Monitoring and Treatment for BK Virus After Kidney Transplantation

Background

The BK nephropathy (BKN) shows a 10% prevalence among cases of kidney transplantation (KT). We assessed the incidence of BK replication in KT recipients as well as our updated screening strategy and the impact of interventions on BK virus infections.

Methods

Since September 2007, our screening protocol for BK virus included examination of urine cytology or BK virus DNA real-time polymerase chain reaction (PCR) detection on postoperative days 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. IR present, we tested urine BK virus DNA PCR quantitation. We applied the updated screening protocol from August 2010. It urine BK DNA PCR quantification was above 10⁷ copies/mL, we checked regularly blood the BK virus DNA PCR quantification. In addition, if the blood BK virus DNA load was above 10⁴ copies/mL and the serum creatinine elevated, we was performed an allograft biopsy. Between September 2007 and December 2011, the 58 recipients who showed BK viremia were enrolled in the present study in 2 groups according to the period of screening protocol (era I, era II).

Results

The time between kidney transplantation and BK viremia detection of era II was shorter than that of era I (16 vs 29 weeks; P = .001). Viremia clearance rate at 6 months in era II was significant higher than that of era I (82% vs 36.8%; P = .001) as well as at 12 months (100% vs 61.1%, P < .001) after intervention. Interestingly, viremia clearance at 12 months after intervention was 100% in era II.

Conclusion

An updated screening protocol for BK virus allowed early detection and accurate diagnosis of BKN. Early detection of BK virus infection enabled early intervention and improved viral clearance rate.     

Comparison of the Incidence of De Novo Malignancy in Liver or Kidney Transplant Recipients: Analysis of 2673 Consecutive Cases in a Single Center

Purpose

An increased incidence of de novo malignancy (dM) is an established complication among solid organ transplant (SOT) recipients compared with the general population. The aims of this study were to describe the incidence and cumulative risk for development of dM among our transplanted population, depending on various clinical and pathologic variables.

Methods

We retrospectively reviewed the medical records and pathologic data of SOT recipients performed from February 1995 to December 2010.

Results

Among 2673 consecutive SOT recipients, the dM that developed in 66 (2.5%) patients included, 16 (0.6%; 24.2% of overall dM) lymphoid dM and 50 (1.9%; 75.8% of overall dM) nonlymphoid dM. Cumulative incidence of dM in liver was significantly higher than that in kidney transplant recipients. A significantly higher cumulative incidence of dM was observed among living donor versus deceased donor SOT. Although the more frequent development of lymphoid dM was observed during the first year posttransplantation, the cumulative risk of nonlymphoid dM increased year by year, reaching a substantially higher incidence than that of lymphoid dM beyond 5 years after SOT. Comparing the various immunosuppressive regimens, the cumulative incidence was greater among the group with basiliximab induction. However, the hazard of occurrence was unaffected by whether tacrolimus or cyclosporine was used for maintenance immunosuppression. The increased risk of dM was not dependent on recipient age or gender.

Conclusion

This study demonstrated distinctive cumulative incidences of dM in different clinical and pathologic settings.     

Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases

Purpose

The aim of this retrospective study was to evaluate the relevance of surgery in non-small cell lung cancer (NSCLC) patients with ipsilateral pulmonary metastases.

Methods

The clinical records of 1,623 consecutive NSCLC patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Overall, 161 (9.9 %) and 21 (1.3 %) patients had additional nodules in the same lobe as the primary lesion (PM1) and additional nodules in the ipsilateral different lobe (PM2), respectively.

Results

The 5-year survival rate was 54.4 % in the PM1 patients and 19.3 % in the PM2 patients (log-rank test: p = 0.001). Tumor size ≤3 cm, N0-1 status and surgical procedures less extensive than bilobectomy were identified as favorable prognostic factors in the PM1 patients. The 5-year survival rate in the PM1-N0-1 patients was 68.7 %, while that in the PM1-N2-3 patients was 29.1 % (p < 0.0001). Compared to the non-PM1 stage IIIA patients, the stage IIIA patients with PM1 disease (PM1-N1) tended to experience longer survival times (p = 0.06). Squamous cell types and bilobectomy or more extensive procedures were found to be unfavorable factors in the PM2 patients. The survival of the PM2 patients was significantly worse than that of the other T4 patients (p = 0.007).

Conclusions

PM1 patients with N0-1 disease are good candidates for surgery, whereas PM2 patients do not appear to benefit from surgery.     

Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion.     

Identification and structure–activity relationship of purine derivatives as novel MTH1 inhibitors

The human mutT homolog‐1 (MTH1) protein prevents the incorporation of oxidized nucleotides such as 2‐OH‐dATP and 8‐oxo‐dGTP during DNA replication by hydrolyzing them into their corresponding monophosphates. It was found previously that cancer cells could tolerate oxidative stress due to this enzymatic activity of MTH1 and its inhibition could be a promising approach to treat several types of cancer. This finding has been challenged recently with increasing line of evidence suggesting that the cancer cell‐killing effects of MTH1 inhibitors may be related to their engagement of off‐targets. We have previously reported a few purine‐based MTH1 inhibitors that enabled us to elucidate the dispensability of MTH1 in cancer cell survival. Here, we provide a detailed process of the identification of purine‐based MTH1 inhibitors. Several new compounds with potency in the submicromolar range are disclosed. Furthermore, the structure–activity relationship and associated binding mode prediction using molecular docking have provided insights for the development of highly potent MTH1 inhibitors.     

Predicting sustained virological response in chronic hepatitis C patients treated with pegylated interferon and ribavirin using a novel highly sensitive Real-time detection PCR assay

The Abbott Real Time HCV assay (lower limit of detection 12 IU/ml) was developed as a highly sensitive HCV RNA quantitative assay using real-time detection PCR(RTD-PCR). We assessed whether the new assay more effectively predicts sustained virological response (SVR) than conventional PCR (PCR) in 38 chronic hepatitis patients infected with HCV genotype 1b and treated with pegylated interferon alpha2b plus ribavirin. Sixteen patients reached SVR, 10 patients relapsed, 9 patients did not respond, 3 patients discontinued treatment. Positive predictive value (PPV) for SVR of undetectable HCV RNA at W4, 8, 12 by RTD-PCR and PCR was (100% vs. 100% at W4), (100% vs. 100% at W8), (83.3% vs. 72.7% at W12). HCV RNA undetectable at W12 had a higher PPV for SVR when measured by RTD-PCR than by conventional PCR.     

Agglutination of Jelly Coat and Cortical Granule Components and the Block to Polyspermy in the Amphibian Xenopus laevis

A block to polyspermy in amphibians is established at fertilization by the conversion of the vitelline envelope to the fertilization envelope. In Xenopus laevis a major ultrastructural change in the envelope at fertilization is the appearance of an electron-dense layer, termed the F layer, between the envelope and the inner-most jelly coat layer, J(1). The F layer is derived, at least in part, from materials released from the cortical granules. Further definition of the origin and chemical nature of the F layer was sought by using isolated cortical granule (CG) exudate and jelly coat layer J(1). In double diffusion experiments, the isolated components interacted in an agglutination reaction producing a band of precipitation. The agglutination involved alpha-galactoside residues and metal ions (Ca(++)). Employing chemically modified jelly, we demonstrated that sulfhydryl-disulfide interchanges were not involved in the agglutination and, with (35)S-labeled jelly, that the agglutinating J(1) component possessed sulfate esters. Both the CG exudate and the J(1) components contained carbohydrate, as evidenced by their lectin reactivity. A number of ionic polymers, both natural and synthetic, were tested as chemical analogs of CG exudate and J(1); none gave an agglutination band. Dissolved jelly coat material from eggs of two different species of frogs agglutinated with CG exudate, while jelly from sea urchin eggs and hyaluronic acid from mammalian eggs did not. Thus, the agglutination reaction was chemically and phylogenetically specific. An electron-dense layer, similar to the F layer, formed on the outer of the vitelline envelope when jellied unfertilized eggs were immersed in CG exudate; such eggs were not fertilizable. We suggest that in Xenopus laevis, and perhaps other organisms as well, an agglutination type of reaction between cortical granule components and egg integuments is a participant in the structural and molecular events establishing a block to polyspermy.