Tolerability of palbociclib in younger and older patients with advanced breast cancer.

INTRODUCTION: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown. METHODS: The primary objective was to evaluate the association of age (<60 vs. ≥60 years) with palbociclib dose reductions or discontinuations secondary to neutropenia. This single-center, retrospective chart review included hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer patients ≥18 years treated with palbociclib between April 2015 and May 2020. Patients <60 years at the time of palbociclib initiation were in the younger group and patients ≥60 years were in the older group. RESULTS: Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose <125 mg (0% vs. 11.9%, p = 0.02). Differences in palbociclib dose reductions or treatment discontinuations secondary to neutropenia were not detected (35.4% vs. 42.4%, p = 0.55). Neither the total number of palbociclib dose reductions (none: 54.2% vs. 49.1%, one: 33.3% vs. 42.4%, two: 12.5% vs. 8.5%, p = 0.61), nor the final dose of palbociclib (125 mg: 54.2% vs. 40.7%, 100 mg: 29.2% vs. 27.1%, 75 mg: 16.7% vs. 32.2%, p = 0.17) differed between younger and older patients. CONCLUSIONS: Age (<60 vs. ≥60 years) was not associated with the rate of palbociclib dose reductions or discontinuations secondary to neutropenia. Older (≥60 years) patients were more likely to start palbociclib at lower doses which may impact neutropenia and non-neutropenic intolerance.

Loss of MLKL (Mixed Lineage Kinase Domain-Like Protein) Decreases Necrotic Core but Increases Macrophage Lipid Accumulation in Atherosclerosis.

OBJECTIVES: During the advancement of atherosclerosis, plaque cellularity is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and nonapoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of plaque macrophages contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 (receptor-interacting protein kinase 1) and RIPK3 (receptor-interacting protein kinase 3) slow atherogenesis, and activation of the terminal step of necroptosis, MLKL (mixed lineage kinase domain-like protein), has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated. Approaches and Results: MLKL expression was knocked down in atherogenic Apoe-knockout mice via the administration of antisense oligonucleotides. During atherogenesis, Mlkl knockdown decreased both programmed cell death and the necrotic core in the plaque. However, total lesion area remained unchanged. Furthermore, treatment with the MLKL antisense oligonucleotide unexpectedly reduced circulating cholesterol levels compared with control antisense oligonucleotide but increased the accumulation of lipids within the plaque and in vitro in macrophage foam cells. MLKL colocalized with the late endosome and multivesicular bodies in peritoneal macrophages incubated with atherogenic lipoproteins. Transfection with MLKL antisense oligonucleotide increased lipid localization with the multivesicular bodies, suggesting that upon Mlkl knockdown, lipid trafficking becomes defective leading to enhanced lipid accumulation in macrophages. CONCLUSIONS: These studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in regulating endosomal trafficking to facilitate lipid handling in macrophages during atherogenesis.

Management of acute or late hematogenous infection after shoulder arthroplasty with irrigation, débridement, and component retention.

BACKGROUND: Irrigation and débridement (I&D) with component retention is an appealing alternative to both patients and surgeons for the management of acute or late hematogenous deep periprosthetic shoulder infection (PSI). However, the success rate and results of I&D are poorly documented. This study reports the outcomes and complications of this treatment strategy for acute and delayed-onset acute hematogenous PSI. METHODS: Between 1980 and 2010, 10 shoulders (9 patients) underwent I&D with component retention for the management on an acute or delayed-onset acute hematogenous PSI at a single institution. Outcome data, including pain, range of motion, need for chronic oral antibiotic suppression therapy, eradication of infection, and need for further surgery were retrospectively collected. RESULTS: Deep infection recurred in 3 shoulders, which were eventually treated with resection arthroplasty. Of the remaining 6 patients (7 shoulders), 5 were prescribed chronic antibiotic suppression. At the most recent follow-up, pain was graded as none in 3 shoulders, mild in 1, moderate with activity in 3, moderate in 2, and severe in 1. Among shoulders with retained components, forward elevation was greater than 110° in 6 (median, 140°; range, 30°-160°), and external rotation was greater than 40° in all shoulders (median, 50°; range, 40°-90°). CONCLUSION: I&D allowed component retention in 70% of shoulders presenting with an acute or delayed-onset acute hematogenous infection. Most patients were prescribed chronic antibiotic suppression, and reasonable motion was maintained.

Two-stage reimplantation for the treatment of deep infection after shoulder arthroplasty.

BACKGROUND: Two-stage reimplantation is the most common treatment modality considered for periprosthetic shoulder infection (PSI). Most studies to date have reported on a relatively small number of shoulders. The purpose of this study was to determine the outcome of 2-stage reimplantation for PSI in terms of both eradication of infection and restoration of function. METHODS: Between 1980 and 2010, 40 shoulders (39 patients) underwent a 2-stage reimplantation for PSI; 35 shoulders (34 patients) met inclusion criteria (10 hemiarthroplasties, 24 anatomic total shoulder arthroplasties, 1 reverse total shoulder arthroplasty). Outcome data included pain, motion, Neer rating, and complications. RESULTS: At most recent follow-up (4.1 years), 2-stage reimplantation had resulted in significant improvements in pain (from 4.4 to 2 on a 5-point scale; P < .0001), mean forward elevation (64°-118°; P < .0001), and mean external rotation (14°-41°; P < .0001). Preoperative testing showed leukocytosis in 1 patient, elevated C-reactive protein concentration in 67%, elevated erythrocyte sedimentation rate in 61%, and positive preoperative aspiration in 69%. Persistent infection, defined as positive cultures in samples obtained at the time of reimplantation, was identified in 5 shoulders (15%); 50% of persistent infections grew Propionibacterium acnes. Reoperations for infection included irrigation and débridement (1), a second 2-stage reimplantation (2), and resection arthroplasty (1); 2 additional patients were treated with chronic suppression. Reoperation for aseptic glenoid loosening was performed in 2 additional shoulders. Results were graded excellent in 10 (28%), satisfactory in 12 (33%), and unsatisfactory in 13 (39%) shoulders. CONCLUSION: Two-stage reimplantation eradicated PSI in 85% of the shoulders. Pain relief and good arcs of motion were achieved in many patients, but there was an overall rate of unsatisfactory results approaching 40%. Preoperative testing was not always reliable for the diagnosis of PSI.

Hyperlipidemia-induced hematopoiesis is repressed by MLKL in endothelial cells of the splenic niche.

Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis.

A Pharmacist-Led Oral Chemotherapy Program's Impact on Chronic Myeloid Leukemia Patient Satisfaction, Adherence, and Outcomes.

Patients with chronic myeloid leukemia (CML) can be treated with oral tyrosine kinase inhibitors (TKIs). Pharmacist-led oral chemotherapy programs (POCPs) can improve TKI adherence rates, but evaluation of patient satisfaction with such programs is rare. The purpose of this analysis was to compare the satisfaction of patients with CML taking TKIs enrolled in a POCP program with that of those not enrolled. Secondary objectives were to assess adherence rates, patient-reported value, early molecular response (EMR) rates, and major molecular response (MMR) rates. This study utilized an anonymous telephone survey of patients who had taken TKIs for at least 3 months. Molecular response was determined by chart review. Of 40 patients surveyed, 50% were enrolled in the POCP, and the POCP group had more African Americans than the non-POCP group. More patients in the POCP were satisfied with their care than in the non-POCP group (100% vs. 75%, p = .047). There were no differences in high patient-reported adherence (55% vs. 60%, p = 1.000), patient-reported value for integrated services (95% vs. 90%, p = 1.000), achievement of EMR (75% vs. 75%, p = 1.000), or MMR (85% vs. 85%, p = 1.000). Patients in the POCP received more structured clinical pharmacy services; however, both groups felt the clinical pharmacist played a major role in their care (85% vs. 90%, p = 1.000). Patients in the non-POCP group reported lower satisfaction than those enrolled resulting from fragmented care that was likely due to external specialty pharmacies. Irrespective of POCP enrollment, patients reported clinical pharmacists play a major role in their therapy and value integration of their specialty pharmacy and medical team.

Impact of Oncology Pharmacists on the Knowledge, Attitude, and Practices of Clinicians to Enhance Patient Engagement of Self-Administered Oral Oncolytics.

Oncology clinical pharmacists are uniquely positioned to make interventions to impact the knowledge, attitudes, and practices of clinicians as well as patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making. As crucial members of the healthcare team, oncology pharmacists can simplify highly complex treatment regimens to facilitate and optimize patients' ownership of their care. This narrative review will focus on the example of venetoclax treatment in acute myeloid leukemia to demonstrate the impact that pharmacists provide that leads to behavioral change of patients and clinicians.

The hospital cost of two-stage reimplantation for deep infection after shoulder arthroplasty.

BACKGROUND: The cost of treating infection after hip and knee arthroplasty is well documented in the literature. The purpose of this study was to determine the cost of two-stage reimplantation for deep infection after shoulder arthroplasty. METHODS: Between 2003 and 2012, 57 shoulders (56 patients) underwent a two-stage reimplantation for deep periprosthetic shoulder infection; implants placed at reimplantation included anatomic total shoulder arthroplasty (a-TSA) in 58%, reverse total shoulder arthroplasty (r-TSA) in 40%, and hemiarthroplasty (HA) in 2%. During the same timeframe, 2953 primary shoulder arthroplasties (2589 patients) were performed at the same institution (a-TSA in 55%, r-TSA in 28%, and HA in 17%). Total direct medical costs were calculated by using standardized, inflation-adjusted costs for services and procedures billed during hospitalization and were adjusted to nationally representative unit costs in 2013 inflation-adjusted dollars. RESULTS: The mean hospital cost (per shoulder) for two-stage reimplantation was $35,824 (95% CI: 33,363 to 38,285) and was significantly higher than for primary procedures (mean: $16,068; 95% CI: 15,823 to 16,314). Both Part A and Part B costs were significantly higher in two-stage reimplantation (p < 0.001). For part A (hospital services), the mean cost for two-stage reimplantation was $29,851 (95% CI: 27,741 to 31,960), compared to $13,508 (95% CI: 13,302 to 13,715) for primaries. For part B (professional costs), mean costs were $5973 (95% CI: 5493 to 6453) versus 2560 (95% CI: 2512 to 2608) respectively. CONCLUSIONS: The hospital cost of two-stage reimplantation for the treatment of an infected shoulder arthroplasty is about two times higher than the cost of a primary shoulder arthroplasty.