Fluorescent-guided surgery and the use of indocyanine green sentinel lymph node mapping in the pediatric and young adult oncology population.

BACKGROUND: Technetium-99 (99m Tc) lymphoscintigraphy with blue dye injection is an accepted method for sentinel lymph node (SLN) mapping, but blue dye has known adverse effects, and injection of 99m Tc may increase time under anesthesia for pediatric patients. Indocyanine green (ICG) may serve as an adjunct to assist with visibility and identification of SLNs. We hypothesized that sensitivity of ICG was similar to blue dye in SLN biopsies. METHODS: Thirty patients (36 procedures with 96 total specimens) underwent preoperative intradermal injection of 99m Tc, followed by intradermal injection of isosulfan blue and ICG. Test characteristics of blue dye, ICG, and 99m Tc included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: ICG had a sensitivity of 87% and PPV of 83% for detection of 99m Tc-hot lymph nodes; blue dye had a sensitivity of 44% and PPV of 97%. For detection of pathologically confirmed lymph nodes, ICG had a sensitivity of 84% and a positive predictive value (PPV) of 91%. 99m Tc had a sensitivity of 82% and a PPV of 94%. ICG had no significant difference in odds of being positive in pathology-confirmed lymph nodes compared to 99m Tc (odds ratio [OR], 0.818; 95% confidence interval [CI], 0.3-2.172; p = .823) and had higher odds than isosulfan blue (OR, 0.025, 95% CI, 0.001-0.148; p < .001). CONCLUSION: This study established the efficacy of ICG as an adjunct to SLNB in the pediatric and young adult population. ICG was safe, more efficacious than blue dye, and may obviate the need for lymphoscintigraphy in selected patients resulting in reduced time under anesthesia.

Pediatric and Young Adult Image-Guided Percutaneous Bone Biopsy-A New Standard of Care?

BACKGROUND: There are no consensus guidelines regarding the use of percutaneous needle biopsy for the diagnosis of soft tissue and bone tumors. The aim of this study was to understand the efficacy of image-guided percutaneous biopsy for pediatric patients with soft tissue and bony masses, the role of intraoperative image guidance, and diagnostic accuracy. PATIENTS AND METHODS: A retrospective institutional chart review was performed on patients who underwent percutaneous biopsy of soft tissue or bone tumors between 2007 and 2017. Data collected included preoperative imaging, type of biopsy, demographics, insurance status, number of samples taken, and pathologic results. RESULTS: One hundred forty-one children and young adults underwent 169 biopsies. Female patients received 48.2% of biopsies. The mean age was 14.3 ± 7.0 years. Core needle biopsies made up 89.4% of procedures, while 10.6% were fine needle aspirate. The mean number of samples per patient was 3.6 ± 2.5. All patients had imaging guidance, with computed tomography used in 44.7% of patients, 9.9% using fluoroscopy, 7.1% using ultrasound for guidance, and 53 (37.6%) patients had more than one modality. Diagnostic specimens were obtained in 97.9% of biopsies. The most common overall pathology was osteoid osteoma. The most common malignant tumors were osteosarcoma and Ewing's sarcoma. CONCLUSION: Image-guided percutaneous biopsy is a safe and effective method of obtaining accurate tissue samples in children and young adults with soft tissue or bone masses. LEVEL OF EVIDENCE: Level 4-Study of diagnostic test.

Cardiac dysfunction in medulloblastoma survivors treated with photon irradiation.

Background: Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment often includes a combination of surgical resection, craniospinal irradiation (CSI), and chemotherapy. Children who receive standard photon CSI are at risk for cardiac toxicities including coronary artery disease, left ventricular scarring and dysfunction, valvular damage, and atherosclerosis. Current survivorship guidelines recommend routine echocardiogram (ECHO) surveillance. In this multi-institutional study, we describe markers of cardiac dysfunction in medulloblastoma survivors. Methods: A retrospective chart review of medulloblastoma patients who had photon beam CSI was followed by ECHO between 1980 and 2010 at Lurie Children's Hospital and Dana-Farber/Boston Children's Hospital. Results: During the 30-year study period, 168 medulloblastoma patient records were identified. Included in this study were the 75 patients who received CSI or spinal radiation and ECHO follow-up. The mean age at CSI was 8.6 years (range, 2.9-20), and the mean number of years between radiation therapy (RT) completion and first ECHO was 7.4 (range, 2-16). Mean ejection fraction (EF) was 60.0% and shortening fraction (SF) was 33.8%. Five patients (7%) had abnormal ECHO results: three with EF <50% and two with SF <28%. Conclusion: The majority of medulloblastoma patients who received CSI have relatively normal ECHOs post-treatment; however, 7% of patients had abnormal ECHOs. The implication of our study for medulloblastoma survivors is that further investigations are needed in this population with a more systematic, longitudinal assessment to determine predictors and screenings.

Linking EORTC QLQ-C-30 and PedsQL/PEDQOL physical functioning scores in patients with osteosarcoma.

PURPOSE: The available questionnaires for quality-of-life (QoL) assessments are age-group specific, limiting comparability and impeding longitudinal analyses. The comparability of measurements, however, is a necessary condition for gaining scientific evidence. To overcome this problem, we assessed the viability of harmonising data from paediatric and adult patient-reported outcome (PRO) measures. METHOD: To this end, we linked physical functioning scores from the Paediatric Quality of Life Inventory (PedsQL) and the Paediatric Quality of Life Questionnaire (PEDQOL) to the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) for adults. Samples from the EURAMOS-1 QoL sub-study of 75 (PedsQL) and 112 (PEDQOL) adolescent osteosarcoma patients were concurrently administered both paediatric and adult questionnaires on 98 (PedsQL) and 156 (PEDQOL) occasions. We identified corresponding scores using the single-group equipercentile linking method. RESULTS: Linked physical functioning scores showed sufficient concordance to the EORTC QLQ-C30: Lin's ρ = 0.74 (PedsQL) and Lin's ρ = 0.64 (PEDQOL). CONCLUSION: Score linking provides clinicians and researchers with a common metric for assessing QoL with PRO measures across the entire lifespan of patients.

Chemotherapy-induced thrombocytopenia in Ewing sarcoma: Implications and potential for romiplostim supportive care.

BACKGROUND: Maintaining dose-dense, interval-compressed chemotherapy improves survival in patients with Ewing sarcoma but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). METHODS: Patients aged between 3 and 33 years with Ewing sarcoma from 2010 to 2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher's exact test was used for univariate analysis and Pearson's correlation coefficient was used for the association between continuous variables. RESULTS: Twenty-seven out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significance (p-value = .056). Ten patients received romiplostim. The median starting dose was 3 µg/kg (range 1-5). Doses were escalated weekly by 1-2 to 4-10 µg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline, r = .73 (p = .04). No romiplostim-related adverse events were identified aside from mild headache. CONCLUSIONS: CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy was safe and feasible, and efficacy was associated with higher romiplostim doses.

Relationship Between Caregiver Uncertainty, Problem-Solving, and Psychological Adjustment in Pediatric Cancer.

OBJECTIVE: The current study examined the roles of constructive and dysfunctional problem-solving strategies in the relationships between illness uncertainty and adjustment outcomes (i.e., anxious, depressive, and posttraumatic stress symptoms) in caregivers of children newly diagnosed with cancer. METHODS: Two hundred thirty-eight caregivers of children (0-19 years of age) newly diagnosed with cancer (2-14 weeks since diagnosis) completed measures of illness uncertainty, problem-solving strategies, and symptoms of anxiety, depression, and posttraumatic stress. RESULTS: A mediation model path analysis assessed constructive and dysfunctional problem-solving strategies as mediators between illness uncertainty and caregiver anxious, depressive, and posttraumatic stress symptoms. Dysfunctional problem-solving scores partially mediated the relationships between illness uncertainty and anxious, depressive, and posttraumatic stress symptoms. Constructive problem-solving scores did not mediate these relationships. CONCLUSIONS: The current findings suggest that illness uncertainty and dysfunctional problem-solving strategies, but not constructive problem-solving strategies, may play a key role in the adjustment of caregivers of children newly diagnosed with cancer. Interventions aimed at managing illness uncertainty and mitigating the impact of dysfunctional problem-solving strategies may promote psychological adjustment.

Long-term follow-up of surgical outcomes for patients with Wilms tumor and neuroblastoma.

BACKGROUND: There are minimal data on long-term surgical outcomes of patients who have undergone resection for Wilms tumor (WT) and neuroblastoma (NB). METHODS: A retrospective review of patients in a long-term survivor clinic between the years 1967 and 2016 in a pediatric tertiary care hospital (>5 years posttreatment) was performed. RESULTS: Eighty-six survivors of WT and 86 survivors of NB who had ongoing follow-up in the survivors' clinic were identified. The median age at diagnosis was 2.5 years (range, 0.4-15.7 years) with a mean follow-up of 22.3 years (±10.4 years) for WT. The median age at diagnosis for patients with NB was 0.9 years (range, 0.1-8.6 months); mean follow-up of 21.7 years (±7.9 years). Twelve patients with WT (14.0%) had at least 1 repeat laparotomy, 11.1% for bowel obstruction, at a median of 3 months from initial surgery. Twelve patients (14.0%) with NB required laparotomy and 8.1% for bowel obstruction, at a median of 12 years after initial surgery. The incidence of hypertension in patients with WT who had undergone nephrectomy was not outside of population norms. Patients who underwent thoracotomy for a NB have a higher incidence of scoliosis and Horner syndrome. CONCLUSIONS: Small bowel obstruction requiring laparotomy is significantly higher than the literature norms for both tumor patient populations and typically occurs in the early postoperative period for patients with WT and remotely in patients with NB. The long-term surgical complications of patients who underwent resection for NB and WT clearly merit follow-up and patient education within multidisciplinary long-term survivorship clinics.

The impact of proton therapy on cardiotoxicity following radiation treatment.

Cardiac disease following radiation therapy represents a major consideration in the treatment of a variety of malignancies. Damage to the heart can manifest in a variety of pathologies including ischemic cardiac disease, cardiomyopathy, valvular dysfunction, arrhythmias, and pericarditis. This damage has been shown to directly relate to cardiac radiation dose and to stem from a range of cellular pathways that are often related to fibrosis. The importance of minimizing radiation dose to the heart is especially critical in the pediatric population and when treating disease sites adjacent to the heart. Proton therapy represents a promising approach to minimize dose to normal tissues such as the heart. The cardiac dosimetry reductions due to proton therapy have been demonstrated in multiple cancers and further long-term follow-up will determine the clinical significance of these reductions to cardiac structures. Future approaches using advanced techniques such as FLASH therapy could provide even further benefit by reducing post-radiation fibrosis.

Can a children's hospital still cut it? Comparing outcomes of pediatric, adolescent and young adult patients undergoing thoracic surgery for lung metastases.

BACKGROUND: Adolescents and young adults (AYAs) with cancer have unique medical challenges compared with younger children and older adults. Dedicated centers have been established to deliver cancer therapy to the AYA population; many of these programs are located in pediatric hospitals. Outcomes of AYA patients on pediatric protocols are generally superior to those on adult protocols. Little is understood about the impact of care within a pediatric environment for surgical care of young adults. METHODS: A retrospective institutional review was performed of patients undergoing thoracic metastectomy between 2012 and 2017. Demographics, procedural factors, cost, and outcomes were analyzed. Patients were divided into two groups: > 18 and <18 years. RESULTS: Ninety-one procedures were performed: 61.5% (n = 56) were in patients <18 years old and 38.5% (n = 35) were > 18 years old. The median age was 6.5 years for <18 years old and 28 years for > 18 years old. Older patients had a significantly longer operative time on thoracoscopic cases; 91 versus 63 minutes. Fifty percent of the > 18 group had > 1 lesion resected compared with one lesion resected in 80.8% in <18 years old. No significant differences were found between the two groups in the duration of chest tube or length of stay. The AYA group demonstrated more "adult type" comorbidities. CONCLUSION: AYA patients have unique developmental and emotional challenges. Surgical intervention in this special population of patients cared for within a pediatric environment shows no significant difference in outcome compared with pediatric patients undergoing the same procedure. AYA patients with "adult type" comorbidities can safely undergo multidisciplinary care including surgery within a pediatric environment without the need to fragment care.

Solitary myofibroma preceding the development of multicentric myofibromatosis: A report of two cases with surveillance recommendations.

Infantile myofibroma is the most common fibrous tumor of infancy. Despite the frequency of these tumors, the natural history is incompletely understood. We present two cases with a unique pattern of disease: solitary myofibromas with subsequent progression to diffuse myofibromatosis. Given the variable spectrum of disease and the corresponding difference in morbidity and potential mortality based on the extent of disease, we propose surveillance recommendations.

Quality of Life of Patients With Osteosarcoma in the European American Osteosarcoma Study-1 (EURAMOS-1): Development and Implementation of a Questionnaire Substudy.

BACKGROUND: The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups. OBJECTIVE: This paper aimed to describe the QoL study development, methodology, accrual details, and characteristics of the QoL cohort. METHODS: A total of 2260 patients registered in the EURopean AMerican Osteosarcoma Study-1 (EURAMOS-1), of whom 97.92% (2213/2260) were eligible for the optional QoL assessment and could participate in terms of questionnaire availability. Overall, 61.86% (1369/2213) of patients and/or proxies completed the QoL evaluation at the first assessment time point (E1) after the start of preoperative treatment. The QoL measures used (self- and/or proxy reports) depending on the patient's age and national study group. Participants and nonparticipants in the ancillary QoL study were compared regarding relevant demographic and disease-related characteristics at registration in the trial. RESULTS: The participation rate at time point E1 did not differ with regard to age, gender, the occurrence of pathological fracture, or the presence of any metastases at diagnosis. No differences were found regarding the primary tumor site. Only the national study group affiliation had an influence on participation. Participation decreased linearly with trial progress up to 20% at the final time point of QoL assessment. CONCLUSIONS: This study demonstrates the feasibility of international cooperation for the purpose of assessing and understanding the QoL of pediatric and adolescent/young adult patients with cancer. Future outcomes of this QoL substudy will help to adapt interventions to improve QoL.

Cardiovascular Toxicities in Pediatric Cancer Survivors.

Advances in cancer therapies have significantly improved patient outcomes. However, with improvements in survival, the toxicities associated with cancer therapy have become of paramount importance and oncologists are faced with the challenge of establishing therapeutic efficacy while minimizing toxicity. Cardiovascular disease represents a significant risk to survivors of childhood cancer and is a major cause of morbidity and mortality. This article outlines the current state of knowledge regarding cardiotoxicity in children undergoing cancer therapies, including the impact of specific oncologic therapies, recommendations for cardiovascular screening, the management of established cardiac disease, and the evolving field of pediatric cardio-oncology.

Outcomes after bloodstream infection in hospitalized pediatric hematology/oncology and stem cell transplant patients.

BACKGROUND: Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients. METHODS: This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture. RESULTS: Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture. CONCLUSIONS: BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.

Quality of life in pediatric acute myeloid leukemia: Report from the Children's Oncology Group.

INTRODUCTION: Objectives were used to describe guardian proxy-report and child self-report quality of life (QoL) during chemotherapy for pediatric acute myeloid leukemia (AML) patients. METHODS: Patients enrolled on the phase 3 AML trial AAML1031 who were 2-18 years of age with English-speaking guardians were eligible. Instruments used were the PedsQL Generic Core Scales, Acute Cancer Module, and Multidimensional Fatigue Scale. Assessments were obtained at the beginning of Induction 1 and following completion of cycles 2-4. Potential predictors of QoL included the total number of nonhematological grade 3-4 Common Terminology Criteria for Adverse Event (CTCAE) submissions. RESULTS: There were 505 eligible guardians who consented to participate and 348 of their children provided at least one self-report assessment. The number of submitted CTCAE toxicities was significantly associated with worse physical health summary scores (ß ± standard error (SE) -3.00 ± 0.69; P < 0.001) and general fatigue (ß ± SE -2.50 ± 0.66; P < 0.001). Older age was significantly associated with more fatigue (ß ± SE -0.58 ± 0.25; P = 0.022). Gender, white race, Hispanic ethnicity, private insurance status, risk status, bortezomib assignment, and duration of neutropenia were not significantly associated with QoL. DISCUSSION: The number of CTCAE toxicities was the primary factor influencing QoL among children with AML. Reducing toxicities should improve QoL; identifying approaches to ameliorate them should be a priority.

Pediatric Cardio-Oncology: Development of Cancer Treatment-Related Cardiotoxicity and the Therapeutic Approach to Affected Patients.

OPINION STATEMENT: The past 5 decades have seen significant improvements in outcomes for pediatric patients with cancer. Unfortunately, children and adolescents who have been treated for cancer are five to six times more likely to develop cardiovascular disease as a result of their therapies. Cardiovascular disease may manifest in a plethora of ways, from asymptomatic ventricular dysfunction to end-stage heart failure, hypertension, arrhythmia, valvular disease, early coronary artery disease, or peripheral vascular disease. A number of treatment modalities are implicated in pediatric and adult populations, including anthracyclines, radiation therapy, alkylating agents, targeted cancer therapies (small molecules and antibody therapies), antimetabolites, antimicrotubule agents, immunotherapy, interleukins, and chimeric antigen receptor T cells. For some therapies, such as anthracyclines, the mechanism of injury is elucidated, but for many others it is not. While a few protective strategies exist, in many cases, observation and close monitoring is the only defense against developing end-stage cardiovascular disease. Because of the variety of potential outcomes after cancer therapy, a one-size-fits-all approach is not appropriate. Rather, a good working relationship between oncology and cardiology to assess the risks and benefits of various therapies and planning for appropriate surveillance is the best model. When disease is identified, any of a number of therapies may be appropriate; however, in the pediatric and adolescent population supportive data are limited.

Study of Delayed Antibiotic in Pediatric Febrile Immunocompromised Patients and Adverse Events.

OBJECTIVES: Bone marrow transplant (BMT) patients or patients receiving chemotherapy for oncologic diagnoses are at risk for sepsis. The association of time to antibiotics (TTA) with outcomes when adjusting for severity of illness has not been evaluated in the pediatric febrile immunocompromised (FI) population. We evaluated the association of TTA with adverse events in a cohort of FI patients presenting to our pediatric emergency department. METHODS: We performed a retrospective review of consecutive FI patients presenting over a 6.5-year period. Adverse events were defined as intensive care admission within 72 hours of emergency department arrival, laboratory signs of acute kidney injury, inotropic support subsequent to antibiotics, and all-cause mortality within 30 days. Vital signs and interventions were used to define severity of illness. Adjusting for severity of illness at presentation, age, and timing of an institutional intervention designed to reduce TTA in FI patients, we analyzed the association of TTA with individual adverse events as well as with adverse events in aggregate. RESULTS: We analyzed 1489 patient encounters. In oncology patients, TTA was not associated with the aggregate measure of whether any adverse event subsequently occurred nor with other individual adverse events. For the BMT subpopulation, TTA >60 minutes did show increased odds of intensive care admission within 72 hours as well as for aggregate adverse events. CONCLUSIONS: Although TTA >60 minutes did show increased odds of aggregate adverse events in the small subgroup of BMT patients, overall TTA was not associated with adverse events in oncology patients as a whole.

Sentinel lymph node biopsy in head and neck rhabdomyosarcoma.

Head and neck rhabdomyosarcoma lymph node staging is challenging due to varied patterns of lymphatic drainage and the suboptimal predictive value of available imaging modalities. Furthermore, regional relapse rates are unacceptably high, and the toxicity of empiric radiation is undesirable in the pediatric and young adult population. In an attempt to improve locoregional control without excess morbidity, we have adopted routine sentinel lymph node biopsy in head and neck rhabdomyosarcoma, which is safe and feasible in pediatric patients. Of six procedures reported here, pathologic findings led to intensification of regional and/or systemic therapy in two patients.