Research Spotlight

Wiederkehr, M. R., A. N. Mehta and M. Emmett (2019). “Case report: Patiromer-induced hypercalcemia.” Clin Nephrol Case Stud 7: 51-53.

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Patiromer is a novel potassium-binding compound which has recently received FDA approval. This ion exchange resin releases calcium when it binds potassium. We describe the development of hypercalcemia after initiation of patiromer. The calcium levels fell when the drug was stopped but recurred when it was later resumed. Patiromer was again discontinued, and the serum calcium level fell back into the normal range. We believe this patient manifested patiromer-induced hypercalcemia.

Tew, B. Y., C. Legendre, M. A. Schroeder, T. Triche, G. C. Gooden, Y. Huang, L. Butry, D. J. Ma, K. Johnson, R. A. Martinez, M. Pierobon, E. F. Petricoin, J. O’Shaughnessy, C. Osborne, C. Tapia, D. N. Buckley, J. Glen, M. Bernstein, J. N. Sarkaria, S. A. Toms and B. Salhia (2019). “Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones.” Neuro Oncol Aug 21. [Epub ahead of print].

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BACKGROUND: The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies. METHODS: We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants. RESULTS: PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intra-cardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in two PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared non-synonymous mutations, and no correlation by gene expression. CONCLUSIONS: We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis.

Tew, B. Y., C. Legendre, M. A. Schroeder, T. Triche, G. C. Gooden, Y. Huang, L. Butry, D. J. Ma, K. Johnson, R. A. Martinez, M. Pierobon, E. F. Petricoin, J. O’Shaughnessy, C. Osborne, C. Tapia, D. N. Buckley, J. Glen, M. Bernstein, J. N. Sarkaria, S. A. Toms and B. Salhia (2019). “Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones.” Neuro Oncol Aug 21. [Epub ahead of print].

Full text of this article.

BACKGROUND: The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies. METHODS: We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants. RESULTS: PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intra-cardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in two PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared non-synonymous mutations, and no correlation by gene expression. CONCLUSIONS: We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis.

Smith, A. G., S. Pereira, A. Jaramillo, S. T. Stoll, F. M. Khan, N. Berka, A. A. Mostafa, M. J. Pando, C. Y. Usenko, M. P. Bettinotti, C. W. Pyo, W. C. Nelson, A. Willis, M. Askar and D. E. Geraghty (2019). “Comparison of sequence-specific oligonucleotide probe vs next generation sequencing for HLA-A, B, C, DRB1, DRB3/B4/B5, DQA1, DQB1, DPA1, and DPB1 typing: Toward single-pass high-resolution HLA typing in support of solid organ and hematopoietic cell transplant programs.” HLA 94(3): 296-306.

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Many clinical laboratories supporting solid organ transplant programs use multiple HLA genotyping technologies, depending on individual laboratory needs. Sequence-specific primers and quantitative polymerase chain reaction (qPCR) serve the rapid turnaround necessary for deceased donor workup, while sequence-specific oligonucleotide probe (SSOP) technology is widely employed for higher volumes. When clinical need mandates high-resolution data, Sanger sequencing-based typing (SBT) has been the “gold standard.” However, all those methods commonly yield ambiguous typing results that utilize valuable laboratory resources when resolution is required. In solid organ transplantation, high-resolution typing may provide critical information for highly sensitized patients with donor-specific anti-HLA antibodies (DSA), particularly when DSA involve HLA alleles not discriminated by SSOP typing. Arguments against routine use of SBT include assay complexity, long turnaround times (TAT), and increased costs. Here, we compare a next generation sequencing (NGS) technology with SSOP for accuracy, effort, turnaround time, and level of resolution for genotyping of 11 HLA loci among 289 specimens from five clinical laboratories. Results were concordant except for SSOP misassignments in eight specimens and 21 novel sequences uniquely identified by NGS. With few exceptions, SSOP generated ambiguous results while NGS provided unambiguous three-field allele assignments. For complete HLA genotyping of up to 24 samples by either SSOP or NGS, bench work was completed on day 1 and typing results were available on day 2. This study provides compelling evidence that, although not viable for STAT typing of deceased donors, a single-pass NGS HLA typing method has direct application for solid organ transplantation.

Shadman, M., D. G. Maloney, B. Storer, B. M. Sandmaier, T. R. Chauncey, N. Smedegaard Andersen, D. Niederwieser, J. Shizuru, B. Bruno, M. A. Pulsipher, R. T. Maziarz, E. D. Agura, P. Hari, A. A. Langston, M. B. Maris, P. A. McSweeney, R. Storb and M. L. Sorror (2019). “Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience.” Bone Marrow Transplant Sep 3. [Epub ahead of print].

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Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.