First-Time Diagnosis After an Emergency Presentation in Children With Cancer.

AIM: To determine the prevalence rate of cancer diagnoses by an emergency route, the related risk factors and whether the emergency diagnosis was associated with poorer outcome. METHODS: Retrospective observational study with identification of patients diagnosed at the Pediatric Oncology Unit of "Sapienza" University between 2008 and 2018. The percentage of patients who received a first-time diagnosis after an emergency presentation was determined. Two-year survival and clinical factors, such as sex, age and histology, associated to emergency presentation were evaluated. RESULTS: Of 207 patients (109 girls and 98 boys; median age, 120 months), with a first-time diagnosis of solid tumor, 5.8% were diagnosed during an emergency admission after a median latency time of 2.5 days. Cases with an emergency diagnosis were younger compared with those who were diagnosed electively (median age, 30 months vs 120 months, P < 0.005). Higher prevalence rate of emergency presentation was detected in patients with lymphoma compared with those with no lymphoma disease (28.6% vs 4.1%; P < 0.0001). All patients were managed to overcome their emergency presentation, 33.3% of these died later. No statistically significant difference for 2-year overall survival was found between patients with an emergency diagnosis and those with elective diagnosis (66.7% vs 81.0%; odds ratio, 2.1; confidence interval, 0.6-7.5; P = 0.22). CONCLUSIONS: A minor but not negligible number of pediatric patients come to a first-time diagnosis of cancer as result of a life-threatening event; risk factors were younger age and lymphoma disease. The emergency event can be successfully treated, and it was not related to a poorer survival.

Abdominal Recurrence after Robotic Nephron-Sparing Surgery for Wilms Tumor in an Adult Patient.

A 31-year-old man was referred to an adult urologist for a renal polar mass that measured 7.2 cm in maximum diameter. Robotic assisted complete tumor excision for suspicious renal cell carcinoma was carried out, preserving the rest of the left kidney. Histopathology showed a Wilms tumor (WT) with positive margins. No postoperative therapy was made, and the patient shortly presented an abdominal recurrence. The patient was referred to our pediatric oncology unit; he received preoperative chemotherapy, followed by surgery (completion nephrectomy and removal of neoplastic deposits in the omentum and parietal peritoneum), postoperative chemotherapy, and abdomen radiotherapy. He is well at the 5-year follow-up. Peritoneal dissemination after laparoscopic nephron-sparing surgery (NSS) in a child with a 10-cm WT was previously reported. We suggest open NSS for large WT may be safer than laparoscopic or robotic NSS because carbon dioxide pneumoperitoneum and traumatic handling of tumor may predispose to tumor cell migration. An abdominal WT relapse in adults can be salvaged by multimodal therapy recommended by current pediatric WT guidelines.

Zero-ischemia testis-sparing surgery for probably benign pediatric testicular tumors.

Permanent ischemia-induced testicular damage may occur as early as 30 min in prepupertal rats. With the goal of potentially enhancing testicular function and fertility preservation, we performed testis-sparing surgery (TSS) without ischemia for testicular lesions in select children with negative markers and high likelihood of benignity on ultrasonography. Preliminary experience suggests that off-clamp TSS should be more liberally encouraged, especially in infants and prepubertal children, given their particularly vulnerable spermatic cord elements.

Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization.

BACKGROUND: The probability of local tumor control after radiotherapy (RT) remains still miserably poor in pediatric rhabdomyosarcoma (RMS). Thus, understanding the molecular mechanisms responsible of tumor relapse is essential to identify personalized RT-based strategies. Contrary to what has been done so far, a correct characterization of cellular radioresistance should be performed comparing radioresistant and radiosensitive cells with the same isogenic background. METHODS: Clinically relevant radioresistant (RR) embryonal (RD) and alveolar (RH30) RMS cell lines have been developed by irradiating them with clinical-like hypo-fractionated schedule. RMS-RR cells were compared to parental isogenic counterpart (RMS-PR) and studied following the radiobiological concept of the "6Rs", which stand for repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and radio-immuno-biology. RESULTS: RMS-RR cell lines, characterized by a more aggressive and in vitro pro-metastatic phenotype, showed a higher ability to i) detoxify from reactive oxygen species; ii) repair DNA damage by differently activating non-homologous end joining and homologous recombination pathways; iii) counteract RT-induced G2/M cell cycle arrest by re-starting growth and repopulating after irradiation; iv) express cancer stem-like profile. Bioinformatic analyses, performed to assess the role of 41 cytokines after RT exposure and their network interactions, suggested TGF-ß, MIF, CCL2, CXCL5, CXCL8 and CXCL12 as master regulators of cancer immune escape in RMS tumors. CONCLUSIONS: These results suggest that RMS could sustain intrinsic and acquire radioresistance by different mechanisms and indicate potential targets for future combined radiosensitizing strategies.

Evaluation of Nephron-Sparing Surgery as Potential Risk Factor for Relapse in Unilateral Wilms Tumor.

BACKGROUND: The aim of the study was to assess the prognostic significance of nephron-sparing surgery (NSS) without tumor size limits as a risk factor for relapse in children with unilateral Wilms Tumor (WT). METHODS: A 28-y retrospective single-center review was performed. Prognostic relevance of age, gender, stage, histology, nephrectomy (N), and NSS was analyzed. RESULTS: Sixty-nine cases (42 females and 27 males) with WT, off-therapy from 21 to 325 mo after chemotherapy mainly based on the International Society of Pediatric Oncology trials, were treated at our institution. Five cases were excluded (three children with synchronous bilateral WT and two adults with unilateral WT). Of 64 children with unilateral WT, 51 underwent N and 13 NSS without tumor size limits. Indeed, two-thirds of children who underwent NSS presented with a tumor diameter >4 cm. Overall, nine patients (14%) had a relapse (male-to-female ratio = 1:8). Initial surgery was N in eight cases and NSS in another one. Relapse rates in N and NSS groups were 15.7% and 7.7% (P = nonsignificant), respectively; the relapse rates in N and NSS groups were 8.6% and 7.7% (P = nonsignificant) for stages I-II unilateral WT cohort, respectively. On univariate analysis, factors correlated with probability of relapse were unfavorable histology (P < 0.002) and stage III disease (P < 0.01). CONCLUSIONS: In unilateral WT, NSS, whenever feasible, does not seem to increase the risk of recurrence. A multicenter prospective trial is required to carefully evaluate this risk.

Bevacizumab-containing regimen in relapsed/progressed brain tumors: a single-institution experience.

AIM: The aim of the study is to assess tumor response, treatment-related toxicities, progression-free survival (PFS), and overall survival (OS) in patients with relapsed/refractory brain tumors treated with bevacizumab-containing regimen. METHODS: Patients that had received I and II line treatments with or without megatherapy were included. Doses and schedule were as follows: bevacizumab (BVZ) 10 mg/kg i.v. with irinotecan (IRI) 150 mg/m2 i.v. every 2 weeks ± temozolamide (TMZ) 200 mg/m2 p.o. daily for 5 days every 4 weeks. TMZ was omitted in heavily pretreated cases. RESULTS: Between 2013 and 2018, 12 patients (3F/9M), median age 161 months (range 66-348), affected with medulloblastoma (n 7), or low-grade glioma (n 2), or high-grade glioma (n 3), received BVZ/IRI association (median courses 20, range 4-67); 3 of them continued single-agent BVZ (median courses 23, range 8-39). TMZ (median courses 8, range 2-26) was administered in eight patients and then stopped in three of them because of myelotoxicity or lack of compliance. Treatment was well tolerated. After 3 months, two complete responses, two partial responses, seven stable diseases, and one progressive disease were observed. Nine cases experienced an improvement in neurological symptoms. Median time to progression was 11 months (95% confidence interval, 4-18 months). Six-month and 2-year PFS were 75% and 42%, respectively. The OS is 33%; interestingly, two cases (one medulloblastoma and one high-grade glioma) are progression-free off-therapy since 30 and 48 months, respectively. CONCLUSIONS: BVZ/IRI association ± TMZ showed encouraging therapeutic activity and low toxicity in this series of relapsed/refractory brain tumors.

Vincristine, Irinotecan, and Bevacizumab in Relapsed Wilms Tumor With Diffuse Anaplasia.

The prognosis of relapsed Wilms tumor (WT) with diffuse anaplasia is dismal, therefore, novel therapeutic strategies need to be explored. We reported on 2 consecutive cases with relapsed anaplastic WT who presented a partial response after 2 courses of vincristine, irinotecan, and bevacizumab association. This regimen may have a role in the treatment of patients with anaplastic advanced WT.

Long-term renal function and hypertension in adult survivors of childhood sarcoma: Single center experience.

AIM: Little data is available on long-term renal impairment in survivors from childhood sarcoma. We investigated the prevalence of renal impairment and hypertension after very long-term follow-up in survivors who reached adulthood after treatment for childhood sarcoma. METHODS: A cross-sectional single center study was performed. Outcomes included estimating glomerular filtration rate (eGFR), albuminuria, glycosuria, serum phosphate and magnesium, tubular reabsorption phosphate (TRP), chronic kidney disease (CKD) according to the "Kidney Disease: Improving Global Outcomes" (KDIGO) guidelines and blood pressure (BP). RESULTS: Out of 87 > 5-year sarcoma survivors, 30 adults (10F/20M, median age at diagnosis 9 years, median age at investigation 26 years, median follow-up 16 years, mean 19 years) were identified. Renal impairment was detected in four cases (13.3%); three of these fulfilled the criteria for CKD. Among the adult survivors, a subgroup of 15 cases (50%) had received ifosfamide without confounding factors such as a diagnosis of genito-urinary rhabdomyosarcoma or administration of other potentially nephrotoxic chemotherapy (platinum-based drugs or methotrexate); no renal dysfunction was detected in this subgroup. In the whole cohort of sarcoma survivors, hypertension was diagnosed in four cases (13.3%); BP was significantly correlated with body mass index [p .014]. CONCLUSION: In our series of adult survivors treated for a diagnosis of sarcoma in their childhood, the prevalence of CKD was 10%. We found survivors treated with ifosfamide as the only nephrotoxic agent did not present glomerular or tubular toxicity at long term follow-up, but further studies including a larger number of cases are required to confirm it.

Sudden benzodiazepine-induced resolution of post-operative pediatric cerebellar mutism syndrome: a clinical-SPECT study.

Post-operative pediatric cerebellar mutism syndrome (PPCMS) is a clinical syndrome arising from cerebellar injury and characterized by absence of speech and other possible symptoms and signs. Rare reports described some benefit after administration of dopamine agonist therapy, but no treatment has proven efficacy. In this paper, we report on the dramatic, sudden resolution of PPCMS induced by midazolam administration in a boy who underwent posterior fossa surgery for choroid plexus papilloma of the fourth ventricle. In addition to clinical improvement, post-midazolam single-photon emission computed tomography also demonstrated amelioration of brain perfusion.

Long-term renal function in unilateral non-syndromic renal tumor survivors treated according to International Society of Pediatric Oncology protocols.

BACKGROUND: The risk of renal impairment among survivors of childhood unilateral non-syndromic renal tumors (RTs) is not well defined. We evaluated the prevalence of and possible risk factors for renal impairment by estimating Glomerular Filtration Rate (eGFR) categories and chronic kidney disease (CKD) according to Kidney Disease: Improving Global Outcomes guidelines. PROCEDURE: Since 1978, 82 patients were treated for RT, according to the International Society of Pediatric Oncology protocols in a single oncology unit. Of the 67 survivors, those who underwent nephron sparing surgery, those with short-term follow-up or those who had bilateral and/or syndromic disease or a second malignancy were excluded. Thirty-five adult survivors (14 M/21F; mean age 25 years; mean follow-up 20 years) were studied by chemistry, kidney ultrasound, blood pressure measurement, urinanalysis. Correlations were investigated between the prevalence of eGFR categories and CKD and gender, age at diagnosis, radiotherapy, chemotherapy, body mass index, time of follow-up, and age at study. RESULTS: Eight (22.9%) survivors presented a mildly decreased eGFR (G2 category), the mean value was 80 ± 9.78 ml/min/1.73m(2) (median 84.5, range 63-89). Three (8.6%) survivors had CKD and a fourth (2.9%) hypertension. No significant correlations between G2 category and clinical variables were found. CONCLUSIONS: A small percentage of survivors had CKD or hypertension after two decades. It is not yet clear whether a mildly decreased eGFR that does not constitute CKD in the absence of other markers (albuminuria and/or kidney ultrasound abnormalities) is likely to progress to CKD. Health promotion programs to avoid comorbidities are required.

Myoepithelial carcinoma treatment in children: a report from the TREP project.

BACKGROUND: Myoepithelial carcinoma (MC) of soft tissues is an aggressive tumor that rarely affects children, for whom no established treatment protocols exist. As part of the TREP (Tumori Rari in Età Pediatrica) project - an Italian network dedicated to children and adolescents with very rare tumors - we present a series of patients with MC, who were treated homogeneously and achieved a satisfactory outcome. PROCEDURE: From 2005 to 2012, seven patients (age 0.5-9.2 years) with a diagnosis of MC were registered in the TREP study. After one patient treated with ifosfamide, cisplatin, and etoposide showed tumor shrinkage and experienced long-term disease remission, all subsequent patients were treated with the same chemotherapy regimen. All patients also received radiotherapy. RESULTS: Initial surgical management involved a biopsy in three cases and tumor resection in 4. Response to initial chemotherapy was evaluable in four patients: two had a partial remission, one a minor response and one stable disease. Four patients received external-beam radiotherapy and three had brachytherapy. Overall, six patients are alive in first complete remission with a median follow-up of 2.5 years (0.9-5.1 years). CONCLUSIONS: Though our experience is limited to a small number of patients, our treatment strategy for patients with MC is appears clinically useful and demonstrates how cooperation within the TREP project has enabled enough data to be collected to propose treatment recommendations for pediatric patients with this very rare tumor.

Long-term follow-up of the "wait and see" approach to localized perinatal adrenal neuroblastoma.

BACKGROUND: Evidence-based guidelines for the management of localized perinatal adrenal neuroblastoma are not yet available. We describe our preliminary experience managing this tumor with a "wait and see" policy. METHODS: A single-center prospective study (February 2002 to December 2009) was conducted with 12 consecutive patients in whom an adrenal mass was detected antenatally or within the first 3 months of life. Diagnostic workup included the following investigations: measurement of urine catecholamine metabolites, imaging studies (ultrasonography, magnetic resonance imaging, or computed tomography), metaiodobenzylguanidine scintigraphy, and/or core needle biopsy. RESULTS: The male/female ratio was 1.4:1.0. Median tumor size at presentation was 29 mm (range 10-50 mm). Eight lesions were detected antenatally. Ten lesions were diagnosed as localized neuroblastoma. Of these ten lesions, four were excised because of parental preference (n = 2), tumor enlargement (n = 1) or tumor persistence (n = 1). The remaining six patients underwent watchful clinical observation, which showed progressive tumor shrinkage and complete regression within 10-39 months (median 12.5 months). The final two lesions were small predominantly cystic lesions without a clear-cut diagnosis. They were managed noninvasively. At an overall median follow-up of 109 months (range 30-122 months), all patients are alive and disease-free, although one patient progressed to stage 4 disease despite early excision of the primary tumor. CONCLUSIONS: Spontaneous regression of localized perinatal adrenal neuroblastoma occurs often, and a "wait and see" strategy seems justified in these small infants. Patients with enlarging or stable lesions that have persisted for several months may benefit from surgery, although prompt excision may not prevent tumor progression.

Chronic kidney disease in children with unilateral renal tumor.

PURPOSE: In patients who have undergone nephrectomy lower stage chronic kidney disease may develop, which is an independent risk factor for cardiovascular disease and overall mortality. We investigated whether the prevalence of lower stage chronic kidney disease is related to the amount of renal parenchyma excised in children with unilateral renal tumor. MATERIALS AND METHODS: A total of 15 patients treated with nephrectomy and 10 treated with nephron sparing surgery were enrolled at a single academic center. The Kidney Disease Outcomes Quality Initiative guidelines were used to classify patients by chronic kidney disease stage based on estimated glomerular filtration rate values. The Modification of Diet in Renal Disease study equation and Schwartz equation were used in patients older and younger than 17 years, respectively. RESULTS: At a mean followup of more than 12 years 8 patients who had undergone nephrectomy and 1 treated with bilateral nephron sparing surgery presented with stage II chronic kidney disease (estimated glomerular filtration rate 60 to 89 ml/min/1.73 m(2)). Sequential measurements from diagnosis to 12 to 17 years postoperatively showed that stage II chronic kidney disease in patients who had undergone nephrectomy manifested as a negligible postoperative increase in mean ± SD estimated glomerular filtration rate (75.7 ± 25.5 vs 79.4 ± 3.9 ml/min/1.73 m(2), p = 0.6). Five of the 8 patients presented with stage II chronic kidney disease even before nephrectomy. The other 7 patients who had undergone nephrectomy and those treated with nephron sparing surgery presented with a significant postoperative increase in mean ± SD estimated glomerular filtration rate (81.1 ± 24 vs 102.3 ± 3 ml/min/1.73 m(2), p = 0.02, and 88.7 ± 2 vs 107.4 ± 14 ml/min/1.73 m(2), p = 0.005, respectively). CONCLUSIONS: A subset of children with unilateral renal tumor presents before and/or after nephrectomy, and not after nephron sparing surgery, with stage II chronic kidney disease, probably due to a reduced renal reserve capacity. Whether patients with preoperative renal dysfunction may benefit from nephron sparing surgery should be studied in a cooperative clinical trial setting.

Vascular endothelial growth factor serum levels in children with newly diagnosed rhabdomyosarcoma.

BACKGROUND: The adverse prognostic impact of elevated levels of circulating Vascular Endothelial Growth Factor (VEGF) is described in several malignancies. However, no information is available in childhood rhabdomyosarcoma (RMS). In the present study, serum VEGF-A (sVEGF-A) was measured at diagnosis in a series of patients with RMS. PROCEDURE: sVEGF-A was assessed retrospectively in 17 newly diagnosed RMS patients. sVEGF-A concentrations were determined by quantitative enzyme-linked immunoabsorbent ELISA kit and their possible associations with age at diagnosis, gender, histology, primary site, primary size, Intergroup Rhabdomyosarcoma Study (IRS) post-surgical group, and outcome were investigated. RESULTS: sVEGF-A median value in patients with RMS was significantly higher than in controls: 499.0 pg/ml, range: 2,648.0 versus 301.5 pg/ml, range: 716.0 (P = 0.013). Although not statistically significant probably due to the limited number of patients, sVEGF-A median levels resulted higher in unfavorable primary sites (277.0 vs. 539.0 pg/ml; P = 0.31), and advanced groups (390.0 vs. 715.0; P = 0.29). Patients with shorter 5-year overall survival (OS) and 5-year progression-free survival (PFS) times also had higher sVEGF-A levels, although again the difference was not statistically significant (P = 0.18 and P = 0.22, respectively). CONCLUSIONS: Circulating VEGF is significantly increased in pediatric patients with newly diagnosed RMS. Further studies in larger series of RMS patients are needed to understand whether measurements of circulating VEGF might have a role in assessing prognosis and modulating treatment.

Metastatic renal cell carcinoma in children and adolescents: a 30-year unsuccessful story.

BACKGROUND: Because of the rare occurrence of renal cell carcinoma (RCC) among children very little is known about this malignancy in pediatric age. We aimed adding knowledge on the clinical characteristics and outcome of metastatic (m) RCC in children and adolescents. PATIENTS AND METHODS: The series included 14 stage 4 RCC patients with a median age at diagnosis of 155.5 months, observed at the Italian Pediatric Hematology and Oncology Association (AIEOP) centers from January 1973 to November 2010. We were able to reevaluate histopatology of 11 out of the 14 patients and perform immunostaining for TFE3 in 9 out of the 11 patients. RESULTS: Of the 14 patients under study, 5 (3 girls) had a translocation morphology TFE+ RCC, 2 were reassigned as papillary type 1 or 2, respectively, 2 tumor specimens with primary clear cell histology had confirmed the initial histologic diagnosis, and 2-whose biopsy specimen was insufficient-had the diagnosis of RCC not further specified with subtyping. In the remaining 3 cases, the initial diagnosis of clear cell carcinoma was left. Overall, 6 patients received chemotherapy, 9 immunotherapy, and 2 adjuvant antiangiogenic therapy. Overall, 11 patients (78.5%) never achieved complete remission and died from progressive disease 1 to 16 months after diagnosis (median overall survival 5.5 mo). Three patients, 2 of whom received adjuvant antiangiogenic therapy, relapsed to lung at 3, 6, and 8 months after diagnosis, and died 18, 32, and 33 months after diagnosis, respectively. CONCLUSIONS: Despite their possibly different biology, childhood and adult mRCC seems to be sharing comparable outcomes. Because of the very low incidence of mRCC (about 20%) in children and adolescents, an international pediatric cooperation to address biological studies and assess the novel targeted approaches is needed.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Barrett esophagus in long-term survivors of childhood solid tumors.

We report on 2 cases of long-term survivors of childhood solid tumors, who developed Barrett esophagus (BE) after treatment for neuroblastoma and Hodgkin lymphoma, respectively. Case 1: A stage 3 neuroblastoma was treated with surgery, carboplatin/etoposide chemotherapy, and supradiaphragmatic radiotherapy (30 Gy). Twelve years later, based on endoscopic and histologic findings, BE was diagnosed on the middle segment. Case 2: A stage IIIB Hodgkin lymphoma received mechloretamine, oncovin, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, dacarbazine chemotherapy and supra/subdiaphragmatic radiotherapy (25 Gy). Nineteen years later, BE was diagnosed associated with an esophageal stricture. In long-term survivors of childhood tumors who had received chest/neck radiotherapy and chemotherapy, the risk of BE may be increased, therefore the diagnosis should be considered in the presence of gastroesophageal symptoms.