Cancer Articles of Interest

Articles

Treatment of Pediatric Adrenocortical Carcinoma with Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children’s Oncology Group ARAR0332 Protocol [1], Rodriguez-Galindo et al. J Clin Oncol 2021 Apr 6.

Childhood adrenocortical carcinoma (ACC) is very rare in the United States (25 cases per year), and management has traditionally followed adult protocols. Low stage and complete resection are good prognostic factors and recurrence is as high as 50% in large tumors. The role of retroperitoneal lymph node dissection (RPLND) is not understood.

This article reports the results of COG protocol ARAR0332 in which stage I patients had tumor resection, stage II (>200cc or 100g) had resection and RPLND, and stage III and IV received chemotherapy and mitotane plus surgery. The results of 77 patients were described. Older patients had higher-stage tumors. Hormonal hypersecretion was present in 90%/ Germline TP53 variation was more common in the Brazilian cohort vs North American (95% vs 50%) and was associated with the lower stage. Normal germline P53 function and mutations in ATRX are associated with a higher stage and a worse outcome. Five-year event-free survival was: stage I 86%, stage II 53%, stage III 81%, and stage IV 7%. Five-year overall survival was: stage I 95%, stage II 79%, stage III 95%, and stage IV 16%. What this study adds is that surgical resection for stage I disease and chemotherapy plus surgery for stage III disease lead to good outcomes and warrant adoption. However, RPLND for stage II disease does not add a clear advantage. Stage IV patients are older and have a poor outcome despite chemotherapy. Furthermore, the mitotane and chemotherapy regimen was poorly tolerated, with one-third of advanced patients being unable to complete the regimen. An optimal regimen requires further evaluation.

Indeterminate Pulmonary Nodules in Osteosarcoma are associated with increased Risk of pulmonary metastasis [2], Seher et al. J Pediatr Hematol Oncol. 2021 Mar 3.

The most common site of metastasis in osteosarcoma is the Lung. Approximately 15-20% of patients have pulmonary metastasis at the time of diagnosis. CT is the main imaging modality for diagnosing pulmonary metastases. Nodules above 5 mm with calcified characters are more likely to be metastatic lesions.  As per EURAMOS (European and American osteosarcoma protocols), Single nodules >10mm or >=3 nodules of 5-9mm are consistent with pulmonary metastasis. However, nodules that don’t meet these criteria are considered indeterminate pulmonary nodules (IPN) with unclear prognostic significance.

This manuscript by Seher et al. is a retrospective cohort study of osteosarcoma patients under age 18, between Jan 2005 to Dec 2018. Of 155 patients 31.6% had IPN. 43% of IPN patients developed pulmonary metastatic disease compared with 26% without IPN (p< 0.001, Relative risk 1.6). This study found that 3 or more IPN almost doubles the risk of subsequent pulmonary mets (p=0.013) and they have lower overall and event-free survival (58% and 35%, and 72% and 46%, respectively) although this was not significant. Most developed metastasis within 2 years. This manuscript illustrates the association between IPN and the increased risk of subsequent pulmonary metastatic disease and these findings are supported by other studies published this year. Further investigations will be required to determine if there is any benefit to biopsy of IPN or if changes in therapy for these patients would be beneficial.

Pleuropulmonary Blastoma in Pediatric Lung Lesions [3], Kunisaki et al. Pediatrics. 2021 Mar 24:e2020028357.

Congenital lung lesions, though rare, are frequently diagnosed on prenatal imaging. There is consensus that congenital lung lesions causing symptoms (respiratory compromise or infection) should be removed. There is no consensus on the management of asymptomatic lesions. There is a smaller subset of patients with congenital lesions who present postnatally. When counseling these families on the need for potential surgical removal, indications for removal may be the future risk for infection or malignancy, but these true risks are unclear. Pleuropulmonary blastoma (PPB) is thought to exist on a continuum with Type II (cystic) progressing to Type II (solid/cystic) and Type III (solid). Early diagnosis and treatment of pleuropulmonary blastoma is important as survival is significantly lower in Type II and Type III PPB.

This multi-institutional retrospective review included all patients undergoing surgery for primary lung lesions (n = 521) at 11 tertiary pediatric centers. It is the practice at all participating institutions to resect all symptomatic and asymptomatic lung lesions. The primary focus of the analysis was to evaluate the postnatally diagnosed patients. Lung lesions diagnosed postnatally were also compared to the lesions diagnosed prenatally. The authors found there were significantly lower APGAR scores and significantly more respiratory distress in the postnatally diagnosed lung lesions. The most common pathologic diagnoses in prenatally diagnosed patients were congenital pulmonary airway malformation (CPAM), bronchopleural sequestration (both intra- and extra-lobar), and CPAM with a feeders vessel. There were no malignancies in lung lesions diagnosed prenatally. In contrast, the most common pathologic diagnoses in postnatally diagnosed lung lesions were CPAM, congenital lobar emphysema, intra-lobar sequestration, and malignancy in 8.7%. Bivariate analysis showed malignancy was associated with suspicion of malignancy on pre-operative imaging, lack of a feeding vessel, and bilateral disease. Eight of 14 patients with pleuropulmonary blastoma (PPB) were positive for DICER 1. Finally, the diagnostic accuracy of preoperative imaging was examined and while sensitivity and positive predictive value were low (33.3% and 71.4% respectively), specificity and negative predictive value were high (98.8% and 94.1% respectively). The authors conclude there is a higher rate of malignancy in postnatally diagnosed lung lesions than previously thought. Furthermore, pediatric surgeons may wish to use DICER 1 testing to help determine the malignant potential of cystic lung lesions diagnosed postnatally given the low sensitivity of cross-sectional imaging.

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study [4], Lautz et al. Int J Cancer 2021; 148(5): 1164-1171.

Osteosarcoma is the most common bone tumor in children and young adults. Fifteen to twenty percent present with metastases at diagnosis with the lung being the most common site. Complete surgical clearance of pulmonary disease is critical for long-term survival and has traditionally been approached via thoracotomy to allow for palpation of lesions. This open approach with palpation has resulted in the resection of more nodules compared to those detected by computerized tomography (CT). Thoracotomy is associated with increased pain, longer hospitalizations, potential long-term morbidity, and increased risk of complications compared to thoracoscopy.

This multi-institutional study retrospectively reviewed 202 pediatric patients with metastatic osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n=154) versus thoracoscopy (n=48) to assess for a survival advantage. A significant difference in the number of total nodules resected was seen between thoracotomy (5) and thoracoscopy (1). The number of pathologically malignant lesions resected via thoracotomy was higher than the number seen on CT in 27% of patients, compared to 2% in thoracoscopy. Mean chest tube duration (three versus one day) and postoperative length of stay (five versus two days) were longer in the thoracotomy patients. Complication differences between the two groups were not statistically significant. Pulmonary relapse was seen in 135 patients (67.5%). There was no significant difference in five-year pulmonary disease-free survival or overall survival between thoracotomy and thoracoscopy. Regardless of approach, survival was superior in oligometastatic disease. In a subset analysis of patients with oligometastatic disease, thoracoscopy had comparable risks of mortality and recurrence.
This large series pooled from multiple institutions suggests that comparable outcomes may be achieved with thoracotomy or thoracoscopy for resection of pulmonary metastatic disease in patients with metastatic osteosarcoma and limited pulmonary disease. The study does have some serious limitations including significant selection bias. Rather than adopt thoracoscopy, surgeons are encouraged to enroll patients in an upcoming recently approved randomized study.

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project [5], Moreno et al. Pediatr Blood Cancer. 2021 Mar;68(3):e28794.

High-risk neuroblastoma, despite improvements with multimodal therapy, continues to have a low overall survival (OS, 50% at five years). An international consensus has broadly defined high-risk as all patients greater than or equal to 18 months of age with metastatic neuroblastoma. This heterogeneous group of patients has a wide range of OS outcomes and yet they are all assigned to receive the same intensive multimodal treatment. There are members of this high-risk group with very poor outcomes (ultra-high-risk) who would potentially benefit from new innovative therapies at an earlier time in their disease process. Previous attempts have been made to stratify ultra-high-risk patients but this has not resulted in treatment modifications.

This study is the first to create and validate a nomogram of high-risk neuroblastoma risk factors and identify those with ultra-high-risk of treatment failure. The nomogram identified MYCN status, elevated lactate dehydrogenase and the presence of bone marrow metastases as validated prognostic factors to identify ultra-high-risk patients. This nomogram allows pediatric surgeons and oncologists to better determine prognosis at diagnosis as well as identify patients with the highest mortality risk. The nomogram allows differentiation of patients with a 30% OS at three years (nomogram score greater than 82) compared with 58% OS for those with a score less than 82. This article produced an effective nomogram that could potentially identify children unlikely to respond to current treatment strategies who have a terrible prognosis and may benefit from alternative experimental therapies. This article will hopefully impact and alter the clinical practice and treatment of high-risk neuroblastoma.

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression [6]. Cheung et al. J Clin Oncol. 2021 Jan 20;39(3):215-226.

Patients with high-risk neuroblastoma frequently have a poor prognosis. Adding anti-GD2 monoclonal antibody to the treatment of high-risk neuroblastoma patients has helped achieve long term survival in 50 to 60% of patients. Further innovations in immunotherapy offer a promising avenue both to manage patients with disease that is refractory to chemotherapy and to provide effective treatments that are associated with minimal morbidity. Additionally, it has been speculated that generation of an antitumor antibody response to tumor antigen by the patient could produce a more durable response than bolus administration of the antibody. Beta-glucans are a heterogeneous group of polysaccharides abundant in the cell walls of yeasts, bacteria and fungi that reportedly induce a trained immunity and are effective vaccine adjuvants. Previously, a small phase I GD2/GD3 vaccine trial described long term survival and a favorable safety profile among patients with a history of disease progression.

The study described in this manuscript was the Phase 2 prospective trial employing the same GD2/GD3 vaccine used in the Phase 1 study plus oral beta-glucan in a larger sample of 102 high-risk neuroblastoma patients who achieved remission, after salvage therapy, following at least one period of disease progression. The primary endpoint was progression-free survival (PFS), while secondary endpoints were quantification of anti-GD2 and anti-GD3 antibody response and correlation of antibody response with PFS and overall survival (OS). Patients had a history of one (63%), two (21%) or three to six (16%) episodes of disease progression. 82% of them progressed following anti-GD2 monoclonal antibody. The PFS was 32% ± 6%, and the OS was 71% ± 7% at 5 years. No grade 3, or higher, morbidities were observed in any patients administered GD2/GD3 vaccine. Combining subcutaneous GD2/GD3 conjugate vaccine with oral β-glucan adjuvant was found to be safe and effective in inducing antibody response. Multivariable analyses showed that anti-GD2 antibody titer ≥ 150 ng/mL by week eight was associated with favorable PFS and OS, while having fewer prior episodes of PD and the time from last PD to vaccine were associated with PFS. This is especially interesting given that most of these patients had disease progression after already being treated with anti-GD2 monoclonal antibody. Given the safety profile of this vaccine, the correlation with antibody response titers and PFS/OS of high-risk neuroblastoma patients and the expression of GD2 and GD3 among many other tumors, GD2/GD3 vaccination remains an intriguing treatment that clearly warrants further investigation.

A prospective study of pediatric and adolescent renal cell carcinoma: A report from the Children’s Oncology Group AREN0321 study [7], Geller et al Cancer 2020 Dec 1;126(23):5156-5164.

Renal cell carcinoma (RCC) is rare in the pediatric and adolescent population but is the second most common solid malignancy of the kidney, after Wilms Tumor, in this age group. Very little is known about this tumor and most published information comes from small retrospective case series or from extrapolation of adult data. It has been reported that RCC tumors are quite distinct biologically from those seen in adults and act differently clinically. Data has been lacking and this has created difficulty for pediatric surgeons and oncologists in treatment planning and discussions with patients and families.
This study’s importance lies in its prospectively and centrally (Children’s Oncology Group) gathered data with rigorous review of pathology, radiology and surgery. The article represents the first such study in the literature on this particular tumor in this group of patients and thus fills an important gap in knowledge in pediatric solid tumors. Most of these tumors were found to contain the TFE3 gene translocation. Overall, the study shows that favorable four-year outcomes can be achieved without adjuvant therapy in children and adolescents with completely resected RCC - independent of lymph node status (event free and overall survivals in the 80 to 90% range). This differs from adult RCC outcomes. Metastatic disease portends a much poorer survival. The article provides new and important insights into treatment, outcomes and prognostic factors. It will likely be the most referenced article on this subject for a long time.

Benefit of delayed primary excision in rhabdomyosarcoma: a report from the Children’s Oncology Group (COG) [8], Lautz et al Cancer 2020

Treatment for pediatric rhabdomyosarcoma (RMS) includes chemotherapy plus surgery and/or radiation therapy (RT) for local control. The majority of patients with RMS have gross disease at the start of chemotherapy and are considered intermediate risk (group III) disease. Delayed primary excision (DPE) after neoadjuvant chemotherapy may allow for reduced doses of adjuvant radiation therapy but may increase surgical morbidity in this high risk population.

Children with group III RMS of bladder/prostate, intrathoracic, retroperitoneal, trunk and extremity primary sites enrolled in COG studies D9803 and ARST0531 were compared (n=369). All children underwent upfront chemotherapy. In D9803, patients underwent DPE after 12 weeks of chemotherapy if the primary tumor appeared resectable. In ARST0531, definitive RT was the preferred mode of local control while DPE was permitted but not encouraged. Surgical morbidity of DPE resulted in loss of organ/function in 22% of cases. However, children who underwent DPE received lower radiation dose in 81% of patients; 51% were reduced to 36 Gy and 30% were reduced to 42 Gy with no difference in local failure rates. Importantly, children who underwent DPE had equivalent or improved overall survival. This is the first study to demonstrate the positive impact of DPE in surgical treatment of pediatric RMS. While DPE poses a risk of surgical morbidity, the long term benefits of reduced RT dose and potential survival benefits highlight the need for careful consideration of risks and benefits when developing treatment plans for patients with group III RMS.

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma [9], Overman et al Pediatr Blood Cancer 2020 May;67(5):e28153.

The treatment of neuroblastoma relies on accurate and complete biopsy results. In addition to histology, assessment of ploidy, MYCN amplification and loss of heterozygosity are variables considered critical in the pathologic evaluation. Biopsy of suspected neuroblastoma has traditionally been performed via an open approach in order to guarantee adequate specimen procurement. In the past decade, however, several institutions have reported on the feasibility and adequacy of percutaneous biopsy. These reports also suggested a lower complication rate and less associated pain.

The study reported a collective retrospective chart review from 12 participating institutions comprising 243 cases of pediatric neuroblastoma. Of the 164 cases that were diagnosed by biopsy (as opposed to excision), 70 were performed percutaneously using core biopsies. Comparing open to percutaneous approaches, the authors found no difference in the ability to establish a principle diagnosis or evaluate for MYCN amplification. The percutaneous biopsy group had a statistically significantly lower rate of ability to identify loss of heterozygosity (56% versus 91%) and tumor ploidy (58% versuss 89%), but these differences were diminished when a pediatric pathologist was present during the biopsy to assess the adequacy of specimens. Blood transfusion and opiate utilization were higher in the open biopsy compared to the percutaneous group but major complications did not differ. The authors concluded that percutaneous biopsy is a viable alternative to traditional open incisional biopsy and that protocolization vis-a-vis pediatric pathologist involvement, needle core size and core biopsy pass attempts would further increase its accuracy and utility.

Predicting Acute Ovarian Failure in Female Survivors of Childhood Cancer: a Cohort Study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE) [10], Clark et al Lancet Oncol 2020 Mar;21(3):436-445.

Survivors of pediatric cancer are at risk for a number of chronic health conditions including infertility. The major risk factors for impaired ovarian function include chemotherapy (alkylating agents, and to a lesser extent cisplatin), radiation (pelvis and pituitary) and stem cell transplant. The effect of therapy on ovarian function can range from reduced ovarian reserve manifesting as infertility and/or premature menopause up to acute ovarian failure with complete loss of ovarian function. Prior efforts have helped to establish threshold doses of these therapies which place patients at an increased risk for infertility but further work is needed to identify the six percent of females who have acute ovarian failure, or complete loss of ovarian function, within five years of treatment.

5800 females from the Childhood Cancer Survivor Study comprised the primary data source and 875 in the St Jude Lifetime Cohort were used for validation. Six percent of survivors in the CCSS cohort were diagnosed with acute ovarian failure. A logistic regression model to determine the risk of acute ovarian failure had high diagnostic accuracy with an area under the curve (AUC) of 0.94. This model has been incorporated into a web-based model available for calculating an individual patients risk of acute ovarian failure.
https://ccss.stjude.org/tools-and-documents/calculators-and-other-tools/cc.... In applying this tool, it should be remembered that the model is designed to predict early, complete loss of ovarian function; patients can still have infertility and impaired ovarian function at lower doses of chemotherapy and radiation. A fertility preservation consultation with discussion and risk assessment should be offered to every patient undergoing cancer therapy and many families will opt for fertility preservation procedures at thresholds much lower than those expected to cause acute ovarian failure.


Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study [11], Hayek et al J Clin Oncol 2020 Jan 20;38(3):232-247.

Maintaining Outstanding Outcomes Using Response- And Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children’s Oncology Group Study ANBL0531 [12], Twist et al J Clin Oncol 2019 Dec; 37(34), 3243-3255.

Understanding the Value of Tumor Markers in Pediatric Ovarian Neoplasms [13], Lawrence et al J Pediatr Surg 2020;55(1):122–125.

The diagnostic accuracy and reliability of tumor markers for malignancy in girls with ovarian neoplasms is unknown. The role of tumor markers requires further clarification. Efforts are being made to promote ovary sparing surgery in the appropriate setting. However, one of the challenges facing surgeons is how best to preoperatively risk stratify the patient who presents with an ovarian neoplasm. Elements of the history, physical exam and imaging must be considered but tumor markers may also provide important information.

This study evaluated a large cohort of over 400 patients. It concluded that tumor marker testing is helpful in preoperative risk stratification of ovarian neoplasms for malignancy. Given the variety of potential tumor types no single marker provides enough reliability and therefore a panel of tumor marker testing is recommended if there is concern for malignancy. Prospective studies may help further elucidate the predictive value of tumor markers in a pediatric ovarian neoplasm population.

The Role of Surgery in High-risk Neuroblastoma [14], Ryan et al J Pediatr Hematol Oncol 2020 Jan;42(1):1-7.

The extent of surgical resection for high risk neuroblastoma has been the subject of debate among surgeons and oncologists with contrasting correlations to survival outcomes.

This review article summarizes the most recent articles on the implication of surgery for the treatment of high risk neuroblastoma and addresses many of the relevant surgical questions. The authors address the extent of surgical resection, describe the timing of surgical intervention and highlight potential complications from surgery as described in the literature and in most recent cooperative group protocols. The authors conclude that the objectives for surgical resection of neuroblastoma may differ from surgical resection goals in other various solid tumors treated by pediatric surgeons. Surgery is beneficial in high risk neuroblastoma although the extent of resection remains controversial. Further prospective trials that are currently collecting data including postsurgical resection data, image defined risk factors and induction response may help guide future surgical treatment.

Lymphatic Leakage after Surgery for Neuroblastoma: A Rare Complication? [15], Froeba-Pohl et al Eur J Pediatr Surg 2020 Jan 20.

Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients with High-Risk Neuroblastoma: A Randomized Clinical Trial [16], Park et al JAMA 2019. 27; 322: 746-755.

Evaluation of the diagnostic biopsy approach for children with hepatoblastoma: A report from the Children’s Oncology Group AHEP0731 Liver Tumor Committee [17], Weldon et al J Pediatr Surg 2019. May 11

Biopsies of unresectable liver tumors are currently being done by open, laparoscopic or percutaneous approaches with no prospective studies comparing their outcomes. Correct histopathological and molecular diagnosis is essential for effective treatment for children with solid organ tumors. For many tumors an open biopsy has been the standard of care. Alternatively, the development of interventional radiology techniques are attractive but raise questions about safety (e.g. bleeding) and diagnostic accuracy (e.g. obtaining enough tissue for molecular studies) compared to the traditional open biopsy.

This study reviewed children with hepatoblastoma enrolled in the Children’s Oncology Group study AHEP0731 who underwent biopsy of the primary tumor for initially unresectable patients. A total of 121 patients were included in the analysis of which 36 (30%) were PRETEXT II, 60 (50%) PRETEXT III and 25 (21%) PRETEXT IV. There were no PRETEXT I patients. Open biopsies were the most commonly performed (63%), followed by percutaneous (23%) and laparoscopic (14%), with no difference in biopsy type by age, PRETEXT group or time to initiating treatment.

Postbiopsy hemorrhage requiring blood transfusion occurred significantly more frequently in the open (36%) and laparoscopic (24%) biopsies compared with percutaneous (0%) (p< 0.01). The six-year cumulative incidence of tumor relapse was 19% (standard error (SE) 10%) in the open group, 19% (SE 10%) in laparoscopic, and 14% (SE 7%) in the percutaneous. Evaluation of the quality of the tumor tissue was not evaluated in this study although all biopsy approaches yielded a pathologic diagnosis.

This is the first analysis to prospectively compare biopsy techniques among children enrolled in a study for advanced stage hepatoblastoma. In the currently active trial AHEP1531 (Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)), the type of biopsy is left to the discretion of the treating institution but the image guided percutaneous core needle biopsy is preferred. This study adds to our knowledge of the safety of the percutaneous biopsy approach compared to open or laparoscopic biopsy. Further study is required to further define the optimal approach to obtain diagnostic and pathologic material as well as material for biological studies in pediatric liver tumors.

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children’s Oncology Group [18], Hibbitts et al Cancer Med 2019 Oct.

The classification and staging of children with rhabdomyosarcoma (RMS) is complex. Histology has traditionally been a major factor in determining risk stratification and treatment. However, identifying better prognostic markers are needed. FOXO1 fusion status is now recognized as a biological marker of disease severity in children with RMS. Recent studies suggest that it is more important prognostic factor than histology with fusion positive status seen in 80% of alveolar rhabdomyosarcomas and rarely seen in embryonal. FOXO1 status has replaced histology for classification in future treatment protocols.

This study pools data from six Children’s Oncology Group clinical trials – two studies each for low, intermediate and high risk patients with RMS. Using event free survival (EFS) as the primary endpoint, a survival tree regression was performed to determine the prognostic impact of risk factors (FOXO1 status, age, clinical group, histology, node status, number of metastatic sites, primary site, sex, tumor size, presence of metastasis at specific sites). The most significant associated factor on EFS for all patients was extent, with five-year EFS of 73% for localized and 30% for metastatic disease. However, within each subset (e.g. localized, metastatic), the tumor’s FOXO1 fusion status was the strongest prognostic factor. For local disease five-year EFS was 78% for fusion negative tumors versus 52% for fusion positive tumors. For metastatic disease the five-year EFS was 46% for fusion negative tumors versus six percent for fusion positive tumors. The overall results of the survival tree analysis allowed proposal of new risk group definitions using FOXO1 status in risk classification and treatment.

Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases: A Report From the Children’s Oncology Group AREN0533 Study [19], Dix et al J Clin Oncol 2018 Jun 1;36(16):1564-1570.

Patients with favorable histology Wilms tumor and lung metastases have a four-year event free survival (EFS) of 74.5% and overall survival (OS) of 86%. These patients were all treated with three-drug chemotherapy (DD4A) and lung radiation (RT). Experience in Europe reported by the International Society of Pediatric Oncology (SIOP) has suggested that complete response of pulmonary nodules following six weeks of three-drug chemotherapy allows for omission of lung RT with maintenance of similar outcomes (five-year EFS 77%; OS 87%). The implications of this are important, because chest radiotherapy is associated with an increased risk of cardiac dysfunction and breast cancer. A subgroup of these patients were further analyzed by SIOP and those with incomplete response, stable disease or progression had a significantly worse prognosis [five-year EFS 17% (stable or progression); EFS 67% (incomplete response)].

This study by Dix uses the response to the first six weeks of chemotherapy to determine subsequent treatment. In this study, patients that had a rapid complete response (RCR), defined by resolution of all lung disease on chest computerized tomography after six weeks of DD4A chemotherapy would then omit lung RT and continue with the same chemotherapy. This represented 45% of all patients and the authors show an improvement in outcomes despite omission of lung RT (four-year EFS to 80%; OS 96%). Incomplete response after six weeks of DD4A was thought to signify more aggressive disease so these patients wound receive lung RT as well as an intensified chemotherapy regimen (Regimen M). This group also showed a significant improvement in outcomes (three-year EFS 88%; OS 92%).

Wilms tumor with lung metastases
Descriptive text is not available for this image
Visual abstract courtesy of Celeste Hollands

Factors Associated With Management of Pediatric Ovarian Neoplasms [13], Lawrence et al Pediatrics. 2019 Jul;144(1).

This is a multicenter retrospective review of 819 girls and women aged two to 21 years who underwent surgery for an ovarian mass at 10 children’s hospitals between 2010 and 2016. The two primary objectives of the study were to identify risk factors for malignancy and identify characteristics associated with oophorectomy in patients with benign pathology. They found that the overall rate of malignancy was 11% and that younger age, abdominal bloating, presence of lymphadenopathy, solid components on imaging and increased size were independently associated with malignancy. For each one-cm increase in lesion size there was an associated 12% increased odds of malignancy. Patients with torsed ovaries and those with solid components on imaging were more likely to undergo oophorectomy for benign disease. In addition, pediatric surgeons and adult gynecologists had significantly increased odds of performing oophorectomy (OR 2.68 CI 1.12-6.41; OR 4.23 CI 2.08-8.62, respectively) for benign disease compared to pediatric gynecologists. For each 1-cm increase in lesion size, there was an associated eight percent increased odds of oophorectomy for benign disease.

pediatric ovarian neoplasms
Descriptive text is not available for this image
Visual abstract couretsy of Sarah Walker

Nationwide Overview of Survival and Management of Appendiceal Tumors in Children [20], Parikh et al J Pediatr Surg 53 2018 1175-1180.

Anterior Mediastinal Masses – A Multidisciplinary Pathway for Safe Diagnostic Procedures [21], Malik et al J Pediatr Surg. 2019 Feb; 54(2):251-254.

Appendicitis in a Neutropenic patient: A Multicentric Retrospective Study [22], Scarpa et al J Pediatr Hem Onc 2017 39:365-369.

Current and Emerging Roles of Whole-Body MRI in Evaluation of Pediatric Cancer Patients [23], Gottumukkala et al Radiographics 2019 Jan 25:180130.

Diagnostic Performance of 18F-FDG PET/CT and Whole-Body Diffusion-Weighted Imaging with Background Body Suppression (DWIBS) in Detection of Lymph Node and Bone Metastases from Pediatric Neuroblastoma [24], Ishiguchi et al Ann Nucl Med 2018, 32:348-362.

Microscopically Positive Resection Margin after Hepatoblastoma Resection: What is the Impact on Prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) Report [25]
Aronson et al Eur J Cancer 106: 126-132, 2019.

In this article, Aronson retrospectively reviewed the patients from SIOPEL 2 (1994 to 1998) and 3 (1998 to 2006) trials and evaluated the impact of microscopically positive resection margins on outcomes. All patients, regardless of tumor size, received multiple cycles of preoperative cisplatin based chemotherapy. There were 312 SIOPEL standard risk patients and 117 SIOPEL high risk patients. Of the 371 patients who achieved a gross complete surgical resection, 58 had microscopically positive margins. An additional 11 had gross residual tumor. Fifty-one patients underwent complete hepatectomy and liver transplantation. With a mean followup of 67 months, local tumor recurrence was 3/58 (5.1%) for patients with microscopically positive resection margins versus 23/371 (6.1%) for tumors that with negative microscopic margins. The five-year event free and overall survival rates were 86% versus 86%, and 91% versus 92% for patients with microscopically positive resection margins and patients with complete resections, respectively. No statistically significant differences in event free and overall survival were observed with subgroup analysis with standard risks and high risks patients. The goal of surgical resection in hepatoblastoma is a complete resection however this retrospective analysis shows that microscopic positive margins seem to have similar outcomes when patients have received postoperative chemotherapy. According to the study reports, no additional measures were taken in the treatment of the patients who had positive microscopic margins.

2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT) [26], Towbin et al Pediatr Radiol 48:536-554, 2018.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration [27], Meyers et al Lancet Oncol 18:122-131, 2017.

Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children’s Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children’s Oncology Group [28], O’Neill et al J Clin Oncol 35:3465-3473, 2017.

Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children’s Oncology Group [29], Appel et al J Clin Oncol 2016 Jul 10;34(20):2372-9.

Children and Adolescents with Marginal Zone Lymphoma have an Excellent Prognosis with Limited Chemotherapy or a Watch-and-Wait Strategy after Complete Resection [30], Ronceray et al Pediatr Blood Cancer 2018 Apr;65(4).

Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015 [31], Turcotte et al JAMA. 2017 317:814-824.

This report studies the long term risk of secondary neoplasms. Briefly, patients who were younger than 21 years of age at time of diagnosis and with an initial diagnosis of leukemia, Hodgkin lymphoma, nonHodgkin lymphoma, central nervous system tumor, Wilms tumor, neuroblastoma, rhabdomyosarcoma or bone cancer were included in the study. The study included patients treated in the United States or Canada between 1970 and 1999. The primary outcome was the cumulative incidence of subsequent neoplasms after treatment and by treatment decades. The most common primary cancers were acute lymphoblastic leukemia, Hodgkin lymphoma and astrocytoma. The most frequently observed subsequent malignancies were breast and thyroid cancers. During the three decades, radiation therapy decreased and the doses of anthracyclines and alkylating agents decreased – even though the number of children treated with these chemotherapeutic agents increased. At 15 years after their initials diagnosis, patients in this cohort had an incidence of subsequent neoplasms of 2.9%, 2.4% and 1.5% if treated during the first, second and third decade respectively. Survivors treated with radiation had the highest cumulative incidence of secondary neoplasm. Female survivors had a relative risk of 1.7 for subsequent malignant neoplasms compared to their male counterparts. Radiation at any dose and alkylating agents were associated with increased risks of malignant neoplasms. The incidence of subsequent neoplasms decreased over five year increments and was associated most significantly with a decrease in the dose of radiation therapy.

Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study [32], Laverdière et al J Natl Cancer Inst 2009 101:1131-40.

Risk of Adverse Health and Social Outcomes Up to 50 Years After Wilms Tumor: The British Childhood Cancer Survivor Study [33], Wong et al J Clin Oncol 2016 34:1772-9.

Breast Cancer After Chest Radiation Therapy for Childhood Cancer [34], Moskowitz et al J Clin Oncol 2014 32:2217-23.

Chronic Health Conditions in Adult Survivors of Childhood Cancer [35], Oeffinger et al N Engl J Med 2006 355:1572-82.

Final Report of Sentinel Node Biopsy versus Nodal Observation in Melanoma [36], Morton et al N Engl J Med 2014;370:599-609

This report describes a randomized phase 3 clinical trial, the Multicenter Selective Lymphadenopathy Trial (MSLT-I), in which adult patients with intermediate thickness or thick primary localized melanoma were randomized to undergo wide local excision with sentinel lymph node biopsy or wide local excision and nodal observation. The purpose of this trial was to determine whether sentinel lymph node biopsy could be used to identify occult nodal metastases. The 10-year disease free survival rates were significantly improved in the sentinel lymph node biopsy group compared to the observation group for both intermediate thickness and thick melanomas. This pivotal trial validated the prognostic value of sentinel lymph node biopsy for localized intermediate thickness and thick melanomas and identified patients who may benefit from immediate completion lymphadenectomy. Biopsy based management led to improved disease-free survival in this trial.

Completion Dissection of Observation for Sentinel Node Metastasis in Melanoma [37],Faries et al N Engl J Med 2017; 376:2211-2222.

This second Multicenter Selective Lymphadenopathy Trial (MSLT-II) built upon the foundation of MSLT-I, which had validated the prognostic utility of sentinel lymph node biopsy for patients with intermediate thickness and thick localized melanoma. This phase 3 clinical trial randomized patients with cutaneous melanoma and sentinel node metastases to either immediate completion lymph node dissection or nodal observation with ultrasonography, with the primary end point of melanoma-specific survival. In both intention-to-treat and per-protocol analyses, immediate completion lymph node dissection was not associated with improved melanoma-specific survival. The 3-year melanoma specific survival in both groups was 86% (p=0.42). The rate of disease-free survival was slightly improved in the immediate dissection group (68%) compared to the observation group (63%) (p=0.05). The rate of lymphedema was 24% in the dissection group compared to 6.3% in the observation group. This trial demonstrated that immediate completion lymph node dissection increased the rate of regional disease control but did not improve melanoma specific survival among patients with melanoma and sentinel lymph node metastases.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update [38], Wong et al Ann Surg Oncol 2018; 25:356-377.

The purpose of this report was to provide expert panel recommendations for guidelines regarding sentinel lymph node biopsy and the need for completion lymph node dissection in adult patients with melanoma. A systematic review of the literature was conducted which included nine observational studies, two systematic reviews and three randomized controlled trials. Recommendations based upon the included relevant studies included indications for sentinel lymph node biopsy for T1b, T2, T3 and some T4 lesions. The panel concluded that for positive sentinel lymph node biopsy, completion lymph node dissection or nodal observation are reasonable options following careful consideration of tumor- and patient-specific clinicopathological factors.

Pediatric Patients with Cutaneous Melanoma: A European Study [39], Brecht et al Pediatr Blood Cancer 2018 Jan

The authors report results from a multinational retrospective study performed by EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) on pediatric cutaneous melanoma. A registry was used to prospectively collect data from certified multinational centers between 2002-2012. Inclusion criteria were as follows: histologically confirmed diagnosis of cutaneous melanoma, age less than 18 years, a follow up of longer than three months and time of diagnosis between 2002 and 2012. 219 patients were included. Data was collected on clinical findings (Clark level, Breslow thickness, ulceration and nodal status) and all patients were reclassified according to the adult American Joint Committee on Cancer (AJCC) staging system. Overall 112 patients underwent SLNB (51%), SLNB was positive in 42 patients (37.5% of those with SLNB). Adjuvant therapy was used in only 33 patients (61% of patients with advanced disease- AJCC stage III/IV). Adjuvant therapies included: interferon alpha (19 patients), immunotherapy (four patients), chemotherapy plus interferon alpha (2 pts), and chemotherapy and Vemurafenib (one patient). There was no significant difference in disease free survival (DFS) or overall survival (OS) between groups treated with adjuvant therapy and those not treated with adjuvant therapy. For all patients, the OS and DFS at 3 years was 91.4% and 84% respectively at median follow up of 41.8 months. Tumor site, ulceration status, tumor size, nodal status and AJCC stage all had a significant influence on DFS which is similar to adult outcome trends. Age at diagnosis did not correlate with survival. The significance of this study is it suggests that pediatric melanomas may behave similar to adult melanomas.

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria [40], Dika et al Pediatr Derm. Vol. 34 No. 1 25-32, 2017.

The authors conducted a PubMed and Cochrane database search to review the current literature on the clinical, dermatoscopic, genetic and histopathologic aspects of spitzoid tumors. While the authors did not adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, they provide a well written summary of an often confusing topic for pediatric surgeons: Spitzoid tumors in children. Spitzoid neoplasms usually affect young patients (less than 20 years of age), are typically solitary lesions and most often occur on the head and neck and extremities. Spitz nevi are benign melanocytic neoplasms characterized by epithelioid or spindle melanocytes or both. Atypical spitz tumors (ASTs) are characterized by atypical histologic features (asymmetric and poorly circumscribed shape, thicker and deeper extension, ulceration, lack or absence of Kamino bodies and the presence of more than 6 mitoses/mm2) and include cases of positive sentinel lymph node(s); however, sentinel lymph node positivity has not been associated with a bad prognosis in ASTs as is the case with malignant melanoma. The article also summarizes the immunohistochemical and cytogenetic similarities and differences between Spitz nevi, ASTs and malignant melanoma. Spitz nevi may spontaneously involute in up to 80% of cases and conservative management with periodic clinical and dermatoscopic follow-up is recommended. Surgical excision is reserved for children with suspicious lesions including those with atypical features (large lesions, ulceration, asymmetry, rapid growth). If the pathologic diagnosis after excision is benign Spitz nevus, no follow-up is required except annual exams. If the pathologic diagnosis is AST, annual clinical exams with periodic nodal ultrasonagraphy is usually sufficient. The utility of sentinel lymph node biopsy in cases of AST is still debated. It is important that highly skilled dermatopathology and molecular characterization be used in the study of spitzoid tumors.

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer [41], Francis et al Thyroid 2015:25, 716-760.

This manuscript is the result of an independent task force commissioned by the American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer to develop recommendations for the treatment of pediatric thyroid nodules and cancers based on an extensive review of the existing literature (405 references). This extensive review provides 34 rated and referenced recommendations and algorithms for the preoperative evaluation, surgical intervention, postoperative treatment and long term care of children and adolescents with thyroid nodules and differentiated (papillary and follicular) thyroid cancer.

Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia Type 2A [42], Skinner et al N Engl J Med. 2005 Sep 15;353(11):1105-13.

The authors evaluate the timing of total thyroidectomy to prevent medullary thyroid carcinoma in 50 children know to have inherited a mutated RET allele characteristic of MEN2a. All patients underwent preoperative calcitonin testing, total thyroidectomy and long term evaluation for persistent or recurrent disease five years or more after total thyroidectomy by calcitonin testing (with pentagastrin or calcium stimulation). Older children were more likely to have elevated preoperative calcitonin levels (median age 11years) and microscopic and/or macroscopic evidence of medullary thyroid cancer (median age 10 years) at operation. In 88% of patients, there was no evidence of persistent or recurrent medullary thyroid cancer by calcitonin testing at five years or longer postoperatively. No child who had resection prior to eight years of age and had no nodal involvement showed evidence of recurrent or persistent disease by calcitonin testing or exam. While this work is one of the initial publications demonstrating the efficacy of early total thyroidectomy for the kindred of MEN2a families with RET oncogene mutation in prevention of medullary thyroid cancer, subsequent work has refined the recommended age of resection be based on the particular RET codon mutation identified as summarized in Wells et al Thyroid; 2015:25, 567-610 (Recommendations 33-36).

Predictors of Nodal Metastasis in Pediatric Differentiated Thyroid Cancer [43], Kim et al J Pediatr Surg 2017 Jan;52(1):120-123.

The authors present a SEER database review of 1,075 children with differentiated thyroid cancer to assess for clinical findings associated with nodal involvement. Their data suggest nodal metastasis in children with differentiated thyroid cancer is associated with larger tumor size (greater than 1.1cm OR 2.02, 95% CI 1.22-3.34, p=0.006), extrathyroidal disease (OR 7.28, 95% CI 4.04-13.01, p< 0.001) and multifocal disease (OR 1.94, 95% CI 1.33-2.84, p=0.001). Follicular thyroid carcinoma and Hürthle cell carcinoma were associated with lower risk of nodal involvement compared to papillary (OR 0.05, 95% CI 0.02-0.19, p< 0.001). Age, sex and race were not associated with increased risk of nodal involvement in differentiated pediatric thyroid cancers.

18F-Fluorodeoxygludose Positron Emission Tomography/Computed Tomography May Exclude Malignancy in Sonographically Suspicious and Scintigraphically Hypofunctional Thyroid Nodules and Reduce Unnecessary Thyroid Surgeries [44], Ruhlmann et al Thyroid 2017 Oct;27(10):1300-1306.

This paper out of Germany is a retrospective study specifically looking at an adult population (65 patients) that had a thyroid nodule that was ultrasound suspicious (TIRAD 4a or greater), Tc-99 negative (cold nodule) and refused, for a variety of reasons, to undergo an fine needle aspiration (FNA). Instead all patients underwent a PET/CT. In 18/65 the PET/CT was positive and patients underwent lobectomy or total thyroidectomy with malignancy detected in 11 of the 18. Of the remaining 47 patients that were PET/CT negative, ultrasound was used for a minimum of five years of follow up and all showed no growth. Thus the PPV was 61% and the NPV was 100%. The significance of this paper, especially in the pediatric population, is that it provides another potential avenue of work up for patients besides an FNA to reliably exclude a thyroid nodule as being malignant and potentially avoid an unnecessary operation. Another potential advantage would be in patients that undergo an FNA and have indeterminate pathology.

Validation of American Thyroid Association Ultrasound Risk Assessment of Thyroid Nodules Selected for Ultrasound Fine-Needle Aspiration [45], Tang et al Thyroid 2017 Aug;27(8):1077-1082.

In 2015, the American Thyroid Association produced the inaugural guidelines for the management of thyroid nodules and differentiated thyroid cancer in children and updated the adult guidelines. Within both, ultrasound is recommended to both determine size and appearance of the nodule with certain sonographic features associated with a malignancy including microcalcifications, taller-than-wide shape, marked hypoechogenicity and irregular margins. Features associated with benign pathology include purely cystic and spongiform appearance. Depending upon size and characteristics, the risk of malignancy is broken down into high (70 to 90%), intermediate (10 to 20%), low (5 to 10%), very low (less than 3%), and benign (less than 1%). In this study, from March of 2015 to May of 2016, 211 nodules were prospectively evaluated with ultrasound (US) and fine needle aspiration. The proportion of nodules that were cytologically malignant or suspicious of malignancy correlated with the US risk pattern: high (77%), intermediate (6%), low (1%) and very low (0%). Also of note within the study, there were 71 nodules with “indeterminate” cytology. Of those that eventually underwent removal, if the US findings were categorized as high, there was a 100% incidence of malignancy. The significance of this study is that it validates the ATA guidelines and will be useful for providing reliable data in discussions with families about risks assessment for thyroid nodules and treatment recommendations.

Pancreaticoduodenectomy for malignancies in children [46], d’Ambrosio et al J Pediatr Surg 2014 Apr;49(4):534-8.

This case series examined five patients who underwent pancreaticoduodenectomy (PD) for malignant tumors. Pathologic diagnoses varied with two patients with pancreatic acinar cell carcinomas, one with a solid pseudopapillary tumor and two patients with rhabdomyosarcoma (RMS) of bile ducts. The patients with RMS of bile ducts also required hepatic resection. Pyloric preservation was performed when possible. Reconstruction of the pancreatic stump was done with intussusception into the roux loop. They noted that four of five patients were on full feeds by second week postoperatively and did not note any dumping syndrome symptoms. Pancreatic enzymatic supplementation was required in three of five children. Two patients developed strictures of the pancreaticojejunal anastomosis and required reoperative surgery. Two patients who underwent surgery for RMS of bile ducts died of disease - the rest are alive and free of disease.

Pancreaticoduodenectomy outcomes in the pediatric, adolescent, and young adult population [47], Mansfield et al J Surg Res 2016 Jul;204(1):232-6.

This study examined a single institution outcome of pediatric, adolescent and young adult patients undergoing pancreaticoduodenectomy over a 15-year period. Twenty-two patients were identified with a median age of 25 years. Eighteen patients had a mass of the pancreas with a mean tumor size of 4.0 cm. Of the patients with pancreatic malignancy one patient required reoperation due to stricture of the hepaticojejunostomy. The most common postoperative complication was intra-abdominal abscess (occurring in three patients) and one pancreatic leak. No patients died within the first 30 days and in observational cohort of adults from the same institution was included for qualitative comparison noting that the pediatric population had a favorable side effect profile.

Pancreaticoduodenectomy for pediatric and adolescent pancreatic malignancy: A single-center retrospective analysis [48], Lindholm et al J Pediatr Surg 2017 Feb;52(2):299-303.

A single center review article of all patients less than 18 years of age over a 22 year span who underwent pancreaticoduodenectomy (PD). Twelve patients were identified in this series. Four patients had previous operations and required PD for recurrent disease. Diagnoses included pancreaticoblastoma (3), Solid pseudopapillary toumor (3), neuroblastoma (2), rhabdomyosarcoma (2) and PNET (2). In 8/12 patients a PD was performed as resection of primary disease and four patients underwent PD to treat metastatic disease in the head of the pancreas. 9/12 patients had underwent preoperative chemo- or radiation therapy. Pylorus sparing procedures were performed in all patients. Pancreatic reconstruction varied with the distal pancreas invaginated into posterior stomach (3), end of the jejunum (3) or sewn to jejunal mucosa (4) . Transfusion was required in half of all patients. Mean length of stay was 10.6 days. Immediate postoperative complications included one intraperitoneal abscess and one patient developed a leak. Long term complications included 10/12 patients requiring pancreatic enzyme supplementation. Delayed gastric emptying was reported in two patients. Five patients with solid pseudopapillary tumor or RMS were long term survivors.

A population-based analysis of a rare oncologic entity, malignant pancreatic tumors in children [49], Mylonas et al J Ped Surg 2014 Oct; 49(12): 1730-3.

The authors used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to identify 114 patients with pancreatic malignancies. Pancreaticoblastomas were most common in children less than 10 years of age while neuroendocrine tumors were the most frequent cell type overall. The overall five-year survival rates for these cell types were 77% and 66%, respectively. Epithelial malignancies were more common in adolescents as were solid pseudopapillary tumors. Controlling for metastatic disease, cancer directed surgery was associated with an improved overall survival.

Solid-pseudopapillary neoplasm of the pancreas in children: Can we predict malignancy? [50], Hwang et al J Ped Surg 2014; 49, 1730-3.

This single institution paper reviews 45 children with solid pseudopapillary neoplasms of the liver who had undergone resection. All children had at least one computerized tomography scan. The median age at treatment was 15 years. Of the cohort, nine had malignant histologic features and three had clinically evident malignant features with peripancreatic soft tissue invasion. Surgical resections included a Whipple variant (27%), distal pancreatectomy (47%) or lesser pancreatic resection (26%). Of the 45 patients, four recurred and were treated aggressively with further surgical resection. Patients with malignant features were larger (10 cm versus 5 cm) and had a higher median solid component ( 88.5% versus 41.5%). Median follow up was 34 months. There were no deaths reported.

Pancreatic tumours in children: diagnosis, treatment and outcome [51], Nasher et al Pediatr Surg Int 2015 Sep;31(9):831-5.

This is a single institution retrospective review over a period of 38 years. There were only 14 patients during this period of whom 12 had complete records. They also reference 41 cases of pancreatic tumors reported to the UK National Registry of Childhood Tumours from 1971 to 2000. The histology of cases in the single center were primarily solid pseudopapillary neoplasms and endocrine pancreatic neoplasms. The diagnoses were very different in the national registry with 11 of 41 (27%) cases being pancreatoblastoma. Specific description of surgical resections and long term outcomes were not provided but it is noteworthy that of 12 with surgical resection, five had an uneventful recovery and there were two pseudocysts, one peripancreatic fluid collection, one hemorrhagic pancreatitis and one death with two unknown outcomes. The conclusion that laparoscopic resection is optimal therapy is not supported by the data presented.

A Prospective, Holistic, Multicenter Approach to Tracking and Understanding Bloodstream Infections in Pediatric Hematology-Oncology Patients [52], Gaur et al
Infect Control Hosp Epidemiol 2017 Apr 12:1-7.

This article reviews and classifies data on 1110 blood stream infections (BSI) from 39 pediatric hematology-oncology units (Childhood Cancer and Blood Disorders Network) collected over 25 months to define the relative contribution of central line associated BSI (CLABSI) to overall BSIs in this population. All centers followed a standardized central line maintenance care bundle for at least two years prior to the study period. BSI events and central line days were tracked monthly. Patients with a positive blood culture and central venous access were assigned to a specific category using National Healthcare Safety Network (NHSN) definitions: CLABSI; secondary BSI; and single positive blood cultures (SPBC). CLABSI infections were further divided into mucosal barrier injury related lab confirmed BSI [MBI-LCBI] and nonMBI-LCBI. 63.8% of all BSIs were designated as CLABSIs, 15.3% were secondary BSIs and 20.9% were SPBCs. 51% of CLABSIs were MBI-LCBI. 65% of non-MBI-LCBI, 91% of MBI-LCBI, 82% of secondary BSI and 75% of SPBC were associated with neutropenia (absolute neutrophil count less than 100 cells/mL). SPBC were associated with Staphylococcus species (54%) and viridans group streptococci (22%). Significantly higher CLABSI rates (88%) and lower secondary BSI rates (12%) were identified over time related to an NHSN update for the definition of BSI.

These data define the contribution of CLABSI to overall BSIs in the pediatric Hematology-Oncology population in a multi-institutional group utilizing a well established standardized central line maintenance care bundle. Identification and removal of MBI-LCBI from CLABSIs appears to reduce the overall CLABSI rate by approximately 50%. The authors suggest "while public reporting of CLABSIs as preventable health-associated infections should continue, the messaging should include the overall context of BSIs and the limits of the definitions used, such that informed interpretations of the reported data can be made."

Preventing CLABSIs among Pediatric Hematology/Oncology Inpatients: National Collaborative Results [53], Bundy et al Pediatr 2014 Dec;134(6):e1678-85.

This study describes implementation a standardized bundle of central venous access care practices and CLABSI surveillance within a 32 Pediatric Hematology/ Oncology collaborative. Pre- and postimplementation rates of central venous line (CVL) infection are documented using Centers for Disease Control and National Healthcare Safety Network (NHSN) surveillance definitions. Baseline CLABSI rate (collected over four years) was 2.85 CLABSIs per 1000 CL-days; by 34 months after adoption the bundle by the collaborative group the mean CLABSI rate was significantly reduced to 2.04 CLABSIs per 1000 CL-days, a reduction of 28% (relative risk: 0.71 [95% confidence interval: 0.55-0.92]). Compliance with CLABSI bundle was initially 38% but increased to 78% within one year. Compliance remained 81% to 86% throughout the remainder of the reporting period without statistically significant changes in CLABSI rates. The odds of a ‘CLABSI-free’ month for any participating unit after implementation of the care bundle were 2.59x the corresponding odds of CLABSI infection during the pre-implementation period when comparing units of similar CVL days. This study demonstrates the feasibility of implementing a standardized CVL maintenance care bundle program in a large collaborative group of pediatric hematology/oncology units and the efficacy of such a program in reducing CLABSIs in the Pediatric hematology/oncology population.

Central Venous Catheter Care for the Patient with Cancer: American Society of Clinical Oncology Clinical Practice Guideline [54], Schiffer et al J Clin Oncol 2013 April 1:31(10);1357-1370.

This paper summarizes the guidelines that were created by the American Society of Clinical Oncology to help practitioners in central venous catheter (CVC) management in patients with cancer including both children and adults. Recommendations were based upon MEDLINE and Cochrane Collaboration Library literature search covering the years 1980 to 2012 and discussions amongst an expert panel. The review included 108 RCT, 25 meta-analyses, and several existing guidelines. The key recommendations include 1) avoidance of femoral vein insertion except for emergencies, 2) CVC’s should be placed by well-trained providers but method of placement (image guided versus landmark) is practitioner dependent, 3) use of a CVC clinical care bundle is recommended to decrease BSI, 4) prophylactic use of systemic antibiotics at the time of insertion is not recommended, 5) if infection is suspected cultures should be obtained prior to starting antibiotics and most BSI’s can be managed with appropriate antimicrobial therapy with catheter removal considered when the infection involves the port or catheter tubing, or if infection with fungi or nontuberculous mycobacteria, or is persistent bacteremia more than 48 to 72 hours after appropriate antimicrobial treatment, 6) routine flushing with saline is recommended, 7) systemic anticoagulation does not appear to decrease CVC related thrombosis and is not recommended, 8) TPA is recommended to restore patency in a nonfunctioning CVC and removal of a CVC in the face of a radiologically confirmed thrombosis that does not respond to three to six months of anticoagulation.

Long-term Central Venous Access in a Pediatric Leukemia Population [55], Fu et al J Surg Res 2016 Oct;205:419-425.

This article is a retrospective review covering all central venous access devices (CVAD) from a single institution over a five year period (2009 to 2014) that were placed in leukemia patients (ALL/AML) and reviewing both perioperative and long term complications associated with the lines with the primary focus being on reasons for removal. This included 292 CVAD’s (240 ports and 52 tunneled lines) for a total of 142,607 catheter days. In the perioperative period 10 catheters were malpositioned and required intervention. No conclusion was reached on how to prevent the malposition but size of the catheter, port versus tunneled line, position of the reservoir on the chest wall, vessel used, or technique were found to be predictors of malposition. With respect to long term complications, 70% had some form of complication with unexplained catheter malfunction (39.7%), infection (31.8%), fibrin sheath (5.1%), and DVT (2.4%) being the top four. A total of 75 lines (25.7%) were removed prematurely as a result of these complications. On multivariate analysis, obesity, preoperative blood transfusion, infection, and unexplained line malfunction were the only factors associated with premature catheter removal. In terms of modifiable factors for the pediatric surgeon, on univariate analysis, port placement below the nipple line (less risk for unexplained catheter malfunction) and delay in placement of the implanted line (use of a PICC first) were associated with less catheters removed prematurely. This study highlights the potential struggles with CVAD in a very fragile population of patients.

Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Change Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies [56], Murawski et al J Clin Oncol. 2016 Apr 1;34(10):1050-6.

This article reports the results of the two most recent prospective International Childhood Liver Tumor Strategy Group trials (SIOPEL 2 and 3). Of 85 patients with hepatocellular carcinoma (HCC), 13 underwent upfront resection and 72 were treated with intensified platinum- and doxorubicin- based neoadjuvant chemotherapy (NAC) regimens in order to render the tumors resectable. Twenty-nine (40%) of the 72 patients had an objective response, but only in 2 (3%) patients did initially unresectable tumors become resectable with NAC. Including 7 patients who had liver transplants (LTX), 34 (40%) of 85 patients had complete resection with negative margins. Overall 5-year survival was dismal at 22%, but 18 (63%) of 27 patients survived after margin-negative resection, 1 of 7 patients (14%) survived with microscopic residual disease after resection, and 2 of 7 patients (29%) survived after LTX. Complete resection was associated with survival (P=0.035). The authors concluded that patients with resectable HCC should undergo upfront resection, that intensified NAC did not improve the survival in patients with HCC, and that LTX is a suitable option for patients with unresectable, non-metastatic HCC and should be considered early after diagnosis.

Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma [57], Honeyman et al Science 2014 Feb 28:343(6174):1010-4.

Fibrolamellar HCC (FL-HCC) is a rare histologic variant of HCC affecting adolescents with no underlying liver disease. Despite its distinct histologic appearance, it shares a poor outcome. This paper documents the discovery of a unique, highly conserved chimeric protein found in all 15 FL-HCC tumors tested. Although there was some variation in the break points, the protein is the product of a 400kb pair deletion on chromosome 19, which joins the promoter and first exon of DNAJB1, a member of the heat shock 40 protein family, to exons 2 to 10 of PRKACA, protein kinase A catalytic subunit alpha. Protein kinase A normally exists in tetramers of catalytic and regulatory subunits. The chimera retains the phosphorylation capacity of PKA, but loses the ability to bind to and be regulated by the regulatory subunit. This retained function, its overexpression in tumor cells compared to wild-type PRKACA, and its presence in 100% of the tumors tested leads the authors to conclude that this is a driving mutation in the development of FL-HCC. The authors also conclude that this distinct DNA, RNA, and protein anomaly may offer a diagnostic and therapeutic target for FL-HCC going forward.

Hepatic Metastasectomy in Children [58], Su et al Cancer 2007 May 15;109(10):2089-93.

While hepatic metastasectomy has proven beneficial in several adult tumors, its use in pediatric solid tumors has been reported much less frequently. This paper reviews the surgical and long-term outcome of 15 patients undergoing hepatic metastasectomy for pediatric solid tumors. The average age at hepatic resection was 6.2 years, 6 of 15 patients had concurrent metastases to other organs, and 12 of 15 resections (80%) were anatomic. There were no intra- or post-operative deaths, and only two minor complications occurred (1 wound infection, 1 biloma). Median survival after hepatic resection was 9 months, only 3 of 15 patients (20%) were long-term survivors, and all deaths were due to disease progression or treatment complications. The authors conclude that, although hepatic metastasectomy in pediatric solid tumors are safe, they must be performed in highly selected patients, preferably with control of the primary site and no evidence of disease outside the liver.

Characteristics and Outcomes in Children with Undifferentiated Embryonal Sarcoma of the Liver: A Report from the National Cancer Database [59], Shi et al Pediatr Blood Cancer 2017 Apr 64(4).

This article is the largest retrospective study of children with undifferentiated embryonal sarcoma of the liver through the National Cancer Database. The authors show a cohort of 103 patients < 18 years. The overall survival (OS) of the group of patients was 86% at 5 years. Children who had combined therapy that included surgical resection and chemotherapy had a 5-year OS of 92%. Best outcomes were associated with tumors smaller than 15cm and surgical resection (with or without chemotherapy). Only 1 of the 22 patients who underwent lymph node sampling was found to have disease within the node. Surgical margins did not correlate with outcome. Metastatic disease was present in 10 patients, and these patients had a 5-year OS of 86% compared to 91% among patients without metastasis. Ten patients underwent liver transplantation as primary treatment and are all alive at 5 years. Of these 10 patients, 9 had chemotherapy in addition to transplant. The multivariate analysis revealed that tumors smaller than 15 cm and combined therapy (surgery and chemotherapy) were independent prognostic indicators associated with the best outcomes.

Widening Spectrum of Liver Angiosarcoma in Children [60], Ackermann et al J Pediatr Gastroenterol Nutr 2011 Dec 53(6): 615-9.

Angiosarcoma of the liver is a rare but very rapidly progressing malignancy seen in children. Due to the relationship with hemangioma and hemangioendothelioma of the liver, which are more commonly seen, it is important to understand scenarios in which patients may be at higher risk of angiosarcoma. This article discusses 3 cases in which children presented with multinodular hemangiomas of the liver that initially responded to nonoperative management including steroid therapy and/or hepatic artery embolization. However, after a period of time, relapse occurred with rapidly progressing metastatic disease and death. These patients were all diagnosed with type 2 hemangioendothelioma or angiosarcoma. The last 2 cases discussed are children presenting after 1 year of age with vascular tumors within the liver. The first patient underwent hemihepatectomy but disease recurred in the liver and lungs and the patient died. The second patient underwent liver transplantation and is alive. Both of these patients also had histologically confirmed angiosarcoma. This paper describes the interesting evolution of hepatic vascular tumors and highlights the potential for multinodular hemangiomas to recur as angiosarcoma, as well as the possibility of tumor sampling error in presumed benign hemangioendothelioma that can miss the angiosarcoma component.

Inflammatory Myofibroblastic Tumor of the Liver in Children [61], Nagarajan et al J Pediatr Gastroenterol Nutr 2013 Sept 57(3): 277-80.

Inflammatory myofibroblastic tumors (IMT) are characterized histologically as spindle cell proliferation with chronic inflammatory infiltrate of plasma cells, lymphocytes, and histiocytes. The tumor is considered benign but in many cases can be locally aggressive. The tumor can arise anywhere in the body and some occur in the liver. The authors present a review of IMT in the liver in children between the ages of 3 months to 15 years, based on data from 35 patients reported in the literature from 1971-2008. Forty percent of patients presented with fever and abdominal pain. Three patients in the published reports experienced resolution of the tumor with NSAID, antibiotic, or no therapy (observation). The majority of patients underwent surgical resection with 6 patients undergoing liver transplantation and all patients surviving without recurrence (minimum follow-up time of 6 months). About 50% of IMT patients are believed to have a gene rearrangement of the anaplastic lymphoma kinase gene, and crizotinib has been used for nonoperative management in these cases with varying results.

Rhabdoid Tumors of the Liver: Rare, Aggressive, and Poorly Responsive to Standard Cytotoxic Chemotherapy [62], Trobaugh-Lotario et al Pediatr Blood Cancer 2011;57:423-8.

This literature review of all published English-language reports from 1970-2010 identified 34 patients with rhabdoid tumor of the liver. The median age at diagnosis was 8 months, the majority of patients had systemic symptoms (fever/lethargy/anorexia/vomiting), and serum AFP was normal or minimally elevated. All 10 tumors tested harbored INI1mutations, now considered necessary for rhabdoid diagnosis. Five (17%) of 29 patients presented with evidence of tumor rupture at diagnosis, and 21 (62%) of 34 patients had metastatic disease at diagnosis. Survival was poor with only 4 (12%) of 34 patients reported surviving. Median time to death from diagnosis was 2 months and nearly all deaths occurred within 1 year of diagnosis. The authors conclude that these tumors are aggressive and poorly responsive to chemotherapy and radiation. They recommend aggressive surgical treatment and intensive chemotherapy to have a chance at cure.

The Evolution of Diagnosis and Management of Pediatric Biliary Tract Rhabdomyosarcoma [63], Curr Pediatr Rev 2016 Jan 17;12:190-98.

This review summarizes decades of reports of this very rare tumor. Although it comprises only 1% of pediatric rhabdomyosarcoma (RMS), biliary tract RMS (BT-RMS) is the most common neoplastic cause of biliary tract obstruction in children. BT-RMS presents at a median age of 3 years, has a slight male predominance, and patients present with jaundice 60-80% of the time. Patients frequently have a conjugated hyperbilirubinemia and an elevated alkaline phosphatase. The diagnosis of BT-RMS is frequently missed due to its rarity and its ability to mimic the more common, benign choledochal cyst in presentation and imaging. The use of CT, MRI, and MRCP can aid in this differential, and any of these showing a soft tissue mass in the porta hepatis should rule out choledochal cyst and raise suspicion for a neoplastic process. Appropriate staging is described, and the importance of biopsy without upfront radical surgery is emphasized. Treatment with RMS-directed chemotherapy and selective radiotherapy and surgery for local control on a case-by-case basis is advocated as the best approach to this rare tumor, which has a good overall survival.

Preserving Fertility in Children and Adolescents with Cancer [64], Children (Basel). 2014 Aug 26;1(2):166-85.

This review paper highlights important concepts regarding approaches to preserving fertility in pediatric oncology patients. The author outlines the importance of fertility preservation programs in the setting of continuously improving survivorship of childhood cancers. Barriers to comprehensive discussion of fertility preservation with pediatric patients and their families by health care professionals are discussed. The author reviews the risks for gonadal toxicity in female patients with oncologic diagnoses, including the concepts of acute ovarian failure and premature menopause. The processes of embryo and oocyte cryopreservation for fertility preservation in post-pubertal females are discussed, as is the approach of ovarian tissue cryopreservation for pre-pubertal females. The importance of monitoring of ovarian function after completion of therapy is outlined. The author reviews the risks for gonadal toxicity in males, as well as the concept of sperm cryopreservation. Algorithms of fertility preservation options for female and for male pediatric patients are presented. The importance of appropriate institutional infrastructure and collaboration between oncologists and reproductive endocrinology experts is discussed in the context of assuring pediatric oncology patients access to fertility preservation programs. An excellent overall review of fertility preservation in children and adolescents with cancer.

Ovarian tissue collection for cryopreservation in pediatric age: laparoscopic technical tips [65], Lima et al J Pediatr Adolesc Gynecol 2014 Apr;27(2):95-7.

This article focuses on surgical technique for collection of ovarian tissue for cryopreservation in the pediatric population. The importance of consideration of approaches to fertility preservation for girls who may sustain chemotherapy- or radiotherapy-induced gonadal toxicity is highlighted. The authors describe their 11-year experience with the use of laparoscopic ovarian tissue collection. They discuss reasoning for their port selection, their rationale for specimen collection from both ovaries, and their technical tips for cutting into the ovaries and achieving hemostasis. They also discuss options for transposition of the ovaries in order to reduce follicle damage in the ovarian tissue left in situ, in cases in which children require pelvic radiotherapy as part of their oncology treatment regimen. A very useful paper to familiarize the pediatric surgeon with the surgical technique for ovarian tissue cryopreservation.

Progress and Prospects for Fertility Preservation in Prepubertal Boys with Cancer [66], Gies et al Curr Opin Endocrinol Diabetes Obes 2015, 22:203-208.

This article is a nice review of what is currently available to the prepubertal boy who is to undergo cancer therapy. According to this paper males have a 46% overall reduction in the likelihood of siring a pregnancy after cancer treatment. The article discusses the option of cryopreservation of spematogonial stem cells (SSC’s) and subsequent autotransplantation. This procedure was first described in mice in 1994. The article goes into detail about the potential cryopreservation techniques available. Of interest is that they discussed the possibility of transplantation of tumor cells into the testis when reimplantation occurs which is an issue with ovarian tissue as well, especially in patients who had leukemia. The authors recommend one large volume biopsy of the testis for preservation which they explained has less risk of devasularization than multiple small biopsies. At this time they also recommend using the technique only for patients at high risk of infertility since there is a small but real risk of the testicular biopsy. They also weighed the options for timing of reimplantation: peripubertal vs as an adult and recommended waiting until adulthood when it is clear the patient is devoid of spermatogenesis and also after they are cured from cancer. This paper was an excellent overview of techniques available and ethical considerations for fertility preservation in the prepubertal male patient.

Fertility Preservation and Reproductive Health in the Pediatric, Adolescent and Young Adult Female Cancer Patient [67], Trudgen et al Curr Opin Endocrinol Obstet Gynecol 2014, 26: 372-380.

One in 530 young adults between the ages of 20-39 is a survivor of childhood cancer so this topic should be in the forefront of those treating these patients. The article details the expected risk to infertility based on treatment. The high risk group are those treated with: cyclophosphamide, ifosphamide, procarbazine, chorambucil, busulfan, melphalan, nitrogen mustard and those undergoing bone marrow ablative chemotherapy for hematopoietic stem cell transplantation (HSCT). The intermediate risk group includes those treated with: cisplatin, carboplatin, doxorubicin. Low risk category are those treated with bleomycin, Actinomicin D, Hodgkin’s protocols with alkylating agents, ABVD, CHOP, CVP and AML/ALL therapies. Very low risk agents are vincristine, vinblastine, methotrexate and 5-FU. The article addressed the fact that not only cancer patients may be at risk for infertility due to these agents since HSCT is being used in other conditions (such as aplastic anemia, Fanconi anemia). These patients are also at risk for infertility and should be counseled accordingly. This article also explained that Anti-Mullerian Hormone (AMH) is a reliable marker to determine ovarian reserve. Also mentioned are some options on the horizon including pharmacologic stimulation of ovarian function with Gonadotropin releasing hormone agonists, mesenchymal stem cell transplantation and egg freezing techniques for patient who have low but present oocyte counts after chemotherapy. They also mentioned when counseling families, discussion should also mention other options available such as donor oocytes or embryos, gestational surrogates and adoption. Very interesting perspective and review of fertility preservation in the young female patient.

The International Pleuropulmonary Blastoma Registry (PPB Registry)

The PPB Registry is an affiliate of the Rare Tumor Sub-Committee of the Children’s Oncology Group (COG). The Registry collects cases of PPB for COG. It is comprised of physicians, scientists, and data analysts from many institutions who have been working together for 20 years to evaluate cases of PPB. The goal of the registry is to collect information on as many cases of PPB as possible. Through this accumulation of information, we have begun to understand some of the biological and treatment issues of this disease. The website provides comprehensive information for families and physicians on this childhood chest tumor, including current treatment recommendations and practices.

Pleuropulmonary Blastoma: A Report on 350 Central Pathology-Confirmed Pleuropulmonary Blastoma Cases by the International Pleuropulmonary Blastoma Registry [68], Messinger et al Cancer 2015;121:276-85.

This is the largest series of PPB cases from the International PPB Registry reporting on 350 centrally reviewed, pathology confirmed cases. The types of PPB were: 33% type I, 35% type II, and 32% type III (or type II/III). The 5 year OS for type I, 91%; type II, 73%; type III, 53%. The strongest predictors of outcome were the type of PPB and presence of distant metastasis. Of the patients tested, 66% were positive for a heterozygous germline DICER1 mutation; however, presence of a DICER1 mutation did not correlate with outcome. PPB is usually found in infants and young children; however, type Ir (regressed) PPB is a cystic lesion without malignant cells found in an older child with a DICER1 mutation or a relative of a PPB patient. About 10% of type I PPB can progress to type II or III. Tumor spillage at surgery, tumor size, or anaplasia did not affect DFS or OS. Interestingly, presence of pneumothorax was associated with a significantly worse DFS and OS in type II and type III patients. Additionally, neoadjuvant chemotherapy significantly improved DFS in type III patients but had no bearing on OS. Nine percent (n=20) of patients presented with metastatic disease. Forty-four patients (19%) had relapse of disease and relapse was the cause of death in 53% of the patients that died.

Type I Pleuropulmonary Blastoma: A Report from the International Pleuropulmonary Blastoma Registry [69], Priest et al J Clin Oncol 2006 Sep 20;24(27):4492-8.

This retrospective study from the International PPB Registry sought to analyze the outcomes of type I PPB patients. Thirty-eight type I PPB cases were identified from the Registry (n=30) and the literature (n=8). Twenty children had surgery alone; eight (40%) experienced recurrence, of whom four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery and chemotherapy group. However, overall survival did not differ. Recommended management includes complete surgical resection and adjuvant chemotherapy. Recommended surveillance included CT chest every 3-6 months, for up to three years after type I diagnosis, to age five given the observed rapid recurrence rate and growth of tumors.

Can congenital pulmonary airway malformations be distinguished from Type I pleuropulmonary blastoma based on clinical and radiological features? [70], Feinberg et al J Pediatr Surg 2016 Jan;51(1):33-7.

This is a retrospective study comparing a cohort of 103 cystic congenital pulmonary airway malformation (CPAM) patients from a single institution to 113 type I PPB patients from the International Pleuropulmonary Blastoma Registry. The purpose of the study was to compare clinical and radiographic characteristics of each entity to help guide treatment in these patients. Of the CPAM cohort, none of the patients were found to have PPB. Features most significantly associated with CPAM were prenatal diagnosis, presence of a systemic feeding vessel (PPB cohort did not have any with a feeding vessel), and presence of simple cyst. Features significantly associated with type I PPB were symptomatic lesion, no hyperinflation, absence of a systemic feeding vessel, and complex cyst. This paper suggests that routine DICER1 mutation analysis take place for patients being considered for observation to alleviate concern for PPB. Other data suggests that an asymptomatic lesion, no family history of DICER1familial syndrome, and lack of multifocality or bilaterality can be safely observed.

Great Vessel/Cardiac Extension and Tumor Embolism in Pleuropulmonary Blastoma: A Report from the International Pleuropulmonary Blastoma Registry [71], Priest et al Pediatr Blood Cancer 2011 Apr;56(4):604-9.

This study combined 179 type II and III PPB cases from the International Pleuropulmonary Blastoma registry with 200 cases of type II and III PPB in the literature to focus on cases with great vessel or cardiac extension. Eleven (3%) cases were found and examined in this study. Nine cases (81%) involved the left heart circulation, one case the right heart, and one case involved both circulations. A vascular embolic event occurred in 7 (64%) patients where 5 had a post operative cerebrovascular accident (both hemorrhagic or ischemic), 1 patient had acute paraplegia secondary to descending aorta occlusion from clot, and 1 patient with multiple cerebral infarcts and acute femoral artery occlusion. Six of these events were between 0-17 days post operative. Six (86%) of these 7 children died of vascular related events. Two (18%) out of the 11 patients survived and both of these patients had neoadjuvant chemotherapy with tumor shrinkage of both the primary tumor and vascular component. The one patient that died due to disease progression after neoadjuvant chemotherapy and surgery had primary tumor shrinkage with chemotherapy, however, the vascular component did not respond. Brain metastasis were found in 3 of the 6 patients that experienced a cerebrovascular accident. The authors hypothesize that surgery itself may precipitate embolization of tumor and later cerebral metastasis development since 11% of type II and 54% of type III PPB develop cerebral metastasis. None of the patients that underwent neoadjuvant chemotherapy experienced a vascular related event.

DICER1 Mutations in Familial Pleuropulmonary Blastoma [72], Hill et al Science 2009;325:965.

About 20% of children with PPB have a family history of other solid tumors such as cystic nephroma of the kidney or rhabdomyosarcoma. A heterozygous, germline mutation of DICER1 was found in common among 11 families with PPB. Mutation in DICER1 is a loss of function mutation. Developing mice deficient in DICER1 show cystic airways, disruption of bronchial branching, and cellular expansion similar to PPB. DICER1 gene is found on chromosome 14q.

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumor predisposition syndrome [73], Slade et al J Med Genet 2011 Apr;48(4):273-8.

This study was undertaken as part of the FACT (Factors Associated with Childhood Tumours) Study in the United Kingdom. The goals of this study were to 1) understand the contribution of DICER1 mutations to non-familial, sporadic PPB; 2) determine if constitutional DICER1mutations predispose to tumors other than PPB; and 3) ascertain if somatic DICER1 mutations contribute to cancer. The authors performed sequencing of over 1600 samples, including constitutional DNA from over 800 patients with broad types of tumors, focusing on tumors associated with PPB, and sequencing of DICER1 in 781 cancer cell lines. 20 cases of PPB were identified through the National Childhood Tumor Registry, none of whom had a family history of PPB. 14 cases were included in this study. A DICER1 mutation was identified in 11 of these cases. This reinforced the knowledge that DICER1 mutation is the major cause of non-familial and familial PBB. When analyzing other tumors commonly associated with PPB, DICER1mutations were seen in 2/3 cases of cystic nephroma and 3/6 ovarian Sertoli-Leydig cell tumors, indicating that these mutations may play a major role in the development of these tumors also. Furthermore, mutational analysis shows that cancer predisposition results from the haplo-insufficiency mechanism. The study also revealed that the majority of patients with DICER1 mutations are well, and that tumor development is variable. This low penetrance and variable phenotype have led the authors to not advocate for the implementation of routine screening of patients with known DICER1 mutations.

Radiographic Screening of Infants and Young Children with Genetic Predisposition for Rare Malignancies: DICER1 Mutations and Pleuropulmonary Blastoma [74], Sabapathy et al AJR Am J Roentgenol. 2015 Apr;204(4):W475-82.

The purpose of this study was to compare the risks of radiation exposure in screening strategies using CXR and CT or CT alone, to detect PPB in DICER-1 positive infants and young children, against the risks of disease and its progression. Given the rarity of such tumors a prospective cohort study of screening strategies is not feasible, thus the authors created a decision analytical model to predict the clinical outcome and cumulative radiation dose for each screening strategy and schedule. This statistics-based model analysis showed that increases in imaging frequency decreased loss of life expectancy for the combined (CXR and CT) screening strategy but increased that for the CT-only strategy. Loss of life expectancy was calculated as a composite of risks of undetected disease and rate radiation induced cancer. Thus, in the combined screening strategy the analysis was largely dominated by risk of undetected disease vs risk radiation induced cancer in the CT only group. For all screening strategies and schedules, overall loss of life expectancy was predicted to be less than that associated with no screening. The current practice of CXR followed by CT in cases with positive findings on CXR is predicted by this model to be the optimal regimen. The study concluded that radiographic screening of infants and young children with cancer-predisposing mutations may result in improved life expectancy compared to an unscreened population, despite the risk of radiation induced cancers in this population.

Translating genomic discoveries to the clinic in pediatric oncology [75], Glade et al Curr Opin Pediatr 2015 Feb;27(1):34-43.

Integrative Clinical Sequencing in the management of refractory or relapsed cancer in youth [76], Mody et al JAMA. 2015 Sep 1;314(9):913-25.

Strategies for the management of adverse events associated with mTOR inhibitors [77], Kaplan et al Transplantation Reviews 28(2014) 126-133.

Risk Stratification for Low and Intermediate Risk Neuroblastoma Advances in Risk Classification and Treatment Strategies for Neuroblastoma [78], Pinto et al J Clin Oncol 2015 Sep 20;33(27):3008-17.

Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers [79], Oberthuer et al Clin Cancer Res 2015 Apr 15;21(8):1904-15.

Expectant Observation in Very Low Risk Neuroblastoma A prospective study of expectant observation as primary therapy for neuroblastoma in your infants: a Children’s Oncology Group study [80], Ann Surg 2012 Oct;256(4):573-80.

Outcomes After Surgical Resection in Low-risk Neuroblastoma Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641 [81], Strother et al J Clin Oncol 2012 May 20;30(15):1842-8.

Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group [82], Monclair et al Pediatr Blood Cancer 2015;62:1536-1542.

Importance of Extent of Resection in High-risk Neuroblastoma Value of surgical resection in children with high-risk neuroblastoma [83], Englum et al Pediatr Blood Cancer 2015 Sep;62(9):1529-35.

Assessment of primary site response in children with high-risk neuroblastoma: an international multicenter study [84], Bagatell et al J Clin Oncol 2016 Mar 1;34(7):740-6.

Minimal Access Surgery in Low-/Intermediate-risk Neuroblastoma Laparoscopic resection of adrenal neuroblastoma without image-defined risk factors: a prospective study on 21 consecutive pediatric patients [85], Mattioli et al Pediatr Surg Int 2014 Apr;30(4):387-94.

High grade osteosarcoma of the extremities metastatic to the lung: Long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005 [86], Briccoli et al Surg Oncol 2010 Dec;19(4):193–199

Review of long-term survival outcomes of 323 patients with high-grade extremity osteosarcoma with resectable lung metastases either at diagnosis or relapsed. The criteria for resectability were: primary tumor cleared, no pleural/pericardial effusions, no additional distant metastatic disease, and adequate residual pulmonary function after all metastatic lesions removed with clear microscopic margins. Patients were monitored with chest CT and extremity radiographs during chemotherapy every 2 months and after completion of chemotherapy every 3 months for 4 years, and every 6 months for 10 years. Lung resections were approached by lateral thoracotomy with manual palpation of the lungs to detect lesions not identified on chest CT scan. Wedge resection was adequate in most cases to achieve gross and microscopic clear margins. Neoadjuvant or adjuvant chemotherapy was administered according to standard first-line regimens and consisted of combinations of Methotrexate, Cisplatin, Doxorubicin, and Ifosfamide. Relapsed patients were treated with salvage chemotherapy with drugs not previously used or in higher doses. The five-year overall survival was 37% with final outcome related to presence or absence of metastasis/stage at presentation, time of first relapse, and presence of local recurrence. Salvage chemotherapy after relapses did not influence outcome. The best prognosis was seen in patients who underwent only one thoracotomy compared to patients undergoing two or more thoracotomies. There were no differences in survival in patients who underwent two or three versus four or five thoracotomies. Compared to patients who relapsed within 12 months, patients who relapsed after 24 months had higher survival. Lung only metastases had better survival compared to relapse with lung metastases and local recurrence. Thoracotomy should be considered despite the number of lung relapses or the number of secondary pulmonary lesions.

What predicts the risk of recurrent lung metastases? [87], Murrell et al J Pediatr Surg 2013 May;48(5):1020–1024.

The authors conducted a review of patients who underwent resection of lung metastases to determine what factors predict recurrent lung metastatic disease in pediatric cancers. The study found that the majority of pediatric patients with recurrent pulmonary metastases are patients with a primary oncologic diagnosis of osteosarcoma (57%). All nodules were identified on chest CT scans. Smaller lesions (8.7mm) had a higher false negative PET scan rate compared to larger nodules (18.2mm). Of all the variables studied (age, gender, race, tumor type, size, lung lobe involved, location of lung nodule, original tumor margin of resection, solitary vs multiple nodules, procedure performed, PET scan positivity, insurance status), the only significant factors influencing recurrence risk were patients with osteosarcoma and an original PET positive study. Recurrent lung nodules in patients with osteosarcoma and those with PET positive nodules are likely to be malignant necessitating surgical intervention.

Sarcomas [88], HaDuong et al Pediatr Clin N Am 2015 Feb;62(1):179-200.

This article provides a review of the multidisciplinary approach to the multimodal management of sarcomas in children. The pathology and biology of osteosarcoma are described, including several genes implicated in its pathogenesis. The authors review the clinical and imaging features that differentiate osteosarcoma from other childhood sarcomas, and describe the Enneking staging system. Prognostic factors for osteosarcoma are reviewed, the most important of which is the presence or absence of metastatic disease. The authors discuss chemotherapeutic regimens and surgical management of osteosarcoma, including approaches to achieve limb-salvage over amputation. An excellent review of management of sarcomas in children, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma soft-tissue sarcoma.

Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study [89], Billmire et al J Pediatr Surg 2003 Mar;38(3):315-8.

This randomized study examined survival (S) and event-free survival (EFS) rates using high-or standard-dose cisplatin-based combination chemotherapy and surgical resection for this subset of germ cell tumors. Twenty-five identified for inclusion had abdomen or retroperitoneum as the primary site. Patients had biopsy or resection at diagnosis and randomization to chemotherapy including etoposide, bleomycin, and either standard-dose (PEB) or high-dose cisplatin (HDPEB). 6-year survival rate was 90.0% +/- 11.6% for PEB and 85.7 +/- 14.5% for HDPEB. Study concluded that malignant germ cell tumors arising in the abdomen and retroperitoneum have an excellent prognosis despite advanced stage in most children. Aggressive resection need not be undertaken at diagnosis, but a concerted attempt at complete surgical removal after chemotherapy is important to distinguish viable tumor from necrotic tumor or benign elements that will not benefit from further chemotherapy.

Malignant mediastinal germ cell tumors: an intergroup study [90], Billmire et al J Pediatr Surg 2001 Jan;36(1):18-24.

This secondary analysis of the randomized study Pediatric Oncology Group (POG) 9049/Children’s Cancer Study Group (CCG) 8882, evaluating clinical and operative findings in patients with primary site in the mediastinum. 36 patients were identified for inclusion in the analysis. Overall, 26 of 36 patients survived, with a 4-year patient survival rate of 71%+/-10%, and a 4-year event-free survival rate of 69%+/-10%. Study concluded that tumor resection may be undertaken at diagnosis or after attempted shrinkage with chemotherapy. Aggressive attempt at complete tumor resection should be offered to all patients even if bulky tumor persists after induction chemotherapy with expectation of a significant salvage rate.

Predictors of survival and incidence of hepatoblastoma in the paediatric population [91], Allan et al HPB 2013;15:741-746.

606 patients in the SEER registry were examined in this study. The authors report that HB has increased 2.2% annually from 1973-2009. Multivariate analysis found that surgical resection, Hispanic ethnicity, local disease at presentation and age < 5 to be independent factors associated with improved survival.

The epidemiology of hepatoblastoma [92], Spector et al Pediatr Blood Cancer 2012;59:776-779.

This review article reports the markedly increased rate of HB in patients with Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndromes. These inherited syndromes are rare and only comprise a small amount of HB patients overall. Birth weight is strongly associated with sporadic HB. With a 20-fold increase in HB among children born with very low birth weight (< 1500 g) and 2-fold increase in those born with moderate low birth weight (1500-2500 g).

Is multifocality a prognostic factor in childhood hepatoblastoma? [93], Saetti et al Pediatr Blood Cancer. 2014 Apr 23.

This single center report found that children with multifocal tumors had a lower event free survival (.40 vs. .95), and overall survival (.42 vs .95) when compared with unifocal lesions. The multivariate analysis suggested a hazard ration of 10, p=0.007 for children with multifocal disease. Multifocality is currently being examined by COG in the AHEP 0731 trial and by SIOPEL and is likely to emerge as a major risk factor which will be important in stratifying future trials.

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Last updated: June 28, 2021