👤 Sidharth Chaudhry

Immunoglobulin M (IgM) paraproteinemia is usually associated with either lymphoplasmacytic lymphoma (LPL) or Waldenström's macroglobulinemia (WM). Manifestations due to IgM paraprotein include hyperviscosity, acquired coagulopathy, cryoglobulinemia, vasculitis, and cold antibody-mediated autoimmune hemolytic anemia. These manifestations are seen in variable percentage of patients with LPL/WM. IgM myeloma constitutes only 0.5-1% of all myeloma cases. We describe a middle-aged female who presented with 5C's: cryoglobulinemia, coagulopathy (acquired von Willebrand disease), cold autoimmune hemolytic anemia, clot (thrombosis due to vasculitis), and cloudy vision (hyperviscosity syndrome) attributable to IgM paraprotein, but was diagnosed later with IgM myeloma. IgM is an important differential diagnosis of WM. The current case highlights such diagnostic challenges and their therapeutic considerations. Show less

This Phase 1b/2 study assessed the efficacy in terms of objective response rate (ORR) of the FGFR1/2/3 kinase inhibitor derazantinib as monotherapy or in combination with atezolizumab in patients with metastatic urothelial cancer (mUC) and FGFR1-3 genetic aberrations (FGFR1-3GA). This multicenter, open-label study comprised 5 substudies. In Substudies 1 and 5, patients with mUC with FGFR1-3GA received derazantinib monotherapy (300 mg QD in Substudy 1, 200 mg BID in Substudy 5). In Substudy 2, patients with any solid tumor received atezolizumab 1200 mg every 3 weeks plus derazantinib 200 or 300 mg QD. In Substudy 3, patients with mUC harboring FGFR1-3GA received derazantinib 200 mg BID plus atezolizumab 1200 mg every 3 weeks. In Substudy 4, patients with FGFR inhibitor-resistant mUC harboring FGFR1-3GA received derazantinib 300 mg QD monotherapy or derazantinib 300 mg QD plus atezolizumab 1200 mg every 3 weeks. The ORR for Substudies 1 and 5 combined was 4/49 (8.2%, 95% confidence interval = 2.3% to 19.6%), which was based on 4 partial responses. The ORR in Substudy 4 was 1/7 (14.3%, 95% confidence interval = 0.4% to 57.9%; 1 partial response for derazantinib 300 mg monotherapy, zero for derazantinib 300 mg plus atezolizumab 1200 mg). In Substudy 2, derazantinib 300 mg plus atezolizumab 1200 mg was identified as a recommended dose for Phase 2. Only 2 patients entered Substudy 3. Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC. Clinicaltrials.gov NCT04045613, EudraCT 2019-000359-15. Show less

The increased frequency of mass shootings, terror attacks, and natural disasters in recent years have presented challenges to provision of quality medical care in both short and long-term stressful situations. While emergency departments and trauma surgeons are usually the face of the response to mass casualty incidents (MCI), other departments such as radiology are often active participants in caring for these patients but may not be as well prepared. In this article, we review nine papers describing the experiences of various radiology departments with specific MCIs and the lessons they learned from those experiences. By analysis of common themes raised in these papers, we hope to enable departments to incorporate these lessons into their disaster plans to enhance their preparedness for such events. Show less

Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%-90% of target antigens in MN. We performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue. MS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2R-negative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7. MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN. Show less

A spectrum of disorders, ranging from rare severe cases of homozygous null lipoprotein lipase deficiency (LPLD)-familial chylomicronemia syndrome (FCS) to heterozygous missense LPLD or polygenic causes, result in hypertriglyceridemia and pancreatitis. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy, and insulin resistance. Areas covered: In this review, authors discuss chronic treatment of FCS by ultra-low fat diets allied with the use of fibrates, omega-3 fatty acids, niacin, statins, and insulin-sensitizing therapies depending on the extent of residual lipoprotein lipase (LPL) activity; novel therapies in development target triglyceride (TG)-rich lipoprotein particle clearance. Previously, a gene therapy approach to LPL-alipogene tiparvovec showed that direct targeting of LPL function reduced pancreatitis events. An antisense oligonucleotide to apolipoprotein-C3, volanesorsen has been shown to decrease TGs by 70-80% and possibly to reduce rates of pancreatitis admissions. Studies are underway to validate its long-term efficacy and safety. Other approaches investigating the role of LPL modulating proteins such as angiopoietin-like petide-3 (ANGPTL3) are under consideration. Expert opinion: Current therapeutic options are not sufficient for management of many cases of FCS. The availability of antisense anti-apoC3 therapies and, in the future, ANGPTL3 therapies may remedy this. Show less

Organic anion transporting polypeptide 1B1 (OATP1B1) is a liver-enriched transporter involved in the hepatocellular uptake of many endogenous molecules and several structurally divergent drugs in clinical use. Although OATP1B1 coding region polymorphisms are known to make an impact on substrate drug disposition in humans, little is known regarding the mechanisms underlying the transcriptional regulation of this transporter. In this study, we note that messenger RNA (mRNA) expression of OATP1B1 in a large human liver bank exhibited marked interindividual variability that was not associated with coding region polymorphisms. Accordingly, we hypothesized that such variability in expression is reflective of nuclear receptor-mediated transcriptional regulation of this transporter. We tested prototypical ligands for the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) α, and farnesoid X receptor (FXR) in a human hepatoma-derived cell line and noted induction of OATP1B1 mRNA when the cells were treated with LXRα or FXR ligands. To confirm a direct role for LXRα and FXR to OATP1B1 expression, we performed detailed promoter analysis and cell-based reporter gene assays resulting in the identification of two functional FXR response elements and one LXRα response element. The direct interaction between nuclear receptors with the identified response elements was assessed using chromatin immunoprecipitation assays. Using isolated primary human hepatocytes, we show that LXRα or FXR agonists, but not PXR or CAR agonists, are capable of OATP1B1 induction. We note that OATP1B1 transcriptional regulation is under dual nuclear receptor control through the oxysterol sensing LXRα and the bile acid sensor FXR. Accordingly, the interplay between OATP1B1 and nuclear receptors may play an important and heretofore unrecognized role during cholestasis, drug-induced liver injury, and OATP1B1 induction-related drug interactions. Show less