Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench.

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

Hematology/Oncology Fellowship Programs' Participation in the Quality Oncology Practice Initiative.

PURPOSE: In the first decade of this millennium, ASCO pioneered a quality measurement tool, the Quality Oncology Practice Initiative (QOPI). Despite an Accreditation Council for Graduate Medical Education (ACGME) requirement since 2012 for oncology fellows to participate in quality improvement (QI) projects, the uptake of QOPI remains modest. METHODS: This study examined reasons for low QOPI participation by surveying participating and nonparticipating HemOnc Fellowship Programs. The survey elicited views toward QI and QOPI as well as ideas about making the program more helpful. RESULTS: Among 69 fellowship programs, only 39% (n = 27) participated in QOPI. Other findings were that (1) the majority of programs considered their fellows' QI projects beneficial but were not fulfilling the ACGME standard for all fellows' QI participation; (2) nonparticipating programs were unfamiliar with but interested in QOPI; (3) participating programs tended to view QI as easier to conduct and more beneficial than nonparticipating programs; and (4) programs that withdrew from QOPI and participating programs alike were dissatisfied with the educational benefit and data abstraction burden for fellows. CONCLUSION: Academic oncology programs generally valued QI but many have not fully engaged in it. Fellows in programs participating in QOPI may have had less difficulty conducting QI and their projects may have been more beneficial than that of nonparticipating programs. However, perceived lack of educational benefits for fellows and the burden of manual data abstraction from the electronic medical record are impediments to satisfaction with the program. Higher faculty involvement and longitudinal reports for each fellow may significantly increase participation.

An advanced molecular medicine case report of a rare human tumor using genomics, pathomics, and radiomics.

Background: Pulmonary Sclerosing Pneumocytoma (PSP) is a rare tumor of the lung with a low malignant potential that primarily affects females. Initial studies of PSP focused primarily on analyzing features uncovered using conventional X-ray or CT imaging. In recent years, because of the widespread use of next-generation sequencing (NGS), the study of PSP at the molecular-level has emerged. Methods: Analytical approaches involving genomics, radiomics, and pathomics were performed. Genomics studies involved both DNA and RNA analyses. DNA analyses included the patient's tumor and germline tissues and involved targeted panel sequencing and copy number analyses. RNA analyses included tumor and adjacent normal tissues and involved studies covering expressed mutations, differential gene expression, gene fusions and molecular pathways. Radiomics approaches were utilized on clinical imaging studies and pathomics techniques were applied to tumor whole slide images. Results: A comprehensive molecular profiling endeavor involving over 50 genomic analyses corresponding to 16 sequencing datasets of this rare neoplasm of the lung were generated along with detailed radiomic and pathomic analyses to reveal insights into the etiology and molecular behavior of the patient's tumor. Driving mutations (AKT1) and compromised tumor suppression pathways (TP53) were revealed. To ensure the accuracy and reproducibility of this study, a software infrastructure and methodology known as NPARS, which encapsulates NGS and associated data, open-source software libraries and tools including versions, and reporting features for large and complex genomic studies was used. Conclusion: Moving beyond descriptive analyses towards more functional understandings of tumor etiology, behavior, and improved therapeutic predictability requires a spectrum of quantitative molecular medicine approaches and integrations. To-date this is the most comprehensive study of a patient with PSP, which is a rare tumor of the lung. Detailed radiomic, pathomic and genomic molecular profiling approaches were performed to reveal insights regarding the etiology and molecular behavior. In the event of recurrence, a rational therapy plan is proposed based on the uncovered molecular findings.

A novel prostate cancer immunotherapy using prostate-specific antigen peptides and Candida skin test reagent as an adjuvant.

OBJECTIVES: Our group developed the use of the Candida skin test reagent as an adjuvant of cell-mediated immunity in designing a human papillomavirus therapeutic vaccine. Here, this technology is being applied for designing a prostate cancer immunotherapy. METHODS: Peptides based on the prostate-specific antigen amino acid sequences were selected, synthesized, and evaluated in terms of their (1) solubility, (2) maturation effects on Langerhans cells by fluorescence-activated cell sorter analysis, and (3) recognition by peripheral immune cells from prostate cancer patients using interferon-γ enzyme-linked immunospot assay. RESULTS: The peptides were soluble in 10 mM succinate at pH of 5 with 5% glycine, and they demonstrated no maturation effects on Langerhans cells from healthy donors. On the other hand, peripheral immune cells from 4 of 10 prostate cancer patients examined had positive responses in enzyme-linked immunospot assay to one or more prostate-specific antigen peptides. CONCLUSION: In summary, a design and a formulation of a novel prostate cancer immunotherapy are described. The immunogenicity of prostate-specific antigen peptides in some prostate cancer patients supports further development of this immunotherapy.

PARP1 Is Up-Regulated in Non-small Cell Lung Cancer Tissues in the Presence of the Cyanobacterial Toxin Microcystin.

Non-small cell lung cancer (NSCLC) is the major form of lung cancer, with adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being its major subtypes. Smoking alone cannot completely explain the lung cancer etiology. We hypothesize that altered lung microbiome and chronic inflammatory insults in lung tissues contribute to carcinogenesis. Here we explore the microbiome composition of LUAD samples, compared to LUSC and normal samples. Extraction of microbiome DNA in formalin-fixed, paraffin-embedded (FFPE) lung tumor and normal adjacent tissues was meticulously performed. The 16S rRNA product from extracted microbiota was subjected to microbiome amplicon sequencing. To assess the contribution of the host genome, CD36 expression levels were analyzed then integrated with altered NSCLC subtype-specific microbe sequence data. Surprisingly phylum Cyanobacteria was consistently observed in LUAD samples. Across the NSCLC subtypes, differential abundance across four phyla (Proteobacteria, Bacteroidetes, Actinobacteria, and Firmicutes) was identified based on the univariate analysis (p-value < 6.4e-4 to 3.2e-2). In silico metagenomic and pathway analyses show that presence of microcystin correlates with reduced CD36 and increased PARP1 levels. This was confirmed in microcystin challenged NSCLC (A427) cell lines and Cyanobacteria positive LUAD tissues. Controlling the influx of Cyanobacteria-like particles or microcystin and the inhibition of PARP1 can provide a potential targeted therapy and prevention of inflammation-associated lung carcinogenesis.

Cancer patient perspectives regarding preparedness for end-of-life care: A qualitative study.

PURPOSE: The extent to which patients feel prepared for end-of-life (EOL) may be associated with important clinical outcomes. Despite growing interest in the concept of "preparedness," however, there is insufficient information about what cancer patients actually need to feel prepared. Such information is foundational for patient-centered care, theory-building, and instrument development. DESIGN: This qualitative study examined patient perspectives regarding preparedness for EOL care. PARTICIPANTS AND METHODS: In-depth interviews were conducted with patients with advanced malignancies and limited life expectancies. Participants were drawn from a large academic cancer center and had a diverse range of malignancies. Thematic text analysis was used to analyze the data. FINDINGS: Six overarching themes emerged. These included readiness to manage concerns about: (1) EOL planning (e.g., goals of care, location of care); (2) interactions with healthcare providers (e.g., communication, symptom control); (3) interactions with family/friends (e.g., perceived burden, support); (4) emotional well-being (e.g., existential distress, fulfillment); (5) spiritual well-being (e.g., spiritual comfort, congregational support); and (6) financial well-being (e.g., medical expenses, estate planning). CONCLUSIONS: Findings highlight areas that patients themselves regard as critical for a sense of preparedness for EOL care. Participants emphasized broader concerns than those previously construed as facets of patient preparedness, and these domains offer modifiable targets for intervention.

Liquid biopsy and its role in an advanced clinical trial for lung cancer.

Liquid biopsy methodologies, for the purpose of plasma genotyping of cell-free DNA (cfDNA) of solid tumors, are a new class of novel molecular assays. Such assays are rapidly entering the clinical sphere of research-based monitoring in translational oncology, especially for thoracic malignancies. Potential applications for these blood-based cfDNA assays include: (i) initial diagnosis, (ii) response to therapy and follow-up, (iii) tumor evolution, and (iv) minimal residual disease evaluation. Precision medicine will benefit from cutting-edge molecular diagnostics, especially regarding treatment decisions in the adjuvant setting, where avoiding over-treatment and unnecessary toxicity are paramount. The use of innovative genetic analysis techniques on individual patient tumor samples is being pursued in several advanced clinical trials. Rather than using a categorical treatment plan, the next critical step of therapeutic decision making is providing the "right" cancer therapy for an individual patient, including correct dose and timeframe based on the molecular analysis of the tumor in question. Per the 21st Century Cures Act, innovative clinical trials are integral for biomarker and drug development. This will include advanced clinical trials utilizing: (i) innovative assays, (ii) molecular profiling with cutting-edge bioinformatics, and (iii) clinically relevant animal or tissue models. In this paper, a mini-review addresses state-of-the-art liquid biopsy approaches. Additionally, an on-going advanced clinical trial for lung cancer with novelty through synergizing liquid biopsies, co-clinical trials, and advanced bioinformatics is also presented. Impact statement Liquid biopsy technology is providing a new source for cancer biomarkers, and adds new dimensions in advanced clinical trials. Utilizing a non-invasive routine blood draw, the liquid biopsy provides abilities to address perplexing issues of tumor tissue heterogeneity by identifying mutations in both primary and metastatic lesions. Regarding the assessment of response to cancer therapy, the liquid biopsy is not ready to replace medical imaging, but adds critical new information; for instance, through a temporal assessment of quantitative circulating tumor DNA (ctDNA) assay results, and importantly, the ability to monitor for signs of resistance, via emerging clones. Adjuvant therapy may soon be considered based on a quantitative cfDNA assay. As sensitivity and specificity of the technology continue to progress, cancer screening and prevention will improve and save countless lives by finding the cancer early, so that a routine surgery may be all that is required for a definitive cure.

Integrating Collaborative Learning and Competition in a Hematology/Oncology Training Program.

New educational methods and structures to improve medical education are needed to face the challenge of an exponential increase and complexity of medical knowledge. Collaborative learning has been increasingly used in education, but its use in medical training programs is in its infancy, and its impact is still unknown; the role of competition in education is more controversial. We introduced these pedagogical methods to the hematology/oncology fellowship program at the University of Arkansas for Medical Sciences to improve attendance and performance at didactic activities and different educational outcomes. One year after the adoption of these methods, the fellowship program has reached many of the expected goals from this intervention without the negative consequences of competition observed in younger learners. The most important conclusion of this project is that collaboration and cross-generational team work provide a healthy and effective learning environment and competition may not add further benefit. Analysis, interpretation, and discussion of our experience are provided. This study was approved by the University of Arkansas for Medical Sciences IRB as a low risk educational intervention not requiring a consent form.

Hyalinizing Clear Cell Carcinoma of the Lung: Case Report and Review of the Literature.

OBJECTIVES: Hyalinizing clear cell carcinoma (HCCC) is common in head and neck sites but extremely rare in the lung. This case report describes an HCCC in the lung of a 54-year-old female patient. METHODS: We summarize the histomorphologic, immunophenotypic, and molecular features for our and three previously reported HCCCs of the lung with emphasis on potential diagnostic pitfalls. RESULTS: Sections of a well-circumscribed 3.5-cm lung mass were characterized by a bronchocentric tumor growing in sheets, nests, and cords in a background of hyalinized stroma. Tumor cell appearance was clear to eosinophilic, lacking significant pleomorphism or mitotic activity. By immunohistochemistry, the tumor cells were strongly positive with antibodies to pan-keratin, p63, and CK5/6 while negative for CK7, CK20, thyroid transcription factor 1, napsin A, chromogranin, and synaptophysin. Next-generation sequencing demonstrated an EWSR1-ATF1 fusion transcript. CONCLUSIONS: Awareness of key morphologic features of pulmonary HCCC is crucial for the recognition of this rare entity in the lung. Ancillary studies, including immunohistochemistry and molecular testing, are essential for the distinction from its mimics.

Targeting nano drug delivery to cancer cells using tunable, multi-layer, silver-decorated gold nanorods.

Multifunctional nanoparticles have high potential as targeting delivery vehicles for cancer chemotherapy. In this study, silver-decorated gold nanorods (AuNR\Ag) have been successfully used to deliver specific, targeted chemotherapy against breast cancer (MCF7) and prostate carcinoma (PC3) cell lines. Doxorubicin, a commonly used chemotherapy, and anti-Epithelial cell adhesion molecule (anti-EpCAM) antibodies were covalently bonded to thiolated polyethylene glycol-coated AuNR\Ag, and the resultant system was used to deliver the drugs to cancer cells in vitro. Furthermore, these nanoparticles have a unique spectral signature by surface enhanced Raman spectroscopy (SERS), which enables reliable detection and monitoring of the distribution of these chemotherapy constructs inside cells. The development of interest in a plasmonic nano drugs system with unique spectroscopic signatures could result in a clinical approach to the precise targeting and visualization of cells and solid tumors while delivering molecules for the enhanced treatment of cancerous tumors.

Addressing Opioid-Associated Constipation Using Quality Oncology Practice Initiative Scores and Plan-Do-Study-Act Cycles.

Using the Quality Oncology Practice Initiative, an affiliate program of ASCO, we outlined opioid-associated constipation (OAC) as a subject in need of quality improvement (QI) in our fellowship program at the University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System. We initiated a fellow-led QI project to advance the quality of patient care and provide a valuable avenue for QI training of young physicians. Fellows organized meetings with all stakeholders, addressed the scope of the problem, and devised strategies for OAC management. Monthly meetings were organized using Plan-Do-Study-Act principles. Mandatory check boxes were inserted into our electronic medical record templates to remind all physicians to identify patients on opioid medications and assess and address OAC. Final chart audit and patient satisfaction surveys were performed 6 months after project initiation. Assessment of OAC improved from 52% at baseline to 92% ( P < .003). This improvement corresponded with high patient satisfaction scores, with 90% of surveyed patients reporting adequate management of their constipation. In this QI initiative, we showed that participation in ASCO's Quality Oncology Practice Initiative helps identify areas in need of QI, and such fellow-led QI projects can serve as models for QI training of young physicians.

Metastatic Renal Cell Carcinoma Presenting as Painful Chewing Successfully Treated with Combined Nivolumab and Sunitinib.

INTRODUCTION: Metastatic renal cell carcinoma (RCC) to the head and neck is rare. It is the third-most common cause of distant metastasis to the head and neck, after breast cancer and lung cancer. Several drugs are available to treat metastatic RCC including high-dose interleukin and targeted therapy. Immunotherapy with nivolumab was recently approved by the US Food and Drug Administration (FDA) as a second-line treatment for patients with metastatic RCC. CASE PRESENTATION: We present a case of metastatic RCC in a 71-year-old man with a single complaint of a 1-year history of pain while chewing food. Positron emission tomography-computed tomography showed diffuse metastatic disease. Nivolumab, off-label use before its recent FDA approval, was combined with sunitinib and resulted in an excellent and ongoing response. DISCUSSION: RCC is the third-most common cause of distant metastasis to the head and neck. The patient described in this case did not have any symptoms commonly seen in RCC, such as painless hematuria, weight loss, anorexia, fatigue, or anemia, despite the bulk of his disease. The other important aspect of this case is the almost complete response of his metastatic disease to the combination of nivolumab and sunitinib that was used off label before the FDA issued the approval. Future clinical trials should look at combining immunotherapy with targeted therapy in metastatic RCC.

Simulating Four Essential Conversations with Hematology/Oncology Trainees: a Qualitative Evaluation.

Hematologists/oncologists have a crucial responsibility to effectively communicate with patients. However, they have been criticized for ineffective communication with patients. To develop effective communication behaviors that meet the needs of patients and families, trainees need practice and feedback about their performance. Medical faculties frequently teach communication skills using simulation-based curricula; however, they often include only general communication skills, without tailored approaches for specialties. This study examined Hematology/Oncology trainees' qualitative perceptions about the value of and techniques used for simulations of specialty specific, essential conversations with patients and families, and debriefing sessions. Results demonstrate a highly effective curriculum and positive learner experiences. While most reports on this topic take place within major academic cancer centers, outcomes from a mid-sized Hematology/Oncology training program are unknown. The study confirms feasibility for implementing a simulation-based communications program in a mid-sized Hematology/Oncology program and describes simulation techniques that were effective.

Improving Communication on Intent of Chemotherapy Using QOPI Scores and PDSA Cycles.

Using the standardized ASCO Quality Oncology Practice Initiative (QOPI) guidelines for assessing quality cancer care, we identified communication about intent of chemotherapy as an area needing improvement in our program at the University of Arkansas for Medical Sciences (UAMS) and the Central Arkansas Veterans Healthcare System (CAVHS). We organized training in communications on intent of treatment (palliative vs curative) and added optional checkboxes to our electronic templates for progress notes. Afterwards, we conducted a retrospective review of electronic medical records of initially often randomly selected patient charts. The first 10 patient charts after 1 month of implementation showed intent of treatment in 80 % of charts compared to 74 % at baseline. We then changed checkboxes from mandatory to optional and reviewed 30 randomly selected patient charts. Intent of treatment was documented in 96.7 % of cases compared to 74 % at baseline. We also assessed patient satisfaction through surveys distributed in clinic. Patient satisfaction scores were close to 100 % for receiving clear information, understanding the reason for which they were receiving chemotherapy, and willingness of oncologists to listen carefully, to take time to answer questions, to explain things clearly, and to spend adequate time with them. In this study, we showed that training in communication of intent of chemotherapy and use of checkboxes in progress note templates could improve competency in communication of intent of therapy in cancer patients.

Myxoid mesenchymal neoplasm presenting as massive arm and chest wall oedema with pleural effusion.

Myxoid mesenchymal tumours are a heterogeneous group of neoplasms characterised histologically by their abundant mucoid and myxoid extracellular matrix (ECM). Encompassing a broad spectrum of clinical behaviour ranging from benign to malignant, there are more than 60 reactive and neoplastic entities currently classified under its domain. Its varied clinical and histopathologic features continue to pose a diagnostic challenge to clinicians and pathologists. Here, we describe a rare case of myxoid mesenchymal tumour presenting as oedema of the upper extremity with pleural metastasis and partial response to chemotherapy, which to the best of our knowledge has not yet been described in the literature.