Radiotherapy for pediatric adrenocortical carcinoma – review of the literature

none13Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.noneWiegering, Verena; Riedmeier, Maria; Thompson, Lester D.R.; Virgone, Calogero; Redlich, Antje; Kuhlen, Michaela; Gultekin, Melis; Yalcin, Bilgehan; Decarolis, Boris; Härtel, Christoph; Schlegel, Paul-Gerhardt; Fassnacht, Martin; Timmermann, BeateWiegering, Verena; Riedmeier, Maria; Thompson, Lester D. R.; Virgone, Calogero; Redlich, Antje; Kuhlen, Michaela; Gultekin, Melis; Yalcin, Bilgehan; Decarolis, Boris; Härtel, Christoph; Schlegel, Paul-Gerhardt; Fassnacht, Martin; Timmermann, Beat

Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific molecule, were examined in an open-label, single-arm, expanded access study (RIALTO). Children (>28 days and <18 years) with CD19+ relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) received up to 5 cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary end point was incidence of adverse events. Secondary end points included complete response (CR) and measurable residual disease (MRD) response within the first 2 cycles and relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (10 January 2020), 110 patients were enrolled (median age, 8.5 years; 88% had ≥5% baseline blasts). A low incidence of grade 3 or 4 cytokine release syndrome (n = 2; 1.8%) and neurologic events (n = 4; 3.6%) was reported; no blinatumomab-related fatal adverse events were recorded. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95% confidence interval [CI]: 11.0-not estimable) and was significantly better for MRD responders vs MRD nonresponders (not estimable vs 9.3; hazard ratio, 0.18; 95% CI: 0.08-0.39). Of patients achieving CR after 2 cycles, 73.5% (95% CI: 61.4%-83.5%) proceeded to alloHSCT. One-year OS probability was higher for patients who received alloHSCT vs without alloHSCT after blinatumomab (87% vs 29%). These findings support the use of blinatumomab as a safe and efficacious treatment of pediatric R/R B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT02187354

Healthcare-associated infections in pediatric cancer patients: results of a prospective surveillance study from university hospitals in Germany and Switzerland

<p>Abstract</p> <p>Background</p> <p>Pediatric cancer patients face an increased risk of healthcare-associated infection (HAI). To date, no prospective multicenter studies have been published on this topic.</p> <p>Methods</p> <p>Prospective multicenter surveillance for HAI and nosocomial fever of unknown origin (nFUO) with specific case definitions and standardized surveillance methods.</p> <p>Results</p> <p>7 pediatric oncology centers (university facilities) participated from April 01, 2001 to August 31, 2005. During 54,824 days of inpatient surveillance, 727 HAIs and nFUOs were registered in 411 patients. Of these, 263 (36%) were HAIs in 181 patients, for an incidence density (ID) (number of events per 1,000 inpatient days) of 4.8 (95% CI 4.2 to 5.4; range 2.4 to 11.7; P < 0.001), and 464 (64%) were nFUO in 230 patients. Neutropenia at diagnosis correlated significantly with clinical severity of HAI. Of the 263 HAIs, 153 (58%) were bloodstream infections (BSI). Of the 138 laboratory-confirmed BSIs, 123 (89%) were associated with use of a long-term central venous catheter (CVAD), resulting in an overall ID of 2.8 per 1,000 utilization days (95% CI 2.3 to 3.3). The ID was significantly lower in Port-type than in Hickman-type CVADs. The death of 8 children was related to HAI, including six cases of aspergillosis. The attributable mortality was 3.0% without a significant association to neutropenia at time of NI diagnosis.</p> <p>Conclusion</p> <p>Our study confirmed that pediatric cancer patients are at an increased risk for specific HAIs. The prospective surveillance of HAI and comparison with cumulative multicenter results are indispensable for targeted prevention of these adverse events of anticancer treatment.</p

Isosexual precocious pseudopuberty during mitotane treatment in a child with adrenocortical carcinoma:A case report

Background Mitotane is employed as adjuvant therapy in managing adrenocortical carcinoma in pediatric patients. While various adverse effects, such as estrogen-like manifestations, are well-documented in adults, there is limited knowledge regarding pediatric-specific toxicity. This report details an uncommon case of isosexual precocious pseudopuberty induced during childhood due to the estrogen-like effects of mitotane. Case report A 2.8-year-old female diagnosed with adrenocortical carcinoma (pT4 pN0 M0) underwent adjuvant treatment with mitotane and cytotoxic chemotherapy following incomplete resection (tumor stage III). Approximately eight months into mitotane treatment, she exhibited signs of puberty (Tanner stage 2), including progressive breast development, uterine enlargement, vaginal discharge, and an advancement of bone age by nearly two years. Gonadotrophin-dependent puberty and endogenous estrogen production were ruled out. The precocious pseudopuberty was attributed to previously reported estrogen-like effects of mitotane therapy. Subsequent administration of the aromatase inhibitor anastrozole in combination with mitotane led to a reduction in clinical signs of puberty. Conclusion Monitoring for estrogen-like effects of mitotane is crucial, particularly in pre-pubertal children, to avert potentially irreversible changes associated with precocious pseudopuberty. Aromatase inhibitors may serve as a prompt therapeutic option, enabling the continuation of mitotane treatment

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Following Blinatumomab-Induced Remission in Pediatric Patients with Relapsed/Refractory (r/r) B-Precursor Acute Lymphoblastic Leukemia (ALL): Preliminary Results from a Phase I/II Stud

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Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

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Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (+/- 0.10) and 45% (+/- 0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial

Background Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan–temozolomide and dasatinib–rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. Methods The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1–25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan–temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2–4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin–dasatinib and irinotecan–temozolomide for four cycles over 8 weeks, then two courses of rapamycin–dasatinib followed by one course of irinotecan–temozolomide for 12 weeks) with irinotecan–temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. Findings Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7–8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31–88), the median progression-free survival was 11 months (95% CI 7–17) in the RIST group and 5 months (2–8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4–24) in the RIST group versus 2 months (2–5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9–7) in the RIST group versus 8 months (4–15) in the control group (HR 0·84 [95% CI 0·51–1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). Interpretation RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Disturbed B cell and DC-Homeostasis in Pediatric cGVHD Patients-Cocultivation Experiments and Review of the Literature

B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated