Initiation of puberty in mice following decellularized ovary transplant

Clinical interventions to preserve fertility and restore hormone levels in female patients with therapy-induced ovarian failure are insufficient, particularly for pediatric cancer patients. Laparoscopic isolation of cortical ovarian tissue followed by cryopreservation with subsequent autotransplantation has temporarily restored fertility in at least 27 women who survived cancer, and aided in pubertal transition for one pediatric patient. However, reintroducing cancer cells through ovarian transplantation has been a major concern. Decellularization is a process of removing cellular material, while maintaining the organ skeleton of extracellular matrices (ECM). The ECM that remains could be stripped of cancer cells and reseeded with healthy ovarian cells. We tested whether a decellularized ovarian scaffold could be created, recellularized and transplanted to initiate puberty in mice. Bovine and human ovaries were decellularized, and the ovarian skeleton microstructures were characterized. Primary ovarian cells seeded onto decellularized scaffolds produced estradiol in vitro. Moreover, the recellularized grafts initiated puberty in mice that had been ovariectomized, providing data that could be used to drive future human transplants and have broader implications on the bioengineering of other organs with endocrine function.     

骨髓间充质干细胞移植联合髓芯减压植骨修复股骨头坏死

背景：单独使用髓芯减压治疗股骨头坏死,易造成股骨头凹陷和内部显微结构的崩溃,因而需要自体骨等材料进行填充支撑,而骨髓干细胞移植能使股骨头塌陷的发生率降低。 目的：观察髓芯减压植骨联合骨髓间充质干细胞移植治疗股骨头坏死的临床效果。 方法：选择2012年12月至2013年5月在沈阳医学院附属中心医院骨外四科住院的33例采用股骨头髓芯减压植骨联合骨髓间充质干细胞注入髓腔内治疗股骨头坏死患者。 结果与结论：股骨头髓芯减压植骨联合骨髓间充质干细胞注入髓腔内治疗股骨头坏死后患者Harris髋关节功能评分增加,疼痛消失,能从事各种劳动;X射线片或CT检查显示股骨头正常30髋,占79%;疼痛明显减轻,行走基本正常或者轻微跛行15髋,占40%;行走间距延长35髋,占92%;髋关节功能障碍明显好转24髋,占63%。提示髓芯减压植骨联合骨髓间充质干细胞移植对改善股骨头缺血性坏死局部血供,促进坏死骨质吸收和骨质修复起到积极的作用。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Upfront Allogeneic Stem Cell Transplantation after Reduced-Intensity/Nonmyeloablative Conditioning for Patients with Myelodysplastic Syndrome: A Study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning induction chemotherapy, we analyzed 128 consecutive patients with myelodysplastic syndrome who received reduced-intensity or nonmyeloablative conditioning (RIC/NMA) allo-SCT. Among them, 40 received azacitidine (AZA) before transplant (AZA group) and 88 were transplanted up front (best supportive care [BSC] group). At diagnosis, 55 patients had intermediate 2 or high-risk scores per the International Prognostic Scoring System and 33 had a high cytogenetic risk score. Progression to a more advanced disease before allo-SCT was recorded in 22 patients. Source of stem cells were blood (n = 112) or marrow (n = 16) from sibling (n = 78) or HLA-matched unrelated (n = 50) donors. With a median follow-up of 60 months, 3-year overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality were, respectively, 53% versus 53% (P = .69), 37% versus 42% (P = .78), 35% versus 36% (P = .99), and 20% versus 23% (P = .74), for the AZA group and BSC group, respectively. Multivariate analysis confirmed the absence of statistical differences in outcome between the AZA and BSC groups, after adjusting for potential confounders using the propensity score approach. The absence of cytoreduction before RIC/NMA allo-SCT did not seem to alter the outcome. However, our results emphasize the need to perform prospective protocols to delineate the role of debulking strategy and to identify subsets of patients who may benefit from this approach.     

Outcome for pediatric cardiac transplantation with and without bridge methods

Heart transplantation is indicated for children with end-stage heart failure or complex inoperable congenital defects. Due to the shortage of pediatric donor hearts, various bridge techniques have been used for pediatric recipients to prolong patient survival until a heart is available. This study evaluates long-term outcome of bridge and nonbridge support for pediatric heart transplantation. Between March 1995 and June 2004, 18 pediatric patients underwent heart transplantation. Six patients (33.3%) underwent biological or mechanical bridge techniques before transplantation. Eight patients (44.4%) required perioperatively extracorporeal membrane oxygenation (ECMO) support. Patient data and records were retrospectively reviewed. Causes of death and long-term outcome were analyzed. Five of eight patients in the ECMO group (62.5%) were successfully decannulated and discharged home with excellent functional classes. No differences in rejection rate, survival rate, and functional class existed between the bridged and nonbridged groups. Overall 1-year and 5-year survival rates were both 83.3% and all have a good functional class. Pediatric heart transplantation can be accomplished with excellent early survival despite multiple prior cardiac operations and relatively severe illness. For the variety in small, low-body-weight pediatric patients, mechanical circulatory support using ECMO is suitable for managing sudden collapse while waiting for heart transplantation, and graft dysfunction after cardiac transplantation. The mortality rate is acceptable in this very high-risk group of patients and long-term outcome is good.     

An interinstitutional review of the value of FNAB in pediatric oncology in resource-limited countries

Fine‐needle aspiration biopsy (FNAB) has been widely accepted as a reliable diagnostic modality in the general pediatric population, but its role in pediatric oncology still remains elusive. With new treatment protocols subscribing to preoperative chemotherapy, the need for a quick, minimally invasive, and accurate diagnostic procedure has arisen. This study assesses the feasibility of FNAB in childhood malignancies to render a specific diagnosis on which treatment can be initiated. An 11‐year retrospective study was done on FNABs in patients 19 years and under referred for clinically malignant mass lesions. Cases were confirmed with histology, immunocytochemistry, flow cytometry, or clinical follow‐up. Of the 357 patients referred for FNABs, 36 patients were lost to follow‐up and 31 FNABS were inadequate. A total of 290 cases were included in the study, of which 68 (23%) cases were benign and 222 (77%) were malignant. The most frequently occurring tumors were nephroblastoma (68), non‐Hodgkin's lymphoma (39), rhabdomyosarcoma (22), Hodgkin's lymphoma (22), and neuroblastoma (22). The sensitivity of the procedure for neoplasia was 96.6%, the specificity 97.0%, positive predictive value 99.0%, and negative predictive value 90.1%, with a diagnostic accuracy of 96.7%. The ability of FNAB to enable a specific diagnosis to be made, that is correct and accurate subtyping of the tumor on which chemotherapy or radiotherapy could be commenced was 75.7%. This study shows that FNAB can be used with confidence to confirm malignancy in children. With clinicoradiological correlation and the aid of ancillary techniques, FNAB allows a rapid and accurate preoperative diagnosis for definitive therapy commencement in most cases. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.     

Antibiotic prophylaxis in children with cancer or who have undergone hematopoietic cell transplantation

Bacterial infections are common in children with cancer and can lead to life-threatening complications. Infections in these patients mainly occur during neutropenic periods, and may be caused by Gram-positive or Gram-negative bacteria. The patients at highest risk of serious infections include those with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), and those undergoing myeloablative hematopoietic cell transplantation (HCT). This is a review with the main aim of making a critical appraisal of the literature, and summarising what is currently known and can be recommended. The most significant studies support the use of floroquinolones (mainly ciprofloxacin) as the most rational approach to treat pediatric patients with probably long-lasting neutropenia, although trimetoprim-sulphametoxazole and amoxicillin/clavulanate may theoretically be valid alternatives. No prophylaxis seems to be needed for children with cancer without severe neutropenia. However, a global evaluation of the studies of antibiotic prophylaxis in children with cancer indicates that there are not enough data to prepare definite guidelines for its use or avoidance in pediatric oncology, and so further studies are needed. It is not only important to define the best antibiotic regimens for the children in whom such prophylaxis is useful, but also to identify precisely those who do not need it. This would avoid the antibiotic misuse that probably occurs at the moment because many low-risk children with cancer are treated. As prophylaxis against infections requires long-term adherence to an antibiotic regimen, the attitudes and beliefs of stakeholders need to be fully considered.     

Literature review: health-related quality of life measurement in pediatric oncology: hearing the voices of the children

OBJECTIVES: The objective of this literature review is to provide an overview of the evidence for pediatric patient self-report in pediatric oncology. Methods A review of the general literature on pediatric health-related quality of life (HRQOL) measurement as background, with pediatric patient self-report data from the Journal of Pediatric Psychology during the past 5 years in pediatric oncology summarized. Utilizing the PedsQL available at (http://www.pedsql.org), data are presented to illustrate child and parent reports in pediatric oncology. Results Data demonstrate that children as young as 5 years of age can reliably and validly self-report their HRQOL when an age-appropriate instrument is utilized. Conclusions The evidence supports including pediatric patients' perspectives in clinical trials. Parent proxy-report is recommended when pediatric patients are too young, too cognitively impaired, too ill or fatigued to complete a HRQOL instrument, but not as a substitute for child self-report when the child is willing and able to provide their perspective.     

Patient-reported outcomes in end-of-life research in pediatric oncology

OBJECTIVE: The purpose of this review of published literature was to identify the number and focus of empirically based papers that included research methods used to directly solicit patient-reported outcomes (PRO) from pediatric oncology patients at end of life. METHODS: Key terms including "pediatric or child and oncology or cancer and end of life or palliative or hospice or dying" were used with five data bases (PubMed, Ovid, Cochrane, PsycInfo & PsycArticles, and CINAHL) for English language literature published between January, 2001 and June, 2006. All retrieved documents were independently reviewed by a panel of six (nurses, physicians, and one psychologist) with backgrounds in pediatric oncology. RESULTS: Thirty-five publications were identified but nine (25.7%) were eliminated from the analysis as they did not meet inclusion criteria. Of the remaining 26, four (15.4%) included patient-reported outcomes, six (23.1%) included parent only-reported outcomes, and five (19.2%) included staff only-reported outcomes. Nine (34.6%) were retrospective medical record reviews. Two (7.7%) included parent and record review data or parent and physician reports. CONCLUSIONS: Empirically-based end-of-life publications in pediatric oncology are relatively few in number and nearly 85% of completed studies do not include PRO.     

Use of linezolid in neonatal and pediatric inpatient facilities—results of a retrospective multicenter survey

The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8?years (interquartile range 0.6-15.5?years; range 0.1-21.2?years; ten patients were older than 18?years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14?days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12?years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.     

Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

OBJECTIVE:

Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation.

METHODS:

Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups.

RESULTS:

Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01).

CONCLUSION:

The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.     

NF-κB参与低氧预适应对自体原位肝移植大鼠JNK通路的影响

背景：在肝脏缺血再灌注损伤中,NF-κB与JNK通路的串扰方式决定了细胞的死亡或存活。而将低氧预适应用于肝移植过程所导致的细胞凋亡现象,尚未见有报道。 目的：探讨低氧预适应后NF-κB的表达对移植肝JNK通路的影响及保护作用。 方法：采用经门静脉灌注法建立大鼠自体原位肝移植模型,SD大鼠随机分为正常对照组：不接受任何处理;自体移植组：行自体原位肝移植;低氧预适应组：移植前体积分数8%氮氧混合气体的低氧预处理90 min,然后行自体原位肝移植。分别于移植后 1,6,24 h处死大鼠取肝脏标本检测肝组织丙二醛、超氧化物歧化酶水平,免疫组化方法测定大鼠肝组织p-JNK蛋白,RT-PCR检测肝脏 NF-κB mRNA含量,透射电子显微镜下观察肝细胞的超微结构变化。 结果与结论：与对照组比较,两移植组肝组织丙二醛水平升高,超氧化物歧化酶水平降低(P < 0.05);与自体移植组比较,低氧预适应组丙二醛水平显著降低、超氧化物歧化酶水平显著升高(P < 0.05)。与正常对照组比较,两移植组各时相p-JNK蛋白的表达、NF-κB mRNA的转录水平显著升高 (P <0.05);与自体移植组比较,低氧预适应组NF-κB mRNA转录水平显著增高(P < 0.05),p-JNK蛋白的表达明显降低(P < 0.05)。透射电镜下自体移植组肝细胞出现典型的凋亡征象,而低氧预适应组肝细胞无明显凋亡形态。提示,肝移植大鼠低氧预适应后可能通过上调NF-κB的表达,减少活性氧释放,抑制JNK通路的持续激活,从而抑制肝细胞凋亡,减轻肝脏缺血再灌注。     

Varicella vaccination in pediatric oncology patients without interruption of chemotherapy

BackgroundMorbidity and mortality from primary varicella-zoster virus (VZV) infection is increased in immunocompromised children. Vaccination of VZV-seronegative cancer patients with live-attenuated varicella vaccine is safe when chemotherapy is interrupted. However, VZV vaccination without interruption of chemotherapy would be preferable.ObjectiveTo vaccinate VZV-seronegative pediatric oncology patients with live-attenuated VZV vaccine without interrupting their chemotherapy.Study-designWe performed a single-center prospective cohort study.ResultsThirty-one patients with either a hematological malignancy (n = 24) or a solid tumor (n = 7) were vaccinated early during their course of chemotherapy. VZV IgG seroconversion occurred in 14 of the 31 patients (45%) after one vaccination. Only 20 patients were revaccinated after 3 months. These were patients who did not seroconvert (5 patients) and patients who serocoverted (15 patients) to induce or sustain seropositivity. Of these 20 patients the final seroconversion rate was 70%. Seven out of the 31 patients (23%) developed a mild rash of which 5 were treated with antivirals and recovered completely without interrupting chemotherapy, and 2 recovered untreated. Of these 31 immunized patients 26 were available for cellular testing. After one vaccination 20 of 26 patients (77%) tested positive for VZV-specific CD4⁺ T cells, of which 7 patients had remained VZV-seronegative. After the second vaccination 11 of 11 patients showed VZV-specific CD4⁺ T cells to sustain positivity, although 4 remained VZV-seronegative.ConclusionsThis study indicates that live-attenuated VZV vaccine can be safely administered to closely monitored pediatric oncology patients without interruption of chemotherapy and adaptive immunity was induced despite incomplete seroconversion.     

Autotransplantation of the adrenal cortex: a morphological and autoradiographic study.

A morphological and autoradiographic study was made of the adrenal gland of adult male rats after autotransplantation. The simple technique involved placement of pieces of the adrenal gland in a dorsal plane between the skin and muscle. Animals for morphological studies were sacrificed at 2, 3, 4, 7, 15, 30, 90, and 180 days after autotransplantation. Those for autoradiographic studies were sacrificed at 2, 3, 7, and 15 days after autotransplantation, with 3H-thymidine being administered intraperitoneally 2 h before sacrifice. Sham-operated animals were used as controls. The majority of glandular adrenal cells suffered necrosis in the first days (2 and 3) after autotransplantation. Up until 15 days and after revascularization, morphological features of the cells were compatible with protein synthesis exhibiting a developed RER, scarce SER, and mitochondria with tubular and lamellar cristae. These data may correspond to a proliferative phase of glandular cells. At day 15, cells showed morphological signs of steroidogenic activity (mitochondria with vesicular cristae, increase of SER), and at day 30, an increased number of microvilli were seen. Between 30 and 90 days zonation of the adrenal was evident with glomerulosa, fasciculata, and reticular zones readily apparent. The quantitative analysis showed a significant increase of the volumetric density of mitochondria and microvilli between the days 7 and 30. Autoradiographic studies showed an intense labelling of fibroblast-like cells at days 2 and 3 and of glandular cells at days 7 and 15, which was confirmed by the quantitative studies. Corticosterone in autotransplanted animals decreased during the first 15 days, but after 30 days the values were similar to controls. The model reported here seems to be good for study of the regeneration of the adrenal gland and can be a simple, useful, and reproducible method for adrenal transplantation.     

Autotransplantation of the adrenal cortex: A morphological and autoradiographic study

A morphological and autoradiographic study was made of the adrenal gland of adult male rats after autotransplantation. The simple technique involved placement of pieces of the adrenal gland in a dorsal plane between the skin and muscle. Animals for morphological studies were sacrificed at 2, 3, 4, 7, 15, 30, 90, and 180 days after autotransplantation. Those for autoradiographic studies were sacrificed at 2, 3, 7, and 15 days after autotransplantation, with ³H-thymidine being administered intraperitoneally 2 h before sacrifice. Sham-operated animals were used as controls. The majority of glandular adrenal cells suffered necrosis in the first days (2 and 3) after autotransplantation. Up until 15 days and after revascularization, morphological features of the cells were compatible with protein synthesis exhibiting a developed RER, scarce SER, and mitochondria with tubular and lamellar cristae. These data may correspond to a proliferative phase of glandular cells. At day 15, cells showed morphological signs of steroidogenic activity (mitochondria with vesicular cristae, increase of SER), and at day 30, an increased number of microvilli were seen. Between 30 and 90 days zonation of the adrenal was evident with glomerulosa, fasciculata, and reticular zones readily apparent. The quantitative analysis showed a significant increase of the volumetric density of mitochondria and microvilli between the days 7 and 30. Autoradiographic studies showed an intense labelling of fibroblast-like cells at days 2 and 3 and of glandular cells at days 7 and 15, which was confirmed by the quantitative studies. Corticosterone in autotransplanted animals decreased during the first 15 days, but after 30 days the values were similar to controls. The model reported here seems to be good for study of the regeneration of the adrenal gland and can be a simple, useful, and reproducible method for adrenal transplantation.     

Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.     

Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia

Bloodstream infection (BSI) is the most common infectious complication of hematopoietic stem cell transplantation (HSCT) and can cause substantial morbidity and mortality. Identification of risk factors for BSI might be helpful in efforts to reduce transplantation-related death. This study analyzed the incidence of BSI and risk factors for BSI after HSCT in pediatric patients with aplastic anemia (AA). BSI occurred in 39 of the 351 patients with AA (11.1%). Onset of BSI occurred at a median of 8 days after HSCT (range, 0 to 92 days). The 5-year overall survival rate was lower in patients with BSI than in patients without BSI (63.32% ± 7.90% versus 93.35% ± 1.44%; P < .0001). Univariate analysis identified the following variables as associated with BSI: history of immunosuppressive therapy with antithymocyte globulin (ATG), transplantation from an unrelated donor, frequent blood transfusion before transplantation, major or major plus minor ABO type mismatch, graft-versus-host disease prophylaxis with tacrolimus and without cyclosporine, and long interval from diagnosis to transplantation. Among these factors, long interval from diagnosis to transplantation was the sole statistically significant risk factor for BSI on multivariate analysis. In patients who underwent HSCT from a related donor, age ≥14 years at transplantation was risk factor for BSI. In contrast, history of immunosuppressive therapy with ATG, frequent blood transfusion before HSCT, graft failure, and major or major plus minor ABO type mismatch were risk factors for BSI in patients who underwent HSCT from an unrelated donor. Because the overall 5-year survival rate without BSI was >90%, even in patients who were received a transplant from an unrelated donor, control of BSI is very important for successful HSCT in pediatric patients with AA.     

Safety and Efficacy of Targeted-Dose Busulfan and Bortezomib as a Conditioning Regimen for Patients with Relapsed Multiple Myeloma Undergoing a Second Autologous Blood Progenitor Cell Transplantation

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration–time curve (AUC) of 20,000 μM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m²) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.     

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P = .001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes.     

IPSS Poor-Risk Karyotype as a Predictor of Outcome for Patients with Myelodysplastic Syndrome following Myeloablative Stem Cell Transplantation

The optimal therapy for myelodysplastic syndrome (MDS) is allogeneic bone marrow (BM) or blood (BSC) stem cell transplantation (SCT), although outcomes are limited by nonrelapse mortality (NRM) and relapse. A retrospective review was performed of 156 patients who underwent SCT (114 BM, 42 BSC) for MDS or secondary acute myelogenous leukemia (sAML) at our institution. Fifty-five patients remain in continuous complete remission: 35 BM recipients and 20 BSC recipients (median follow-up 139 and 89 months, respectively). Estimated 7-year event-free survival (EFS), NRM, and risk of relapse (ROR) are 33% (95% confidence intervals [CI] 25%-43%), 42% (CI 33%-51%), and 25% (CI 17%-33%) for the BM cohort and 45% (CI 32%-64%, P = .07), 32% (CI 18%-47%, P = .15), and 23% (CI 11%-37%, P = .79) for the BSC cohort. Multivariate analysis showed IPSS poor-risk cytogenetics (P < .001), time from diagnosis to SCT (P < .001), FAB subgroup (P = .001), recipients not in complete remission (CR1) at SCT (P = .005), and the development of acute graft-versus-host disease (aGVHD) (P = .04) were all predictive of an inferior EFS. The FAB subgroup (P = .002), poor-risk karyotype (P = .004), and non-CR1 status also correlated with ROR in multivariate analysis. EFS for poor-risk karyotype patients was superior after receiving BSC compared to BM (39% versus 6%, P < .001). SCT outcomes in MDS/sAML are strongly associated with the IPSS cytogenetic risk group, although the use of BSC in poor-risk karyotype patients may lead to a more favorable long-term EFS.