0.04), ICU stay (1.9 vs. 1.0days, p=0.02), and total phlebotomy (7.7 vs. 5.3 draws, p=0.007) were significantly less in the protocol group. A decrease in direct hospital costs was also observed ($11,965 vs. $8795, p=0.09). Complication rates (1.8% vs. 3.9%, p=0.86, no deaths) were similar. CONCLUSIONS: An expedited, hemodynamic-driven, pediatric solid organ injury protocol is achievable across hospital systems and surgeons. Through implementation we maintained quality while impacting length of stay, ICU utilization, phlebotomy, and cost. Future protocols should work to further limit resource utilization. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level II.

Experience with retroperitoneal partial nephrectomy in bilateral Wilms tumor.

INTRODUCTION: Retroperitoneal partial nephrectomy has not been studied as a surgical approach for children with bilateral Wilms tumor. There are advantages to this technique, including isolation of urine leaks to the retroperitoneum, decreased risk of bowel injury, and decreased time to resuming a diet. Presently, all bilateral Wilms tumors are treated with neoadjuvant chemotherapy and attempted nephron-sparing surgery. In this study, we compare the outcomes of the retroperitoneal and transabdominal approaches in doing partial nephrectomy for bilateral Wilms tumor. METHODS: With the institutional review board approval, we reviewed records of 14 pediatric patients with metachronous or synchronous bilateral Wilms tumors who underwent surgery after chemotherapy between 1994 and 2014. Only operative procedures with the intent to cure were included (n=15) and of these, 5 procedures were retroperitoneal and 10 were transabdominal in approach. Individual kidneys operated upon (n=26) were analyzed using the preoperative radius exophytic/endophytic nearness anterior/posterior location nephrometry score to ensure that resected tumors were comparable between the two surgical groups. Charts were retrospectively analyzed for intraoperative parameters and postoperative course. Differences between parameters were evaluated using Mann-Whitney and chi-square tests. RESULTS: Resected tumors in both surgical treatment groups had comparable sizes, nephrometry scores, and rates of anaplasia. Operative time, blood loss, and transfusion requirement were similar between the two groups. The extent of lymph node sampling and rates of R0 resection were equivalent. One adverse intraoperative event, a bowel enterotomy, was seen in the transabdominal group. Patients after retroperitoneal partial nephrectomy required half the time to return to an oral diet as compared with those after a transabdominal surgery, approaching statistical significance (p=0.08). Rates of the postoperative urine leak were similar, though two in the transabdominal group required reoperation for drainage. There were four recurrences, all in the transabdominal group. CONCLUSION: Our experience demonstrates that the retroperitoneal approach is equivalent to the transabdominal technique with regards to intraoperative complications, lymph node dissection, and R0 resection. Advantages include less time to resumption of oral feeding, decreased risk of bowel injury, and isolation of urine leaks to the retroperitoneum. It should be considered a viable surgical option in the treatment of bilateral Wilms tumors.

RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds.

BACKGROUND: Multiple endocrine neoplasia 2A (MEN 2A) is a genetic syndrome manifesting as medullary thyroid carcinoma (MTC), hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia 2A results from mutations in the RET proto-oncogene. Hirschsprung disease (HSCR) is a rare manifestation of MEN 2A and has been described in known MEN 2A families. METHODS: Here we describe 2 MEN 2A families that were only identified after the diagnosis of HSCR. RESULTS: Kindred 1: A boy presented in infancy with HSCR. Genetic screening revealed a C609Y mutation, which is consistent with MEN 2A. Evaluation of his sister, father, and grandmother revealed the same mutation. All 3 had thyroidectomies demonstrating C-cell hyperplasia. The grandmother had a microscopic focus of MTC. Kindred 2: An infant boy and his sister were diagnosed with HSCR as neonates. Genetic testing demonstrated a C620R gene mutation consistent with MEN 2A. Total thyroidectomies revealed metastatic MTC in the father and C-cell hyperplasia in both children. CONCLUSIONS: Hirschsprung disease can be the initial presentation of MEN 2A. We strongly recommend that genetic screening be performed in patients presenting with HSCR, looking for the known RET mutations associated with MEN 2A. If a mutation consistent with MEN 2A is detected, genetic screening of all first-degree relatives in the kindred is recommended.

Establishing "normal" values for liver function tests after reconstruction of biliary injuries.

BACKGROUND: Abnormalities of liver function tests (LFT) are sometimes taken as evidence of a less than optimal result after repair of a biliary injury. Rather than indicating liver or anastomotic dysfunction, moderate LFT elevations can be "normal" for these patients. This study's aim was to determine LFT reference values after biliary-enteric anastomosis for biliary injury repair in persons who have had an excellent postoperative course for > 6 months. STUDY DESIGN: Of 113 patients repaired, 73 were identified with the following characteristics: LFT available at > or = 6 months after repair, no biliary tract symptoms, no underlying liver disease, and biliary injury sustained during cholecystectomy. Outside LFT results were standardized to Barnes-Jewish Hospital reference values. One set of LFT per patient was collected at the following times points after repair: 6 months to 2 years, 2 to 5 years, and > 5 years. RESULTS: For each distribution, the 97.5(th) p97.5ercentile values for alkaline phosphatase (> or = 166 IU/L) and total bilirubin (> or = 1.3 mg/dL) were elevated relative to Barnes-Jewish Hospital standard values. Values for alanine aminotransferase and aspartate aminotransferase were more variable. CONCLUSIONS: Moderate LFT elevations exceeding standard reference values are common after repair of a biliary injury in patients who have had excellent results. Alkaline phosphatase values fall with time after repair so that comparisons should take into account time from repair. Values < or = 97.5(th) percentile limits described here should not be taken as evidence of liver or anastomotic dysfunction.

Evidence-based approach to the management of sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare malignancy of the thyroid C cells. It occurs in hereditary (25% of cases) and sporadic (75%) forms. Sporadic MTCs frequently metastasize to cervical lymph nodes. Thorough surgical extirpation of the primary tumor and nodal metastases by compartment-oriented resection has been the mainstay of treatment (level IV evidence). Surgical resection of residual and recurrent disease is effective in reducing calcitonin levels and controlling complications of central neck disease (level IV evidence). Radioactive iodine, external beam radiation therapy, and conventional chemotherapy have not been effective. Newer systemic treatments, with agents that target abnormal RET proteins hold promise and are being tested in clinical trials for patients with metastatic disease.

Pheochromocytoma penetrance varies by RET mutation in MEN 2A.

BACKGROUND: The occurrence of pheochromocytoma in multiple endocrine neoplasia type 2A (MEN 2A) carriers varies greatly. This study aims to determine PC expression for specific MEN 2A RET mutations. METHODS: Charts of MEN 2A patients enrolled in our multiple endocrine neoplasia program from 1990 to 2001 were reviewed retrospectively. Statistical analysis was performed using SAS software (SAS Institute, Inc, Cary, NC). RESULTS: RET mutation data and pheochromocytoma data were compiled for 323 patients. Overall, penetrance of pheochromocytoma occurred in 102 of 323 patients (32%). Bilateral pheochromocytomas were observed in 67 patients (66%). The following codon-specific expression of pheochromocytoma was observed: 1 of 24 patients expressed codon 609 (4%), 0 of 5 patients expressed codon 611 (0%), 23 of 105 patients expressed codon 618 (22%), 4 of 45 patients expressed codon 620 (9%), and 74 of 149 patients expressed codon 634 (50%) (P < .001). An association between pheochromocytoma expression and amino acid substitutions at codon 618 was observed as follows: 0 of 7 patients with C618F, 5 of 21 patients with C618G (24%), 11 of 27 patients with C618R (41%), 7 of 41 patients with C618S (17%), and 0 of 9 patients with C618Y (P = .04.) In our cohort, no deaths were attributable to PC with a median follow-up of 9 years. CONCLUSIONS: The penetrance of PC varies between MEN 2A RET codon mutations. Furthermore, we observed variable expression with different amino acid substitutions at the same codon. These results may help guide screening and therapy for MEN 2A patients.

Current approaches to medullary thyroid carcinoma, sporadic and familial.

Medullary thyroid carcinoma (MTC) is a rare malignancy of the thyroid C cells. It occurs in hereditary (25% of cases) and sporadic forms, and aggressiveness is related to the clinical presentation (hereditary vs. sporadic) and the type of RET mutation present. In hereditary cases, early diagnosis makes preventative surgery possible. In established cases, thorough surgical extirpation of the primary tumor and nodal metastases has been the mainstay of treatment. Radioactive iodine, external beam radiation therapy (EBRT), and conventional chemotherapy have not been effective. Newer systemic treatments, with agents that target abnormal RET proteins, hold promise and are being tested in clinical trials for patients with metastatic disease.