Adolescent and young adult oncology-past, present, and future.

There are nearly 70,000 new cancer diagnoses made annually in adolescents and young adults (AYAs) in the United States. Historically, AYA patients with cancer, aged 15 to 39 years, have not shown the same improved survival as older or younger cohorts. This article reviews the contemporary cancer incidence and survival data through 2015 for the AYA patient population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results registry program and the North American Association of Central Cancer Registries. Mortality data through 2016 from the Centers for Disease Control and Prevention's National Center for Health Statistics are also described. Encouragingly, absolute and relative increases in 5-year survival for AYA cancers have paralleled those of childhood cancers since the year 2000. There has been increasing attention to these vulnerable patients and improved partnerships and collaboration between adult and pediatric oncology; however, obstacles to the care of this population still occur at multiple levels. These vulnerabilities fall into 3 significant categories: research efforts and trial enrollment directed toward AYA malignancies, access to care and insurance coverage, and AYA-specific psychosocial support. It is critical for providers and health care delivery systems to recognize that the AYA population remains vulnerable to provider and societal complacency.

Risk Factors for Readmission Following Febrile Neutropenia in Pediatric Oncology Patients.

Febrile neutropenia is the most common reason for admission from the emergency department for pediatric oncology patients. We identified pediatric inpatients age 1 to 21 years with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code of malignancy and either fever with neutropenia or fever alone over a 6-year period (2007-2012) using the PHIS+ database. We evaluated factors associated with readmission within 7 days after index hospitalization. There were 4029 index hospitalizations among 2349 patients in 6 hospitals, 294 encounters (7.3%) were followed by readmission within 7 days. Factors associated with increased odds of readmission included being in the lowest quartile for median household income (odds ratio [OR]=1.64, P =0.009), diagnosis of acute lymphoblastic leukemia (OR=1.37, P =0.016), lack of anerobic coverage during index hospitalization (OR=1.48, P =0.026), and absolute neutrophil count <200 cells/µL at discharge from index hospitalizations (OR=1.55, P =0.008). Patients who required readmission had a longer median length of stay and greater hospitalization costs during the index hospitalization. There was a trend towards increasing hospitalization rates for febrile neutropenia over time. While absolute neutrophil count is incorporated into many risk stratification strategies for fever management, further work should focus on addressing socioeconomic factors which may impact readmission rates.

Intraventricular topotecan in the successful treatment of recurrent CNS pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the pleura and pulmonary mesenchyme, associated with pathogenic germline DICER1 mutations. Although the most common site of metastasis is the central nervous system (CNS), patients with CNS metastasis have dismal outcome. We report a case of a patient presenting with type II PPB and intracranial and bone metastases. We describe a multimodal therapy approach and highlight the use of intraventricular topotecan for isolated CNS recurrence. In addition, a new pathogenic germline mutation heterozygous for the c.1234delT of DICER1 was identified. Patient remains in remission 3 years after recurrence.

Salvage regimens for pediatric patients with relapsed nasopharyngeal carcinoma.

There is no established salvage regimen for pediatric patients with relapsed nasopharyngeal carcinoma (NPC) and outcomes are dismal. We performed a multicenter retrospective review to determine outcomes after first salvage therapy for pediatric patients with relapsed NPC. Fourteen patients were treated with varied regimens. Two of the 14 patients received oxaliplatin-containing regimens and achieved a long-term complete response. Although definitive recommendations cannot be made based on outcomes for 14 patients who received varied regimens, we discuss justification for an oxaliplatin-containing regimen in combination with gemcitabine as a reasonable choice for first-line salvage therapy for pediatric patients with relapsed NPC.

Platinum plus bortezomib for the treatment of pediatric renal medullary carcinoma: Two cases.

Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum-based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.

Successful liver transplantation for non-resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome.

Desmoplastic spindle cell tumors of liver are rare tumors of low malignant potential characterized by well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma. While surgery remains the definitive treatment, there have been reports of tumor recurrence locally and metastasis which respond poorly to chemotherapy. Hepatic transplant has been attempted in cases of recurrence or large size of primary tumor. Long-term follow-up and imaging surveillance are required as these tumors have shown a tendency for recurrence many years after initial therapy.

Comparison of survival at adult versus pediatric treatment centers for rare pediatric tumors in an adolescent and young adult (AYA) population in the State of Georgia.

BACKGROUND: The type of treatment center where 15-21-year-old adolescent and young adult (AYA) patients with rare pediatric tumors achieve their best clinical outcome is unknown. PROCEDURE: We performed a retrospective analysis using the Georgia Cancer Registry (GCR) of 15-21-year old patients with a malignant, rare pediatric tumor diagnosed during the period from 2000-2009. Patients were identified as being treated at one of five Georgia pediatric cancer centers or at an adult center. Data were analyzed for 10 year overall survival, patient characteristics associated with death, and patient characteristics present at diagnosis associated with choice of treatment center. RESULTS: There was a total of 479 patients in our final study population, of which 379 (79.1%) were treated at an adult center and 100 (20.9%) were treated at a pediatric center. Patients treated at an adult center had a 10 year overall survival of 86% compared to 85% for patients treated at a pediatric center (P = 0.31). Race and poverty were not significantly associated with death. Patients with nasopharyngeal carcinoma (OR = 7.38; 95% CI = 2.30-23.75) and 'other carcinomas' (OR = 2.64; 95% CI = 1.25-5.60) were more likely to be treated at a pediatric center. Patients with higher-stage disease (OR = 4.24; 95% CI = 1.71-10.52) and higher poverty (OR = 2.32; 95% CI = 1.23-4.37) were also more likely to be treated at a pediatric center. CONCLUSION: Our data suggest that there is no difference in survival for 15-21-year old patients with rare pediatric tumors when treated at an adult or pediatric center.

Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid rhabdoid tumors (AT-RT) are pediatric tumors of the central nervous system with limited treatment options and poor survival rate. We investigated whether enhancing chemotherapy toxicity by depleting intracellular glutathione (GSH; a key molecule in cisplatin resistance) with high dose acetaminophen (AAP), may improve therapeutic efficacy in AT-RT in vitro. PROCEDURE: BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidant N-acetylcysteine (NAC). Cell viability, GSH and peroxide concentrations, mitochondrial damage, and apoptosis were evaluated in vitro. RESULTS: AAP enhanced cisplatin cytotoxicity in cisplatin-resistant BT16 cells but not cisplatin-sensitive BT12 cells. Baseline GSH levels were elevated in BT16 cells compared to BT12 cells, and AAP decreased GSH to a greater magnitude in BT16 cells than BT12 cells. Unlike BT12 cells, BT16 cells did not have elevated peroxide levels upon treatment with cisplatin alone, but did have elevated levels when treated with AAP + cisplatin. Both cell lines had markedly increased mitochondrial injury when treated with AAP + cisplatin relative to either drug treatment alone. The enhanced toxic effects were partially reversed with concurrent administration of NAC. CONCLUSIONS: Our results suggest that AAP could be used as a chemo-enhancement agent to potentiate cisplatin chemotherapeutic efficacy particularly in cisplatin-resistant AT-RT tumors with high GSH levels in clinical settings.

Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas.

BACKGROUND: Patients with relapsed pediatric sarcomas have a poor outcome and are in need of novel effective therapies. METHODS: We retrospectively reviewed the records of patients at Children's Healthcare of Atlanta who were treated with gemcitabine (675 mg/m(2)) intravenously (IV) on Day 1 and Day 8, and docetaxel (75 mg/m(2)) IV on Day 8, repeated every 3 weeks. RESULTS: Nineteen patients with a median age of 11 years were treated from 2006-2010 and received 123 total courses. Two patients (11%), both with rhabdomyosarcoma, demonstrated objectives responses [one complete response (CR) and one partial response (PR)]. Seven other patients (39%) had stable disease (SD). The 1-year progression-free survival (PFS) of the entire cohort was 24% ± 10% with a median time to progression of 2 months (range: 0.5-14 months). The 1-year overall survival (OS) was 43% ± 11%. Grade 3 or 4 toxicities occurred in 14 patients (74%) and 52 courses (42%), and were most commonly hematologic (neutropenia = 37, anemia = 17, and thrombocytopenia = 23 courses). CONCLUSIONS: The dismal outcomes for patients with relapsed and refractory sarcomas and the lack of effective sarcoma salvage regimens highlight the need for new approaches. This report of the therapeutic activity of gemcitabine and docetaxel (GEMDOX) in rhabdomyosarcoma and other pediatric reports describing activity in osteosarcoma and Ewing sarcoma suggest that this combination should be considered for formal evaluation in a pediatric specific clinical trial. At a minimum, it appears to offer a reasonable, tolerable, palliative option.

Management of thyroid carcinoma in children and young adults.

Thyroid cancers represent the largest group of pediatric carcinomas. Unlike other cancers of childhood, they have not been prospectively studied; instead adult data has been extrapolated to childhood and adolescent treatment. In this article we review the treatment of both well differentiated thyroid cancer (WDTC), as well as medullary thyroid cancer (MTC). The approach to both cancers relies on a low threshold of suspicion, and a willingness to biopsy suspicious lesions. Surgery remains the primary method of curing these patients, although radioactive iodine (RAI) may offer some benefit in WDTC for selected patients. For patients with MTC new medications, such as Vandetanib, may offer some adjuvant benefit following surgery. Lastly, suppression of thyroid stimulating hormone (TSH) may be one of the most beneficial treatments for WDTC.

Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child.

Isolated endobronchial inflammatory myofibroblastic tumors (IMT) are rare, accounting for about 1% of primary endobronchial tumors in children. The mainstay of treatment for this tumor has been surgical resection. Recently, the identification of anaplastic lymphoma kinase (ALK) gene mutations in half of IMTs and promising results of treatment with ALK inhibitors in other ALK-positive tumors have opened the possibility of alternative approaches. We present a 4-year-old child with an ALK-positive endobronchial IMT, treated with endoscopic resection and neoadjuvant therapy with crizotinib, without evidence of tumor recurrence 2 years after the initial resection.

The use of zoledronic acid in pediatric cancer patients.

BACKGROUND: The third generation bisphosphonate zoledronic acid has demonstrated efficacy in reducing skeletal-related events in adult patients with multiple cancer types that have skeletal disease. The use of zoledronic acid in pediatric oncology patients with bone metastases for the purpose of reducing pain, improving bone strength and altering the progression of metastatic disease has not been thoroughly evaluated. PROCEDURE: From October 2005 to December 2008, 19 patients at the Aflac Cancer Center received one or more doses of zoledronic acid as part of their therapy. A retrospective review of these patients was performed and information was collected including indication for treatment, toxicities, and outcomes. RESULTS: Most patients (n = 15) received zoledronic acid following relapse of their malignancy with metastatic disease present in one or more bony sites. Hypocalcemia and hypophosphatemia were frequent, but did not result in clinical symptoms. More significant toxicities associated with zoledronic acid, including clinically apparent renal insufficiency and osteonecrosis of the jaw, were not seen. Overall, zoledronic acid was well tolerated in this population. CONCLUSIONS: The benefits of zoledronic acid seen in randomized trials of adults with bone metastases have sparked interest in its use for children with metastatic cancer. The administration of zoledronic acid in pediatric oncology appears safe, and may result in improved bone strength and pain control. Further evaluation is warranted to prospectively evaluate its efficacy and long-term safety in pediatric patients with cancer and skeletal metastases.

Utility of lymph node assessment for atypical spitzoid melanocytic neoplasms.

BACKGROUND: Atypical spitzoid melanocytic neoplasms (ASMN) are cutaneous lesions of uncertain malignant potential, which can be difficult to distinguish from cutaneous melanoma. Sentinel lymph node (SLN) biopsy is a safe and useful prognostic tool for staging melanoma, but its role in staging ASMNs is not established nor is the significance of positive SLNs in these patients known. This study attempts to characterize the significance of nodal disease in ASMN. METHODS: Patients with ASMNs who presented to the melanoma service from 1992 to 2007 were identified from a prospective database. Histological review was performed by two dermatopathologists. Demographic, treatment, and outcome data were reviewed. RESULTS: A total of 58 patients with ASMNs were treated during the time analyzed; 31 (53%) underwent wide local excision and observation (WLE); 27 underwent wide excision and SLN biopsy. Median age was 24 (range, 6-60) years. Mean Breslow thickness was 2.9 (range, 0.5-10) mm. Median follow-up was 56 (range, 1-160) months. Ten of 58 (17%) patients had nodal metastasis. Four (13%) of 31 patients who underwent WLE developed nodal recurrences, and 6 of 27 (22%) patients had a positive SLN biopsy. Of patients with positive SLNs, none have recurred after undergoing completion lymphadenectomy. One patient presented with synchronous brain metastasis and inguinal lymphadenopathy and died of disease. CONCLUSIONS: Nodal status does not seem to convey the same prognosis that it does in standard melanoma. There may be a limited ability for progression within the nodal basin in patients with these lesions. This subset of patients would benefit from genetic data complementing histologic analysis.

Intracavitary cisplatin therapy for pediatric malignancies.

BACKGROUND: Local control is essential for the successful treatment of pediatric solid tumors. Complete excision is often not possible and local control therapies are limited. Intracavitary cisplatin (IC-CDDP) may be utilized to supplement local control. The aim of the study was to determine the toxicity and efficacy of locally instilled intracavitary cisplatin in patients with recurrent tumors in closed body cavities. PROCEDURE: From 2001 to 2009, 12 patients (1-20 years) with recurrent or unresectable malignant tumors were treated with IC-CDDP. Nine had pulmonary lesions. Three patients had abdominal tumors. CDDP (200 mg/m(2)) was instilled by chest tube or Tenckhoff catheter. Patients were shifted every 15-30 min to allow distribution. After 4 hr, residual was drained by gravity. In 10/13 courses, sodium thiosulfate (STS) was administered to prevent nephrotoxicity. Three other patients received amifostine. RESULTS: Malignant pleural effusions resolved in 5/7 patients. This response was temporary in three patients. No patients had ascites prior to treatment. Three patients are alive and disease-free, 18 months, 4 years, and 6 years from treatment. They also had surgery and chemotherapy. Transient renal toxicity was noted in most patients. One patient, treated with amifostine, had persistent renal dysfunction. CONCLUSIONS: IC-CDDP was effective in treating malignant pleural effusions and may be a palliative option for refractory disease. Long-term survival was achieved in two patients, treated at first diagnosis. The benefit of IC-CDDP in these patients is difficult to assess. Renal dysfunction is usually mild, and typically resolves, but warrants preventive measures with IC-CDDP therapy.

Liver Transplantation for Pediatric Liver Cancer.

Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.

Melanoma in children and adolescents.

Melanoma is rarely described in the pediatric population. However, recent studies show that the incidence may be increasing. The diagnosis of melanoma presents unique challenges in this age group. There may be predisposing factors that affect children more than adults. A high index of suspicion is necessary in order to make a timely diagnosis. Prompt surgical treatment by individuals with expertise in care of patients with melanoma with potentially curative excision and appropriate lymph node evaluation is important to optimize survival. Careful review of all specimens by an experienced dermatopathologist is important. Through cooperation with adult trials and potential inclusion of pediatric patients in evaluations of new therapies, further progress against this disease can hopefully be addressed in all age groups.

Subretinal Bone Formation in a Patient with Giant Cell Tumor of the Sphenoid.

BACKGROUND/AIMS: To report a case of subretinal bone formation after the treatment with denosumab for a giant cell tumor of the sphenoid, which had recurred after surgical resection. METHODS: The clinical history and fundus findings including imaging, histologic and immunohistochemical features of the primary tumor and subretinal lesion were reviewed. RESULTS: A 14-year-old boy was evaluated for a suprasellar mass. Resection of the lesion showed giant cell tumor of bone (GCT). An MRI study at the 1-month follow-up appointment showed tumor progression, and denosumab was initiated. Two months after the initial presentation, the patient developed a worsening scotoma of the right eye. Dilated fundus examination showed a yellow-tan-colored subretinal mass temporal to the fovea. The subretinal lesion was removed and showed lamellar bone with associated fibrocellular tissue. CONCLUSION: Denosumab therapy for GCT of the sphenoid may be associated with subretinal bone formation.

Mucinous adenocarcinoma of the lung in association with congenital pulmonary airway malformation.

Congenital pulmonary airway malformation (CPAM) is a rare developmental abnormality of the lung that has been associated with the presence of rhabdomyosarcoma, pleuropulmonary blastoma, and most commonly bronchioalveolar carcinoma (BAC) of the lung. Here, we report the case of an 8-year-old patient who developed KRAS mutation positive stage IV mucinous adenocarcinoma of the lung in association with CPAM. This case reflects the previously recognized progression of CPAM to malignancy and suggests that BAC arising in CPAM may take a more aggressive course than previously recognized.