Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience.

BACKGROUND: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL. PATIENTS AND METHODS: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed. RESULTS: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time. CONCLUSIONS: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment.

Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients.

Pediatric refractory or relapsed acute lymphoblastic leukemia (ALL) poses unique therapeutic challenges, with novel immunotherapy approaches offering potential cure opportunities. In this frame, the use of Blinatumomab may induce durable remissions, serving as a successful bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we retrospectively summarize the Greek experience on pediatric relapsed/refractory B-cell precursor ALL patients that were treated with Blinatumomab in a compassionate, off-label setting as an effort to achieve disease clearance and proceed to allo-HSCT. In our cohort of 9 patients, 6/9 (66.7%) responded to Blinatumomab, achieving complete morphological remission (CR) after the 1st cycle, while minimal/measurable residual disease (MRD)-negativity (<10-4) after the 1st cycle was achieved in 2/2 patients (100.0%) with prior CR. A successful bridge to HSCT was feasible in 5/9 patients (55.6%). Median relapse-free survival (RFS) was 3.0 months (range 0.5-21.4 months) and median overall survival (OS) was 8.7 months (range 1.4-47.1 months) for the whole pediatric cohort. There was a trend of prolonged survival among patients who achieved MRD response after the 1st Blinatumomab administration. MRD response (defined as the >=2-log reduction of MRD value before and after Blinatumomab administration), was associated with a median RFS/OS of 7.4/7.6 months, while lack of MRD response was associated with a median RFS/OS of 0.5/3.0 months, respectively. Novel therapeutic maneuvers, in order to overcome disease resistance, i.e. increased usage of Blinatumomab dose (45 µg/m2/day), combination with donor lymphocyte infusions (DLIs), use of other immunotherapy salvage approaches (inotuzumabozogamicin), are herein discussed. Additionally, the optimal number of Blinatumomab cycles, the CD19-negative relapses and lineage switch, are also addressed. Our data although referred to a limited, however refractory or relapsed and heavily pretreated number of patients, strongly suggest that Blinatumomab may well induce sustained remissions and serve as an effective bridge to HSCT. Whether immunotherapy combined with chemotherapy can outweigh the need for subsequent allo-HSCT, if incorporated into frontline high-risk ALL therapy, remains an optimistic issue to be verified in future randomized clinical trials.

ETV6/RUNX1-positive childhood acute lymphoblastic leukemia (ALL): The spectrum of clonal heterogeneity and its impact on prognosis.

The prognostic significance of the ETV6/RUNX1-fusion and of the accompanying aberrations is disputable; whether co-existing sub-clones are responsible for delayed MRD-clearance and thus, moderate outcome, remains to be clarified. We studied, in a paediatric cohort of 119 B-ALLs, the relation between the ETV6/RUNX1 aberration and the co-existing subclones with (a) presenting clinical/biological features, (b) early response to treatment(MRD) and (c) long-term outcome over a 12-year period. Patients were homogeneously treated according to BFM-based-protocols. 27/119 patients (22.7%) were ETV6/RUNX1-positive; 19/27 (70.4%) harbored additional genetic abnormalities while 9/19 (33.3%) presented with clonal heterogeneity. The most common abnormalities were del12p13 (37%), 3-6×21q22 (22.2%), del9p21 (18.5%) and 2-3xETV6/RUNX1 (18.5%). MRDd15-positivity (≥10-3) was detected in 44% of the cohort; the corresponding MRD among patients carrying subclones rises to 88.9%. Common features of all relapses were sub-clonal diversity, FCM-MRDd15-positivity and additional del(9p21) while there were no censored relapses among ETV6/RUNX1-positive patients with sole translocation and absence of additional aberrations, within a median follow-up time of 90 months. In our study, the presence of clonal heterogeneity and impaired FCM-MRD clearance among ETV6/RUNX1-positive patients, ultimately influenced prognosis. Longer follow-up is needed in order to further validate these initial results.

Ectopic nephrogenic rest in the inguinal canal in a 6-month-old girl and a review of published studies.

Ectopic nephrogenic rests in the inguinal canal are rare. Usually discovered incidentally during surgery, these rests should raise the suspicion of an early extrarenal Wilms tumor. The differential diagnosis between the two entities is not only difficult but also essential, since they imply different treatment decisions. We report a rare case of an inguinal ectopic nephrogenic rest found in a 6-month-old girl and discuss the clinicopathological implications of this condition. The patient was admitted for a routine repair of a presumed inguinal hernia; during surgery, a nodular mass was noted in the inguinal canal. Pathological diagnosis confirmed the diagnosis of an extrarenal hyperplastic nephrogenic rest. Five previous cases of ectopic nephrogenic rests originating in the inguinal canal have been reported, all of which were associated with a patent processus vaginalis. In this case, the nephrogenic rest was not associated with a congenital inguinal hernia.

Blood stream infections throught the entire course of acute lymphoblastic leukemia treatment.

The incidence, type and mortality of bacteremias were evaluated in a pediatric patient cohort, during the entire course of treatment for acute lymphoblastic leukemia (ALL). Eighty-six patients with newly diagnosed ALL were studied. A bacteremic episode was defined as blood isolation of a pathogen in the presence of clinical symptomatology of septicaemia. Bacteremias were analyzed according to the treatment element being delivered and the degree of neutropenia. A central venous catheter (CVC) was inserted at diagnosis in all patients. Fifty-two episodes of bacteremias were encountered in 38/86 (44%) patients, while 48/86 patients had no positive blood culture. Three out of the 38 patients had bacteremia and CVC area infection, simultaneously. Most blood stream infections (29/52, 56%) were documented during the induction phase. Isolated Gram-positive organisms were 48%, Gram-negative 50% and 2% of the positive blood cultures represented fungaemias. The most common Gram-positive isolates were Staphylococcus species (N=22) and the commonest Gram-negative isolated pathogens were Escherichia coli and Pseudomonas aeruginosa. The majority of bacteremias (75%) occurred during neutropenia. The initial antibiotic treatment was ceftazidime or piperacillin/tazobactam and amikacin or tobramycin. CVC was not removed in the majority of bacteremias (94%). No infection related fatality was recorded. Bacteremias constituted a severe and common complication in our patient cohort. However, infection-related fatality rate was negligible, most probably due to the prompt initiation of broad coverage antimicrobial therapy.

Burnout, staff support, and coping in Pediatric Oncology.

GOALS OF WORK: The goals of the study were the following: (1) to study the rate of burnout of the staff in Pediatric Oncology and compare it with that of a group of staff in other pediatric specialties, (2) to find out if job satisfaction, role clarity, staff support, and ways of coping are related to the burnout of these two groups, and (3) as a secondary aim, to identify other parameters, i.e., profession, experience, having children, etc., which might affect burnout, staff support, and ways of coping. MATERIALS AND METHODS: The study group (n = 58) consisted of the staff of two Pediatric Oncology units and a Bone Marrow Transplantation unit, and the control group (n = 55) consisted of the staff of two Pediatric departments and one Pediatric Orthopedics department. The Maslach Burnout Inventory, the Staff Support Questionnaire, the Shortened Ways of Coping Questionnaire-Revised, and the Social Readjustment Scale were used. MAIN RESULTS: No differences were found in burnout between Pediatric Oncology staff and that of other specialties, the existing staff support, and the ways of coping. Decreased role clarity and wishful thinking, as a way of coping, were positively correlated to emotional exhaustion, whereas a negative correlation of the lack of role clarity existed with personal accomplishment. Not having children and less experience increased burnout in both groups studied. CONCLUSIONS: The hospital management and the heads of departments should be knowledgeable of ways to prevent burnout in their staff. Strategies targeting role clarity and wishful thinking are useful toward this goal.

Membrane filtration of olive mill wastewater and exploitation of its fractions.

Olive mill wastewater (OMW) produced from small units scattered in rural areas of Southern Europe is a major source of pollution of surface and subsurface water. In the present work, a treatment scheme based on physical separation methods is presented. The investigation was carried out using a pilot-plant unit equipped with ultrafiltration, nanofiltration, and reverse osmosis membranes. Approximately 80% of the total volume of wastewater treated by the membrane units was sufficiently cleaned to meet the standards for irrigation water. The concentrated fractions collected in the treatment concentrates were characterized by high organic load and high content of phenolic compounds. The concentrates were tested in hydroponic systems to examine their toxicity towards undesired herbs. The calculations of the cost of the overall process showed that fixed and operational costs could be recovered from the exploitation of OMW byproducts as water for irrigation and/or as bioherbicides.

Diffuse intraabdominal desmoplastic small round cell tumor: a ten-year experience.

BACKGROUND: Intraabdominal desmoplastic small round cell tumors (IDSRCT) are rare in children and predominantly affect male adolescents and young adults. We present our experience in the management of five children with diffuse IDSRCT, managed with aggressive chemotherapy, surgery, radiotherapy and peripheral blood stem cell transplantation. MATERIAL AND METHODS: During the last decade five patients, four males and one female (mean age 9.6 years), with diffuse IDSRCT were managed in our department. The main symptoms were abdominal distention, vague abdominal pain, and vomiting. Three patients with inoperable tumor on admission were submitted initially to open biopsy followed by aggressive chemotherapy. Regression of the tumor was followed by a second laparotomy and radical excision of any macroscopically distinguishable masses, followed by chemotherapy. In the remaining two patients a debulking procedure was done initially, followed by chemotherapy. The accurate diagnosis of the disease was established by immunohistochemistry, additionally confirmed in the last two patients by molecular analysis. RESULTS: Three patients who had radical excision of the tumor and adjuvant chemotherapy had recurrence after two to six months. In the remaining two patients, recurrence was evident after two and eighteen months, respectively, following debulking. In addition, one patient with recurrence received radiotherapy and two others underwent peripheral blood stem cell transplantation. All but one patient died within three years from diagnosis. The last patient, who was submitted to a debulking procedure, is still alive eight months after the operation. CONCLUSIONS: Intrabdominal desmoplastic small round cell tumor is a highly aggressive malignancy with a very poor prognosis. Multiagent chemotherapy usually leads initially to a temporary regression of the tumor, but recurrence is the rule. Radical surgical excision, radiotherapy and peripheral blood stem cell transplantation does not seem to improve prognosis significantly. Despite all therapeutic modalities the outcome is dismal and surgical efforts can be considered only as palliative.

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

Gonadal function in young patients successfully treated for Hodgkin disease.

BACKGROUND: Gonadal function in pediatric and young adult survivors of Hodgkin disease is not very well defined. This study evaluates the outcome following the Multiple Drug Protocol (MDP) and the results are compared to the published experience. PROCEDURE: Ovarian and testicular function was assessed in 65 patients (36 males) with Hodgkin disease in first or second complete remission after treatment with either radiation (RT, n = 13), chemotherapy (CT, n = 9), or both (n = 43). Chemotherapy consisted of six cycles of the MDP (doxorubicin, procarbazine, prednisone, vincristine, and cyclophosphamide). Median age at diagnosis was 13.1 years (range, 2.4-22.6) and median age at evaluation was 22.6 years (range, 15.1-33.7), which was 6.7 years (range, 2.0-19.8) after the completion of all treatments. For the purpose of analysis, patients were divided into three groups: group A, patients who received only RT that did not include the pelvis (8 females, 5 males); group B, patients who received CT but no pelvic RT (15 females, 25 males); and group C, patients who received CT plus pelvic RT (6 females, 6 males). RESULTS: All patients progressed spontaneously through puberty and evaluable patients were found to be sexually mature (Tanner stage IV and V). Serum follicle stimulating hormone (FSH) was increased in 0/5, 13/25, and 5/6 and testicular volume was decreased in 1/3, 4/11, and 2/3 group A, B, and C male patients, respectively. Leydig cell dysfunction was uncommon; 91% and 88% of males had normal serum concentrations of luteinizing hormone (LH) and testosterone, respectively. FSH and LH were increased in 0/8, 3/15, and 2/6 group A, B, and C female patients, respectively, at last follow-up, indicating a 17% prevalence of ovarian dysfunction. Serial data in seven females whose initial levels of FSH/LH were elevated revealed normalization in four. Six females delivered eight normal children. CONCLUSIONS: The majority of males who received CT +/- RT have evidence of germ cell dysfunction, while Leydig cell function is unaffected in most. In females, although abnormal function early after the end of treatment was observed, ovarian function remained or returned to normal in most young women. Thus, in females the results of hormone testing performed early after treatment may not be predictive of their eventual reproductive potential.

Growth and final height after treatment for childhood Hodgkin disease.

PURPOSE: To evaluate in children the impact of contemporary treatment for Hodgkin disease on the pattern of growth and final height. PATIENTS AND METHODS: We studied 80 patients (54 males) aged <14 years at diagnosis, with newly diagnosed, pathologically confirmed Hodgkin disease, treated at a single institution. Forty six patients received chemotherapy (CT) + radiotherapy (RT), 23 patients received RT alone, and 11 patients received CT alone. Heights were obtained at diagnosis, at the end of treatment, 1, 2, and 3 years after the end of treatment and at attainment of final height. Heights were converted to age- and sex-adjusted SD scores (SDS). RESULTS: There was a significant change in height SDS at the end of treatment compared to height SDS at diagnosis for all three groups (CT + RT: -0.33, p<0.001; RT: +0.09, p=0.027; CT: -0.24, p=0.012). Over the 3 years following treatment, the rate of change of height SDS was not statistically different between the three treatment groups. Final height SDS was decreased for patients receiving RT + CT (-0.41 SDS, p=0.02; n=31). The change in final height SDS for patients receiving RT or CT only was -0.36 (n=14) and +0.42 (n=4), respectively. Loss of final height SDS correlated with younger age at diagnosis (p=0.005). Patients receiving higher RT doses tended to fare worse (p=0.08). CONCLUSIONS: Pediatric patients treated for Hodgkin disease with the combination of RT and CT suffer a small but significant decrease in their final height SDS. Younger patients and those treated with higher RT doses appear to experience the greatest loss of height potential.

In vitro sensitivity of post-bone marrow transplantation CFU-GM and BFU-E to TNF-alpha and IFN-gamma.

Graft failure remains one of the limitations of successful marrow transplantation. T cell-depleted (TCD) bone marrow transplantation (BMT) is reported to have a higher incidence of graft failure than unmodified (UM) BMT. In most cases of secondary graft failure, no cellular immune mechanism has been identified and etiology remains unclear. In an effort to delineate a cytokine-mediated mechanism of secondary graft failure, we investigated colony-forming unit-granulocyte/macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth and pattern of inhibition by tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma) in the early posttransplant period (day 28). Gradient-separated bone marrow mononuclear cells (BMMNC) from 38 recipients of TCD BMT, 15 recipients of UM BMT, and 23 normal donors (NLD) were plated in cultures of semisolid, serum-containing medium with the addition of stem cell factor (SCF), erythropoietin (Epo), and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Three to seven times more CFU-GM and BFU-E colonies were cultures from NLD BM-derived BMMNC than from BMMNC of recipients of TCD or UM BMT (p = 0.0001). There was no difference in colony number between recipients of UM and TCD BMT on day 28 posttransplant, however. Under G-CSF culture conditions, CFU-GM colonies from recipients of UM and TCD BMT were more susceptible (p < or = 0.05) to suppression by IFN-gamma at concentrations of 1 and 100 U/mL than NLD BMMNC-derived colonies. No other difference in IFN-gamma inhibition was detected among the three groups. Under G-CSF and GM-CSF culture conditions, maximal inhibition was obtained at TNF-alpha concentrations > 10 ng/mL. Although early posttransplant BMMNC was more sensitive to inhibition than NLD-derived BMMNC, overall, no difference in colony growth or percent of inhibition induced by TNF-alpha or IFN-gamma was observed between recipients of unmodified and T. cell-depleted transplants. In this series, two recipients of TCD BM and one recipient of UM BMT developed graft failure; no distinct pattern of colony growth or colony inhibition was evident for those patients. The optimized in vitro conditions and specific cytokines used in this study do not indicate any quantitative or qualitative differences in the hematopoietic progenitors present in recipients of unmodified and T cell-depleted bone marrow early posttransplant to explain an increased risk of graft failure following a T cell-depleted BMT compared to an unmodified BMT.

Serum granulocyte colony-stimulating factor (G-CSF) levels after allogeneic T cell-depleted marrow transplantation.

Endogenously produced and exogenously administered granulocyte colony-stimulating factor (G-CSF) has correlated with myeloid engraftment in a number of hematopoietic progenitor cell transplantation settings. Given the increased susceptibility of T cell-depleted (TCD) bone marrow transplants (BMT) to graft failure, a cohort of 36 (21 male and 15 female) recipients of TCD BMT was evaluated prospectively during the first month post-transplant for circulating serum G-CSF levels, to examine the correlation between myeloid engraftment and G-CSF levels. All recipients of TCD BM had measurable G-CSF levels, with a median peak level of 1750 pg/ml (range 540-26,250 pg/ml) occurring at a median of 5 days (range 1-18 days) after BM infusion. There was no association between G-CSF kinetics within 1 month post-transplant and the development of primary non-engraftment or secondary graft failure. One patient with primary non-engraftment and 6 patients with secondary graft failure exhibited median G-CSF peak levels of 1600 pg/ml and 1850 pg/ml (range 600-16,250 pg/ml) occurring 5 and 5.5 days (range 4-7 days) after BM infusion, respectively. Additionally, the patient with primary non-engraftment demonstrated a high G-CSF level in response to a low absolute neutrophil count (ANC). An inverse relationship between serial G-CSF levels and concomitant ANC was documented (log G-CSF = 6.19-0.009 ANC, P < 0.001). Higher peak G-CSF levels were associated with older recipient age (P = 0.01) and lower BM cell dose (P = 0.02), while administration of anti-thymocyte globulin post-transplant did not alter G-CSF levels.

Rhabdoid tumor of the kidney with humoral hypercalcemia and parathyroid hormone-related protein production.

This is a report of a 7-month-old infant with malignant rhabdoid tumor of the kidney (RTK). The patient (pt) demonstrated clinical and biochemical evidence of humoral hypercalcemia of malignancy (HHM). The hypercalcemia responded promptly to calcitonin treatment and tumor removal. Despite aggressive surgery and chemotherapy, the patient expired four months after diagnosis. The primary tumor displayed adenylate cyclase-stimulating activity (ACSA) indicating the production of parathyroid hormone-related protein (PTHrP) by the primary tumor. This is the first report of ACSA documented in a pt with RTK.

Differential effect of pre-transplant cytoreduction on recovery of day zero host circulating cells.

Host lymphocytes, reactive against donor specific HLA antigens, emerge at the time of graft rejection following T cell-depleted BMT. Thirty patients receiving different cytoreduction regimens were evaluated for the presence of circulating residual, in vitro expandable, host cells on day 0. Twenty-five patients received TBI-containing regimens and 5 patients received non-TBI containing regimens. Patients prepared with thiotepa or TBI-containing regimens had 10-fold lower numbers of circulating host PBMC pre-transplant on day 0 compared with patients cytoreduced with BU/CY. Cell proliferation was observed only in patients who received BU/CY. The phenotype of the in vitro expanded cells was predominantly CD3+ (88-97%), CD8+ (45-70%), HLA-DR+ (43-88%), although natural killer cell function and phenotype (CD56+: 6-21%) was also documented. Host cells expanded from a patient who received BU/CY exhibited specific cytotoxicity against feeder cell targets, indicating that BU/CY cytoreduction might not be an optimal BMT preparative regimen for patients at high risk of graft failure. The published experience of similar studies to date is also summarized.