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Background: Feeding problems are common in children with complex medical problems or acute critical illness and enteral nutrition may be required. In certain situations, gastric tube feeding is poorly tolerated or may not be feasible. When feed intolerance persists despite appropriate adjustments to oral and gastric enteral regimens, jejunal tube feeding can be considered as an option for nutrition support., Methods: A multidisciplinary expert working group of the Australasian Society of Parenteral and Enteral Nutrition was convened. They identified topic questions and five key areas of jejunal tube feeding in children. Literatures searches were undertaken on Pubmed, Embase, and Medline for all relevant studies, between January 2000 and September 2022 (n = 103). Studies were assessed using National Health and Medical Research Council guidelines to generate statements, which were discussed as a group, followed by voting on statements using a modified Delphi process to determine consensus., Results: A total of 24 consensus statements were created for five key areas: patient selection, type and selection of feeding tube, complications, clinical use of jejunal tubes, follow-up, and reassessment., Conclusion: Jejunal tube feeding is a safe and effective means of providing nutrition in a select group of pediatric patients with complex medical needs, who are unable to be fed by gastric tube feeding. Appropriate patient selection is important as complications associated with jejunal tube feeding are not uncommon, and although mostly minor, can be significant or require tube reinsertion. All children receiving jejunal tube feeding should have multidisciplinary team assessment and follow-up., (© 2024 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Meropenem is currently the most common carbapenem in clinical applications. Industrially, the final synthetic step is characterized by a heterogeneous catalytic hydrogenation in batch mode with hydrogen and Pd/C. The required high-quality standard is very difficult to meet and specific conditions are required to remove both protecting groups [i.e., p -nitrobenzyl (pNB) and p -nitrobenzyloxycarbonyl (pNZ)] simultaneously. The three-phase gas-liquid-solid system makes this step difficult and unsafe. The introduction of new technologies for small-molecule synthesis in recent years has opened up new landscapes in process chemistry. In this context, we have investigated meropenem hydrogenolysis using microwave (MW)-assisted flow chemistry for use as a new technology with industrial prospects. The reaction parameters (catalyst amount, T, P, residence time, flow rate) in the move from the batch process to semi-continuous flow were investigated under mild conditions to determine their influence on the reaction rate. The optimization of the residence time (840 s) and the number of cycles (4) allowed us to develop a novel protocol that halves the reaction time compared to batch production (14 min vs. 30 min) while maintaining the same product quality. The increase in productivity using this semi-continuous flow technique compensates for the slightly lower yield (70% vs. 74%) obtained in batch mode.

Background: Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making., Methods: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival., Results: We identified 119 patients. Common tumor types included low-grade glioma (N = 51), high-grade glioma (N = 29), and medulloblastoma (N = 11). Common driver mutations included TP53 inactivation (N = 16), BRAF-KIAA1549 fusion (N = 16), FGFR1 amplification (N = 12), BRAF V600E mutation (N = 12), NF1 loss (N = 12), and H3F3A K28M mutation (N = 6). Median TMB was one mutation/megabase (mut/Mb, range = 0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high-grade tumors (p = .009, HR 84.3), and high-grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high-grade histology (p = .015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N = 15, 44%) than in low-TMB tumors (N = 19, 35%)., Conclusions: High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies., (© 2022 Wiley Periodicals LLC.)

Continuous-flow chemistry has become a mainstream process and a notable trend among emerging technologies for drug synthesis. It is routinely used in academic and industrial laboratories to generate a wide variety of molecules and building blocks. The advantages it provides, in terms of safety, speed, cost efficiency and small-equipment footprint compared to analog batch processes, have been known for some time. What has become even more important in recent years is its compliance with the quality objectives that are required by drug-development protocols that integrate inline analysis and purification tools. There can be no doubt that worldwide government agencies have strongly encouraged the study and implementation of this innovative, sustainable and environmentally friendly technology. In this brief review, we list and evaluate the development and applications of continuous-flow processes for antibiotic synthesis. This work spans the period of 2012-2022 and highlights the main cases in which either active ingredients or their intermediates were produced under continuous flow. We hope that this manuscript will provide an overview of the field and a starting point for a deeper understanding of the impact of flow chemistry on the broad panorama of antibiotic synthesis.

Cefonicid is a second-generation cephalosporin sold under the brand name Sintocef™. It is an injectable drug obtained via a freeze-drying process and is also available for oral preparations. The high-quality standard required is very challenging to satisfy, and current production protocols are characterized by steps that are lengthy and cumbersome, making the product unattractive for the international market. Industrial R&D is constantly working on the process optimization for API synthesis, with the aim of increasing productivity and decreasing production costs and waste. We herein report a new and efficient method for the synthesis of the cefonicid benzathine salt that provides a good yield and high product stability. The double-nucleophilic and lipophilic nature of N ', N ″-dibenzylethylene diacetate enables the deformylation of the OH-protected group on the mandelic moiety and also enables product crystallization to occur. We demonstrate that the formyl group in the peculiar position has high reactivity, promoting an amidation reaction that deprotects a hydroxy group and generates a new C-N bond in the reaction by-product. Several amines and OH-protected groups have been studied, but none were able to replicate the excellent results of benzathine diacetate.

Background: Infant acute myeloid leukemia is a rare but aggressive form of leukemia., Observation: We report 2 children who presented with hyperleukocytosis, subsequently diagnosed with infant acute myeloid leukemia, and both developed isolated central nervous system relapse while on chemotherapy. Both infants underwent successful bone marrow transplantation with myeloablative conditioning (thiotepa, busulfan, and cyclophosphamide) without radiation, followed by 12 empiric post-transplant lumbar punctures with intrathecal cytarabine. Both patients tolerated these therapies well, and are without infections, chronic graft-versus-host disease, or any post-transplant sequelae., Conclusion: Nonradiation-based conditioning followed by empiric central nervous system-directed intrathecal chemotherapy may be considered for high-risk infants with leukemia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lung cancer and abdominal aortic aneurysms (AAAs) possess multiple shared risk factors. Whereas both have screening guidelines in place, they vary in methodology despite having significant overlap in populations of patients screened., Methods: Our hospital system's Lung Cancer Program database was used to identify patients diagnosed with primary lung cancer within the past 15 years. Demographic and risk factor data were obtained, and patients' original positron emission tomography-computed tomography scans were re-read for measurements of the abdominal aorta (aortic diameter ≥3.0 cm). A cancer-free control group was obtained for comparison. Multilinear regression modeling was used to evaluate the independent associations of multiple variables on the presence of AAA., Results: Among 814 patients with primary lung cancer, 90 (11.1%; 95% confidence interval [CI], 8.9%-13.3%) had AAA compared with 4 of 200 (2%; 95% CI, 0.1%-3.9%) in the control group (P = .0001). Patients who smoked were more likely than nonsmokers to have AAA (11.9% [95% CI, 9.8-14.6] vs 2.2% [95% CI, 0.1-8.1]; P = .0021). In patients with AAA, 12% (11/90) had aneurysms that required treatment, and 76.6% had early-stage lung cancer. Women in our study also had a high prevalence of AAA (4.6%). Logistic regression analysis showed male sex (odds ratio [OR], 3.70; P <.001), increasing age (OR, 1.07 per year; P <.001), smoking amount (OR, 1.01 per pack-year; P = .004), and hypertension (OR, 2.30; P = .020) to be independent risk factors for AAA., Conclusions: Patients with lung cancer have a high prevalence of AAA. If future studies can demonstrate a reduction in AAA mortality by screening for AAA and lung cancer simultaneously, it may prove worthwhile to extend the low-dose computed tomography scan through the lower abdomen in select patients., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: "Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma., Methods: Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction., Results: Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ± 5% and 62 ± 5% for all patients, 61 ± 8% and 77 ± 7% for localized medulloblastoma, and 35 ± 7% and 52 ± 7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ± 6% and 89 ± 6% compared with 26 ± 6% and 53 ± 7% for classic and 38 ± 13% and 46 ± 14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ± 8% for ND and 21 ± 5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average., Conclusion: We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG., Methods: Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII). Treatment included Induction with 4-5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation., Results: We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9-55%) and 38% (95% CI 14-63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression., Conclusions: Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets., Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment., Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%)., Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

Background: Endovascular aortic repair has become increasingly popular the last years for the treatment of abdominal aortic aneurysms (EVAR) and thoracic aortic aneurysms. EVAR is less invasive compared with the classic open approach, related to a decreased immediate postoperative morbidity and mortality. Those beneficial characteristics of EVAR do not come without a cost, since EVAR requires that the patient will be exposed to a significant amount of radiation during preoperative planning, graft placement, and consecutive follow-up. This systematic review examines the periprocedural radiation exposure to patients and staff as well as ways to ameliorate it., Methods: A systematic literature search was conducted using the MEDLINE electronic database. All articles reporting radiation exposure to alive humans during EVAR were eligible for review. Only studies publishing numerical data regarding radiation exposure were included in the Results section. Other relevant articles were used for further discussion., Results: Twenty-four studies, both prospective and retrospective in nature, were included. These studies revealed that the radiation exposure depends on the specific type of procedure, with more complex procedures carrying greater radiation burden. Variations in the positioning and operating of the fluoroscopic unit may significantly alter radiation dose to both patients and staff. There was an apparent lack of education among vascular specialists and trainees in terms of radiation safety awareness. At follow-up, a significant number of patients needed additional procedures, and all required radiographic imaging, further increasing the radiation exposure to alarming levels., Conclusions: Every effort should be made to decrease radiation exposure related to endovascular aortic procedures. Attempts must be directed towards maximizing the operator's awareness, welcoming new imaging technology emitting less radiation, and shifting to follow-up strategies that require minimal or no radiation., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Perforator vein aneurysms (PVAs) of the lower extremity have not been defined or reported. This study reports the clinical presentation of patients, the PVA characteristics, and the clinical outcome of their management., Methods: Patients with signs and symptoms of chronic venous disease who had a PVA were included. Diagnosis of a PVA was made with duplex ultrasound. Normal perforator veins have a diameter of <3 mm. A PVA was defined as a diameter dilation of >9 mm, and it was always found below the deep fascia. The topography and morphology of the aneurysms were described in detail. All PVAs were treated with subfascial ligation with or without aneurysm excision. All patients were followed up for a minimum of 3 months with clinical examination and duplex ultrasound, and complications were noted., Results: There were 21 aneurysms identified in 19 patients. Fourteen (73.7%) patients were female. The mean age at diagnosis was 49 years with a standard deviation of 9. Aneurysm size ranged from 9.8 to 22.2 mm, with a mean diameter of 15.7 mm and a standard deviation of 3.8. Seventeen aneurysms were fusiform, one was saccular, and one was multilobar. The perforators of the great saphenous vein distribution were most frequently involved, whereas only one involved deep vein disease. Few patients had symptoms, such as pressure and pain directly over the affected perforator. There was no association between the location and size of the PVA and the severity of chronic venous disease. Fourteen patients were treated surgically; five patients preferred conservative treatment with elastic compression stockings. Fourteen patients (73.7%) had ligation with (n = 9) or without (n = 5) excision of the aneurysm. All underwent concomitant phlebectomies, and eight of them also had ultrasound-guided foam sclerotherapy. Endovenous thermal ablation of saphenous veins was performed in seven patients, whereas two had ligation and stripping. There were four minor postoperative complications in four patients, all of which resolved within 6 weeks. The median follow-up was 21 months, ranging from 3 to 52 months. There were no recurrences of a PVA. Five patients preferred conservative treatment. The diameter changed from 0 to 13 mm during the follow-up, and the patients' symptoms remained the same or had mild worsening., Conclusions: PVAs are rare without causing significant symptoms locally. Diagnosis is made with duplex ultrasound because the affected vein is located below the deep fascia. As only one case in our series of 19 involved the deep veins, we believe that PVAs originate from superficial veins. The condition is relatively benign, and the treatment outcomes are very good with limited complications experienced. However, selective treatment of PVAs may not be needed for most of them as treatment of the superficial veins connecting with the PVA may be sufficient., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Information on ovarian vein thrombosis (OVT) is limited to some retrospective studies. The purpose of this prospective study was to evaluate the natural history and treatment outcomes of OVT., Methods: Patients with documented symptomatic OVT who were treated with anticoagulation and had at least 3 months of follow-up were included. Outcomes of interest were recanalization rates, pain resolution, pelvic congestion syndrome, recurrent deep venous thrombosis (DVT), and mortality. All patients underwent clinical examination and duplex ultrasound; computed tomography venography was selectively performed., Results: There were 23 women with a mean age of 44 years (range, 23-68 years). Fifteen (65%) right, 5 (22%) left, and 3 (23%) bilateral OVTs were detected. The median follow-up was 27 months (range, 3 months-7 years). The most common presentation was abdominal pain in nine patients (39%), followed by flank pain in six (26%). Two patients (9%) presented with dyspnea due to pulmonary embolism. The most prevalent condition was the puerperium (n = 9; 39%). Complete recanalization occurred in 16 veins (61%), partial recanalization in four veins (15%), and occlusion in six veins (24%) while patients were receiving anticoagulation. Four patients (17%) had lower extremity DVT during follow-up after the interruption of anticoagulation. Three patients (13%) developed pelvic congestion syndrome. All four deaths (17%) were due to cancer-related complications., Conclusions: Symptomatic OVT is rare. Patients fare well with anticoagulation; complete recanalization occurs in about two thirds of the patients. Recurrent DVT is found in lower extremity veins after the interruption of anticoagulation in 17% of patients; mortality was seen only in cancer patients., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

We have studied 790 workers working abroad, for 2005-2010, divided into 3 main groups for recommended and mandatory vaccination schemes, specific for geographic areas, in co-administration. After the standardized prevaccine screening, 780 (98.7%) workers were eligible for vaccination, 10 (1.2%) workers showed temporary contraindications and personal precautions need. The post vaccination evaluation has shown that a percentage from 9 to 20% of workers had local adverse effects, mild injection site.

Background: Children with acute lymphoblastic leukemia (ALL) are at risk for developing musculoskeletal complications during and after their medical treatment. The objective of this study was to examine the feasibility of an in-hospital physical therapy- and home exercise program during the first four phases of medical treatment, for children with newly diagnosed ALL., Procedure: Nine patients, between the ages of 2-14 years old were enrolled within 2 weeks of diagnosis in the study. Each patient was evaluated at study entry, after each of the first four phases of therapy and each time patients were re-admitted to the hospital. Following the initial physical therapy evaluation an individualized home exercise program was developed, consisting of stretching, strengthening, and aerobic exercises. The following end points were measured at each evaluation: gross motor assessment as measured by gross motor function measure (GMFM), health-related quality of life as measured by the PedsQL and parent satisfaction questionnaire., Results: This study was feasible with 98% of the evaluation sessions completed. The GMFM and PedsQL improved steadily throughout the study; however, the PedsQL slightly decreased from interim maintenance to delayed intensification. The parents reported being satisfied with the physical therapy program., Conclusion: We demonstrated that an in-hospital- and home exercise physical therapy program during the first four phases of medical treatments is feasible for children with ALL. Future randomized studies are needed to confirm whether an initial physical therapy program at diagnosis in children with ALL will limit functional impairments, improve overall fitness and increase health-related quality of life., (Copyright © 2011 Wiley-Liss, Inc.)

Children with acute lymphoblastic leukemia (ALL) are at risk for developing musculoskeletal complications. Few studies have examined the role of physical therapy (PT) for addressing these complications. The study objective was to examine why and when in the medical treatment, children with ALL receive a referral to PT. Retrospective chart review of 35 children, diagnosed with ALL in 2006 and 2007 at Penn State Children's Hospital was carried out. A questionnaire was completed by 6 pediatric oncologists, to identify their referral patterns. The chart review demonstrated that 25 of the 35 patients had reports of musculoskeletal complications sometime during their treatment, but only 10 (30%) were referred to PT. The most common reason for referral was decreased functional mobility. Patients were referred evenly through all phases of therapy. Vincristine was reduced in 5 patients, the most common cause being peripheral neuropathy and foot drop. The majority (5/6) of the physicians reported that they "sometimes" refer patients to PT, through different phases of therapy, with 1/3 reporting all phases. The results show that although physicians identified the musculoskeletal complications, only a minority of patients were referred for PT. This supports the need for increasing the awareness of physicians about benefits of early integration of PT into the medical treatment.

IPEX syndrome (immune deficiency, polyendocrinopathy, enteropathy, X-linked) is a disorder or regulatory T cell (Treg) function which can result in early death due to infection or complications related to autoimmunity. Therapeutic options for these patients can include allogeneic stem cell transplantation (SCT) or the use of immunosuppressive regimens to control the manifestations of autoimmunity. We report a patient with IPEX syndrome who was managed with rapamycin and subsequently developed EBV induced lymphoma., ((c) 2008 Wiley-Liss, Inc.)

Background: Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR)., Procedures: Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR., Results: Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy., Conclusions: ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients., ((c) 2007 Wiley-Liss, Inc.)

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.

T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I-II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III-IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein-Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.

We carried out an in-depth evaluation of psychosocial status in a sample of 18 children (mean age 6.8 yr, range 4.4-10.8 yr) who had suffered from severe liver disease and undergone orthotopic liver transplantation (OLT). Mean age at OLT was 3.4 yr. The assessment was psychoanalytically oriented and included individual sessions and testing procedures for children--the Children Apperception Test (CAT), the Weschsler Intelligence Scale for Children (WISC-R), the Weschsler Preschool and Primary Scale of Intelligence (WIPPSI), and the Human Figure Test--and a semi-structured interview with a separate questionnaire for parents. Patients were compared with an age- and gender-matched control group. The main findings in patients compared with controls were: IQ 91.6 (range 70-117) vs. 118 (range 94-135) (p<0.0001); immaturity of ego and drives (72.2% vs. 27.7%; p=0.018), fear of death (61.1% vs. 11.1%; p=0.04), anxiety of loss (50%, vs. 27.7%; p=NS), and depressive feelings (61.1% vs. 22.2%; p=0.04); a mild defect of body image (44.4% vs. 33.3%; p=NS) associated with recurrent representations of motionless (72.2% vs. 38.8%; p=NS) and inexpressive (88.8% vs. 16.6%; p<0.0001) human figures. Fantasies about OLT as a 'magic rebirth' or a 'body transformation' were detected in few patients (30%). Although a recurrent set of feelings, conflicts, and fantasies about OLT were expressed by children, individual specific psychological responses to this experience were often detected. In spite of the fact that approximately 50% of the parents mentioned emotional or behavioral disturbances of their child, only three parents were seriously concerned about this problem. The theme of transplantation was most often absent from communication between the child and their parents. Our results suggest that psychic 'working through' of the chronic liver disease and OLT experience is difficult for children. Further studies are necessary to verify whether changes of parental attitude to OLT as a 'family secret' may facilitate integration of the OLT experience in the child's personality development.

Reconstitution of the immune system following T-cell-depleted bone marrow transplantation (BMT) in children has yet to be fully elucidated. Thus, we prospectively studied the recovery of immune function in 64 children who underwent T-lymphocyte-depleted marrow transplants using either matched family member donors or matched unrelated donors. We measured in vitro posttransplantation proliferative responses to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, and Candida albicans antigen and assessed unidirectional allogeneic mixed-lymphocyte culture (MLC) responses at various times. A total of 129 healthy individuals served as normal controls for these assays. Responses to T-cell mitogens normalized within 12 months posttransplantation, while MLC responses normalized by 9 months. The presence of graft-versus-host disease (grade II or greater) and cytomegalovirus infection was associated with delays in immune function recovery. Importantly, immune function recovery correlated temporally with a rise in peripheral lymphocyte count. In contrast, the CD4/CD8 ratio was not predictive of immune recovery. Knowledge of immune function recovery may guide clinicians in devising strategies to minimize the risk of infection post-BMT.

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.