SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion.

Genes that regulate osteoclast (OC) development and function in both physiologic and disease conditions remain incompletely understood. Shp2 (the Src homology-2 domain containing protein tyrosine phosphatase 2), a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, is implicated in regulating M-CSF and receptor activator of nuclear factor-κB ligand (RANKL)-evoked signaling; its role in osteoclastogenesis and bone homeostasis, however, remains unknown. Using a tissue-specific gene knockout approach, we inactivated Shp2 expression in murine OCs. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of bone volume (BV)/total volume (TV) (+42.8%), trabeculae number (Tb.N) (+84.1%), structure model index (+119%), and a decrease of trabecular thickness (Tb.Th) (-34.1%) and trabecular spacing (Tb.Sp) (-41.0%). Biochemical analyses demonstrate that Shp2 is required for RANKL-induced formation of giant multinucleated OCs by up-regulating the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), a master transcription factor that is indispensable for terminal OC differentiation. Shp2 deletion, however, has minimal effect on M-CSF-dependent survival and proliferation of OC precursors. Instead, its deficiency aborts the fusion of OC precursors and formation of multinucleated OCs and decreases bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclast fusion in vitro. These findings uncover a novel mechanism through which Shp2 regulates osteoclastogenesis by promoting preosteoclast fusion. Shp2 or its signaling partners could potentially serve as pharmacological targets to regulate the population of OCs locally and/or systematically, and thus treat OC-related diseases, such as periprosthetic osteolysis and osteoporosis.

Patient preferences regarding intraoperative versus external beam radiotherapy following breast-conserving surgery.

The TARGIT-A Trial is an international randomized, prospective trial comparing intraoperative radiotherapy (IORT) for equivalence to external beam radiotherapy (EBRT) following lumpectomy for invasive breast cancer in selected low-risk patients; early results suggest that outcomes are similar. In addition to effectiveness data and cost considerations, the preferences of patients should help inform practice. This study was undertaken to explore and quantify preference in choosing between IORT and the current standard, EBRT. Eligible subjects were current or past candidates for breast-conserving surgery and radiation being seen at the University of California, San Francisco Breast Care Center. A trade-off technique varying the risk of local recurrence for IORT was used to quantify any additional accepted risk that these patients would accept to receive either treatment. Patients were first presented with a slideshow comparing EBRT with the experimental IORT option before being asked their preferences given hypothetical 10-year local recurrence risks. Patients were then given a questionnaire on demographic, social and clinical factors. Data from 81 patients were analyzed. The median additional accepted risk to have IORT was 2.3 % (-9 to 39 %), mean 3.2 %. Only 7 patients chose to accept additional risk for EBRT; 22 accepted IORT at no additional risk; and the remaining 52 chose IORT with some additional risk. Patients weigh trade-offs of risks and benefits when presented with medical treatment choices. Our results show that the majority of breast cancer patients will accept a small increment of local risk for a simpler delivery of radiation. Further studies that incorporate outcome and side effect data from the TARGIT-A trial clarify the expected consequences of a local recurrence, and include an expanded range of radiation options that could help guide clinical decision making in this area.

Cost-effectiveness analysis of intraoperative radiation therapy for early-stage breast cancer.

BACKGROUND: Shortened courses of radiation therapy have been shown to be similarly effective to whole-breast external-beam radiation therapy (WB-EBRT) in terms of local control. We sought to analyze, from a societal perspective, the cost-effectiveness of two radiation strategies for early-stage invasive breast cancer: single-dose intraoperative radiation therapy (IORT) and the standard 6-week course of WB-EBRT. METHODS: We developed a Markov decision-analytic model to evaluate these treatment strategies in terms of life expectancy, quality-adjusted life years (QALYs), costs, and the incremental cost-effectiveness ratio over 10 years. RESULTS: IORT single-dose intraoperative radiation therapy was the dominant, more cost-effective strategy, providing greater quality-adjusted life years at a decreased cost compared with 6-week WB-EBRT. The model was sensitive to health state utilities and recurrence rates, but not costs. IORT was either the preferred or dominant strategy across all sensitivity analyses. The two-way sensitivity analyses demonstrate the need to accurately determine utility values for the two forms of radiation treatment and to avoid indiscriminate use of IORT. CONCLUSIONS: With less cost and greater QALYs than WB-EBRT, IORT is the more valuable strategy. IORT offers a unique example of new technology that is less costly than the current standard of care option but offers similar efficacy. Even when considering the capital investment for the equipment ($425 K, low when compared with the investments required for robotic surgery or high-dose-rate brachytherapy), which could be recouped after 3-4 years conservatively, these results support IORT as a change in practice for treating early-stage invasive breast cancer.

Managing Opioid Use Disorder During and After Acute Hospitalization: A Case-Based Review Clarifying Methadone Regulation for Acute Care Settings.

OBJECTIVE: Treatment with an opioid agonist such as methadone or buprenorphine is the standard of care for opioid use disorder. Persons with opioid use disorder are frequently hospitalized, and may be undertreated due to provider misinformation regarding the legality of prescribing methadone for inpatients. Using a case-based review, this article aims to describe effective management of active opioid withdrawal and ongoing opioid use disorder using methadone or buprenorphine among acutely ill, hospitalized patients. METHODS: We reviewed pertinent medical and legal literature and consulted with national legal experts regarding methadone for opioid withdrawal and opioid maintenance therapy in hospitalized, general medical and surgical patients, and describe a real-life example of successful implementation of inpatient methadone for these purposes. RESULTS: Patients with opioid use disorders can be effectively and legally initiated on methadone maintenance therapy or buprenorphine during an inpatient hospitalization by clinical providers and successfully transitioned to an outpatient methadone maintenance or buprenorphine clinic after discharge for ongoing treatment. CONCLUSIONS: Inpatient methadone or buprenorphine prescribing is safe and evidence-based, and can be used to effectively treat opioid withdrawal and also serves as a bridge to outpatient treatment of opioid use disorders.