Treatment of X-linked childhood cerebral adrenoleukodystrophy by the use of an allogeneic stem cell transplantation with reduced intensity conditioning regimen

Childhood cerebral form of X-linked adrenoleukodystrophy (X-ALD) is a rapidly progressive demyelinating condition affecting the cerebral white matter, which rapidly leads to total disability and death. The only known curative treatment for this condition is allogeneic hematopoietic stem cell transplantation (HSCT). Procedure-related toxicity is assumed to be the cause of death of patients with X-ALD. Three cases of ALD successfully transplanted with the use of non-myeloablative fludarabine based conditioning are described. Patients showed smooth peri-bone marrow transplantation course with fast and stable engraftment. In the 3- to 5 yr follow-up period, patients showed no deterioration in their clinical and neurological condition. Levels of very long chain fatty acids were very variable and had a tendency to decrease in at least one of the three patients. In another patient, an improvement of magnetic resonance imaging changes was found. Non-myeloablative HSCT should be considered as an early treatment for X-ALD.     

Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients

This study aimed to evaluate the outcome following myeloablative allogeneic hematopoietic stem cell transplantation (SCT) among patients older than 50 yr of age. A total of 215 patients with a median age of 57 yr underwent allogeneic hematopoietic SCT for early (41%) or advanced (59%) hematologic malignancies. After a median follow-up of 36 months a 10-yr survival estimate of 56 +/- 6% could be assessed for patients in early disease stages while patients with advanced diseases showed a significantly decreased survival probability of 31 +/- 5% (p < 0.0002). Transplant related mortality (TRM) at day 100 and 365 post-transplant was 13% and 30% for early but increased to 21% and 49% for advanced disease stages. As major determinants of TRM advanced disease stage (p < 0.0001) and occurrence of grades II-IV graft-vs.-host disease (GVHD) (p < 0.0001) were identified. These results show that hematopoietic SCT following myeloablative conditioning is also applicable to elderly patients whereas disease stage and high-grade GVHD represent the essential prognostic factors for outcome.     

Clinicopathologic analysis of renal biopsies after haematopoietic stem cell transplantation

Aim: The ever‐growing number and increasing survival of haematopoietic stem cell transplantation (HSCT) allow better recognition of its associated renal injuries. We aimed to study the clinicopathologic features of renal biopsies after HSCT by reviewing 13 percutaneous renal biopsies in our institute (Queen Mary Hospital). Methods: A retrospective clinicopathologic study of all renal biopsies archived to the Department of Pathology, Queen Mary Hospital during the period January 1999 to December 2006 was performed. Biopsies from patients with HSCT were selected. Clinical data on presentation and follow up were retrieved from hospital records and physicians. Results: In the 8‐year period, a total of 2233 native renal biopsies were archived. Thirteen renal biopsies were selected from 12 patients with HSCT (11 allogeneic, one autologous). All but one patient were male. The age at renal biopsy ranged from 7 to 63 years (median: 32 years). The median interval of renal biopsy after HSCT was 24 months (range 1–134 months). Evidence of graft‐versus‐host disease was found in nine patients. The most common presentation was significant proteinuria (10 cases) and renal impairment (eight cases). The predominant histological changes were membranous glomerulonephritis (n = 4) and thrombotic microangiopathy (n = 4). One case of focal segmental glomerulosclerosis, IgA nephropathy, minimal change disease, acute tubular necrosis and hypertensive nephrosclerosis were also recorded. Four of our patients died at 0–11 months after renal biopsy. Of the remaining eight patients with a mean follow up of 43.6 months (range, 10–98 months), chronic renal impairment were found in three (37.5%) patients and significant proteinuria also persisted in three. One patient had cytogenetic evidence of relapse of underlying haematological malignancy after HSCT. Conclusion: Among the various renal lesions after HSCT, membranous glomerulonephritis and thrombotic microangiopathy were the most common. Mechanisms of renal injury varied from graft‐versus‐host disease‐associated immune complex deposition to non‐immune complex injury on endothelial cells, glomerular epithelial cells and tubular epithelium. Pathologists and clinicians should attend to the histological and temporal heterogeneity of renal injury when managing patients after HSCT.     

Laparoscopic cytoreductive nephrectomy for metastatic renal cell carcinoma

OBJECTIVE: To critically analyse the results of laparoscopic cytoreductive surgery for renal cell carcinoma (RCC), as phase III evidence supports cytoreductive nephrectomy before immunotherapy, and there is an overall shift towards minimally invasive renal surgery for this disease. PATIENTS AND METHODS: Since October 2000, 22 patients were treated by laparoscopic cytoreductive nephrectomy for metastatic RCC (group 1). All patients had radiological evidence of metastatic disease, with biopsy confirmation in 10. To put the results into perspective, 25 consecutive contemporary patients with large organ-confined nonmetastatic RCC (>7 cm, clinical stage T2) undergoing laparoscopic radical nephrectomy (group 2) were compared retrospectively. The baseline demographics were comparable between the groups. RESULTS: The mean tumour size was 8 cm in group 1 and 9.6 cm in group 2 (P = 0.07). Variables during and after surgery were comparable between the groups, with a mean operative duration of 3.1 vs 3.2 h (P = 0.82), blood loss of 285 vs 308 mL (P = 0.79), complications in two vs eight (P = 0.08), morphine sulphate equivalent requirements of 51.7 vs 44.1 mg (P = 0.1) and a median length of hospital stay of 1.7 vs 1.6 days (P = 0.68). In group 1 the median (range) time to immunotherapy was 35 (13-136) days. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy is safe and effective in selected patients. Currently the procedure is offered to candidates eligible for immunotherapy and with tumours of < or = 15 cm, and no evidence of adjacent organ invasion or inferior vena caval thrombus. Significant perihilar adenopathy and numerous parasitic vessels can increase the complexity of the surgery. Adequate laparoscopic experience is necessary.     

Reduced-intensity stem cell transplantation in two cases of metastatic renal cell carcinoma

Allogeneic hematopoietic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematological malignancies. There is also evidence of such an effect in patients with solid tumors. We report two patients with metastatic renal cell carcinoma who underwent RIST. In both patients, disease progression was observed 6 months after transplantation. However, one patient had transient symptoms of tumor progression after the occurrence of acute graft-versus-host disease, consistent with graft-versus-tumor effects.     

二次非清髓异基因造血干细胞移植治疗恶性血液病六例报告

目的 探讨2次非清髓异基因造血干细胞移植(NAST)治疗恶性血液病的疗效。方法 对6例恶性血液病患者进行了主动或被动2次NAST。结果 6例患者中第1次NAST后发生排斥反应3例，难治复发白血病呈混合嵌合性植入3例。经2次NAST，5例均经过或不经过混合嵌合性植入达完全供者植入，无病存活6～27个月，1例为混和嵌合性植入。发生移植物抗宿主病(GVHD)的患者少而轻，无移植相关性死亡。结论 主动2次NAST是挽救难治复发或难植入、易排斥的恶性血液病患者生命的一条重要途径。     

Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure

We evaluated the results in 20 recent patients treated with a second hematopoietic stem cell transplantation (HSCT) after graft failure (GF). There were 10 children <18 yr of age. Ten patients had a non-malignant disease, and the other 10 had a malignant disease. In most of the transplantations, fludarabine-based reduced intensity conditioning (RIC) was given. Bone marrow was given to 11 patients, peripheral blood system cell (PBSC) in seven and cord blood to two patients. For the second transplantation (n = 20), a new donor was used in nine cases, while the initial donor was used in 11 transplants. Eight patients (40%) suffered from a second GF. Five of these patients were treated with a third HSCT. The probability of survival was 65% one yr and 60% three yr after the second HSCT. No difference in survival was found between patients transplanted with a new donor (56%) compared to those using the original donor (64%). The three-yr survival was 70% for children compared to 50% for adults (p = ns). Patients with a non-malignant disorder showed a three-yr survival of 90% compared to 20% in patients with a malignant disease (p = 0.005). We concluded that re-transplantation using RIC is a valid option for GF, especially in patients with non-malignant disorders.     

自体造血干细胞移植后序贯异基因造血干细胞移植治疗浆母细胞淋巴瘤一例

正浆母细胞淋巴瘤(plasmablastic lymphoma,PBL)是一种罕见的非霍奇金淋巴瘤,来源于B细胞,侵袭性高、预后差,具有独特的临床特征。宁波市第一医院血液科采用自体造血干细胞移植(autologous hematopoietic stem cell transplantation,auto-HSCT)后序贯异基因造血干细胞移植(allogeneic     

Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience

BACKGROUND: Dendritic cells (DC) are the most potent antigen-presenting cells and induce host antitumor immunity through the T-cell response. A clinical study of immunotherapy using cultured DC loaded with tumor antigen, for patients with metastatic renal cell carcinoma (RCC) was performed. METHODS: Dendritic cells were generated by culturing monocytes from peripheral blood for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. On day 6 the DC were pulsed with lysate from autologous tumor as the antigen and with keyhole limpet hemocyanin (KLH) as immunomodulator. The patients were given four doses of lysate-pulsed DC by intradermal injection with a 2-week interval between doses. Clinical effect and immune response were, respectively, evaluated by radiological examination and delayed-type hypersensitivity (DTH) test. RESULTS: Three patients were enrolled and the immunotherapy was well tolerated without significant toxicity. The vaccination induced a positive DTH reaction to tumor lysate in two patients and to KLH in all patients. Clinical responses consisted of one case of no change and two cases of progression of disease. However, we did not see a significant reduction of tumor volume in any case. CONCLUSION: Dendritic cell vaccination can safely induce an immunological response against RCC. Further trials are needed to fully evaluate its efficacy.     

单倍型异基因造血干细胞移植治疗儿童难治性或复发白血病30例

目的 探讨单倍型异基因造血干细胞移植(allo-HSCT)治疗儿童难治性或复发白血病的疗效和安全性.方法 2007年6月至2011年6月间难治性或复发白血病患儿30例接受亲缘单倍型相合allo-HSCT.患儿的原发病为急性髓系白血病(AML) 14例,急性淋巴细胞白血病(ALL) 16例.30例中,首次复发11例,2次或以上复发16例,原发难治性3例.获取供者骨髓+外周血干细胞用于移植.预处理药物采用阿糖胞苷、白消安(Bu)、氟达拉滨及全身照射等.联合使用环孢素A(CsA)+短程甲氨蝶呤(MTX)+吗替麦考酚酯(MMF)+抗人胸腺细胞球蛋白(ATG)等预防移植物抗宿生病(GVHD).结果 30例均获造血重建,中性粒细胞≥0.5×109/L及血小板≥20×109/L的平均时间分别为18.5d及24.2 d,均为完全供者植入.患儿随访时间中位数为22.5个月,随访期间共12例发生急性GVHD,6例发生慢性GVHD.因GVHD死亡4例,感染死亡3例,复发死亡6例,其余1 7例患儿仍无病存活,2年无病存活率为55％.结论 单倍型allo-HSCT治疗儿童难治性或复发白血病安全、可行.     

舒尼替尼在晚期肾细胞癌二线序贯治疗中的临床应用研究

目的:探讨舒尼替尼在晚期肾细胞癌(renal cell carcinoma,RCC)患者二线序贯治疗中的临床效果与安全性。方法:对11例曾接受其他靶向药物治疗的晚期RCC患者在我院行二线舒尼替尼治疗,观察其客观缓解率(ORR)、疾病控制率(DCR)、中位无进展生存期(PFS)及总生存期(OS)等疗效指标及不良反应发生情况。结果:11例患者中2例因不良反应进行药物减量,1例终止治疗。平均接受舒尼替尼治疗时间10.2个月,9例死亡,2例仍存活。DCR 90.9%,中位PFS为7.4个月,中位OS为22.6个月。主要不良反应包括血小板减少症、白细胞减少症、手足皮肤反应、甲状腺功能低下、高血压等。结论:舒尼替尼序贯治疗对于接受过其他靶向药物治疗后进展的晚期RCC患者仍具有良好的疗效和安全性。     

Renal transplant in plasma cell dyscrasias with lenalidomide treatment after autologous stem cell transplantation

Plasma cell dyscrasias (PCD) are a spectrum of diseases characterized by clonal proliferation of plasma cells secreting a monoclonal immunoglobulin. Although considered an incurable disease, a combination of autologous stem cell transplant with novel therapies, including lenalidomide, has improved the overall and progression‐free survival of these patients. Renal impairment is an important complication of the disease that, in some cases, progresses to end‐stage renal disease. Due to the characteristics of PCD, traditionally these patients have not been candidates for renal transplantation. However, treatment improvement allows a reconsideration of this perception, especially in younger patients with good performance status and treatment response. We report two cases of patients diagnosed with PCD undergoing renal transplantation after autologous stem cell transplantation, both cases under treatment with lenalidomide. We also report their perioperative management and their outcome.     

三磷酸腺苷结合转运蛋白G超家族成员2（ABCG2）与肾癌干细胞关系的初步研究

目的探讨三磷酸腺苷结合转运蛋白G超家族成员2（ABCG2）在肾癌组织中的表达及其与肾癌干细胞之间的关系。方法采用免疫组化方法检测65例手术切除肾癌组织（透明细胞癌）和15例癌旁正常组织中ABCG2的表达情况。结果ABCG2阳性染色主要定位于癌细胞的细胞膜,胞质中也有部分表达。ABCG2在肾癌组织中呈较高表达,其中ABCG2在低分化肾癌组织中的表达高于中、高分化者（P〈0．05）;ABCG2的表达与肾癌患者的临床分期无关（P〉0．05）。癌旁正常组织中ABCG2呈弱表达或无表达,与肾癌组织相比差异有显著性（P〈0．05）。结论ABCG2在肾癌组织中表达较高,其可能参与了肾癌的发生和发展,可以作为肾癌干细胞研究的重要标志物。     

Transitional cell carcinoma in renal transplant recipients: A single center experience

Objective:   To present a single center experience in managing transitional cell carcinoma (TCC) in Chinese renal transplant (RTx) recipients.
Methods:   In a cohort of 1429 patients who received RTx operation, 27 patients (six males and 21 females) were pathologically diagnosed with TCC in their native urologic system. The data were analyzed retrospectively.
Results:   The incidence of TCC was 1.89% and accounted for 41.5% of the patients with post-transplant de novo malignancies among 1429 recipients. Among the 27 recipients with TCC, 77.8% were female, 59.3% had taken a Chinese herb that contains aristolochic acid for at least 2 months before RTx, 51.9% had painless gross hematuria, while 40.7% had microscopic hematuria and/or repeated urologic infection. Two patients were found to have asymptomatic hydronephrosis during a routine check-up. The patients with upper tract carcinoma underwent simultaneous bilateral nephroureterectomy or unilateral nephroureterectomy and bladder cuff resection. Transurethral resection of the bladder tumor was carried out in patients with concomitant or solitary superficial bladder lesions. Intravesical chemotherapy was started and immunosuppressants were adjusted in all patients immediately after the surgery. Tumor recurrence in the bladder was noted in five patients. In one patient, residual and/or recurrent carcinoma in the contralateral pelvis was detected.
Conclusions:   Transitional cell carcinoma is the predominant malignancy in Chinese RTx recipients. Female sex, the Chinese herb containing aristolochic acid and immunosuppression are markedly associated with the development of TCC. Risk-adapted screening, strict follow up, standard surgical intervention and dose reduction of immunosuppressants are very important for early diagnosis and treatment of TCC.     

减低强度预处理异基因造血干细胞移植治疗高危骨髓增生异常综合征的效果

目的 探讨减低强度预处理异基因造血干细胞移植(allo-HSCT)治疗高危骨髓增生异常综合征(MDS)的疗效和安全性.方法 应用减低强度预处理allo-HSCT治疗2012年1月至2014年1月我科收治的10例高危骨髓增生异常综合征患者,其中男6例,女4例,平均年龄30.3岁,确诊至移植的中位时间为4.5个月,7例为HLA配型全相合,3例为HLA配型不合,供者接受粒细胞集落刺激因子动员,采用骨髓加外周血干细胞联合移植,预处理方案为降低预处理强度氟达拉滨(FLU)、环磷酰胺(CTX)及抗人淋巴细胞免疫球蛋白(ATG),移植物抗宿主病(GVHD)预防采用联合免疫抑制剂(包括环孢素A、氨甲蝶呤等).移植后观察全部患者毒副反应、GVHD和无病生存等情况.结果 全组患者均获造血重建,中性粒细胞≥0.5×109/L及血小板≥20×109/L的平均时间分别为分别19.7d及23.8d,植入证据检测为100％完全供者造血.随访至2014年10月,中位随访时间20.5个月(8～32个月).2例患者死于复发,并发症死亡1例,其他患者目前仍处于完全缓解状态,无病生存率达到70％,最长无病生存时间已达32个月.结论 Allo-HSCT是治疗高危MDS的可行方法,疗效好、安全系数大,可在临床广泛开展.     

Living donor renal transplantation with incidental renal cell carcinoma from donor allograft

To report our series of cases with living donor kidney transplant by laparoscopic nephrectomy with incidental renal cell carcinomas (RCC) at the time of transplant. We performed a search of cases of renal allografts from living donors with incidental tumors which were confirmed as RCC in final pathology. The graft nephrectomy was performed via hand‐assisted laparoscopic procedure. All cases underwent partial nephrectomy of the tumor during the back‐table preparation of the graft and sent for pathological analysis. We performed 435 living donor kidney transplants at our Institution and identified four cases consistent with the diagnosis of RCC. Two of them were clear cell type, one papillary and one multilocular RCC. All the tumors presented at stage I of TNM classification. After a median follow‐up of 36 months, three patients remain free of dialysis with good allograft function. One noncompliant patient presented with a glomerular filtration rate (GFr) below 15 ml/min after a BK viral infection. At the end of follow‐up period, all patients had remained free of tumor. Donors with suspicious renal masses might be accepted for living donation. Partial nephrectomy before transplantation could offer a cure for the disease without risks for the recipient with therapeutic benefit for the donor.