Treatment of Multiple Myeloma With Daratumumab in a Kidney Transplant Patient.

CLINICAL FEATURES: A middle-aged man with history of kidney transplantation was diagnosed with multiple myeloma (MM); he was treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for induction therapy. However, a repeat bone marrow biopsy after treatment revealed 10% clonal plasma cell involvement. Given residual disease, his treatment regimen was changed to daratumumab, bortezomib, and dexamethasone in an attempt to achieve minimal residual disease. THERAPEUTIC CHALLENGE: Daratumumab was recently approved for treatment of relapsed or refractory MM; there are no data regarding the safety and effectiveness in solid organ transplant patients. SOLUTION: Our patient was treated with a daratumumab-based regimen for MM. His renal function was monitored closely along with donor-specific antibody to assess for risk of graft rejection. His renal function remained stable with minimal proteinuria and negative donor-specific antibody during the treatment course.

The association of SBP with mortality in patients with stage 1-4 chronic kidney disease.

OBJECTIVES: Hypertension is a risk factor for chronic kidney disease (CKD) progression and mortality. However, the optimal blood pressure associated with decreased mortality in each stage of CKD remains uncertain. METHODS: In this retrospective cohort study, we included 13 414 individuals with CKD stages 1-4 from NHANES general population datasets from 1999 to 2004 followed to 31 December 2010. Multivariate analysis and Kaplan--Meier curves were used to assess SBP and risk factors associated with overall mortality in each CKD stage. RESULTS: In these individuals with death rates of 9, 12, 30 and 54% in baseline CKD stages 1 through 4, respectively, SBP less than 100 mmHg was associated with significantly increased mortality adjusted for age, sex and race in stages 2,3,4. After excluding less than 100 mmHg, as a continuous variable, higher SBP is associated with fully adjusted increased mortality risk in those on or not on antihypertensive medication (hazard ratio 1.006, P = 0.0006 and hazard ratio 1.006 per mmHg, P < 0.0001, respectively). In those on antihypertensive medication, SBP less than 100 mmHg or in each 20 mmHg categorical group more than 120 mmHg is associated with an adjusted risk of increased mortality. Increasing age, men, smoking, diabetes and comorbidities are associated with increased mortality risk. CONCLUSION: For patients with CKD stages 1-4, the divergence of SBP above or below 100-120 mmHg was found to be associated with higher all-cause mortality, especially in those patients on antihypertensive medication. These findings support the recent guideline of an optimal target goal SBP of 100-120 mmHg in patients with CKD stages 1-4.

Management of Immunosuppression in Kidney Transplant Recipients Who Develop Malignancy.

The risk of cancer increases after transplantation. However, the consensus on immunosuppression (IS) adjustment after diagnosis of malignancy is lacking. Our study aims to assess the impact of IS adjustment on mortality of post-kidney transplant patients and allograft outcomes. We retrospectively reviewed the data in our center of 110 subjects. Our results showed IS dose adjustment was not statistically associated with mortality risk (HR 1.94, 95%CI 0.85-4.41, p = 0.12), and chemotherapy was the only factor that was significantly related to mortality (HR 2.3, 95%CI 1.21-4.35, p = 0.01). IS reduction was not statistically associated with worsening graft function (OR 3.8, 95%CI 0.77-18.71, p = 0.10), nor with graft survival (SHR 4.46, 95%CI 0.58-34.48, p = 0.15) after variables adjustment. Creatinine at cancer diagnosis and history of rejection were both negatively associated with graft survival (SHR 1.72, 95%CI 1.28-2.30, p < 0.01 and SHR 3.44, 95%CI 1.25-9.49, p = 0.02). Reduction of both mycophenolate and calcineurin inhibitors was associated with worsening graft function and lower graft survival in subgroup analysis (OR 6.14, 95%CI 1.14-33.15, p = 0.04; HR 17.97, 95%CI 1.81-178.78, p = 0.01). In summary, cancer causes high mortality and morbidity in kidney transplant recipients; the importance of cancer screening should be emphasized.

Unusual Presentation of Hemophagocytic Lymphohistiocytosis in a Kidney Transplant Patient.

We are presenting a case of a middle-aged woman with history of remote kidney transplantation who had multiple admissions for septic shock-like picture, recurrent fever, and hypotension. Her shock manifestation would resolve after stress dose steroid administration and less than 24 hours of vasopressor administration. Initially, extensive workup was performed without revealing etiology. Eventually, a bone marrow biopsy was carried out leading to the diagnosis of hemophagocytic lymphohistiocytosis, most likely related to recent cytomegalovirus infection.

2-Trifluoromethyl-2-Hydroxypropionamide Derivatives as Novel Reversal Agents of ABCG2 (BCRP)-Mediated Multidrug Resistance: Synthesis and Biological Evaluations.

It has been postulated that one of the biggest impediments to a successful chemotherapy is the phenomena of multidrug resistance (MDR) in cancer cells. One of the main mechanisms of MDR is overexpression of the ATP-binding cassette (ABC) transporters in cancer cells which alters absorption, distribution, metabolism, and excretion of various chemotherapeutic drugs. Efforts have been made to find effective inhibitors of ABC transporters. However, none has been approved clinically. This study shows that a novel compound 3-chloro-N-(2-hydroxyphenyl)-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropanamido) benzamide (compound 7d), one of the 2-trifluoromethyl-2-hydroxypropionamide derivatives could reverse ABCG2 (BCRP)-mediated MDR. Cytotoxicity studies show that compound 7d sensitizes the ABCG2-overexpressing cells to chemotherapeutic drugs mitoxantrone and SN-38, which are well-established substrates of the ABCG2 transporter. Western blotting results indicate that compound 7d does not significantly alter the protein level of the ABCG2 transporter. Accumulation and efflux studies demonstrate that compound 7d increases intracellular accumulation of mitoxantrone by inhibiting the function of ABCG2. Overall, these findings indicate a potential use for compound 7d as an adjuvant agent for chemotherapy to inhibit the function of the clinically relevant ABC transporter and sensitize tumor cells to chemotherapeutic drugs. J. Cell. Biochem. 118: 2420-2429, 2017. © 2017 Wiley Periodicals, Inc.

Quality of meta-analyses for randomized trials in the field of hypertension: a systematic review.

OBJECTIVES: Doubling on average every 6 years, hypertension-related meta-analyses are now published twice weekly and are often considered the highest level of evidence for clinical practice. However, some hypertension specialists and guideline authors view meta-analyses with skepticism. This article evaluates the quality of hypertension-related meta-analyses of clinical trials. METHODS: A systematic search was conducted for meta-analyses of clinical trials recently published over 3.3 years. Specific criteria reproducibly assessed 26 features in the four domains of meta-analysis quality, domains justified by fundamental analytics and extensive research: analyzing trial quality, analyzing heterogeneity, analyzing publication bias, and providing transparency. RESULTS: A total of 143 meta-analyses were identified. A total of 44% had 8+ deficient features with no relation to journal impact factor: odds ratio relating 8+ deficient features to the upper third versus lower third of impact factor = 1.3 (95% confidence limit 0.6-2.9). A total of 56% had all four domains deficient. Quality did not improve over time. Thirty articles (21%) reported statistically significant results (P < 0.05) from inappropriate DerSimonian-Laird models, whereas unreported, appropriate, Knapp-Hartung models gave statistical nonsignificance; 88% of these 30 articles reported the incorrect results in their abstracts. A total of 60% of all meta-analyses failed to conduct analyses in subgroups of quality when indicated, 63% failed to report Tau and Tau, 57% omitted testing for publication bias, none conducted a cumulative analysis for publication bias, and 71-77% omitted mentioning in their abstracts problems of trial quality, heterogeneity, and publication bias. CONCLUSION: Although widespread, deficiencies in hypertension-related meta-analyses are readily corrected and do not represent flaws inherent in the meta-analytic method.

Fragmented polymer nanotubes from sonication-induced scission with a thermo-responsive gating system for anti-cancer drug delivery.

Uniform purified long polymer nanotubes with crosslinked poly(glycidyl methacrylate) as the backbone and a pendant poly(N-isopropyl acrylamide) layer attached to the inner surface as a thermo-responsive gating system were synthesized by a two-fold "grafting-from" strategy inside cylindrical alumina nanopores. To adapt such long polymer nanotubes to be efficient nanocarriers for the intracellular delivery of anti-cancer drugs, a sonication-induced scission method was used to 'cut' the long nanotubes into short fragments. The discontinuous volume transition property in response to the temperature change for the pendant poly(N-isopropyl acrylamide) layer inside the nanotubes results in a reversible 'closing/opening' gating mechanism to control loaded drug release from the nanotubes. Using doxorubicin (DOX) as a model drug, in vitro thermo-responsive drug release behaviour and the related kinetics were studied in detail. The pristine fragmented polymer nanotubes were found to have good biocompatibility in the test with KB-3-1 cancer cells although toxic in their monomeric forms. More importantly, cell toxicity assays for DOX-loaded fragmented polymer nanotubes presented excellent temperature and concentration-dependent cytotoxicity with a low IC50 of 1.4 µmol L-1. These results indicated that such polymer nanotubes with a thermo-responsive gating system have potential as effective anti-cancer drug delivery vehicles.

Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP).

AIM: This study aimed to investigate the mechanism of reversal of multidrug resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors. MATERIALS & METHODS: ABCB1- and ABCG2-overexpressing cell lines were treated with respective substrate antineoplastic agents in the presence or absence of tivozanib. RESULTS: The results indicate that tivozanib can significantly reverse ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux assays showed that tivozanib increased the intracellular accumulation of substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2. CONCLUSION: We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters.