Roadmap for new practitioners to navigate the multiple myeloma landscape.

Multiple myeloma (MM) is a blood cancer in which monoclonal plasma cells cause end organ damage resulting in hypercalcemia, renal failure, anemia, and bone lesions. MM is considered incurable, however, recent advances in treatment have improved survival. Historically, MM has been treated with immunomodulatory drugs (IMiDs), proteosome inhibitors (PIs), and corticosteroids. While newer therapeutic approaches such as monoclonal antibodies and cellular therapies have broadened the treatment horizon, the selection and sequencing of these therapies has become more complex. This review aims to help advanced practice providers navigate through the diagnosis, staging, treatment, and supportive care considerations in the MM space.

Advanced Practitioners: Collaborators in Radiation Oncology.

Advanced practitioners (APs), including physician assistants (PAs) and nurse practitioners (NPs), are medical professionals with advanced training, degrees, and certifications that qualify them to diagnose and treat medical conditions in a wide variety of health-care settings. As such, APs have been collaborators in radiation oncology practice for decades to complement the role of radiation oncologists. In 1999, Kelvin and Moore-Higgs first reported data on how APs participated in radiation oncology practice. Over the 20 years since that publication, more articles have described how APs have been collaborators to varying degrees in nearly all aspects of radiation oncology practice. However, significant legislative, regulatory, and educational barriers may limit the optimal practice of APs in radiation oncology. In order to mitigate projected shortages of radiation oncology services while maintaining high levels of patient satisfaction, enhanced collaboration with APs in radiation oncology practice is needed.

Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.

OBJECTIVE: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). METHODS: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. RESULTS: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state-a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. CONCLUSIONS: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.

Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32.

OBJECTIVE: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. METHODS: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. RESULTS: Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (theta = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765-106,368,585. No segregating copy number variations were found within the disease interval. CONCLUSIONS: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant.

Agency for Toxic Substances and Disease Registry's 1997 priority list of hazardous substances. Latent effects--carcinogenesis, neurotoxicology, and developmental deficits in humans and animals.

In support of Superfund re-authorization legislation, the Division of Toxicology of the Agency for Toxic Substances and Disease Registry (ATSDR) prepared a chemical-specific consultation document for Congress that identified those chemicals with carcinogenic, neurological, or developmental adverse effects having a latency period longer than 6 years. The review was limited to the top 50 substances listed on ATSDR's 1997 Priority List of Hazardous Substances (Priority List). Among the top 50 chemicals, a review of the technical literature indicated that 38 (76%) were classified as "reasonably anticipated," "possibly," or "probably" capable of causing cancer in humans, based either on human and animal data. Eight chemicals (16%) had well-established cancer latency periods in humans of 6 years or more following exposure. Three substances (6%)--arsenic, creosote, and benzidine--had data indicating latency periods longer than 6 years. The technical literature review likewise confirmed the potential for neurological and developmental effects with a latency of 6 years. Twenty-seven (54%) of the top 50 substances caused acute and/or chronic neurotoxic effects; a number of these also caused neurological effects that persisted beyond 6 years (or the equivalent in animal studies) such as: behavioral problems, neurological deficiencies, reduced psychomotor development, cognitive deficiencies, and reduced IQ. Twenty-eight substances (56%) caused adverse developmental effects in offspring of exposed individuals or animals including increased fetal and infant mortality, decreased birth weights and litter sizes, and growth delays. Latency periods for related chemicals are expected to be similar due to structural and toxicological similarities.