Mammalian target of rapamycin inhibition after solid organ transplantation: can it,and does it,reduce cancer risk?

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been increasingly used as immunosuppressants for recipients of solid organ transplants. Over the years, potential advantages unique to this class of immunosuppressants have been recognized, including chemoprevention by virtue of their antiproliferative effects. Prevention of malignancy after transplant through mTOR inhibitor‐based immunosuppression may have a specific practical application in transplant recipients with preexisting malignancy including hepatocellular carcinoma or cholangiocarcinoma. This review will reveal how the biochemistry of the mTOR pathway, as it pertains to chemoprevention, can support a clinical role for mTOR inhibitors in the prevention of malignancies, recurrent or de novo, after solid organ transplantation in selected patients.     

Cause-Specific Deaths in Non–Dialysis-Dependent CKD

CKD is associated with higher risk of death, but details regarding differences in cause-specific death in CKD are unclear. We examined the leading causes of death among a non–dialysis-dependent CKD population using an electronic medical record-based CKD registry in a large healthcare system and the Ohio Department of Health mortality files. We included 33,478 white and 5042 black patients with CKD who resided in Ohio between January 2005 and September 2009 and had two measurements of eGFR<60 ml/min per 1.73 m² obtained 90 days apart. Causes of death (before ESRD) were classified into cardiovascular, malignancy, and non-cardiovascular/non-malignancy diseases and non–disease-related causes. During a median follow-up of 2.3 years, 6661 of 38,520 patients (17%) with CKD died. Cardiovascular diseases (34.7%) and malignant neoplasms (31.8%) were the leading causes of death, with malignancy-related deaths more common among those with earlier stages of kidney disease. After adjusting for covariates, each 5 ml/min per 1.73 m² decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio [HR], 1.10; 95% confidence interval [95% CI], 1.08 to 1.12) and non-cardiovascular/non-malignancy diseases (HR, 1.12; 95% CI, 1.09 to 1.14) but not to malignancy. In the adjusted models, blacks had overall-mortality hazard ratios similar to those of whites but higher hazard ratios for cardiovascular deaths. Further studies to confirm these findings and explain the mechanisms for differences are warranted. In addition to lowering cardiovascular burden in CKD, efforts to target known risk factors for cancer at the population level are needed.     

Human Herpesvirus 8–Related Primary Effusion Lymphoma After Liver Transplantation

Primary effusion lymphoma is a rare subclass of non‐Hodgkin lymphoma associated with human herpesvirus 8 infection and principally seen in human immunodeficiency virus–positive patients. We report on the case of a 72‐year‐old human immunodeficiency virus–negative male with a hepatic transplant 10 years prior, who presented with a symptomatic right‐sided pleural effusion and was found to have primary effusion lymphoma by flow cytometric and cytopathologic examination. Immunohistochemistry of his lymphoma cells was positive for human herpesvirus 8. Both he and his donor had no identifiable risk factors for human herpesvirus 8 infection. The patient was intolerant of antiviral therapy and chemotherapy, dying 7 months after diagnosis. Posttransplant primary effusion lymphoma is exceedingly rare and carries a very poor prognosis. Individualized treatment strategies are necessary given the scant body of published literature with guidance based solely on case reports.     

非清髓性造血干细胞移植治疗血液病预处理中ATG／ALG的应用及作用

目的：探讨抗胸腺细胞球蛋白（ATG）和抗淋巴细胞球蛋白（ALG）在血液病非清髓性异基因造血干细胞移植中的作用，以及ATG/ALG的毒副作用，对移植并发症的影响。方法：以ATG／ALG为基础降低化疗剂量的非清髓性预处理方案，对16例恶性血液病、17例重型再生障碍性贫血（SAA）实施骨髓、骨髓加外周血造血干细胞或脐血造血干细胞移植；对5例恶性血液病实施逐渐增加剂量的供者淋巴细胞输注（DLI），1例S从实行供者干细胞输注（DSI）。GVHD的预防：恶性血液病采用环孢菌素A联合短程甲氨喋呤，SAA患者采用CSA联合甲泼尼龙。采用糖皮质激素和甾体类消炎药等防治ATG／ALG毒副作用和并发症。结果：3例患者在移植后早期感染死亡。其余30例患者恢复造血功能，ANC〉0．5×10^8/L和PLT〉20×10^9／l平均时间为12．2（3-35）d和20．1（5～80）d。移植后7例为供者型完全嵌合体（CC），3例无植入证据；23例为混合性嵌合体（MC），其中7例逐渐转为CC，6倒是在DLI或者DSI后实现MC向CC转变。移植后早期均无aGVHD，3～8次DLI并发Ⅰ度aGVHD1例、Ⅱ度aGVHD3例，2例皮肤局限型cGVHD、2例为广泛型cGVHD。并发严重的细菌感染3例、病毒感染4例、真菌感染5例。ATG／ALG使用过程中全部出现寒战、发热症状，大部分出现皮疹、一过性血压下降、少数出现一过性心律不齐，经积极防治不需中断治疗。结论：ATG／ALG促进异基因造血干细胞的植入，延迟和减少GVHD的发生率并降低严重程度．是否增加病毒、真菌感染的机会有待进一步观察。     

Progression of KRAS mutant pancreatic adenocarcinoma during vemurafenib treatment in a patient with metastatic melanoma

Vemurafenib is a tyrosine kinase inhibitor of BRAF that prolongs survival in patients with BRAF V600‐mutant metastatic melanoma. Secondary cutaneous malignancies are a well‐documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild‐type, RAS‐mutant cells. Vemurafenib could also promote growth of non‐cutaneous secondary malignancies by a similar mechanism. We present a case of an individual who received vemurafenib for metastatic melanoma and experienced rapid growth of a pre‐existing KRAS‐mutant pancreatic adenocarcinoma.     

Cancer Risk after Cyclophosphamide Treatment in Idiopathic Membranous Nephropathy

Background and objectives

Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.

Design, setting, participants, & measurements

Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose–response relationship between cyclophosphamide and cancer.

Results

Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6–9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.

Conclusion

Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.