Beyond monoclonal gammopathy of undetermined significance, clinical spectrum of immunoglobulin M gammopathy: a case series with focus on the diagnostic and management challenges.

Immunoglobulin M monoclonal gammopathy is detected in Waldenström macroglobulinemia (WM), a rare lymphoplasmacytic lymphoma with serum immunoglobulin M. We report three rare presentations with focus on diagnostic and management challenges of type I cryoglobulinemia, type II cryoglobulinemia, and Bing-Neel syndrome. In approximately 10% of WM cases, macroglobulins can precipitate to cryoglobulins. Type I and II cryoglobulinemia, representing 10-15% and 50-60% of WM cases, respectively, present with vasculitis and renal failure. Bing-Neel syndrome, representing 1% of WM patients, is a rare neurological complication with lymphoplasmacytic infiltration in the brain. WM diagnosis includes bone marrow biopsy, immunophenotypic analysis, and MYD88 L265P mutation. We initiated management of cryoglobulinemia with dexamethasone, rituximab, and cyclophosphamide; in Bing-Neel, bortezomib and dexamethasone, followed by a Bruton tyrosine kinase inhibitor.

Lymphoplasmacytic lymphoma (LPL) is an aberrant proliferation of plasma cells which may present as Waldenström macroglobulinemia, a disease characterized by high levels of immunoglobulin M that may result in deposition in bone marrow, spleen, and lymph nodes. The current understanding of clinical presentation is limited: patients with LPL may present with a wide range of symptoms related to paraproteinemia or tumor infiltration. This case series elucidates on specific and rare subsets of LPL, namely types I and II cryoglobulinemia and Bing­Neel syndrome. This report showcases the uncommon symptomatology of immunoglobulin M kappa deposition, such as kidney failure and neurological defects. The diagnostic and management challenges are of specific interest in this report, considering criteria, such as bone marrow biopsy, immunofixation, and cerebrospinal analysis. Literature on treatment protocols is equally limited and this report considers dexamethasone-rituximab-cyclophosphamide protocol and Bruton tyrosine kinase inhibitors compared to other common regimens. This report can be of great use to clinical oncologists by adding to the working knowledge on the rare manifestations of LPL and how to approach diagnostic and management challenges.

Special Considerations for Supportive Care and Management of Complications in Elderly Patients With Multiple Myeloma.

Multiple myeloma is a progressive and incurable hematologic malignancy. It is predominantly a disease of older individuals, with a third of these patients considered to be elderly. In recent years, there has been a focus and emphasis on identifying and stratifying patients based on their functional status and frailty. There are several hallmark complications of the disease-hypercalcemia, renal insufficiency, anemia, bone pain-along with thromboembolism and compromised immunity that are common in patients with multiple myeloma. Due to the wide range of patient ages and functional status, there are, accordingly, different considerations for management of the above complications based on numerous factors, including frailty status. This review focuses on considerations and management of common complications of multiple myeloma in elderly patients. These include renal failure, skeletal complications, anemia, thromboembolism, and infectious complications.

Severe Pediatric TBI Management in a Middle-Income Country and a High-Income Country: A Comparative Assessment of Two Centers.

Background: Traumatic brain injury (TBI) is a global public health issue with over 10 million deaths or hospitalizations each year. However, access to specialized care is dependent on institutional resources and public health policy. Phoenix Children's Hospital USA (PCH) and the Neiva University Hospital, Colombia (NUH) compared the management and outcomes of pediatric patients with severe TBI over 5 years to establish differences between outcomes of patients managed in countries of varying resources availability. Methods: We conducted a retrospective review of individuals between 0 and 17 years of age, with a diagnosis of severe TBI and admitted to PCH and NUH between 2010 and 2015. Data collected included Glasgow coma scores, intensive care unit monitoring, and Glasgow outcome scores. Pearson Chi-square, Fisher exact, T-test, or Wilcoxon-rank sum test was used to compare outcomes. Results: One hundred and one subjects met the inclusion criteria. NUH employed intracranial pressure monitoring less frequently than PCH (p = 0.000), but surgical decompression and subdural evacuation were higher at PCH (p = 0.031 and p = 0.003). Mortality rates were similar between the institutions (15% PCH, 17% NUH) as were functional outcomes (52% PCH, 54% NUH). Conclusions: Differences between centers included time to specialized care and utilization of monitoring. No significant differences were evidenced in survival and the overall functional outcomes.

Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review.

Multiple myeloma is the second most common hematologic malignancy and remains incurable. Patients who fail multiple lines of therapy typically have a poor prognosis despite recent advances in myeloma treatment. Chimeric antigen receptor T (CAR T) cell treatment has emerged as a promising therapy for many hematologic malignancies, including recently approved and emerging applications for myeloma treatment. A systematic review of the available clinical trial data for CAR T therapies in multiple myeloma was undertaken. All multiple myeloma trials registered at ClinicalTrials.gov were reviewed and studies mentioning CAR T and studying relapsed/refractory multiple myeloma (R/R MM) were included. PubMed, Google Scholar, and conference proceedings were also reviewed to determine which trials had reported data. Twenty-seven registered clinical trials in humans with published data were identified as of March 10, 2021. The majority of these trials were CAR T cells targeting B-cell maturation antigen (BCMA), and many were Phase I studies. Data demonstrated promising short-term (<12 months) efficacy with low incidence of grade 3 or higher toxicities. CAR T cell therapy in R/R MM remains a promising treatment modality. While one biologic has recently received FDA-approval, the majority of products remain investigational and in early-phase trials. More investigation is needed to determine which CAR T constructs and combination therapies optimize patient outcomes.

Molecular Imaging of Glucose Metabolism for Intraoperative Fluorescence Guidance During Glioma Surgery.

PURPOSE: This study evaluated the use of molecular imaging of fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as a discriminatory marker for intraoperative tumor border identification in a murine glioma model. PROCEDURES: 2-NBDG was assessed in GL261 and U251 orthotopic tumor-bearing mice. Intraoperative fluorescence of topical and intravenous 2-NBDG in normal and tumor regions was assessed with an operating microscope, handheld confocal laser scanning endomicroscope (CLE), and benchtop confocal laser scanning microscope (LSM). Additionally, 2-NBDG fluorescence in tumors was compared with 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. RESULTS: Intravenously administered 2-NBDG was detectable in brain tumor and absent in contralateral normal brain parenchyma on wide-field operating microscope imaging. Intraoperative and benchtop CLE showed preferential 2-NBDG accumulation in the cytoplasm of glioma cells (mean [SD] tumor-to-background ratio of 2.76 [0.43]). Topically administered 2-NBDG did not create sufficient tumor-background contrast for wide-field operating microscope imaging or under benchtop LSM (mean [SD] tumor-to-background ratio 1.42 [0.72]). However, topical 2-NBDG did create sufficient contrast to evaluate cellular tissue architecture and differentiate tumor cells from normal brain parenchyma. Protoporphyrin IX imaging resulted in a more specific delineation of gross tumor margins than intravenous or topical 2-NBDG and a significantly higher tumor-to-normal-brain fluorescence intensity ratio. CONCLUSION: After intravenous administration, 2-NBDG selectively accumulated in the experimental brain tumors and provided bright contrast under wide-field fluorescence imaging with a clinical-grade operating microscope. Topical 2-NBDG was able to create a sufficient contrast to differentiate tumor from normal brain cells on the basis of visualization of cellular architecture with CLE. 5-Aminolevulinic acid demonstrated superior specificity in outlining tumor margins and significantly higher tumor background contrast. Given the nontoxicity of 2-NBDG, its use as a topical molecular marker for noninvasive in vivo intraoperative microscopy is encouraging and warrants further clinical evaluation.

Microvascular anastomosis under 3D exoscope or endoscope magnification: A proof-of-concept study.

BACKGROUND: Extracranial-intracranial bypass is a challenging procedure that requires special microsurgical skills and an operative microscope. The exoscope is a tool for neurosurgical visualization that provides view on a heads-up display similar to an endoscope, but positioned external to the operating field, like a microscope. The authors carried out a proof-of-concept study evaluating the feasibility and effectiveness of performing microvascular bypass using various new exoscopic tools. METHODS: We evaluated microsurgical procedures using a three-dimensional (3D) endoscope, hands-free robotic automated positioning two-dimensional (2D) exoscope, and an ocular-free 3D exoscope, including surgical gauze knot tying, surgical glove cutting, placental vessel anastomoses, and rat vessel anastomoses. Image quality, effectiveness, and feasibility of each technique were compared among different visualization tools and to a standard operative microscope. RESULTS: 3D endoscopy produced relatively unsatisfactory resolution imaging. It was shown to be sufficient for knot tying and anastomosis of a placental artery, but was not suitable for anastomosis in rats. The 2D exoscope provided higher resolution imaging, but was not adequate for all maneuvers because of lack of depth perception. The 3D exoscope was shown to be functional to complete all maneuvers because of its depth perception and higher resolution. CONCLUSION: Depth perception and high resolution at highest magnification are required for microvascular bypass procedures. Execution of standard microanastomosis techniques was unsuccessful using 2D imaging modalities because of depth-perception-related constraints. Microvascular anastomosis is feasible under 3D exoscopic visualization; however, at highest magnification, the depth perception is inferior to that provided by a standard operative microscope, which impedes the procedure.

MinION rapid sequencing: Review of potential applications in neurosurgery.

BACKGROUND: Gene sequencing has played an integral role in the advancement and understanding of disease pathology and treatment. Although historically expensive and time consuming, new sequencing technologies improve our capability to obtain the genetic information in an accurate and timely manner. Within neurosurgery, gene sequencing is routinely used in the diagnosis and treatment of neurosurgical diseases, primarily for brain tumors. This paper reviews nanopore sequencing, an innovation utilized by MinION and outlines its potential use for neurosurgery. METHODS: A literature search was conducted for publications containing the keywords of Oxford MinION, nanopore sequencing, brain tumor, glioma, whole genome sequencing (WGS), epigenomics, molecular neuropathology, and next-generation sequencing (NGS). In total, 64 articles were selected and used for this review. RESULTS: The Oxford MinION nanopore sequencing technology has had successful applications within clinical microbiology, human genome sequencing, and cancer genotyping across multiple specialties. Technical details, methodology, and current use of MinION sequencing are discussed through the prism of potential applications to solve neurosurgery-related scientific and diagnostic questions. The MinION device has proven to provide rapid and accurate reads with longer read lengths when compared with NGS. For applications within neurosurgery, the MinION device is capable of providing critical diagnostic information for central nervous system (CNS) tumors within a single day. CONCLUSIONS: MinION provides rapid and accurate gene sequencing with better affordability and convenience compared with current NGS methods. Widespread success of the MinION nanopore sequencing technology in providing accurate, rapid, and convenient gene sequencing suggests a promising future within research laboratories and to improve care for neurosurgical patients.

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis.

Chimeric antigen receptor modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 chimeric antigen receptor-T therapy for B-cell hematologic malignancies. A total of 16 studies with 195 patients were identified. The pooled analysis showed an overall response rate of 61% (118/195) with complete response of 42% (81/195) and partial response of 19% (37/195). Major adverse events were cytokine release syndrome 33%, neurotoxicity 33% and B-cell aplasia 54%. Collectively, the results indicate encouraging response in relapsed/refractory B lymphoma and leukemia, especially in acute lymphoblastic leukemia (ALL) patients.

Regulators of Lysosome Function and Dynamics in Caenorhabditis elegans.

Lysosomes, the major membrane-bound degradative organelles, have a multitude of functions in eukaryotic cells. Lysosomes are the terminal compartments in the endocytic pathway, though they display highly dynamic behaviors, fusing with each other and with late endosomes in the endocytic pathway, and with the plasma membrane during regulated exocytosis and for wound repair. After fusing with late endosomes, lysosomes are reformed from the resulting hybrid organelles through a process that involves budding of a nascent lysosome, extension of the nascent lysosome from the hybrid organelle, while remaining connected by a membrane bridge, and scission of the membrane bridge to release the newly formed lysosome. The newly formed lysosomes undergo cycles of homotypic fusion and fission reactions to form mature lysosomes. In this study, we used a forward genetic screen in Caenorhabditis elegans to identify six regulators of lysosome biology. We show that these proteins function in different steps of lysosome biology, regulating lysosome formation, lysosome fusion, and lysosome degradation.

Plerixafor as a salvage mobilization strategy for haploidentical peripheral blood allogeneic stem cell transplantation.

In allogeneic stem cell mobilization, peripheral blood stem cell mobilization with filgrastim can be considered standard of care. Poor mobilizers may be at risk for inadequate stem cell collection during apheresis. He we present a successful case of salvage plerixafor use with filgrastim in a haploidentical identical transplant patient.