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Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity. [ABSTRACT FROM AUTHOR]

Background: Objective, treatment-independent markers of cancer-related fatigue are needed to advance clinical trials. In the current study, the authors evaluated physical, neurocognitive, and serologic markers for correlation with self-reported fatigue before and after (neo)adjuvant chemotherapy for patients with early-stage breast cancer.Methods: Women with AJCC TNM Stage I-III breast cancer consented to assessment before and after the completion of 4 cycles of dose-dense doxorubicin and cyclophosphamide. Assessment included self-reported fatigue (using the Brief Fatigue Inventory), depression (using the Center for Epidemiologic Studies-Depression Scale [CES-D]), Pittsburgh Sleep Quality Index, and 28 objective measures (grip strength in dominant and nondominant hands, 6-minute walk, daily total energy expenditure, 14 neurocognitive tests, and 10 serologic markers). Generalized linear regression models of fatigue were constructed (1 model per marker), and adjusted for depression, timing before/after chemotherapy, menopausal status, obesity, and educational level. P values were adjusted to control the False Discovery Rate.Results: Of 28 subjects, 3 withdrew without completing baseline assessments. Prechemotherapy and postchemotherapy data were available for the evaluation of physical measures (25 subjects aged 50.6 ± 9.5 years), neurocognitive tests (22 subjects), and serologic markers (10 subjects). On covariate-adjusted analysis, interleukin (IL)-12 was found to be associated with fatigue at both assessments (P<.01). Serum eotaxin (P < .01), IL-1RA (P < .01), monocyte chemoattractant protein 1 (MCP-1) (P<.01), and performance on 2 neurocognitive (Trail Making) tests (P<.01 and P = .02, respectively) were found to be inversely associated with fatigue before chemotherapy but not afterward, whereas daily energy expenditure, serum MCP-1, and serum macrophage inflammatory protein 1a (MIP-1a) were found to be associated with fatigue after receipt of chemotherapy but not before (P<.01 for each). The association between energy expenditure and fatigue was detectable only if an actively athletic subject with outlier values of energy expenditure was excluded.Conclusions: Serum IL-12 merits confirmatory testing as an objective, treatment-independent measure of fatigue in patients with early-stage breast cancer. Cancer 2017;123:1810-1816. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. [ABSTRACT FROM AUTHOR]

The article focuses on the significant hurdles faced by persons with physical, cognitive, or sensory disabilities in entering, continuing, and completing training in health professional fields.

Purpose: The purpose of this study is to validate the Bodybugg (BB), a caloric expenditure measuring device, in breast cancer patients undergoing adjuvant and neoadjuvant chemotherapy for early-stage breast cancer. Methods: Twenty-five women with stages I-III breast cancer who were to receive adjuvant dose-dense doxorubicin/cyclophosphamide were recruited. Participants were asked to wear the BB and record activity logs for seven pretreatment days (prior to commencing chemotherapy) and seven posttreatment days (upon completing cycle 4 of chemotherapy). The BB's caloric expenditure measurements were used to calculate metabolic equivalent (MET) values of patients' recorded activities. BB-calculated METs were compared with matching METs from the 2011 Compendium of Physical Activities Tracking Guide to assess accuracy of the device. Results: The overall patient sample wore the device for an average of 5.32 (SD 1.75) pre- and 4.88 (SD 2.01) posttreatment days. The mean pairwise difference between BB and Compendium METs was 0.043 (SD 0.77) for 308 pretreatment activities recorded by 12 patients and 0.065 (SD 0.61) for 108 posttreatment activities recorded by 6 patients, indicating close to zero bias between the BB's and Compendium's measurements. Hierarchical linear modeling showed that Compendium METs strongly predict for BB METs ( P < 0.00001). Conclusions: The BB is feasible to use in study designs involving defined time periods of measurement and provides accurate and objective measurements of caloric expenditure in breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Herceptin (trastuzumab) is a humanized monoclonal antibody that is approved for the treatment of metastatic breast cancer patients whose tumors overexpress Her2 (erbB2/neu). Up to 70% of Her2-positive breast cancers demonstrate a response to Herceptin-based therapies, but resistance almost inevitably arises within a year of the initial response. To help understand the mechanism of Herceptin resistance, we isolated clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to Herceptin. These cell lines exhibit sustained PI3K/Akt signaling as an essential component of Herceptin-resistant proliferation. Several genes in the protein kinase A (PKA) signaling network have altered expression in BT/HerR cells, including PPP1R1B, which encodes a 32 kDa protein known as Darpp-32 and its amino-terminal truncated variant, t-Darpp. The purpose of the current work was to determine the role of Darpp-32 and t-Darpp in Herceptin resistance. Methodology and Results: We determined expression of Darpp-32 and t-Darpp in BT/HerR cells selected for resistance to Herceptin. Subsequently, cDNAs encoding the two isoforms of Darpp-32 were transfected, separately and together, into Her2-positive SK-Br-3 breast cancer cells. Transfected cells were tested for resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. DNA binding activity by the cAMP response element binding protein (CREB) was also measured. We found that BT/HerR cells overexpressed t-Darpp but not Darpp-32. Moreover, t-Darpp overexpression in SK-Br-3 cells was sufficient for conferring resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. Darpp-32 co-expression reversed t-Darpp's effects on Herceptin resistance and Akt phosphorylation. t-Darpp overexpression led to increased CREB binding activity, which was also reversible by Darpp-32. Conclusions: t-Darpp and Darpp-32 appear to have antagonistic effects on Herceptin resistance. We present a unified model by which these effects might be mediated via the PKA regulatory network. [ABSTRACT FROM AUTHOR]

Background: We previously reported that (neo)adjuvant chemotherapy adversely altered metabolic syndrome (MetS) components, body composition, and related biomarkers after a 12 to 18-week chemotherapy treatment course in women. Here, we sought to determine whether these measures worsened within 4–5 years post-chemotherapy among the same sample of early stage breast cancer survivors. Methods: Twenty-eight breast cancer survivors were reassessed within 4–5 years post-chemotherapy. Participants were tested for MetS, lipid profile (total cholesterol; TC, low-density lipoprotein cholesterol; LDL-C), glucose metabolism (insulin, homeostatic model- insulin resistance; HOMA-IR, glycosylated hemoglobin; HbA1c), inflammation (C-reactive protein; CRP) and body composition (body weight; BW, percent body fat; BF, fat mass; FM) during follow-up physical exams. A comparison of measurements between post-chemotherapy and follow-up periods was performed using repeated measures analysis of covariance. Results: Most study patients were Caucasian (44%) or Hispanic (30%) with a mean age of 48.2 years. Average time from completion of chemotherapy was 4.75 years. At follow-up, MetS components significantly increased (p < 0.01) compared with the post chemotherapy assessment. Additionally, BF, FM, lipids (TC, LDL), glucose metabolism (HOMA-IR, insulin, HbA1c), and inflammation (CRP) significantly increased (p < 0.01). Notably BW significantly increased; mean weight gain after chemotherapy was 6.1 kg and increased an additional 8.2% at follow-up (p < 0.01). Conclusion: MetS components, body composition, and biomarkers continued to worsen within 4–5 years post-chemotherapy in breast cancer survivors. Energy balance interventions should target breast cancer patients to reduce the exacerbation of MetS. [ABSTRACT FROM AUTHOR]

Background: Yellow nail syndrome is a rare condition considered secondary to functional anomalies of lymphatic drainage. Yellow nail syndrome is diagnosed through the triad of intrathoracic findings (30% being pleural effusions), nail discoloration, and lymphedema, with any two features sufficient for diagnosis. We report the second case of post-operative yellow nail syndrome.Case Presentation: After coronary artery bypass grafting, our patient presented with chylothorax on post-operative day 13 and yellow toenail discoloration on post-operative day 28, diagnosing yellow nail syndrome. Initial conservative management with pigtail catheter drainage and low-fat diet with medium-chain triglycerides reduced chylous drainage from 350 mL/day on post-operative day 14 to < 100 mL/day on post-operative day 17. However, by post-operative day 18, drainage returned to 350 mL/day that persisted despite attempts to readjust the catheter position, replacement of catheter with chest tube, and transition to total parenteral nutrition and octreotide while nil per os. Lymphangiogram on post-operative day 32 did not identify the thoracic duct or cisterna chyli, precluding embolization. Talc and doxycycline pleurodeses performed on post-operative days 33 and 38, respectively, resolved his chylothorax and nail discoloration.Conclusions: Both yellow nail syndrome and chylothorax as a complication of coronary artery bypass grafting are rare entities. The proposed mechanism of post-operative chylothorax is iatrogenic injury to thoracic duct or collateral lymphatic vessels. Diagnosing yellow nail syndrome in patients with post-operative chylothorax (through co-existing yellow nail discoloration and/or lymphedema) may suggest predisposition to impaired lymphatic drainage, portending a difficult recovery and potentially indicating need for surgical management. [ABSTRACT FROM AUTHOR]

Background: The authors sought to determine the effect of chemotherapy on the development of metabolic syndrome (MetS) in premenopausal and postmenopausal women undergoing (neo)adjuvant therapy for early-stage breast cancer.Methods: A total of 86 women with early-stage (AJCC stage I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 of 5 components of MetS) were prospectively tested for the presence of the 5 components of MetS within 1 week before initiating and after completing (neo)adjuvant chemotherapy. The 5 components of MetS measured were waist circumference; blood pressure; and fasting levels of blood glucose, triglycerides, and high-density lipoprotein cholesterol. Anthropometrics (body weight, percentage body fat, fat mass), lipid profile (total cholesterol, low-density lipoprotein cholesterol), glucose metabolism (insulin, homeostatic model assessment of insulin resistance, glycated hemoglobin), and inflammation (C-reactive protein) also were examined before initiating and after completing treatment.Results: The current study included 46 premenopausal and 40 postmenopausal women. All individual MetS components and the overall MetS score were found to be statistically significantly increased (P<.01) after chemotherapy. Body weight, percentage body fat, fat mass, lipids, glucose metabolism, and inflammation also were found to be statistically significantly increased (P<.01).Conclusions: A 12-week to 18-week course of chemotherapy appears to statistically significantly increase MetS and related anthropometrics, biomarkers of glucose metabolism, and inflammation in patients with early-stage breast cancer with no preexisting MetS. Lifestyle interventions such as diet and exercise may be preventive approaches for use during chemotherapy to reduce the onset of MetS in patients with breast cancer. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2016;122:2646-2653. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown.Methods: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis.Results: Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls.Conclusions: Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer. [ABSTRACT FROM AUTHOR]

Background: Data that directly associate utilization of novel systemic therapies with survival trends in metastatic breast cancer (MBC) are limited. In the setting of de novo MBC, large registry analyses cite positive temporal trends in survival, but the extent to which advances in systemic therapy have contributed to these gains is not clear. Methods: The City of Hope Cancer Registry was used to identify a consecutive series of patients with de novo MBC who received their first line of therapy between 1985 and 2004. Comprehensive clinicopathologic and treatment-related data were collected for each patient. Univariate analyses were conducted via Cox regression to identify factors associated with improved survival. Multivariate analysis was also conducted via Cox regression and the stepwise procedure was used to identify independent predictors of survival. Results: A total of 324 patients with de novo MBC were identified. After application of exclusion criteria, including the sole presence of supraclavicular node metastasis, 274 patients were retained in the analysis. The treatment-related characteristics associated with improved survival included: use of endocrine therapy (hazard ratio [HR] 0.60, 95%CI 0.47-0.77; P<0.0001), and addition of bisphosphonates (HR 0.70, 95%CI 0.52-0.96; P=0.02). However, recipients of novel cytotoxic agents (defined as drugs approved for MBC since 1994) had no improvement in survival relative to patients treated with older cytotoxic agents. On multivariate analysis, age (< 50), receipt of aromatase inhibitors, and receipt of zoledronic acid were independent predictors of survival. Conclusions: The overall survival of women with de novo metastatic breast cancer has improved over the past 20 years. However, the contribution of conventional cytotoxic agents to this improvement is minimal. [ABSTRACT FROM AUTHOR]