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.     

Clinical and molecular epidemiology of human rhinovirus infections in patients with hematologic malignancy

BackgroundHuman rhinoviruses (HRVs) are common causes of upper respiratory tract infection (URTI) in hematologic malignancy (HM) patients. Predictors of lower respiratory tract infection (LRTI) including the impact of HRV species and types are poorly understood.ObjectivesThis study aims to describe the clinical and molecular epidemiology of HRV infections among HM patients.Study designFrom April 2012–March 2013, HRV-positive respiratory specimens from symptomatic HM patients were molecularly characterized by analysis of partial viral protein 1 (VP1) or VP4 gene sequence. HRV LRTI risk-factors and outcomes were analyzed using multivariable logistic regression.ResultsOne hundred and ten HM patients presented with HRV URTI (n = 78) and HRV LRTI (n = 32). Hypoalbuminemia (OR 3.0; 95% CI, 1.0–9.2; p = 0.05) was independently associated with LRTI, but other clinical and laboratory markers of host immunity did not differ between patients with URTI versus LRTI. Detection of bacterial co-pathogens was common in LRTI cases (25%). Among 92 typeable respiratory specimens, there were 58 (64%) HRV-As, 12 (13%) HRV-Bs, and 21 (23%) HRV-Cs, and one Enterovirus 68. LRTI rates among HRV-A (29%), HRV-B (17%), and HRV-C (29%) were similar. HRV-A infections occurred year-round while HRV-B and HRV-C infections clustered in the late fall and winter.ConclusionsHRVs are associated with LRTI in HM patients. Illness severity is not attributable to specific HRV species or types. The frequent detection of bacterial co-pathogens in HRV LRTIs further substantiates the hypothesis that HRVs predispose to bacterial superinfection of the lower airways, similar to that of other community-acquired respiratory viruses.     

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.     

STK11 Domain XI Mutations: Candidate Genetic Drivers Leading to the Development of Dysplastic Polyps in Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype–phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one‐third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI‐related cancers is currently unknown but our results highlight a novel STK11 genotype–phenotype association as the basis for future genetic counseling and basic research studies.     

Secondary malignancies after allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning and outpatient conduction

Background

Patients given allogeneic hematopoietic stem cell transplants (HSCT) may develop secondary malignant neoplasms (SMN). Several variables have been identified but there are no data about the incidence of this complication in individuals given HSCT using reduced-intensity conditioning (RIC) methods.

Objective

Define the incidence of SMN in patients given HSCT using a RIC preparative regimen conducted on an outpatient basis.

Materials and methods

Patients given HSCT in two institutions between October 1998 and 2012 were analyzed. To appraise the SMN appearance, those patients dead were also regarded as censored at that moment, as well as those lost to follow up and those alive at the closing of the study. 95% Confidence intervals (CI) for the survival or failure estimate were calculated with the Greenwood's method.

Results

A total of 416 allografted patients with a Karnofsky performance index of 100% were included in the study. All patients received peripheral blood stem cells allografts. The conditioning regimen was delivered as an outpatient procedure in all individuals. No patient was given radiotherapy nor antithymocyte globulin during the conditioning. Three hundred and sixty five patients (88%) were never admitted to the hospital, whereas 12% were admitted because of grade III–IV acute graft versus host disease (aGVHD), fever, or mucositis. Median survival time was 15.7 months. Survival at 6 months (95% CI): 66.4% (61.5–70.8%), at 12 months: 53.3% (48.1–58.1%), at 60 months: 30.6% (30.5–41.5%). Eight patients with a SMN were identified in the group of 416 allografted patients, SMN rates (95% CI) were: one year post graft: 1.9% (0.7–4.9%), 5 years: 3.8% (1.6–9.2%), 10 years: 6.8% (2.6–17.7%) and 13 years post-graft: 20.2% (5.5–59.2%), the cumulative probability of SMN being 6.8 at 10 years. Since the number of expected cases in the general population is 0.62, the ratio of observed to expected cases is 12.9 (P < 0.001). This figure means that the risk of developing a malignant neoplasm in allografted individuals using our method is 12.9 times higher than that in the general population. There were three non-Hodgkin's lymphomas, two M2 acute myelogenous leukemias, one hairy cell leukemia, one tongue epidermoid carcinoma, and one breast carcinoma.

Conclusions

We have found a low incidence of SMN in this group of Mexican patients allografted with the Mexican RIC method. Possible explanations for this difference are discussed, focusing on the RIC preparative regimen.