Serotype-dependent recombinant adeno-associated vector (AAV) infection of Epstein-Barr virus-positive B-cells, towards recombinant AAV-based therapy of focal EBV + lymphoproliferative disorders.

BACKGROUND: B-cell proliferative disorders, such as post-transplant lymphoproliferative disease (PTLD), are increased among persons afflicted by T-cell compromise. Most are Epstein-Barr virus (EBV) + and can first present with a focal lesion. Direct introduction of oncolytic viruses into localized tumors provides theoretical advantages over chemotherapy, immunotherapy and radiation therapy by reducing systemic toxicity. Despite extensive study as a vehicle for gene therapy, adeno-associated viruses (AAV) have rarely been applied to human cancer research due to technical and theoretical obstacles. Moreover, human B-cells have historically been described as resistant to AAV infection. Nonetheless, advances using different recombinant (r)AAV serotypes with unique tropisms to deliver cytotoxic therapy suggested a localized anti-tumor approach was feasible. METHODS: As a prelude to the development of a therapeutic vehicle, the ability of fifteen distinct EGFP-bearing rAAV serotypes to transduce human B-cells, including primary, immortalized, and B-cell tumor lines ± EBV was assessed by confocal microscopy, flow cytometry and subsequently cell viability assay. RESULTS: Rank order analysis revealed augmented transduction by rAAV6.2 and closely related virions. EBV infection of EBV-negative B-cell tumor lines and EBV immortalization of primary B-cells increased susceptibility to rAAV6.2 transduction. As a proof of concept, transduction by rAAV6.2 encoding herpes simplex virus type 1 (HSV1)-thymidine kinase (TK) eliminated TK-negative rhabdomyosarcoma cells and diminished viability of transduced B-cell lines upon incubation with ganciclovir. CONCLUSIONS: rAAV serotypes differentially transduce human B-cell lines reversing the dogma that human B-cells are refractory to AAV infection. EBV + B-cells display increased susceptibility to rAAV6.2 infection, uncovering a new method for improved nucleic acid transfer into transfection-resistant B-cell lines. The introduction of a functional suicide gene into the rAAV6.2 genome identifies a candidate vector for the development of rAAV-based oncolytic therapy targeting focal EBV-bearing B-lymphoproliferative disorders.

Diagnostic accuracy of cardiac testing for coronary artery disease in potential liver transplant recipients: A systematic review and meta-analysis.

BACKGROUND: The incidence of coronary artery disease (CAD) in Liver transplant (LT) patients is much higher than prior estimates and the morbidity and mortality are significant in this group of patients. Coronary angiography is the gold standard for detection of CAD, a non-invasive test that allows appropriate risk stratification would be preferred. In this systematic review and meta-analysis, we sought to assess the pooled diagnostic accuracy of various noninvasive cardiac imaging tests in detecting CAD in patients listed for LT. METHODS: We performed a systematic review and meta-analysis of studies comparing sensitivity and specificity of non-invasive tests to that of coronary angiography in diagnosing coronary artery disease in patients undergoing liver transplantation. RESULTS: Five studies (616 participants) evaluated myocardial perfusion imaging (MPI); five studies (1243 participants) dobutamine stress echocardiography (DSE); and three (87 participants), other tests. MPI had a pooled sensitivity of 0.62 (95% CI 0.37, 0.83), specificity of 0.60 (95% CI 0.39, 0.79), diagnostic odds ratio (DOR) of 2.5 (95% CI 1.7, 5.64) and Area under the curve (AUC) 0.649. DSE had a pooled sensitivity of 0.25 (95%CI 0.09, 0.51), specificity of 0.68 (95% CI 0.44, 0.84) and DOR of 0.7 (95% CI 0.12, 3.84). CONCLUSIONS: Our results show that both MPI and DSE are not effective screening tools for detecting CAD in patients with end-stage liver disease (ESLD). Future studies are needed to evaluate the role of real-time myocardial contrast echocardiography (RTMCE) and coronary artery calcium score (CAC) with coronary CT angiography in patients with ESLD.

An Unusual Case of Neurosyphilis Manifesting as Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH).

BACKGROUND Syphilis has increased in prevalence in the United States by 72.7% from 2013 to 2017, with the highest rates recorded in men who have sex with men. There is an increased incidence of syphilis in patients with a concomitant HIV infection, estimated at a 77-fold increase. CASE REPORT This report documents an unusual case of neurosyphilis manifesting as syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a 56-year-old man with HIV/AIDS. A 56-year-old man who has sex with men with HIV/AIDS presented with a 4-day history of periumbilical abdominal pain, nausea, and constipation. A physical exam revealed slowing of baseline cognition, but was otherwise unremarkable. Urine and serum osmolality studies were consistent with SIADH as defined by the Bartter and Schwartz Criteria: serum osmolality <275 mOsm/kg, urine osmolality >100 mOsm/kg, urine sodium >20-40 mmol/L, euvolemia, and no other cause for hyponatremia identified. He was fluid-restricted, with improvement in laboratory abnormalities, further supporting the diagnosis of SIADH. A diagnostic work-up included a CT abdomen/pelvis with perirectal lymphadenopathy, colonoscopy negative for malignancy, chest CT with lymphadenopathy, and a head MRI negative for intracranial processes. The patient was ultimately found to have positive results on rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests, and was diagnosed as having neurosyphilis. He underwent penicillin desensitization and received a 14-day course of penicillin G, with recovery of sodium to normal range on discharge. CONCLUSIONS Our case highlights SIADH as an initial presenting sign of neurosyphilis with HIV infection, which has only been documented in 2 prior case reports. Our case highlights the importance of recognizing atypical presentations of neurosyphilis in patients with HIV to prevent long-term complications.

A Unique Presentation of Cutaneous Diffuse Large B-Cell Lymphoma.

Cutaneous B-cell lymphomas (CBCL) are rare heterogeneous neoplastic diseases composing about 22.5% of all cutaneous lymphomas. These diseases can be divided into primary and secondary cutaneous variants with primary cutaneous B-cell lymphoma (PCBCL) divided into three distinct entities including primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Secondary cutaneous diffuse large B-cell lymphoma (CDLBCL) and PCDLBCL, LT are more aggressive neoplasms compared to the aforementioned CBCL with survival rates of 37% and 50% after 5 years, respectively. CDLBCL can present as cutaneous or subcutaneous nodules, papular lesions, or indurated plaques. Here, we present a case of CDLBCL of an 88-year-old female that was mistaken for lower extremity cellulitis with phlegmon. Our patient failed two courses of antibiotic therapy as an outpatient and received a third as an inpatient before a cutaneous biopsy clinched the diagnosis.