Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer.

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial-mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7-NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.

Physician Disruptive Behavior Compromising Safe Care Delivery.

The negative impact and management of disruptive behavior are discussed in the article by Monika Kumar, et al.

Preventing Future Harm: Identifying the Drivers of an Unsafe Discharge to Improve Safety on an Inpatient Oncology Service.

Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.This article describes the care of a young patient with aggressive breast cancer, declining performance status, and multiple hospital admissions who died shortly after being discharged home without essential medications or an adequate plan for follow-up. The patient's death due to her malignancy was unavoidable, but she had inadequate resources before her death, leading to avoidable suffering. This outcome resulted from a series of minor errors attributable to inadequate handoffs, challenges establishing realistic goals of care, and hierarchy within and between medical teams that resulted in major lapses at the time of discharge. We explore these issues and discuss how this case led to the establishment of programs designed to empower health care providers and increase engagement of outpatient oncologists at critical points of patients' disease courses.

Reassessing Geographic, Logistical, and Cold Ischemia Cutoffs in Liver Transplantation.

INTRODUCTION: Liver acceptance patterns vary significantly between transplant centers. Data pertaining to outcomes of livers declined by local and regional centers and allocated nationally remains limited. PROJECT AIM: The objective was to compare post-liver transplant outcomes between liver allografts transplanted as a result of national and local-regional allocation. DESIGN: This was a retrospective evaluation of 109 nationally allocated liver allografts used for transplant by a single center. Outcomes of nationally allocated grafts were compared to standard allocation grafts (N = 505) during the same period. RESULTS: Recipients of nationally allocated grafts had lower model for end stage liver disease scores (17 vs 22, P = .001). Nationally allocated grafts were more likely to be post-cross clamp offers (29.4% vs 13.4%, P = .001) and have longer cold ischemia times (median hours 7.8 vs 5.5, P = .001). Early allograft dysfunction was common (54.1% vs 52.5%, P = .75) and did not impact hospital length of stay (median 5 vs 6 days, P = .89). There were no differences in biliary complications (P = .11). There were no differences in patient (P = .88) or graft survival (P = .35). In a multivariate model, after accounting for differences in cold ischemia time and posttransplant biliary complications, nationally allocated grafts were not associated with increased risk for graft loss (HR 0.9, 95% CI 0.4-1.8). Abnormal liver biopsy findings (33.0%) followed by donor donation after circulatory death status (22.9%) were the most common reasons for decline by local-regional centers. CONCLUSION: Despite longer cold ischemia times, patient and graft survival outcomes remain excellent and comparable to those seen from standard allocation grafts.

Intracranial nanomedicine-gel with deep brain-penetration for glioblastoma therapy.

Glioblastoma Multiforme (GBM) is one of the challenging tumors to treat as it recurs, almost 100%, even after surgery, radiation, and chemotherapy. In many cases, recurrence happens within 2-3cm depth of the resected tumor margin, indicating the inefficacy of current anti-glioma drugs to penetrate deep into the brain tissue. Here, we report an injectable nanoparticle-gel system, capable of providing deep brain penetration of drug up to 4 cm, releasing in a sustained manner up to >15 days. The system consists of ∼222 nm sized PLGA nanoparticles (NP-222) loaded with an anti-glioma drug, Carmustine (BCNU), and coated with a thick layer of polyethylene glycol (PEG). Upon release of the drug from PLGA core, it will interact with the outer PEG-layer leading to the formation of PEG-BCNU nanocomplexes of size ∼33 nm (BCNU-NC-33), which could penetrate >4 cm deep into the brain tissue compared to the free drug (< 5 mm). In vitro drug release showed sustained release of drug for 15 days by BCNU-NP gel, and enhanced cytotoxicity by BCNU-NC-33 drug-nanocomplexes in glioma cell lines. Ex vivo goat-brain phantom studies showed drug diffusion up to 4 cm in tissue and in vivo brain-diffusion studies showed almost complete coverage within the rat brain (∼1.2 cm), with ∼55% drug retained in the tissue by day-15, compared to only ∼5% for free BCNU. Rat orthotopic glioma studies showed excellent anti-tumor efficacy by BCNU-NP gel compared to free drug, indicating the potential of the gel-system for anti-glioma therapy. In effect, we demonstrate a unique method of sustained release of drug in the brain using larger PLGA nanoparticles acting as a reservoir while deep-penetration of the released drug was achieved by in situ formation of drug-nanocomplexes of size <50 nm which is less than the native pore size of brain tissue (> 100 nm). This method will have a major impact on a challenging field of brain drug delivery.

Clinical Outcomes in COVID-19 Patients Treated with Immunotherapy.

Introduction: The full impact of COVID-19 infections on patients with cancer who are actively being treated with chemotherapy or immune checkpoint inhibitors (ICIs) has not been fully defined. Our goal was to track clinical outcomes in this specific patient population. Methods: We performed a retrospective chart review of 121 patients (age > 18 years) at the University of Alabama at Birmingham from January 2020 to December 2021 with an advanced solid malignancy that were eligible to be treated with ICIs or on current therapy within 12 months of their COVID-19 diagnosis. Results: A total of 121 patients were examined in this study, and 61 (50.4%) received immunotherapy treatment within 12 months. One quarter of the patients on ICIs passed away, compared to 13% of the post-chemotherapy cohort. Patients who were vaccinated for COVID-19 had lower mortality compared to unvaccinated patients (X2 = 15.19, p < 0.001), and patients with lower ECOG (0.98) were associated with lower mortality compared to patients with worse functional status (0.98 vs. 1.52; t = 3.20; p < 0.01). Conclusions: COVID-19-related ICI mortality was higher compared to patients receiving chemotherapy. However, ICI cessation or delay is unwarranted as long there has been a risk−benefit assessment undertaken with the patient.

Non-small cell lung cancer in the era of immunotherapy.

Immunotherapy for non-small cell lung cancer (NSCLC) has revolutionized treatment for those with advanced disease, and recent data have emerged providing evidence for its benefits in earlier stages of the disease. Several pivotal clinical trials provide compelling data that adaptive immune cells may be highly effective and possibly even curative for NSCLC. Immune checkpoint inhibitors (ICIs) can unleash highly reactive memory immune responses to tumor antigens with durable effects against advanced or recurrent disease. Despite these encouraging results, many critical questions remain in the field including, for example, how to identify the subsets of NSCLC patients who most benefit from ICI treatment, and how ICI efficacy might be enhanced by utilizing combinations or sequencing of agents. A deeper understanding of biological mechanisms involved in lung cancer offers a unique opportunity to further explore the interaction between the adaptive immune landscape and NSCLC. Given the high incidence of lung cancer in Veterans and many Veterans being treated with immunotherapy for this disease, it is timely to have their adequate representation in future clinical trials. New clinical trials focused on Veterans can assist in exploring ways to mitigate resistant mechanisms as well as to investigate predictive and prognostic biomarkers for response to ICIs and other treatments. This paper will review current data and indications for immunotherapy in NSCLC, introduce new areas of research within immunotherapy, and discuss its applicability to the Veteran population.

Patterns of Failure and Optimal Treatment Paradigm for Large, Inoperable, Node-Negative Non-small Cell Lung Cancer.

OBJECTIVES: The ideal non-operative treatment for patients with large, node-negative non-small cell lung cancer (NSCLC) is poorly defined. To inform optimal treatment paradigms for this cohort, we examined patterns of failure and the impact of radiation therapy (RT) and chemotherapy receipt. MATERIALS AND METHODS: Node-negative NSCLC patients with 5+ cm primary tumors receiving definitive RT at our institution were identified. Sites of initial progression were analyzed. Local progression, regional/distant progression, progression-free survival, and overall survival were analyzed via cumulative incidence function and Kaplan-Meier. Associations between local vs. regional/distant progression with treatment and clinicopathologic variables were assessed via univariable and multivariable competing risks regression. RESULTS AND CONCLUSION: We identified 88 patients for analysis. Among patients with recurrent disease (N = 36), initial patterns of failure analysis showed that isolated distant (27.8%) and isolated regional progression (22.2%) were most common. Distant or regional failure as a component of initial failure was seen in 88.9% of patients who progressed, while isolated local failure was uncommon (11.1%). Univariable and multivariable competing risks regression showed that receipt of SBRT was associated with reduced risk of local progression (HR 0.23, P = .012), and receipt of chemotherapy was associated with reduced risk of regional/distant progression (HR 0.12, P = .040). In conclusion, patients with large, node-negative NSCLC treated with definitive RT are at high risk of regional and distant progression. SBRT correlates with a reduced risk of local failure while chemotherapy is associated with reduced regional/distant progression in this patient population. Ideal treatment may include SBRT when feasible with appropriate systemic therapy.

Impact of COVID-19 on Hematology-Oncology Fellowship Programs: A Quantitative and Qualitative Survey Assessment of Fellowship Program Directors.

PURPOSE: The COVID-19 pandemic led to unprecedented challenges in medical training, and we sought to assess the specific impact of COVID-19 on hematology-oncology (HO) fellowship programs. METHODS: We conducted a cross-sectional anonymous online survey of 103 HO program directors (PDs) in conjunction with the American Society of Hematology (ASH) and ASCO. We sought to assess the specific impact of COVID-19 on HO fellowship programs' clinical, educational, and research activities, evaluate perceptions regarding PD and trainee emotional and mental health, and identify ways to support programs. Data were analyzed using descriptive statistics, parametric and nonparametric tests, and multivariable logistic regression models. Responses to open-ended questions were analyzed with thematic analysis. RESULTS: Significant changes to fellowship activities included transitioning fellow training from outpatient clinics to telehealth (77.7%), shifting to virtual education (94.2%), and moving to remote research work (63.1%). A minority (21.4%) of PDs reported that their fellows were redeployed to cover non-HO services. Most PDs (54.4%) believed COVID-19 had a slight negative impact on fellowship training. PD self-reported burnout increased significantly from 15.5% prepandemic to 44.7% during the pandemic, and most PDs witnessed minor signs of fellow burnout (52.4%). Common PD concerns included inadequate supervision for telehealth activities, reduced opportunities for fellow advancement and promotion, lack of professional development activities, limited research operations and funding, program financial constraints, and virtual recruitment. CONCLUSION: We encourage institutions and national societies to allocate resources and develop programs that can support fellowships and mitigate the potential negative effects of COVID-19 on trainee and PD career development.

Impact of COVID-19 on Hematology-Oncology Trainees: A Quantitative and Qualitative Assessment.

PURPOSE: Graduate medical and research training has drastically changed during the COVID-19 pandemic, with widespread implementation of virtual learning, redeployment from core rotations to the care of patients with COVID-19, and significant emotional and physical stressors. The specific experience of hematology-oncology (HO) fellows during the COVID-19 pandemic is not known. METHODS: We conducted a mixed-methods study using a survey of Likert-style and open-ended questions to assess the training experience and well-being of HO fellows, including both clinical and postdoctoral trainee members of the American Society of Hematology and ASCO. RESULTS: A total of 2,306 surveys were distributed by e-mail; 548 (23.8%) fellows completed the survey. Nearly 40% of fellows felt that they had not received adequate mental health support during the pandemic, and 22% reported new symptoms of burnout. Pre-existing burnout before the pandemic, COVID-19-related clinical work, and working in a primary research or nonclinical setting were associated with increased burnout on multivariable logistic regression. Qualitative thematic analysis of open-ended responses revealed significant concerns about employment after training completion, perceived variable quality of virtual education and board preparation, loss of clinical opportunities to prepare for independent clinical practice, inadequate grant funding opportunities in part because of shifting research priorities, variable productivity, and mental health or stress during the pandemic. CONCLUSION: HO fellows have been profoundly affected by the pandemic, and our data illustrate multiple avenues for fellowship programs and national organizations to support both clinical and postdoctoral trainees.

Spotlight on International Quality: COVID-19 and Its Impact on Quality Improvement in Cancer Care.

This report from ASCO's International Quality Steering Group summarizes early learnings on how the COVID-19 pandemic and its stresses have disproportionately affected cancer care delivery and its delivery systems across the world. This article shares perspectives from eight different countries, including Austria, Brazil, Ghana, Honduras, Ireland, the Philippines, South Africa, and the United Arab Emirates, which provide insight to their unique issues, challenges, and barriers to quality improvement in cancer care during the pandemic. These perspectives shed light on some key recommendations applicable on a global scale and focus on access to care, importance of expanding and developing new treatments for both COVID-19 and cancer, access to telemedicine, collecting and using COVID-19 and cancer registry data, establishing measures and guidelines to further enhance quality of care, and expanding communication among governments, health care systems, and health care providers. The impact of the COVID-19 pandemic on cancer care and quality improvement has been and will continue to be felt across the globe, but this report aims to share these experiences and learnings and to assist ASCO's international members and our global fight against the pandemic and cancer.

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

Guideline Concordance With Durvalumab in Unresectable Stage III Non-Small Cell Lung Cancer: A Single Center Veterans Hospital Experience.

BACKGROUND: Durvalumab is recommended by national guidelines for patients with unresectable stage III non-small cell lung cancer (NSCLC) following concurrent chemoradiation therapy (CRT). Nonadherence to guidelines is associated with adverse outcomes. We studied the adherence and identified barriers to durvalumab usage at the Birmingham Veterans Affairs Medical Center (VAMC) Oncology Clinic in Alabama. METHODS: Using retrospective analysis, we assessed the use of consolidative durvalumab among veterans at Birmingham VAMC. The health records of all veterans with stage III unresectable NSCLC from October 2017 to August 2019 were reviewed. Data collected included demographics, barriers to CRT initiation and completion, durvalumab usage, and reasons for not prescribing durvalumab. RESULTS: In our data review, 34 patients were found to have stage III unresectable NSCLC. Twenty (58.8%) of those 34 initiated CRT, but only 16 (47.1%) completed CRT treatment and 7 (20.6%) underwent further treatment with durvalumab. Of the 14 patients who did not initiate CRT, the most common reasons were poor performance status and/or the presence of comorbidities. Of the evaluable cohort of 34, 11 (32.4%) patients with stage III NSCLC received durvalumab. Of the 9 eligible patients who did not receive durvalumab, the most common reasons cited were toxicities experienced during or following CRT (11.8%). CONCLUSIONS: Just one-third of patients were eligible to receive durvalumab at Birmingham VAMC. This was likely due to the difference between clinical trial and real-world patient populations. Interventions to address socioeconomic and system level barriers to improve our center's delivery of lung cancer treatment are planned.

Transplant outcomes using kidneys from high KDPI acute kidney injury donors.

Kidney transplant (KT) outcomes from high kidney donor profile index (KDPI ≥85%) donors with acute kidney injury (AKI) remain underreported. KT from 172 high KDPI Acute Kidney Injury Network (AKIN) stage 0-1 donors and 76 high KDPI AKIN stage 2-3 donors from a single center were retrospectively assessed. The AKIN 2-3 cohort had more delayed graft function (71% vs. 37%, p < .001). At one year, there were no differences in the estimated glomerular filtration rate (44 ± 17 vs. 46 ± 18, p = .42) or fibrosis on protocol biopsy (ci, p = .85). Donor terminal creatinine (p = .59) and length of delayed graft function (p = .39) did not impact one-year eGFR. There were more primary nonfunction (PNF) events in the high KDPI AKIN 2-3 group (5.3% vs. 0.6%, p = .02). With a median follow-up of 3.8 years, one-year death-censored graft failure was 3.5% for AKIN 0-1 and 14.5% for AKIN 2-3 (HR 2.40, 95% CI 1.24-4.63, p = .01). Although AKIN stage 2-3 high KDPI kidneys had comparable one-year eGFR to AKIN stage 0-1 high KDPI kidneys, there were more PNF occurrences and one-year death-censored graft survival was reduced. Given these findings, additional precautions should be undertaken when assessing and utilizing kidneys from severe AKI high KDPI donors.

How Do We Align Health Services Research and Quality Improvement?

Quality improvement (QI) initiatives and health services research (HSR) are commonly used to target health care quality. These disciplines are increasingly important because of the movement toward value-based health care as alternative payment and care delivery models drive institutions and investigators to focus on reducing unnecessary health care use and improving care coordination. QI efforts frequently target medical error and/or efficiency of care through the Plan-Do-Study-Act methodology. Within the QI framework, strategies for data display (e.g., Pareto charts, run charts, histograms, scatter plots) are leveraged to identify opportunities for intervention and improvement. HSR is a multidisciplinary field of study that seeks to identify the most effective way to organize, deliver, and finance health care to maximize the quality and value of care at both the individual and population levels. HSR uses a diverse set of quantitative and qualitative methodologies, such as case-control studies, cohort studies, randomized control trials, and semistructured interview/focus group evaluations. This manuscript provides examples of methodologic approaches for QI and HSR, discusses potential challenges associated with concurrent quality efforts, and identifies strategies to successfully leverage the strengths of each discipline in care delivery.

Reducing Infusion Clinic Wait Times Using Quality Improvement.

PURPOSE: Long wait times are a common occurrence for chemotherapy infusion patients and are a source of decreased patient satisfaction. Our facility sought to decrease outpatient infusion clinic wait times by 20% using the Model for Improvement, quality improvement tools, and Plan-Do-Study-Act cycles. METHODS: A multidisciplinary team was formed to address clinic wait times. Patient interviews, time studies, process mapping, brainstorming sessions, affinity diagrams, fishbone diagrams, and surveys were used to define the problem and to develop an intervention. Wait times from check-in until medication administration were analyzed using statistical process control charts. Our Plan-Do-Study-Act cycle led to the addition of a "fast-track" clinic title for patients not waiting for laboratory results on the day of treatment and changes in clinic communication. The fast-track clinic signaled for those patients to have priority for vital sign collection and earlier notification to pharmacy to begin preparing medications. RESULTS: Baseline wait times for patients not requiring laboratories on the day of treatment averaged 1 hour and 33 minutes. After intervention, using statistical process control charts, a shift was observed with a new average wait time of 1 hour and 12 minutes (a 23% decrease). Wait times for patients requiring laboratories on the day of treatment did not change significantly. CONCLUSION: Implementation of a fast-track clinic title and improving communication resulted in a significant reduction in wait times for patients not requiring laboratories on the day of treatment. Future efforts will focus on sustainment and improving wait times for all patients.

Evaluation of efficacy of intermaxillary fixation screws versus modified arch bar for intermaxillary fixation.

AIM: This study aimed to evaluate the efficacy of intermaxillary fixation (IMF) screws and modified arch bar. MATERIALS AND METHODS: This study is a randomized clinical trial in which all participants were divided into two groups of ten in each group and designated as Group A and Group B. In Group A, IMF was achieved by the use of four to six 2×8mm stainless steel IMF screws. In Group B, IMF was achieved by modified screw arch bar. RESULTS: In the present study, a total of twenty patients were analyzed. The average working time for Group A and Group B was 16 min and 29 min, respectively. Oral hygiene scores through modified Turesky Gilmore plaque index were calculated at immediate postoperative period and after 15 days, 30 days, and 45 days. Maximum hygiene was maintained in IMF screw group than modified arch bar group, but maximum stability was observed in the modified arch bar group than IMF screw group. CONCLUSION: This study emphasizes the use of IMF screws as a quick and easy method than modified arch bar. Oral hygiene maintenance was comparatively better in patients with IMF screws than those with modified arch bar. Modified arch bar was significantly stable when compared with IMF screws; therefore, for patients who require long-term IMF, modified arch bars can be a viable option, but the perforation in the original arch bar may lead to the weakening of the arch bar, and therefore the prefabricated modified arch bar would be a better option.

Management of maxillary first molar with six canals using operating microscope.

The purpose of this article was to highlight the importance of having a thorough knowledge about the root canal morphology. This case report highlights the unusual anatomy of a maxillary first molar with three mesiobuccal (MB) canals, two palatal canals, and one distobuccal canal which is extremely rare. The use of operating microscope was crucial, both for the detection and for the management of the additional canals. The use of surgical operating microscope and digital radiograph showed that MB root had Type 3-1 of Gulabivala classification and palatal canal showed Vertucci's Type II canal morphology This report describes and discusses the identification of variation in canal morphology of maxillary first molar and the use of latest adjuncts in successfully diagnosing and negotiating them.