Primary Care Considerations for the Baseball Athlete.

PURPOSE OF REVIEW: To summarize current guidance and best practices surrounding non-orthopedic medical concerns in baseball. RECENT FINDINGS: Discussion of COVID19-related practice changes pertaining to the prevention and screening of communicable respiratory illness, concussion protocol updates, the enhanced role of a multi-disciplinary team of mental health professionals. Prevention, appropriate screening, and early identification remain cornerstones of effective primary care both within the general population as well as for the baseball athlete.

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

Personalized Treatment for a Patient With a BRAF V600E Mutation Using Dabrafenib and a Tumor Treatment Fields Device in a High-Grade Glioma Arising From Ganglioglioma.

BACKGROUND: Gangliogliomas are slow-growing, low-grade central nervous system tumors affecting children and young adults. However, some patients will experience tumor recurrence and/or malignant progression. This article reports on the clinical history, molecular findings, and treatment response in a patient with BRAF V600-mutated high-grade glioma arising from ganglioglioma. METHODS: Hematoxylin-eosin staining and comprehensive genomic profiling via Foundation One were performed on the tumor sample from a male patient undergoing treatment at the Department of Neuro-Oncology at Baylor University Medical Center. RESULTS: The patient was eligible for participation in a clinical trial (ClinicalTrials.gov identifier: NCT00916409) of a tumor treatment fields (TTFields) device, NovoTTF-100A, with concurrent radiation and chemotherapy (CCRT). His disease relapsed 4 months after completion of his CCRT, with MRI showing areas of enhancement. Temozolomide was discontinued and he was offered dabrafenib, an oral selective inhibitor of BRAF V600E, with continued use of NovoTTF. At the time of this report, after 2 years of treatment with dabrafenib and TTFields, the patient shows a durable complete response in all areas with no active lesions or new areas of enhancement. CONCLUSIONS: This report suggests that TTFields delivered in combination with targeted therapy dabrafenib yielded a remarkable clinical and radiologic response in this recurrent high-grade glioma. Targeted therapy matched to genomic alterations combined with TTFields treatment could provide clinical benefit and should be prospectively explored in the near future.

Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council.

UNLABELLED: Most patients who undergo surgical procedures experience acute postoperative pain, but evidence suggests that less than half report adequate postoperative pain relief. Many preoperative, intraoperative, and postoperative interventions and management strategies are available for reducing and managing postoperative pain. The American Pain Society, with input from the American Society of Anesthesiologists, commissioned an interdisciplinary expert panel to develop a clinical practice guideline to promote evidence-based, effective, and safer postoperative pain management in children and adults. The guideline was subsequently approved by the American Society for Regional Anesthesia. As part of the guideline development process, a systematic review was commissioned on various aspects related to various interventions and management strategies for postoperative pain. After a review of the evidence, the expert panel formulated recommendations that addressed various aspects of postoperative pain management, including preoperative education, perioperative pain management planning, use of different pharmacological and nonpharmacological modalities, organizational policies, and transition to outpatient care. The recommendations are based on the underlying premise that optimal management begins in the preoperative period with an assessment of the patient and development of a plan of care tailored to the individual and the surgical procedure involved. The panel found that evidence supports the use of multimodal regimens in many situations, although the exact components of effective multimodal care will vary depending on the patient, setting, and surgical procedure. Although these guidelines are based on a systematic review of the evidence on management of postoperative pain, the panel identified numerous research gaps. Of 32 recommendations, 4 were assessed as being supported by high-quality evidence, and 11 (in the areas of patient education and perioperative planning, patient assessment, organizational structures and policies, and transitioning to outpatient care) were made on the basis of low-quality evidence. PERSPECTIVE: This guideline, on the basis of a systematic review of the evidence on postoperative pain management, provides recommendations developed by a multidisciplinary expert panel. Safe and effective postoperative pain management should be on the basis of a plan of care tailored to the individual and the surgical procedure involved, and multimodal regimens are recommended in many situations.

STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

BACKGROUND: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. METHODS: Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). RESULTS: Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. CONCLUSIONS: For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

UNLABELLED: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting. SIGNIFICANCE: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.

Efficient, chemoenzymatic process for manufacture of the Boceprevir bicyclic [3.1.0]proline intermediate based on amine oxidase-catalyzed desymmetrization.

The key structural feature in Boceprevir, Merck's new drug treatment for hepatitis C, is the bicyclic [3.1.0]proline moiety "P2". During the discovery and development stages, the P2 fragment was produced by a classical resolution approach. As the drug candidate advanced through clinical trials and approached regulatory approval and commercialization, Codexis and Schering-Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis of P2 where the net reaction was an oxidative Strecker reaction. The key part of this reaction sequence is an enzymatic oxidative desymmetrization of the prochiral amine substrate.

A case of seronegative HIV-1 infection.

Patients infected with human immunodeficiency virus type 1 (HIV-1) typically seroconvert within weeks of primary infection. In rare cases, patients do not develop antibodies against HIV-1 despite demonstrable infection. We describe here a human leukocyte antigen (HLA)-B*5802-positive individual who presented with acquired immune deficiency syndrome despite repeatedly negative HIV-1 antibody screening test results. Phylogenetic analysis of env clones revealed little sequence diversity, and weak HIV-1-specific CD8(+) T cell responses were present to Gag epitopes. The patient seroconverted after immune reconstitution during receipt of highly active antiretroviral therapy. Lack of an antibody response to HIV-1 is rare and appears to be due to a defect in HIV-1-specific immunity rather than infection with attenuated virus.

Genetic diagnosis of primary immune deficiencies.

Gene testing in primary immune deficiencies (PIDs) once was limited to expert academic laboratories, but now is easily available to physicians with a broad range of clinical expertise. Such testing can establish or confirm a suspected diagnosis and also may predict future disease risk in advance of clinical signs and symptoms, inform reproductive decision making, and guide clinicians in selecting the most appropriate therapeutic options. This article, based on the authors' experience and a review of the published literature, discusses some of the advances and challenges currently encountered in the clinical molecular genetic diagnosis of PIDs.