Pre‐transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post‐kidney transplantation

Previous studies that have assessed the association of pre‐transplant antiphospholipase A2 receptor autoantibody (PLA2R‐Ab) concentration with a recurrence of membranous nephropathy (rMN) post‐kidney transplant have yielded variable results. We tested 16 consecutive transplant patients with a history of iMN for pre‐transplant PLA2R‐Ab. Enzyme‐linked immunosorbent assay titers (Euroimmun, NJ, USA) >14 RU/mL were considered positive. A receiver operating characteristic (ROC) analysis was performed after combining data from Quintana et al. (n = 21; Transplantation February 2015) to determine a PLA2R‐Ab concentration which could predict rMN. Six of 16 (37%) patients had biopsy‐proven rMN at a median of 3.2 yr post‐transplant. Of these, five of six (83%) had a positive PLA2R‐Ab pre‐transplant with a median of 82 RU/mL (range = 31–1500). The only patient who had rMN with negative PLA2R‐Ab was later diagnosed with B‐cell lymphoma. One hundred percent (n = 10) of patients with no evidence of rMN (median follow‐up = five yr) had negative pre‐transplant PLA2R‐Ab. In a combined ROC analysis (n = 37), a pre‐transplant PLA2R‐Ab > 29 RU/mL predicted rMN with a sensitivity of 85% and a specificity of 92%. Pre‐transplant PLA2R‐Ab could be a useful tool for the prediction of rMN. Patients with rMN in the absence of PLA2R‐Ab should be screened for occult malignancy and/or alternate antigens.     

Generalized Multifactor Dimensionality Reduction (GMDR) Analysis of Drug-Metabolizing Enzyme-Encoding Gene Polymorphisms may Predict Treatment Outcomes in Indian Breast Cancer Patients

Background

Prediction of response and toxicity of chemotherapy can help personalize the treatment and choose effective yet non-toxic treatment regimen for a breast cancer patient. Interplay of variations in various drug-metabolizing enzyme (DME)-encoding genes results in variable response and toxicity of chemotherapeutic drugs. Generalized multi-analytical (GMDR) approach was used to determine the influence of the combination of variants of genes encoding phase 0 (SLC22A16); phase I (CYP450, NQO1); phase II (GSTs, MTHFR, UGT2B15); and phase III (ABCB1) DMEs along with confounding factors on the response and toxicity of chemotherapeutic drugs in breast cancer patients.

Methods

In an Indian breast cancer patient cohort (n = 234), response to neo-adjuvant chemotherapy (n = 111) and grade 2–4 toxicity to chemotherapy were recorded. Patients were genotyped for 19 polymorphisms selected in four phases of DMEs by PCR or PCR–RFLP or Taqman allelic discrimination assay. Binary logistic regression and GMDR analysis was performed. Bonferroni test for multiple comparisons was applied, and p value was considered to be significant at <0.025.

Results

For ABCB1 1236C>T polymorphism, CT genotype was found to be significantly associated with response to NACT in uni-variate and multi-variate analysis (p = 0.018; p = 0.013). The TT genotype of NQO1 609C>T had a significant association with (absence of) grade 2–4 toxicity in uni-variate analysis (p = 0.021), but a non-significant correlation in multi-variate analysis. In GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, and ABCB1 1236C>T polymorphisms yielded the highest testing accuracy for response to NACT (CVT = 0.62). However, for grade 2–4 toxicity, CYP2C19*2 and ABCB1 3435C>T polymorphisms yielded the best interaction model (CVT = 0.57).

Conclusion

This pharmacogenetic study suggests a role of higher order gene–gene interaction of DME-encoding genes, along with confounding factors, in determination of treatment outcomes and toxicity in breast cancer patients. This can be used as a potential objective tool for individualizing breast cancer chemotherapy with high efficacy and low toxicity.

     

DNA interaction,anti-proliferative effect of copper oxide nanocolloids prepared from metallosurfactant based microemulsions acting as precursor,template and reducing agent

In the present study, we have synthesized mixed cuprous/copper oxide nanosuspensions by metallosurfactant based microemulsion technique. Three metallosurfactants were synthesized which includes two non-ionic double chained metallosurfactants with C₁₂, C₁₆ chains with coordinated copper i.e. Cudda and Cuhexa, respectively. Another cationic double chained metallosurfactant with loosely bound metal (Cuctac) was also prepared. The prepared metallocomplexes were characterized using FTIR, elemental analysis, and NMR. The effect of the position of metallosurfactant in microemulsion on the fabrication and properties of nanosuspensions was elucidated. In this method, no external reducing agent and capping agent were added and tween 80 acted both as reducing and stabilizing agent for the nanoparticles. The synthesized nanoparticles were characterized and it was observed that mixed copper and cuprous oxide particles are present in colloidal suspension for all the three studied metallosurfactants. The kinetics of formation of mixed copper/cuprous oxide nanosuspensions (Ns) and their stability was estimated using Uv-visible spectroscopy. Further, the binding and interactions of copper nanosuspensions with calf Thymus DNA (CT-DNA) were assessed using Uv–vis spectroscopy, circular dichroism and gel electrophoresis. Additionally, the antioxidant activity of the Cu Ns was checked using DPPH assay. The role of positive charge on nanoparticles as evaluated from Zeta potential was responsible for DNA affinity. The DNA conformational changes in the presence of nanosuspensions and relevant scavengers were investigated. Further, the anti-proliferative activity of copper Ns was assessed using HeLa cells and Cuhexa derived Ns were proved to be active with highest activity at a low concentration and were nontoxic towards normal cell lines. In summary, this work demonstrates a softer approach for the synthesis of copper nanosuspensions with a size range of 2–5?nm and evaluated the role of type and structure of metallosurfactant on size, stability of particles and anti-proliferative activity.     

Biomechanical comparison of extended trochanteric osteotomy and slot osteotomy for femoral component revision in total hip arthroplasty

BACKGROUND: Depending upon the clinical presentation and need for exposure in revision hip arthroplasty, an extended trochanteric osteotomy or slot osteotomy could be used for removal of an inaccessible distal cement mantle, infected material, or distal fragment of a broken stem. This study is a biomechanical comparison of these two osteotomy techniques. METHODS: A press-fit femoral component with a 20-cm straight stem was implanted in each of ten synthetic femurs. The stiffness of these components implanted in the femurs was measured for a compressive load condition simulating the stance phase of level walking. Half of the femurs then received an extended trochanteric osteotomy, and the other half a slot osteotomy. Stiffness testing was repeated both after the osteotomized bone was removed, and after it was fixed back in place by cerclage wiring. FINDINGS: The stiffness of the femoral component/synthetic femur constructs in the slot osteotomy group was significantly greater than in the extended trochanteric osteotomy group. INTERPRETATION: This study demonstrated that in the laboratory setting, the slot osteotomy was significantly stiffer than the more traditional extended trochanteric osteotomy. However, the clinical implications of this increased stiffness are unknown. The ultimate choice of the type of osteotomy depends upon the exposure requirements for a given clinical situation.     

Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up.     

Ultra‐short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients

We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R?). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R ? transplants.     

Long-Term Outcomes of Pancreas After Kidney Transplantation in Small Centers: Is It Justified?

Background

Currently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied.

Methods

In this retrospective analysis, we report short- and long-term outcomes in a small center performing 2–9 PT annually.

Results

Forty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy.

Conclusions

Compared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.