The State of Peptide Receptor Radionuclide Therapy and Its Sequencing among Current Therapeutic Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Virtual teaching of preventive cardiology: A student experience.

Preventive cardiology is a subspecialty of Internal Medicine focused on reducing atherosclerotic cardiovascular disease (ASCVD) risk through medical management of known risk factors and identification of genetic predispositions. Oregon Health & Science University (OHSU) provides a preventive cardiology course designed to engage students in targeted, multidisciplinary care to address the increasing ASCVD prevalence. Following the onset of the COVID-19 pandemic, OHSU transitioned this course to a virtual platform to allow students to continue their medical education. Course adaptations include utilization of video-conferencing platforms and cloud-based storage websites, allowing students access to didactic materials, instructional sessions, and engage with patients in a telehealth setting. As the first cohort of students to complete this course, we share our experience with the virtual platform, including the virtual course structure, student role, and benefits and limitations of this model. Through our experience, we have found that adaptation to a virtual platform provides a feasible and effective means through which to continue preventive cardiology education during the COVID-19 pandemic.

Gas-containing iliopsoas bursitis in the setting of degenerative osteoarthritis.

This is a case of a 77-year-old woman with a 4.0 cm gas-containing iliopsoas bursa collection in the setting of mild-to-moderate degenerative joint disease. Given the limited extent of this patient's osteoarthritis and the absence of infectious signs or symptoms, both of which are typically related to gas collections at the hip, it was difficult to determine the aetiology of the patient's gas collection, whether it was related to her pain, and how best to manage her symptoms. Even in the setting of her MRI findings, which showed the gas collection lifting the iliopsoas tendon off the bone, the gas-containing bursa ultimately appeared to be a minor component of the patient's pain and definitive treatment of her underlying joint disease with a total hip arthroplasty allowed for successful pain management. Our case report demonstrates an unusual presentation of iliopsoas bursitis with a surprising response to medical, interventional and surgical management.

Oncology Patients Are High Cost Outliers in Total Joint Replacement Bundled Payment Systems.

BACKGROUND: In 2016, the Centers for Medicare and Medicaid Services began its first mandatory bundled payment program, the Comprehensive Care for Joint Replacement (CJR) model, which covers a 90-day episode of care. This study determined whether oncology patients enrolled in the CJR bundle incur higher hospital costs than patients with osteoarthritis (OA). METHODS: A retrospective review of all patients enrolled in the CJR bundled payments system from April 1, 2016 to June 31, 2018 at a single academic medical center was conducted. To determine whether tumor patients had higher total episode costs, this group was compared to patients diagnosed with OA using a 2-tailed t-test. To adjust for moderators of total hospital costs, we used generalized linear regression with a log-link, including multiple variables abstracted from chart review. RESULTS: Three hundred fourteen patients met inclusion criteria (12 primary or metastatic tumors, 302 OA). Fifty-eight percent of tumor patients were over the target price vs 16% of OA patients. The mean tumor patient had $40,862 for total internal hospital costs compared to $16,356 in the OA group (P < .001). Length of stay was greater in the tumor group (6.75 vs 2.0 days, P < .001). A greater percentage of tumor patients were discharged to a skilled nursing facility (67% vs 27%, P = .006) with significantly higher skilled nursing facility episode costs ($18,852 vs $7731, P = .04). With adjustment for fracture status, tumor patients were 5.36 times more likely to exceed the CJR target price than OA patients (risk ratio 5.36, confidence interval 3.44-8.35, P < .001) and 50 times more likely to be outliers over the regional threshold than OA patients (risk ratio 50.33, confidence interval 16.33-155.19, P < .001). CONCLUSION: Oncology patients enrolled in the CJR bundled payment model incur significantly higher costs and have higher cost variability than patients with OA. We recommend that oncology patients be excluded from the CJR bundle.

The synthetic triterpenoid TP-222 inhibits RANKL stimulation of osteoclastogenesis and matrix metalloproteinase-9 expression.

OBJECTIVE: Receptor activator of nuclear factor-kappaB ligand (RANKL) promotes osteoclast differentiation from monocyte precursors by inducing a cohort of genes, including tartrate-resistant acid phosphatase (TRAP) and matrix metalloproteinase-9 (MMP-9). A family of synthetic triterpenoids with antiinflammatory and pro-apoptotic properties was described to modulate differentiation in monocytic cell lineages. We therefore investigated the ability of the potent and bioavailable synthetic triterpenoid TP-222 to inhibit RANKL-induced osteoclast formation and MMP-9 expression from monocytic precursor cells. METHODS: Osteoclast formation was assayed by staining for TRAP-positive multinucleated cells. MMP-9 expression was measured by quantitative RT-PCR, Western blot, immunohistochemistry, and gel zymography. In vivo effects of TP-222 were assessed by daily intraperitoneal injection of 4-week-old mice for 7 days followed by measurement of osteoclast number and MMP-9 expression at the cartilage/bone junction of the epiphyseal growth plate. RESULTS: RANKL promoted and TP-222 (300 nM) inhibited osteoclast formation in cultures of RAW264.7 cells or bone marrow-derived monocytes. RANKL also induced MMP-9 expression in RAW264.7 cells and this was reduced by concurrent or subsequent addition of TP-222. TP-222 treatment significantly reduced the mean number of osteoclasts present at the cartilage/bone interface compared to vehicle-injected control mice. Morphometric analyses of tissue sections showed that TP-222 treatment reduced the amount of immunoreactive MMP-9 present in both mononucleated pre-osteoclasts and osteoclasts. CONCLUSION: Our data demonstrate that TP-222 inhibits osteoclast formation and MMP-9 expression in vitro and in vivo, and suggest that triterpenoids may be useful compounds for modulating bone resorption diseases.

Interleukin-1 beta induction of matrix metalloproteinase-1 transcription in chondrocytes requires ERK-dependent activation of CCAAT enhancer-binding protein-beta.

Interleukin-1 beta (IL-1beta) is a central mediator of inflammation and connective tissue destruction in rheumatoid arthritis. IL-1beta activates articular chondrocytes to produce matrix metalloproteinase-1 (MMP-1), an enzyme capable of dismantling the collagen scaffold of articular cartilage. To define the transcription factors and signaling intermediates that activate MMP-1 transcription in chondrocytes, we performed transient transfection of MMP-1 promoter constructs followed by reporter assays. These studies identified an IL-1beta-responsive region of the human MMP-1 promoter that contains a consensus CCAAT enhancer-binding protein (C/EBP) binding site. Deletion of this site reduced overall transcriptional activity of the MMP-1 promoter, as well as decreased fold induction by IL-1beta. IL-1beta stimulation of chondrocytes increased binding of C/EBP-beta to the MMP-1 C/EBP site. Extracellular signal regulated kinase (ERK) pathway-dependent phosphorylation of C/EBP-beta on threonine 235 activates this transcription factor. Here we show that IL-1beta stimulation of chondrocytes induced phosphorylation of C/EBP-beta on threonine 235, and that the ERK pathway inhibitor PD98059 reduced this phosphorylation. We further show that PD98059 reduces IL-1beta-induced MMP-1 mRNA expression in chondrocytes. Moreover, inhibition of the ERK pathway by expression of dominant-negative forms of ERK1 and ERK2 impaired the ability of IL-1beta to transactivate the MMP-1 promoter. Our findings demonstrate a novel role for C/EBP-beta in IL-1beta-induced connective tissue disease and define a new nuclear target for the ERK pathway in MMP-1 gene activation.