Psychosocial characteristics and quality of life among sexual and gender minority patients with cancer.

BACKGROUND: Underserved and minoritized patients with cancer often experience more psychosocial concerns and inferior quality of life (QOL) compared with majority populations. This study compared patient-reported psychosocial characteristics and QOL among self-identified sexual and gender minority patients with cancer vs cisgender-heterosexual patients with cancer treated at a National Cancer Institute-designated comprehensive cancer center in the United States. METHODS: Self-report data from 51 503 patients were obtained from an institutional standard-of-care electronic patient questionnaire that was completed prior to, or on the day of, the patient's initial visit. The electronic patient questionnaire collects demographic information, including sexual orientation and gender identity, psychosocial variables, and QOL using the validated Short Form Health Survey-12. Sexual orientation and gender identity information was used to identify self-identified sexual and gender minority and cisgender-heterosexual persons (ie, non-self-identified sexual and gender minority). Using parametric analyses, psychosocial variables and QOL measures were compared for self-identified sexual and gender minority vs non-self-identified sexual and gender minority patients with cancer. RESULTS: Compared with non-self-identified sexual and gender minority patients (n = 50 116), self-identified sexual and gender minority patients (n = 1387, 2.7%) reported statistically significantly greater concerns regarding getting help during treatment (2.6% vs 4.3%, respectively; P = .001) and concerns with ability to seek care (16.7% vs 21.6%, respectively, P < .001). Self-identified sexual and gender minority patients reported statistically significantly elevated mental health concerns and daily emotional and pain interference (all P < .001), whereas there was no statistically significant difference in daily interference due to physical functioning. CONCLUSION: These data reveal real-world disparities among self-identified sexual and gender minority patients with cancer, which can be used to develop psychosocial interventions tailored to address the unique psychosocial and QOL needs of this underserved and minoritized population and to ultimately improve cancer care.

Qualitative Findings From a Survey on Patient Experiences and Satisfaction with Lung Cancer Screening.

BACKGROUND: To reveal successes and potential limitations of the lung cancer screening program, we conducted a survey that included both quantitative and open-ended questions to measure patient experiences and satisfaction with screening. METHODS: We report on the five open-ended items related to barriers to returning for screening, experience with other cancer prevention screenings, positive and negative experiences, and suggestions for improving future appointments. The open-ended responses were analyzed using constant comparison method and inductive content analysis. RESULTS: Respondents (182 patients, 86% response rate for open-ended questions) provided generally positive comments about their lung cancer screening experience. Negative comments were related to desire for more information about results, long wait times for results, and billing issues. Suggestions for improvements included: scheduling on-line appointments and text or email reminders, lower costs, and responding to uncertainty about eligibility criteria. CONCLUSION: Findings provide insights about patient experiences and satisfaction with lung cancer screening which is important given low uptake. Ongoing patient-centered feedback may improve the lung cancer screening experience and increase follow-up screening rates.

Recurrence Patterns for Regionally Metastatic Melanoma Treated in the Era of Adjuvant Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: The purpose of this systematic review was to examine the timing and patterns of recurrence for patients with regionally metastatic melanoma on the basis of nodal management and receipt of adjuvant therapy. METHODS: We identified randomized controlled trials and non-randomized studies published between 2010 and 2020 that reported timing and/or patterns of recurrence. We evaluated recurrence-free survival (RFS), location of recurrence, and surveillance strategy on the basis of receipt of adjuvant systemic therapy and nodal management with observation versus completion dissection. We compared differences in patterns of recurrence across studies using RevMan. RFS was evaluated graphically using point estimates and confidence intervals. RESULTS: Among the 19 publications, there was wide variation in study populations, imaging surveillance regimens, and format of recurrence reporting. Patterns of disease recurrence did not differ between adjuvant and placebo/observation groups. A total of 11 studies reported RFS at variable time intervals, which ranged in adjuvant therapy groups (38-88% at 1 year, 29-67% at 2 years, 33-58% at 3 years, and 34-53% at 5 years) and placebo/observation groups (47-63% at 1 year, 39-47% at 2 years, 33-68% at 3 years, and 57% at 5 years). Anti-PD-1 immune therapy and BRAF/MEK inhibitor therapy were superior to placebo at year 1. DISCUSSION: We found that adjuvant treatment improved RFS but did not alter the patterns of disease recurrence compared with patients managed without adjuvant systemic treatment. Future studies should separately report sites of disease recurrence on the basis of specific adjuvant systemic treatment and surveillance practices to better advise patients about their patterns and risk of recurrence.

Volume doubling time and radiomic features predict tumor behavior of screen-detected lung cancers.

BACKGROUND: Image-based biomarkers could have translational implications by characterizing tumor behavior of lung cancers diagnosed during lung cancer screening. In this study, peritumoral and intratumoral radiomics and volume doubling time (VDT) were used to identify high-risk subsets of lung patients diagnosed in lung cancer screening that are associated with poor survival outcomes. METHODS: Data and images were acquired from the National Lung Screening Trial. VDT was calculated between two consequent screening intervals approximately 1 year apart; peritumoral and intratumoral radiomics were extracted from the baseline screen. Overall survival (OS) was the main endpoint. Classification and Regression Tree analyses identified the most predictive covariates to classify patient outcomes. RESULTS: Decision tree analysis stratified patients into three risk-groups (low, intermediate, and high) based on VDT and one radiomic feature (compactness). High-risk patients had extremely poor survival outcomes (hazard ratio [HR] = 8.15; 25% 5-year OS) versus low-risk patients (HR = 1.00; 83.3% 5-year OS). Among early-stage lung cancers, high-risk patients had poor survival outcomes (HR = 9.07; 44.4% 5-year OS) versus the low-risk group (HR = 1.00; 90.9% 5-year OS). For VDT, the decision tree analysis identified a novel cut-point of 279 days and using this cut-point VDT alone discriminated between aggressive (HR = 4.18; 45% 5-year OS) versus indolent/low-risk cancers (HR = 1.00; 82.8% 5-year OS). CONCLUSION: We utilized peritumoral and intratumoral radiomic features and VDT to generate a model that identify a high-risk group of screen-detected lung cancers associated with poor survival outcomes. These vulnerable subset of screen-detected lung cancers may be candidates for more aggressive surveillance/follow-up and treatment, such as adjuvant therapy.

Assessing the effectiveness of a LGBT cultural competency training for oncologists: study protocol for a randomized pragmatic trial.

BACKGROUND: LGBT patients may have unique psychosocial cancer care needs, and healthcare providers should have knowledge and understanding of these unique needs to effectively address disparities through the delivery of personalized healthcare. As such, our group developed and piloted a web-based LGBT cultural competency training designed specifically for oncologists called the Curriculum for Oncologists on LGBT populations to Optimize Relevance and Skills (COLORS). We designed a randomized pragmatic trial for oncologists to compare the effectiveness of the COLORS training versus a general online LGBT cultural competency training in improving LGBT-related knowledge, attitudes, and clinical practices. METHODS/DESIGN: Study procedures include an 8-step approach for recruitment, randomization, retention, and completion of the interventions. Oncologists of any subspecialty who are currently practicing physicians will be identified from the American Medical Association Masterfile. Approximately 5000 oncologists will be sent a FedEx envelope with an invitation letter and study timeline. Electronic consent is obtained using a secure REDCap (Research Electronic Data Capture) portal hosted at the Moffitt Cancer Center (Tampa, FL) where the oncologists will complete the eligibility questionnaire, pre-training assessments, and then will be randomized to complete the COLORS training or an online general healthcare training offered by the National LGBT Health Education Center. Effectiveness of both trainings will be assessed utilizing self-reported measures of LGBT-related knowledge, attitudes, and affirming clinical practices. The measures will be collected before and directly after training completion, as well as 3-month post-training completion. The primary outcomes are changes in knowledge, attitudes, and practice behaviors regarding LGBT cancer patients from pre-test to post-test training in the COLORS training vs. the comparison training. DISCUSSION: The overarching premise of this trial is to assess the effectiveness of the COLORS cultural competency training program. If successful, among oncologists who completed the COLORS training should yield statistically significantly improvements in knowledge, attitudes, and affirming practice.

Blockade of beta adrenergic receptors protects the blood brain barrier and reduces systemic pathology caused by HIV-1 Nef protein.

Combination antiretroviral therapy (cART) targets viral replication, but early viral protein production by astrocytes may still occur and contribute to the progression of HIV-1 associated neurocognitive disorders and secondary complications seen in patients receiving cART. In prior work with our model, astrocytic HIV-1 Nef expression exhibits neurotoxic effects leading to neurological damage, learning impairment, and immune upregulation that induces inflammation in the lungs and small intestine (SI). In this follow-up study, we focus on the sympathetic nervous system (SNS) as the important branch for peripheral inflammation resulting from astrocytic Nef expression. Male and female Sprague Dawley rats were infused with transfected astrocytes to produce Nef. The rats were divided in four groups: Nef, Nef + propranolol, propranolol and naïve. The beta-adrenergic blocker, propranolol, was administered for 3 consecutive days, starting one day prior to surgery. Two days after the surgery, the rats were sacrificed, and then blood, brain, small intestine (SI), and lung tissues were collected. Levels of IL-1ß were higher in both male and female rats, and treatment with propranolol restored IL-1ß to basal levels. We observed that Nef expression decreased staining of the tight junction protein claudin-5 in brain tissue while animals co-treated with propranolol restored claudin-5 expression. Lungs and SI of rats in the Nef group showed histological signs of damage including larger Peyer's Patches, increased tissue thickness, and infiltration of immune cells; these findings were abrogated by propranolol co-treatment. Results suggest that interruption of the beta adrenergic signaling reduces the peripheral organ inflammation caused after Nef expression in astrocytes of the brain.

Surveillance of Sentinel Node-Positive Melanoma Patients Who Receive Adjuvant Therapy Without Undergoing Completion Lymph Node Dissection.

INTRODUCTION: Adjuvant therapy trials required completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma prior to systemic treatment, but nodal surveillance without CLND is now common. For patients receiving adjuvant therapy without CLND, patterns of recurrence are unknown and the value of regional nodal ultrasound alongside cross-sectional imaging is not well-defined. METHODS: In a retrospective cohort of SLN-positive melanoma patients managed with nodal surveillance from June 2014 to June 2019, we evaluated the association between adjuvant treatment and location of first recurrence (locoregional, nodal, distant, or multisite) using Chi-square tests. We compared methods of recurrence detection and cost by surveillance intensity using Chi-square and Dunn's tests. RESULTS: Among 177 nodal surveillance patients, 66 (37%) received adjuvant therapy. Median follow-up was 24 months, during which 48 patients (27%) recurred. Adjuvant treatment did not alter patterns of initial recurrence (p = 0.76). Adjuvant therapy recipients more often had both nodal ultrasound and cross-sectional imaging surveillance (p < 0.01). Among 13 isolated nodal recurrences, 85% were within the first year and 85% were detected by examination and/or ultrasound. Increasing surveillance intensity was not associated with recurrence detection rates but increased overall cost and cost per detected recurrence. CONCLUSION: Regardless of adjuvant treatment, most nodal recurrences occurred in the first year and were initially detected clinically or by ultrasound. Findings support continued use of examination and nodal basin ultrasound in addition to any planned cross-sectional imaging surveillance.

Immunoblot Validation of Phospho-Specific Antibodies Using Lung Cancer Cell Lines.

The cancer phenotype is usually characterized by deregulated activity of a variety of cellular kinases, with consequent abnormal hyper-phosphorylation of their target proteins. Therefore, antibodies that allow the detection of phosphorylated versions of proteins have become important tools both preclinically in molecular cancer research, and at the clinical level by serving as tools in pathological analyses of tumors. In order to ensure reliable results, validation of the phospho-specificity of these antibodies is extremely important, since this ensures that they are indeed able to discriminate between the phosphorylated and unphosphorylated versions of the protein of interest, specifically recognizing the phosphorylated variant. A recommended validation approach consists in dephosphorylating the target protein and assessing if such dephosphorylation abrogates antigen immunoreactivity when using the phospho-specific antibody. In this chapter, we describe a protocol to validate the specificity of a phospho-specific antibody that recognizes a phosphorylated variant of the Retinoblastoma (Rb) protein in lung cancer cell lines. The protocol consists in the dephosphorylation of the Rb-containing protein lysates by treating them with bovine intestinal phosphatase, followed by assessment of the dephosphorylation by immunoblot.

Zoledronic Acid Abrogates Restraint Stress-Induced Macrophage Infiltration, PDGF-AA Expression, and Ovarian Cancer Growth.

Multiple studies suggest that chronic stress accelerates the growth of existing tumors by activating the sympathetic nervous system. Data suggest that sustained adrenergic signaling can induce tumor growth, secretion of pro-inflammatory cytokines, and macrophage infiltration. Our goal was to study the role of adrenergic-stimulated macrophages in ovarian cancer biology. Cytokine arrays were used to assess the effect of adrenergic stimulation in pro-tumoral cytokine networks. An orthotopic model of ovarian cancer was used to assess the in vivo effect of daily restraint stress on tumor growth and adrenergic-induced macrophages. Cytokine analyses showed that adrenergic stimulation modulated pro-inflammatory cytokine secretion in a SKOV3ip1 ovarian cancer cell/U937 macrophage co-culture system. Among these, platelet-derived growth factor AA (PDGF-AA), epithelial cell-derived neutrophil-activating peptide (ENA-78), Angiogenin, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-5 (IL-5), Lipocalin-2, macrophage migration inhibitory factor (MIF), and transferrin receptor (TfR) were upregulated. Enriched biological processes included cytokine-mediated signaling pathways and positive regulation of cell proliferation. In addition, daily restraint stress increased ovarian cancer growth, infiltration of CD68+ macrophages, and expression of PDGF-AA in orthotopic models of ovarian cancer (SKOV3ip1 and HeyT30), while zoledronic acid, a macrophage-depleting agent, abrogated this effect. Furthermore, in ovarian cancer patients, high PDGFA expression correlated with worse outcomes. Here, it is shown that the adrenergic regulation of macrophages and PDGFA might play a role in ovarian cancer progression.

Peritumoral and intratumoral radiomic features predict survival outcomes among patients diagnosed in lung cancer screening.

The National Lung Screening Trial (NLST) demonstrated that screening with low-dose computed tomography (LDCT) is associated with a 20% reduction in lung cancer mortality. One potential limitation of LDCT screening is overdiagnosis of slow growing and indolent cancers. In this study, peritumoral and intratumoral radiomics was used to identify a vulnerable subset of lung patients associated with poor survival outcomes. Incident lung cancer patients from the NLST were split into training and test cohorts and an external cohort of non-screen detected adenocarcinomas was used for further validation. After removing redundant and non-reproducible radiomics features, backward elimination analyses identified a single model which was subjected to Classification and Regression Tree to stratify patients into three risk-groups based on two radiomics features (NGTDM Busyness and Statistical Root Mean Square [RMS]). The final model was validated in the test cohort and the cohort of non-screen detected adenocarcinomas. Using a radio-genomics dataset, Statistical RMS was significantly associated with FOXF2 gene by both correlation and two-group analyses. Our rigorous approach generated a novel radiomics model that identified a vulnerable high-risk group of early stage patients associated with poor outcomes. These patients may require aggressive follow-up and/or adjuvant therapy to mitigate their poor outcomes.

Impact of a natural disaster on access to care and biopsychosocial outcomes among Hispanic/Latino cancer survivors.

Cancer is the leading cause of death in Puerto Rico (PR). Hurricane Maria (HM) and its aftermath lead to widespread devastation on the island, including the collapse of the healthcare system. Medically fragile populations, such as cancer survivors, were significantly affected. The goal of this study was to assess the impact of HM on barriers to care, emotional distress, and inflammatory biomarkers among cancer survivors in PR. This exploratory longitudinal study was conducted in health care facilities and community support groups from PR. Cancer survivors (n = 50) and non-cancer participants (n = 50) completed psychosocial questionnaires and provided blood samples that were used to assess inflammatory cytokines levels. Among this cohort, we identified 41 matched cancer survivors/non-cancer participants pairs. Data were analyzed through descriptive, frequencies, correlational, and regression analyses. Cancer survivors that were affected by HM reported increased barriers in accessing medical care, which were directly associated with anxiety, perceived stress, and post-traumatic symptomatology. Moreover, being a cancer survivor, predicted more barriers to receiving health care, especially in the first six weeks after the event, after which the effect was attenuated. Several inflammatory cytokines, such as CD31, BDNF, TFF3, Serpin E-1, VCAM-1, Vitamin D BP, and PDGF-AA, were significantly upregulated in cancer survivors while MMP9 and Osteopontin both had significant positive correlations with barriers to care. HM significantly impacted Puerto Ricans psychosocial well-being. Cancer survivors had significant barriers to care and showed increased serum inflammatory cytokines but did not show differences in anxiety, stress, and post-traumatic symptoms compared to non-cancer participants.

Hyper-phosphorylation of Rb S249 together with CDK5R2/p39 overexpression are associated with impaired cell adhesion and epithelial-to-mesenchymal transition: Implications as a potential lung cancer grading and staging biomarker.

Prediction of lung cancer metastasis relies on post-resection assessment of tumor histology, which is a severe limitation since only a minority of lung cancer patients are diagnosed with resectable disease. Therefore, characterization of metastasis-predicting biomarkers in pre-resection small biopsy specimens is urgently needed. Here we report a biomarker consisting of the phosphorylation of the retinoblastoma protein (Rb) on serine 249 combined with elevated p39 expression. This biomarker correlates with epithelial-to-mesenchymal transition traits in non-small cell lung carcinoma (NSCLC) cells. Immunohistochemistry staining of NSCLC tumor microarrays showed that strong phospho-Rb S249 staining positively correlated with tumor grade specifically in the squamous cell carcinoma (SCC) subtype. Strong immunoreactivity for p39 positively correlated with tumor stage, lymph node invasion, and distant metastases, also in SCC. Linear regression analyses showed that the combined scoring for phospho-Rb S249, p39 and E-cadherin in SCC is even more accurate at predicting tumor staging, relative to each score individually. We propose that combined immunohistochemistry staining of NSCLC samples for Rb phosphorylation on S249, p39, and E-cadherin protein expression could aid in the assessment of tumor staging and metastatic potential when tested in small primary tumor biopsies. The intense staining for phospho-Rb S249 that we observed in high grade SCC could also aid in the precise sub-classification of poorly differentiated SCCs.

A Selection of Important Genes and Their Correlated Behavior in Alzheimer's Disease.

In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

Detection of Retinoblastoma Protein Phosphorylation by Immunoblot Analysis.

The retinoblastoma tumor suppressor protein (pRb) is a preeminent tumor suppressor that acts as a cell cycle repressor, specifically as an inhibitor of the G1-S transition of the cell cycle . pRb is a phosphoprotein whose function is repressed by extensive phosphorylation in several key residues, and therefore, pRb's phosphorylation status has become a surrogate for pRb activity. In particular, hyperphosphorylation of pRb has been associated with pathological states such as cancer, and therefore, assessing pRb's phosphorylation status is increasingly gaining diagnostic and prognostic value, may be used to inform therapeutic decisions, and is also an important tool for the cancer biologists seeking an understanding of the molecular etiology of cancer. In this chapter, we discuss an immunoblot protocol to detect pRb phosphorylation in two residues, serine 612 and threonine 821, in protein extracts from cancer cells.

Immunohistochemical Detection of Retinoblastoma Protein Phosphorylation in Human Tumor Samples.

The retinoblastoma protein (pRb) is an important tumor suppressor and cell cycle repressor. pRb is a phosphoprotein whose function is regulated primarily at the level of phosphorylation, and therefore, detecting pRb's phosphorylation status in human tissue samples can be clinically informative. Unfortunately, detection of phosphorylated pRb residues can be technically challenging, as these residues can often be weak antigens. In this chapter, we describe an enhanced sensitivity immunohistochemistry protocol for the staining of phosphorylated serine 249 in pRb, in human lung tumor samples.

Identification of potential biomarkers from microarray experiments using multiple criteria optimization.

Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization procedure to compare different experiments is no longer necessary.