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In primary mediastinal large B‐cell lymphoma, central nervous system (CNS) relapse is an uncommon event with a dismal prognosis. We report about the successful management of CNS relapse with chemoimmunotherapy according to MATRix (methotrexate, cytarabine, thiotepa, and rituximab) protocol followed by autologous stem cell transplant.

Background Haploidentical HSCT is a good option for children with PIDs lacking an HLA-matched donor. Co-transplantation of MSCs during haploidentical HSCT in patients with PIDs may enhance engraftment, decrease the risk of GVHD, and ensure stable donor chimerism. Methods Twenty-seven pediatric patients (median age, 1.4 years; range, .3-10.9) with PIDs undergoing thirty haploidentical HSCT with TCR αβ depletion and co-transplantation of MSCs were enrolled to study. Most patients (73.3%) received myeloablative conditioning consisting of treosulfan or busulfan, fludarabine, and thiotepa. The median duration of follow-up was 14.3 months (range, 1-69 months). Results Acute GVHD occurred in 7 patients (grade I-II n = 5, grade III-IV n = 2). Chronic GVHD was observed in only one patient. Twenty-one patients (70.2%) had 100% donor chimerism in all cell lines including T-cell and B-cell lineages. Primary graft failure was observed in 7 patients (25.9%). The cumulative incidences of TRM were 20% at day 100, and 26.7% at one year and five years. Probabilities of OS were 80% at day 100, and 71.9% at 1 year and 5 years. Infants transplanted younger than 6 months of age had the highest 5-year survival rate (85.7%). Conclusion We conclude that use of TCR αβ depleted haploidentical transplantation with MSCs may ensure a rapid engraftment rate, low incidence of significant acute and chronic GVHD, and acceptable post-transplantation morbidity, especially in patients diagnosed with SCID and may be considered in children with PIDs. In younger patients (≤6 months), survival is comparable between HLA-matched graft and CD3+ TCRαβ depleted HLA-mismatched graft recipients.

For patients with bone marrow failure syndromes (BMFS) who may tolerate gradual donor engraftment and achieve adequate disease control with stable mixed chimerism, RIC regimens may be preferable to myeloablative regimens. We performed a retrospective analysis of outcomes for patients who underwent HSCT at our institution between 2009 and 2017 for BMFS using an irradiation-free RIC regimen. Fourteen pediatric patients with BMFS received fludarabine (30 mg/m2 IV daily × 3), thiotepa (5 mg/kg IV every 12 hours × 2), and melphalan (70 mg/m2 IV daily × 2) prior to HSCT. Our cohort included the following diagnoses: SAA (n = 7), CAMT (n = 4), SCN (n = 1), DBA (n = 1), and non-Fanconi congenital BMF (n = 1). Seven patients underwent a MSD transplant; seven underwent an unrelated donor transplant. All patients are alive with median follow-up of 1112 days (range 455-2549 days). The median time to neutrophil engraftment was 16 days (range 10-26 days). All were transfusion independent by day + 100. The highest grade of aGVHD was grade 2; 8 (57%) did not develop aGVHD. Four (28.5%) developed extensive cGVHD, 4 (28.5%) developed limited cGVHD, and 6 (43%) did not develop cGVHD. No patients developed SOS. None died from GVHD or infectious complications. HSCT with RIC with fludarabine, thiotepa, and melphalan for BMFS was effective with a tolerable safety profile. Probability of OS at 100 days and 1 year was 100%.

TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.

X-linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan-based regimen with resultant autologous reconstitution. At 6 months post-HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow-up of 20 months have 100% chimerism. Treosulfan-based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.

Key clinical message Primary central nervous system lymphoma (PCNSL) remains a therapeutic challenge due to impaired drugs diffusion as a result of the blood‐brain barrier and high risk of relapse. Patients with good performance status, chemo‐sensitive disease, and eligible for autologous stem cell transplant (ASCT) may benefit from salvage therapy and therapeutic intensification that may allow long‐term remission.

The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa-based conditioning (n = 180) with those receiving Cy/ TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC+AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT(NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n=11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC+AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (3 non-protocol adherence, 5 teratoma, 5 palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9%(95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC+AuSCR was 0%(0-0%) and 14%(3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55%vs.9%; p=0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC+AuSCR with/without re-irradiation; which both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC+AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible. This article is protected by copyright. All rights reserved.

BACKGROUNDRisk factors for impairment in psychosexual development and satisfaction among adult survivors of childhood cancer are poorly understood. The authors compared psychosexual outcomes between survivors and healthy controls, and tested whether at-risk survivors can be identified by 1) treatment neurotoxicity or 2) diagnosis.METHODSA total of 144 young adult survivors of childhood cancer and 144 matched controls completed questionnaires regarding psychosexual development, sexual satisfaction, and satisfaction with relationship status. Survivors were aged 20 to 40 years and were 5 to 34 years after diagnosis. Using medical chart data, survivors were divided into non-neurotoxic (48 survivors), low-dose (36 survivors), and high-dose (58 survivors) neurotoxic treatment groups.RESULTSApart from having fewer lifetime sex partners, survivors did not appear to differ from controls. However, survivors of brain tumors and any survivor who received high-dose neurotoxic treatment reported the lowest rates of achieving milestones of psychosexual development, whereas sexual and relationship status satisfaction were found to be related to relationship status. Neurotoxic treatment intensity further distinguished between survivors of brain tumors with and without psychosexual impairment.CONCLUSIONSThe intensity of neurotoxic treatment may be a valuable indicator of risk for psychosexual impairment relative to diagnosis alone. Health care providers should assess romantic/sexual problems among survivors at risk and make referrals if needed. Cancer 2017;123:1869-1876. (c) 2017 American Cancer Society.The results of the current study indicate that adult survivors of childhood cancer do not differ from healthy controls with regard to their psychosexual development, sexual satisfaction, and relationship status satisfaction. However, more intense neurotoxic treatment appears to be associated with a higher risk of psychosexual impairment, and may be a more meaningful risk indicator than diagnostic category alone.

In this study, we analyzed a thiotepa-based conditioning regimen for allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia, using the EBMT database. A total of 323 patients were identified. The median age was 43 years. Disease status at transplant was first complete remission (CR1) in 48.9%, CR2 in 21.7%, CR3 in 6.2%, while 23.2% of the patients had an active disease at the time of transplant. This was performed from a HLA-matched sibling (49.8%) or a matched-unrelated donor (51.2%). The incidence of acute graft-vs.-host disease (GvHD) (grade > II) was 26.6%, while chronic GvHD occurred in 35.9% of the patients at 1 year (24.6% with extensive disease). With a median follow-up of 16.8 months, the nonrelapse mortality was 12.4 and 25.3% at 100 days and 1 year, respectively. The relapse incidence at 1 year was 33.3% with no difference for patients in CR1 (27%). The one-year leukemia-free survival (LFS) and overall survival (OS) were 57 and 66%, respectively for the entire cohort and 50 and 66%, respectively in patients in CR1. Thiotepa/busulfan ± melphalan (n = 213) in comparison to thiotepa/other (n = 110) conditioning regimen resulted in higher relapse incidence at 1 year (34.9 vs. 30.3%, P = 0.016) and lower LFS (38.8 vs. 45.9%, P = 0.0203), while nonrelapse mortality (23.8 vs. 26.3%, n.s.) and OS (59.6 vs. 51.1%, P = 0.109) did not differ. This large study suggests that a thiotepa-based conditioning for allogeneic transplantation in acute lymphoblastic leukemia is feasible and effective, with the main outcomes being comparable to those achieved with other regimens. Am. J. Hematol. 92:18-22, 2017. © 2016 Wiley Periodicals, Inc.

Background Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. Procedure To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n = 71, AML n = 47, MDS/MPS n = 40, other leukemia/lymphoma n = 25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. Results Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45 ± 4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P = 0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P = 0.048) and a trend toward better EFS. Conclusions Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single-unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74-98%] with a median of 18 d (range, 10-48). CI of acute graft-versus-host disease (GvHD) grades II-IV was 30% (95% C.I., 17-44%), while the incidence of chronic GVHD was 42% (95% C.I., 23-77%). The non-relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13-46%) and 47% (95% C.I., 29-65%), respectively. EBV-related post-transplant lymphoproliferative disease (EBV-PTLD) accounted for more than one-third of transplant-related death, with an estimate incidence of 26% (95% C.I., 9-44). The incidence of relapse at 4 yr was 25% (95% C.I., 9-42%). Four-year event-free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV-PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.

Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD.

Background Oncology drug shortage is associated with increased patient adverse events and decreased enrollment on clinical trials for adult patients; however, the impact of oncology drug shortages has not been well studied in children with cancer. Procedure The Children's Oncology Group (COG) distributed a 5-item survey to 226 COG site-specific principal investigators (PI's) and 14-item survey to 161 COG pharmacists to gather data the impact of chemotherapeutic shortages on clinical trials and patient care. Results The response rate was 66.4% (150/226) for PI's and 29.8% (48/161) for pharmacists. COG PI's reported daunorubicin (73%), methotrexate (56%), asparaginase/PEG-asparaginase (42%), doxorubicin (26%), thiotepa (21%), and cytarabine (20%) were most commonly in shortage, while COG pharmacists reported daunorubicin (80%), methotrexate (66%), vincristine (21%), thiotepa (41%), asparaginase/PEG-asparaginase (34%), and cytarabine (34%) were most commonly in shortage over the past two years. Pharmacists were twice as likely to report a shortage compared with PI's (OR 2.1, 95% CI: 1.6–2.7, P

In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.

Background Treosulfan (treo) is an alkylating agent with a low acute toxicity profile that is increasingly used in hematopoietic stem cell transplantation, predominantly in non-malignant diseases. Treosulfan is usually combined with additional agents, but there is scant evidence to allow comparison between different conditioning protocols using treosulfan. We present the experience of three pediatric transplantation centers in Israel using different treosulfan-based conditioning regimens. Procedure Data were collected retrospectively on 44 children who underwent 45 hematopoietic stem cell transplantations using treosulfan in combination with either fludarabine (flu) and thiotepa (tt) (n = 20), cyclophosphamide (cy) (n = 6) or fludarabine alone (n = 19). Results Overall survival (OS) was 70.5%. Disease free survival (DFS) was 54.6%. There was no statistically significant difference between treatment groups in either OS or DFS. Overall survival in patients younger than one year was higher (88.2%). There were significantly more patients with 100% donor chimerism transplanted with flu/treo/tt compared with flu/treo or treo/cy (94.7% compared to 66.7% and 16.7%, respectively). Further prospective studies are required to determine the optimal treosulfan-based preparative regimen for children with non-malignant diseases. Pediatr Blood Cancer 2015;62:299–304. © 2014 Wiley Periodicals, Inc.

Introduction Intensive postsurgical therapies have improved survival in children with primitive neuroectodermal tumour, but there is concern that the combination of chemotherapy and radiotherapy may result in a compound injury to normal brain. The purposes of this analysis were to characterise what types of imaging abnormalities occur, identify risk factors and explore how treatment-related changes may be distinguished from tumour. Method One hundred fifty-three MRI studies in 14 children treated with sequential chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa were retrospectively analysed at a paediatric national referral centre. Results We observed 11 episodes of new focal enhancing lesions, 5 of which were transient and judged to be treatment related. In addition, 7/14 (50%) of children demonstrated moderate to severe brain volume loss featuring a leukodystrophy pattern. Conclusion Treatment-related brain MRI abnormalities occurred frequently in this series with a risk of misdiagnosis as tumour. A proportion of patients suffer generalised white matter injury, which has not been appreciated as a side effect of this particular therapy.

Background To assess the feasibility and effectiveness of high-dose chemotherapy (HDC) with stem cell support followed by conventional craniospinal radiotherapy (RT) as treatment for children older than 5 years of age with newly diagnosed high-risk medulloblastoma (MB) or supratentorial PNET (sPNET). Procedure Between May 2001 and April 2010, 24 children older than 5 years of age (MB = 21; sPNET = 3), fulfilling inclusion criteria at diagnosis, were treated at Gustave Roussy. After conventional chemotherapy, they received two courses of high-dose thiotepa (600 mg/m2) followed by craniospinal RT. Results The median follow-up was 4.4 years (range, 0.8–11.3 years). For children with metastatic MB, the 5-year event-free survival (EFS) and overall survival (OS) were 72% and 83%, respectively. The toxicity was manageable. No toxic death occurred. At the most recent evaluation, among the 24 children who had at least one Full Scale Intellectual Quotient (FSIQ) examination at a median follow-up of 3.79 years after diagnosis, the mean estimated FSIQ was 82 (range, 56–114). Conclusions In children with metastatic MB, tandem HDCT with ASCT followed by conventional craniospinal RT proved its feasibility without jeopardizing survival. Pediatr Blood Cancer 2014; 61:1398–1402. © 2014 Wiley Periodicals, Inc.

Summary Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 109/l leucocytes, >20 × 109/l platelets and >0·1 × 109/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (GvHD) grade II and III-IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality (TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor.

Background The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan–thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). Procedure Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m2 and thiotepa at a dose of 900 mg/m2 followed by ASCT. Focal RT was delivered at least 70 days after ASCT. Results The median follow-up was 40.5 months (range, 14.5–191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45–84%) and 84% (95% CI 61–94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. Conclusions This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort. Pediatr Blood Cancer 2014;61:907–912. © 2014 Wiley Periodicals, Inc.

Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.

Background Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study. Procedure Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m2/day IV × 5 days, topotecan 1 mg/m2/day IV continuous infusion × 5 days, vinorelbine 20 mg/m2/week IV × 3 weeks, thiotepa 15 mg/m2/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). Results The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%). Conclusions TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia. Pediatr Blood Cancer 2014;61:431–435. © 2013 Wiley Periodicals, Inc.

The prognosis for metastatic malignant rhabdoid tumor (MRT) is poor, and metastatic (stage IV) MRT was resistant to conventional treatment, with less than 20% of cure rate. Moreover, there have been no reports of patients who have survived relapsed stage IV MRT. Here we report a long-term survivor of relapsed MRT with lung metastasis at diagnosis. He was diagnosed as MRT of the kidney at 5-month-old. After resection of the renal tumor, he was treated with ICE (ifosfamide, carboplatin, and etoposide), total abdominal irradiation 10.8 Gy and high-dose chemotherapy using thiotepa and melphalan. Six months after initial treatment, a relapse in the lung was detected, and he received chemotherapy including doxorubicin/pirarubicin for 78 weeks. He is alive at five years of follow up, without any evidence of disease. Our report suggests the important role of anthracycline in treatment of MRT.

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease-related mortality rises to 14% in adolescents and young adults. Overall and disease-free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant-associated late effects, the feasibility of a highly immunosuppressive reduced-intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow-up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.

Background Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations. Methods Thirty six children with high risk NBL, diagnosed 1995–2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987–1994 was updated. Results Ten year event-free survival (EFS) from diagnosis was 0.44+/−0.10 of the old and 0.43+/−0.085 of the new cohort. EFS from the last ASCT was 0.53 +/−0.12 and 0.48+/−0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/−0.15 for single and 0.73+/−0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died. Conclusions Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190–1197. © 2012 Wiley Periodicals, Inc.

anorexia,andpancytopenia.Eightof 32 (25%)assessable childrendied from regimen-related toxicity. Pulmonary failure occurred in seven patients. Seven patients had grade 3–4 neurotoxicity. The 3-year eventfree survival (EFS) was 25%. Conclusions. We determined the maximum tolerated regimen to be thiotepa 600 mg/m 2 and carmustine 300 mg/m 2 followed by thiotepa 600 mg/m 2 and carboplatin 1,200 mg/m 2 . Pulmonary toxicity was considerable. The toxic death rate was similar to other trials of HDC/SCR for children with recurrent brain tumors performed during the same time period. The regimen resulted in prolonged time to progression for a significant number of patients and long-term survival for some patients with recurrent medulloblastoma and rhabdoid tumor. Pediatr Blood Cancer 2011;57:506– 513. 2010 Wiley-Liss, Inc.

Background We determined the maximum tolerated dose (MTD) of clofarabine when administered with topotecan, vinorelbine, thiotepa, and dexamethasone (TVTC) for children with relapsed or refractory acute leukemia, and observed the efficacy and toxicities of this therapy. Procedure Twelve patients with acute lymphoblastic or myeloblastic leukemia were given a 14-day remission induction therapy. Clofarabine was administered at a dose of 30 or 40 mg/m2/day over 2 hr for five consecutive days in six patients each. Patients who achieved a remission proceeded to a stem cell transplant (HSCT). A second cycle could be administered prior to HSCT. Results Of the six patients at the 30 mg/m2 clofarabine dose, two achieved a complete response (CR) and one a PR and proceeded to BMT. Three patients had progressive disease. Five of the six patients at the 40 mg/m2 achieved a CR. Four proceeded to HSCT, and one relapsed prior to HSCT. One patient died on day 45 with marrow hypoplasia without evidence of leukemia. Hematologic and infectious adverse events were universal. The one dose limiting non-infectious toxicity observed was prolonged marrow hypoplasia. Conclusion TVTC has significant anti-leukemic activity in both acute lymphoblastic and myeloblastic leukemia. The MTD of clofarabine is 40 mg/m2/day in this combination. This is the recommended dose for the phase II study in patients with refractory or relapsed leukemia, a population which has limited therapeutic options. Pediatr Blood Cancer 2010;54:687–693. © 2010 Wiley-Liss, Inc.

Background Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin. Procedures Thirty-one patients with IMO who underwent hematopoietic stem cell transplantation with fludarabine, treosulphan, thiotepa, and antithymocyte globulin at our center from 2012 to 2017 are retrospectively reviewed in this study. Twenty-six patients were transplanted from 10/10 matched donors (13 from siblings, 11 from unrelated, and two from extended family donors), four from 9/10 matched unrelated donors, and one from a 9/10 matched family donor. Results Overall survival was 100% with a median follow-up of 363 days (range 74-1891). There were 12 cases of acute graft versus host disease (GvHD) (38.7%), no cases of veno-occlusive disease, and eight cases of hypercalcemia (25.8%). Almost 80% of patients suffered viral reactivations with two cases of Epstein-Barr-virus-driven post-transplant lymphoproliferative disease. All cases of GvHD and viral reactivation were successfully treated. Conclusions We conclude that transplantation in children with IMO using fludarabine, treosulphan, thiotepa, and antithymocyte globulin is safe and effective and should be performed as early as possible following diagnosis, prior to the development of severe disease sequelae.

Background Thiotepa and carboplatin are known to be active in central nervous system tumors. Topotecan potentiates the anti-cancer effects of alkylators and crosses the blood–brain barrier. We present ten patients with recurrent or progressive central nervous system malignancies treated on a myeloablative regimen using these drugs. Methods Treatment included: Thiotepa 300 mg/m2 on days −8, −7, and −6; topotecan 2 mg/m2 on days −8, −7, −6, −5, and −4; and carboplatin ∼500 mg/m2 (Calvert formula—area under the curve = 7) on days −5, −4, and −3. Stem cell rescue was on day 0. Results Age at study entry ranged from 2.5 to 20 years old (median age 8.7 years). Five had medulloblastoma (MB), four had high grade glioma (HGG), and one had trilateral retinoblastoma/pineoblastoma (tRB/PB). Prior treatment for all patients included surgery and chemotherapy (1–7 regimens, median 2). Nine patients received radiotherapy; one patient did not receive radiotherapy pre-study. Three patients had residual disease at the time of transplant. There were two toxic deaths. Four patients are event-free survivors at a median of 6 years (range 2.8–7.6 years) after treatment including 2/5 MB patients, 1/4 HGG patients, and the tRB/PB patient. Four of the seven patients with no evidence of disease/minimal residual disease status at the time of stem cell rescue are long-term survivors versus 1/3 with measurable disease. Conclusion Thiotepa/topotecan/carboplatin may help consolidate remission of poor prognosis pediatric central nervous system tumors. Diagnosis and extent of disease prior to stem cell rescue may have an impact on outcome. Pediatr Blood Cancer 2010;54:591–595. © 2009 Wiley-Liss, Inc.

Towards the elimination of the reproductive capacity of parthenogenetic females of Aphis fabae (Homoptera: Aphididae) after contact treatment with chemosterilants Aqueous solutions of hempa (1%, 2%), tepa (0.01%-0.04%), metepa (0.1%-0.4%), and thiotepa (0.1%-0.3%) have been administered respectively for 30 min or 60 min by contact (filter paper soaked with 1 ml and put in 9 cm ∅ petri dishes) to members of the 2. and 3./4. larval stages of the broad bean aphid, Aphis fabae Scop. Treatment with hempa or metepa caused death rates up to 20% higher than in untreated controls, but no reliable decrease of birth rates. Tepa and thiotepa affected no increase of mortality, and tepa only a slight decrease of fertility. Thiotepa (0.3%), administered for 60 min to the 2. instar, affected a more than 90% decrease of birth rate. An outline is given for thiotepa administration to the adult stage of winged generations (migrating sexuparae) and for the sterilization of their offsprings (sexualis- ♂ ♂, or -♀♀ resp.) in connection with the field application of the sterile partner technique by using a formerly proposed apparatus (Steffan 1973b, 1975) for attraction and selfsterilization of aphids. Zusammenfassung Blattlause des 2. und 3./4. Larvenstadiums von Aphis fabae wurden fur 30–60 Minuten auf Filtrierpapier gesetzt, das mit waβrigen Losungen von Hempa (1–2%), Tepa (0,01 bis 0,04%), Metepa (0,1-0,4%) und Thiotepa (0,1-0,3%) getrankt war. Hempa und Metepa verursachten Sterblichkeitsraten, die bis zu 20% hoher als bei der Kontrolle lagen, zeigten aber keine deutliche Beeintrachtigung der Nachkommensrate. Tepa und Thiotepa bewirkten kein Ansteigen der Sterblichkeit, aber Tepa eine Abnahme der Fruchtbarkeit. Thiotepa (0,3%, 60 Min., LII) fuhrte zu mehr als 90% Verminderung der Geburtsrate. Es wird eine Anleitung zur Anwendung von Thiotepa auf die Adulten von geflugelten Generationen und zur Sterilisation ihrer Nachkommen auf der Grundlage der Freilandanwendung der Sterilpartner-Methode mittels eines bereits fruher (Steffan 1973b, 1975) beschriebenen Apparates gegeben.

Twenty-six test compounds which include 21 alkylating (14 aziridines and 7 alkyl-alkane-sulphonates), 2 thiozolium salts and 3 miscellaneous compounds (derivatives of phosphoramides and S-triazines) were studied for mortality, fertility and longevity of the pupae and adults of Trogoderma granarium Everts. The aqueous solutions of the test compounds were administered by dipping the pupae and by contact of adults with treated glass and filter paper surfaces on which film deposits were obtained as 1 mg AI/cm2. Of all the compounds tested by the above methods, thiotepa has proven to be the best chemosterilant for the pupae and adults, followed by tepa, metepa and Ent 61969 (Bis [1-aziridinyl) phosphine sulphide, amine). Zusammenfassung Versuche mit 26 Verbindungen zur Sterilisation von Trogoderma granarium Everts Von 26 Substanzen, darunter 21 Alkylverbindungen, wurde die Wirkung hinsichtlich Sterblichkeit, Fertilitat und Lebensdauer nach Behandlung der Puppen und Kafer getestet. Als am wirksamsten erwies sich Thiotepa, gefolgt von Tepa, Metepa und Ent 61969.

In this study, the possible effect of thiotepa on the reproductive biology of the gypsy moth Porthetria dispar L. and its spermatogenesis was evaluated. An explanation of the mechanism of induction of sterility was given based on the changes that occurred in the spermatogenic cells after treatment with thiotepa. The eggs and pupae were not affected by treatment with this sterilant. Feeding the early fifth instar larvae on an artificial diet containing 0.3 °% thiotepa caused a higher degree of sterility in the emerged moths more than if other stages were treated. The sterility induced was due to the death of spermatogonia and halting the succession of spermatogenesis for a certain period. Spermatocytes were also affected resulting in the formation of some functionless abnormal spermatozoa. Exposure of the male moths to residues of thiotepa at the concentration of 10mg/sq. foot for 4–8 hours led to a high degree of sterility. A progressive increase in sterility occurred with increase in the holding time between exposure of the moths to residues of thiotepa and allowing them to mate with females. The sterility induced in the males was probably correlated to dominant lethal mutations or inactivation of sperms. Male moths sterilised with thiotepa can compete successfully with normal untreated males in mating opportunities with normal females which mate only once. Thiotepa has no adverse effect on the longevity of the male. Zusammenfassung Sterilisation und Spermatogenese beim Schwammspinner, Porthetria dispar L. unter dem Einflus von Thiotepa Es wurden die moglichen Wirkungen von Thiotepa auf die Reproduktion des Schwammspinners untersucht. Der Mechanismus der Entstehung der Sterilitat wird aus den Veranderungen abgeleitet, die in den Spermatogonien bildenden Zellen nach der Behandlung mit Thiotepa sichtbar werden. Die Eier und Puppen wurden durch die sterilisierende Substanz nicht beeinflust. Nach Futterung der Raupen des fruhen 5. Stadiums mit einer kunstlichen Diat, welcher 0,3% Thiotepa beigemischt war, ergab sich ein hoherer Anteil an sterilisierten Faltern als bei Applikation zu einem anderen Zeitpunkt der Entwicklung. Ursachen der Sterilitat waren das Absterben der Spermatogonien und der Stillstand der Spermatogenese fur eine bestimmte Zeit bzw. auch die Entstehung funktionsloser abnormaler Spermatozoen. Wurden mannliche Falter mit Thiotepa (10 mg/foot2 4–8 h) in Beruhrung gebradit, fuhrte dies zu einem hohen Sterilitatsprozent, das um so hoher war, je weniger Zeit zwischen der Einwirkung auf das Mannchen und der Kopulation verstrich. Die beim mannlichen Falter induzierte Sterilitat war wahrscheinlich korreliert mit dem Auftreten dominanter letaler Mutationen oder der Inaktivierung der Spermien. Durch Thiotepa sterilisierte Mannchen konnen mit normalen, unbehandelten Weibchen hinsichtlich der Kopulation erfolgreich konkurrieren. Das ist fur eine eventuelle biotechnische Bekampfung um so wichtiger, als das Weibchen nur einmal kopuliert. Auf die Lebensdauer des Mannchens nahm Thiotepa keinen Einflus.

Thiotepa [tris (1-aziridinyl) phosphine sulphide] employed as contact sterilant for two hours induced either total or partial sterility accompanied by mortality, decrease in the reproduction period and in the total life span of the pea aphid, Acyrthosiphon pisum. Concentrations of 2.5% and 5% were toxic while concentrations of 0.5% and 1% were less toxic. They greatly decreased the fecundity of aphids. Zusammenfassung Wirkungen des Sterilants Thiotepa auf die Erbsenblattlaus Acyrthosiphon pisum (Harris) (Aphididae, Homoptera) Thiotepa fuhrte bei A. pisum nach 2stundigem Kontakt entweder zu totaler oder partieller Sterilitat, begleitet von Mortalitat sowie Verkurzung der Reproduktionsperiode und der Lebensdauer. Konzentrationen von 2,5 und 5% waren toxisch, 0,5 und 1% nur gering toxisch. Sie senkten die Eizahl von A. pisum stark ab.

BACKGROUND: The role of myeloablative chemotherapy in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors (MB/ST-PNET) is controversial, in particular in patients who develop recurrent disease after craniospinal radiotherapy. METHODS: In this retrospective analysis, the authors investigated the outcome of children with recurrent MB/ST-PNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue at Childrens Hospital Los Angeles. RESULTS: Thirty-three children were referred for myeloablative chemotherapy: Fourteen of those children were never transplanted because of pre-transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant. Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles. The 3-year post-transplant event-free survival rate in unirradiated versus previously irradiated children was 83% ± 15% versus 20% ± 12%, respectively (P = .04). One child who had never been exposed to radiotherapy died of toxicity; the other children received post-transplant radiotherapy and remained disease free. Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of

The results of the combined use of Beta Irradiation, topical Thio-Tepa and dexamethasone in the post-operative treatment of pterygium in 169 patients (213 eyes) are reported. The recurrence rate has been evaluated statistically only in eyes with true pterygia, and for this purpose the material has been divided into 3 groups: group 1 includes all the bilateral cases who either had both eyes treated with Beta therapy or not, group 2 includes all the unilateral cases, and group 3 is made up of the total number of eyes operated. In the group comprising the bilateral cases, the recurrence rate was 2/60 in the eyes treated with Beta rays and 4/18 in the non-treated ones (P less than 0.10). In the group comprising the unilateral cases, the recurrence rate was 8/73 in the Beta rays treated eyes and 18/41 in the non-treated ones (P less than 0.025). When the total number of eyes was considered, the recurrence rate was 10/135 in the eyes treated with Beta rays and 22/61 in the non-treated ones (P less than 0.05). The difference in the recurrence rate between the eyes submitted to Beta therapy and those not submitted is considered statistically significant.

Summary: Ihe effect of pretreatment of Candida albicans with two antineoplasbc agents thiotepa and methotrexate on experimental cendidosis in mice was studied. In vitro treatment of C. albicans with these two cytotoxic drugs altered its pathogenicity in two different ways. Pretreatment with thiotepa seems to definitely enhance the pathogenicity of C. albicans as evidenced by macroscopic and microscopic findings. In contrast, pretreatment with methotrexate seems to exert a beneficial effect as measured by the same criteria. Pretreatment of the host with thiotepa gave similar enhancement as that observed with thiotepa-treated microogranisms. However, treating the host with methotrexate gave a contrasting picture to that obtained by treating the yeast itself with this drag. These findings suggest that thiotepa enhances the pathogenicity of C. albicans in one of two ways: 1 By exerting an effed on the yeast itself and as such, making it more invasive. 2 By exerting an effect on the host, compromising its defence system and making it more susceptible to infection by this organism. By comparison, the mechanism by which methotrexate potentiates the effects on C. albicans is through an effect on the host solely and not through the oxganism. The clinical implication of these findings is discussed. Zusammenfassung. Zunachst wurde der Einflus einer Vorbehandlung von Candida albicans mit zwei Cytostatica Thiotepa und Methotrexat auf die experimentelle Candidose bei Mausen untersucht. Die Vorinkubation von Candida albicans mit diesen beiden cytotoxischen Medikamenten beeinfluste ihre Pathogenitat in zweierlei Weise. Wie makroskopische und mikroskopische Untersuchungen zeigen, scheint eine Vorbehandlung mit Thiotepa eindeutig die Pathogenitat von Candida albicans zu steigern. Im Gegensatz dazu lies sich bei Vorbehandlung mit Methotrexat eher ein gunstiger Effekt aufzeigen. Die Vorbehandlung des Wirtsorganismus mit Thiotepa ergab eine ahnliche Steigerung der Pathogenltat, wie sie bei der Vorbehandlung der Hefen mit Thiotepa beobachtet worden waren. Im Gegensatz dazu zeigte sich bei Vorbehandlung des Wirtsorganismus mit Methotrexat em Bild, das von dem abwich, wie es erhalten wurde, wenn die Hefe mit Methotrexat vorbehandelt wurde. Die Untersuchungsergebnisse lassen darauf schliesen, das Thiotepa die Pathogenitat von Candida albicans in unterschiedlicher Weise steigert: 1. durch einen direkten Effekt auf die Hefe, wodurch ihre Fahigkeit zur Gewebeinvasion gesteigert wird. 2. durch Beeinflussung des Wirtes, wobei seine Abwehr geschwacht wird und eine hohere Empfanglichkeit fur Infektionen mit diesem Organismus entstehen. Demgegenuber beeinflnst Methotrexat die Empfanglichkeit fur Candida albicans lediglich durch Beeinflussung des Wirtes und nicht durch Einwirkungen auf den Mirkroorganismaus. Die klinische Bedeutang dieser Ergebnisse wird diskutiert.

Summary: The effect of four antineoplastic agents1) on the growth and ultrastructure of the yeast Candida albicans was investigated. Growth and MIC studies showed that two of the four drugs produced inhibition, with thiotepa being more active than methotrexate. Furthermore, SEM studies showed that both these drugs caused morphological changes. Methotrexate induced germtube production resulting in transformation from the yeast to hyphal form. Thiotepa caused cell lysis. The other two drugs, VIS and ENA, caused little or no significant alterations in gross morphology and no growth inhibition. It is proposed that these drugs affect cellular DNA but in subtly different ways resulting in different manifestations on growth and morphology. The frequent occurrence of aberrant filamentous yeasts from cancer patients may be due to the result of chemotherapy. Zusammenfassung: Die Wirkung der vier zytostatischen Praparate Methotrexat (MET), Thiotepa (THT), Vincristinsulfat (VIS) and Endoxan-Asta (ENA) auf Wachstum und Feinstruktur der Hefe Candida albicans wurde untersucht. Untersuchungen des Wachstums und MHK-Bestimmungen ergaben Hemmreaktionen bei zwei der vier Praparate, wobei Thiotepa starkere Aktivitat zeigte als Methotrexat. Daruber hinaus zeigten SEM-Untersuchungen morphologische Veranderungen, die durch diese Praparate verursacht worden waren. Methotrexat induzierte die Keunschlauchbildung und damit eine Konversion von der Blastosporen- in die Pseudomyzelform. Thiotepa verursachte eine Lyse der Zellen. Die beiden anderen Praparate VIS and ENA zeigten nur geringe oder keine signifikanten Veranderungen in der Gesamtmorphologie und keine Wachstumshemmung. Die Ergebnisse werden so gedeutet, das diese Praparate die zellulare DNS in verschiedener Weise beeinflussen, was zu unterschiedlichen Veranderungen in Wachstum und Morphologie fuhrt. Das haufige Vorkommen anomaler hyphenbildender Hefen bei Karzinompatienten mag eine Folge der chemotherapeutischen Behandlung sein.

SUMMARY The results of intravesical Thiotepa therapy in 30 patients are reviewed. Eight have improved, 10 worsened and 12 appear unaffected. These results are comparable with other reports. The previously unrecorded appearance of recurrences at sites shielded by the catheter reported, and it is suggested that the balloon be deflated during therapy. Provided that the hazards of bone marrow depression are recognised, intravesical Thiotepa therapy appears to have a place in the management of low-grade tumours, where direct treatment by cystodiathermy has failed.

BACKGROUND: High-dose therapy with autologous stem cell support after standard dose induction is a promising approach for therapy of primary central nervous system lymphoma (PCNSL). High-dose methotrexate (HD-MTX) is a standard drug for induction of PCNSL; however, data about the capacity of HD-MTX plus granulocyte–colony-stimulating factor (G-CSF) to mobilize hemopoietic progenitors are lacking. STUDY DESIGN AND METHODS: This investigation describes the data from stem cell mobilization and apheresis procedures after one or two cycles of HD-MTX for induction of PCNSL within the East German Study Group for Haematology and Oncology 053 trial. Eligible patients proceeded to high-dose busulfan/thiotepa after induction therapy and mobilization. RESULTS: Data were available from nine patients with a median age of 58 years. The maximal CD34+ cell count per µL of blood after the first course of HD-MTX was 13.89 (median). Determination was repeated in six patients after the second course with a significantly higher median CD34+ cell count of 33.69 per µL. Five patients required two apheresis procedures and in four patients a single procedure was sufficient. The total yield of CD34+ cells per kg of body weight harvested by one or two leukapheresis procedures was 6.60 × 106 (median; range, 2.68 × 106-15.80 × 106). The yield of CD34+ cells exceeded the commonly accepted lower threshold of 3 × 106 cells per kg of body weight in eight of nine cases. Even in the ninth, hemopoietic recovery after stem cell reinfusion was rapid and safe. CONCLUSION: HD-MTX plus G-CSF is a powerful combination for stem cell mobilization in patients with PCNSL and permits safe conduction of time-condensed and dose-intense protocols with high-dose therapy followed by stem cell reinfusion after HD-MTX induction.

Purpose—Children and adolescents with malignant astrocytomas recurring after initial treatment have a dismal prognosis, with only rare patients surviving one year beyond recurrence. The purpose of this study was to attempt to improve their survival. Methods—Twenty-seven children and adolescents with malignant astrocytomas (17 glioblastoma multiforme and 10 anaplastic astrocytoma) following initial tumor progression, received myeloablative chemotherapy followed by autologous marrow rescue with one of three thiotepa and etoposide-based chemotherapy regimens, administered alone (n=11) or combined with carmustine (n=5) or carboplatin (n=11). Time to progression and death following myeloablative chemotherapy for these patients was compared non-randomly with outcome of a contemporaneously treated cohort of similar patients who received only conventional chemotherapy following initial tumor progression. The two cohorts were compared for age, histology, prior therapies, extent of surgical resection at progression and time from initial diagnosis to progression. Results—Five of 27 children (two with glioblastoma multiforme and three with anaplastic astrocytoma) survive event-free from 8.3 to 13.3 years (median of 11.1 years) following myeloablative chemotherapy. Of 56 children with recurrent malignant astrocytoma who received

BACKGROUND Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. METHODS The authors reviewed the medical records of 23 adult patients (age ≥18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). RESULTS HDC with ASCT was associated with increased survival (P = .044) and a longer time to disease progression (TTP) (P = .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. CONCLUSIONS Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors. Cancer 2008. © 2008 American Cancer Society.

Purpose To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Methods Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, “Head Start” I and “Head Start” II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. Results The 5-year event-free (EFS) and overall survival (OS) rates (±SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 ± 11% and 70 ± 10%, 64 ± 13% and 79 ± 11%, and 29 ± 17% and 57 ± 19%, respectively. The 5-year EFS and OS ( ± SE) for patients with desmoplastic and classical medulloblastoma were 67 ± 16% and 78 ± 14%, and 42 ± 14 and 67 ± 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. Conclusion This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality. Pediatr Blood Cancer 2008;50:1169–1175. © 2008 Wiley-Liss, Inc.

The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients.For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8.In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy,or = 4,000 mg/m2) before 3F8 treatment (P0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at120 days, P0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated90 days post-MAT versus 13/23 treated90 days post-MAT (P0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P0.001), including 5/7 whose 3F8 treatment began90 days post-MAT.HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.

Bone marrow transplantation is the only therapeutic option that can potentially eliminate thalassemic disease. Early results indicated that children in Class 3 Lucarelli had a much worse outcome because of high nonrejection mortality and high rejection rate. In the present study, reduced intensity stem cell transplantation (RIT) was performed in eight Class 3 Lucarelli patients conditioned by busulfan, fludarabine, and antilymphpcute globulin. One of the eight patients additionally received thiotepa, and total lymphoid irradiation (TLI), while one only received TLI. All patients received hydroxyurea 20 mg/kg/day daily >/=3 months before RIT. Peripheral blood stem cell (PBSCs) were given to a target number of CD34(+) cells more than 5 x 10(6) cells/kg of recipient weight. Seven patients received T cell nondepleted PBSCs from matched siblings while one patient received purified CD34(+) cells from two HLA antigen mismatched maternal PBSCs. The graft-versus-host disease (GvHD) prophylaxis included cyclosporine or tacrolimus and mycophenolate mofetil. Initially, an engraftment of donor cells was observed in all eight patients, but subsequently only six of eight patients had stable full donor engraftment. There were no deaths or Grade 3-4 acute GvHD in our patients. The present study lends support that the regimens described here produced minimal toxicity and resulted in stable full donor engraftment in the majority of the severe Class 3 Lucarelli thalassemia patients.

Background: The purpose of this study is to investigate the efficacy of an intensive chemotherapy induction regimen followed by myeloablative chemotherapy and autologous hematopoietic stem cell rescue (AHSCR) in children with newly diagnosed ependymoma. Patients and Methods: Twenty-nine children less than 10 years of age at diagnosis of ependymoma were enrolled on the “Head Start” studies. Twenty-four patients with localized disease received an induction regimen including five cycles of chemotherapy (cisplatin, vincristine, etoposide cyclophosphamide, and high dose methotrexate for patients with metastatic disease). Following induction, individuals without evidence of disease proceeded to marrow-ablative chemotherapy (thiotepa, carboplatin, and etoposide) with AHSCR. Results: The estimated 5-year event free survival (EFS) and overall survival (OS) from diagnosis were 12% (±6%) and 38% (±10%), respectively. The toxic mortality amongst this group of 29 patients was 10.3%. Younger age (less than 18 months at diagnosis) was the only statistically significant prognostic factor. The estimated 5-year OS rate for the five patients with metastatic disease at presentation was 80% (±18%). Overall, radiation-free survival at 5 years from diagnosis was 8% (±5%). Conclusions: The use of an intensive induction chemotherapy regimen including myeloablative chemotherapy followed by AHSCR in newly diagnosed young children with ependymoma is not superior to other previously reported chemotherapeutic strategies. Pediatr Blood Cancer 2007;49:34–40. © 2006 Wiley-Liss, Inc.

Background Umbilical cord blood transplantation (CBT) is an established alternative source of stem cells in the setting of unrelated transplantation. When compared with other sources, single-unit CBT (sCBT) is associated with a delayed hematologic recovery, which may lead to a higher infection-related mortality (IRM). Co-infusion with the sCBT of CD34+ peripheral blood stem cells from a third-party donor (TPD) (sCBT + TPDCD34+) has been shown to markedly accelerate leukocyte recovery, potentially reducing the IRM. However, to our knowledge, no comparative studies have focused on severe infections and IRM with these 2 sCBT strategies. Methods A total of 148 consecutive sCBT (2000–2010, median follow-up 4.5 years) were included in a multicenter retrospective study to analyze the incidence and risk factors of IRM and severe viral and invasive fungal infections (IFIs). Neutrophil engraftment occurred in 90% of sCBT (n = 77) and 94% sCBT + TPDCD34+ (n = 71) recipients at a median of 23 and 12 days post transplantation, respectively (P