Brief Report on Global Clinician Practices in the First-Line Management of Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION: In the dynamic landscape of metastatic NSCLC (mNSCLC) management, marked by several frontline options and the integration of next generation sequencing (NGS) for informed decision-making, barriers persist despite advancements. This includes challenges in clinical trial recruitment. To gain global insights into clinicians' practices, we conducted a survey on their testing and management approaches for patients with mNSCLC. METHODS: The survey, conducted from July 12 to August 20, 2023, utilized multiple-choice questions and qualitative research questions, employing the Likert Scale for comprehensive insights. RESULTS: A total of 127 individuals responded, with 72% affiliated with academic health systems, and 55% practicing in the USA. Regarding testing practices, 93% consistently ordered NGS for non-squamous histology, while 54% did so for squamous cell histology. Concurrent tissue and liquid biopsies were routinely ordered by 28%, while 39% reported ordering both testing platforms concurrently for select cases only. Respondents cited logistical barriers, such as insufficient tissue and lack of infrastructure, as the most common hindrance to molecular testing (76%), followed by reimbursement challenges (56%) and concerns about delayed turnaround time (50%). While most respondents were confident in interpreting NGS results, 22% lacked confidence. Concerning treatment decisions, 72% preferred awaiting molecular testing results before initiating systemic therapy. Less than 50% routinely referred patients for clinical trials in the frontline setting for mNSCLC. For patients with disease expressing high PD-L1 levels, most oncologists preferred pembrolizumab monotherapy. For disease with low PD-L1 expression, a platinum doublet chemotherapy regimen combined with pembrolizumab was favored. In disease cases with negative PD-L1 expression, a platinum doublet chemotherapy regimen with pembrolizumab was preferred. Key factors influencing oncologists' preferred immune checkpoint inhibitor (ICI) included experience with one ICI over another, preferred status per national guidelines, availability of trial data with a significant follow-up period, and consideration of drug cost. CONCLUSION: Although this study demonstrates an improved awareness and adoption of ordering NGS for the management of mNSCLC, it underscores the persistence of various barriers that must be addressed to improve upon the quality of care for patients diagnosed with mNSCLC.

A Review of the Current Approach and Treatment Landscape for Stage III Non-Small Cell Lung Cancer.

The therapeutic landscape of the management of stage III non-small cell lung cancer (NSCLC) has drastically evolved with the incorporation of immunotherapy and targeted therapy. Stage III NSCLC accounts for one-third of the cases and the treatment strategy of these locally advanced presentations are diverse, ranging from surgical to non-surgical options; with the incorporation of chemo-immunotherapy, radiation, and targeted therapies wherever applicable. The staging of this disease has also changed, and it is essential to have a strong multidisciplinary approach to do justice to patient care. In this article, we aim to navigate the nuanced approaches in the diagnosis and treatment of stage III NSCLC and expand on the evolution of the management of this disease.

Precision Immuno-Oncology in NSCLC through Gender Equity Lenses.

Precision immuno-oncology involves the development of personalized cancer treatments that are influenced by the unique nature of an individual's DNA, immune cells, and their tumor's molecular characterization. Biological sex influences immunity; females typically mount stronger innate and adaptive immune responses than males. Though more research is warranted, we continue to observe an enhanced benefit for females with lung cancer when treated with combination chemoimmunotherapy in contrast to the preferred approach of utilizing immunotherapy alone in men. Despite the observed sex differences in response to treatments, women remain underrepresented in oncology clinical trials, largely as a result of gender-biased misconceptions. Such exclusion has resulted in the development of less efficacious treatment guidelines and clinical recommendations and has created a knowledge gap in regard to immunotherapy-related survivorship issues such as fertility. To develop a more precise approach to care and overcome the exclusion of women from clinical trials, flexible trial schedules, multilingual communication strategies, financial, and transportation assistance for participants should be adopted. The impact of intersectionality and other determinants of health that affect the diagnosis, treatment, and outcomes in women must also be considered in order to develop a comprehensive understanding of the unique impact of immunotherapy in all women with lung cancer.

Major Stressful Life Events and the Risk of Pancreatic, Head and Neck Cancers: A Case-Control Study.

BACKGROUND: Major stressful life events have been shown to be associated with an increased risk of lung cancer, breast cancer and the development of various chronic illnesses. The stress response generated by our body results in a variety of physiological and metabolic changes which can affect the immune system and have been shown to be associated with tumor progression. In this study, we aim to determine if major stressful life events are associated with the incidence of head and neck or pancreatic cancer (HNPC). METHODS: This is a matched case-control study. Cases (CAs) were HNPC patients diagnosed within the previous 12 months. Controls (COs) were patients without a prior history of malignancy. Basic demographic data information on major stressful life events was collected using the modified Holmes-Rahe stress scale. A total sample of 280 was needed (79 cases, 201 controls) to achieve at least 80% power to detect odds ratios (ORs) of 2.00 or higher at the 5% level of significance. RESULTS: From 1 January 2018 to 31 August 2021, 280 patients were enrolled (CA = 79, CO = 201) in this study. In a multivariable logistic regression analysis after controlling for potential confounding variables (including sex, age, race, education, marital status, smoking history), there was no difference between the lifetime prevalence of major stressful event in cases and controls. However, patients with HNPC were significantly more likely to report a major stressful life event within the preceding 5 years when compared to COs (p = 0.01, OR = 2.32, 95% CI, 1.18-4.54). CONCLUSIONS: Patients with head, neck and pancreatic cancers are significantly associated with having a major stressful life event within 5 years of their diagnosis. This study highlights the potential need to recognize stressful life events as risk factors for developing malignancies.

Analytic Validation of Optical Genome Mapping in Hematological Malignancies.

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Standard-of-care (SOC) methods such as karyotyping and fluorescence in situ hybridization (FISH), which have been employed globally for the past three decades, have significant limitations in terms of resolution and the number of recurrent aberrations that can be simultaneously assessed, respectively. Next-generation sequencing (NGS)-based technologies are now widely used to detect clinically significant sequence variants but are limited in their ability to accurately detect SVs. Optical genome mapping (OGM) is an emerging technology enabling the genome-wide detection of all classes of SVs at a significantly higher resolution than karyotyping and FISH. OGM requires neither cultured cells nor amplification of DNA, addressing the limitations of culture and amplification biases. This study reports the clinical validation of OGM as a laboratory-developed test (LDT) according to stringent regulatory (CAP/CLIA) guidelines for genome-wide SV detection in different hematological malignancies. In total, 60 cases with hematological malignancies (of various subtypes), 18 controls, and 2 cancer cell lines were used for this study. Ultra-high-molecular-weight DNA was extracted from the samples, fluorescently labeled, and run on the Bionano Saphyr system. A total of 215 datasets, Inc.luding replicates, were generated, and analyzed successfully. Sample data were then analyzed using either disease-specific or pan-cancer-specific BED files to prioritize calls that are known to be diagnostically or prognostically relevant. Sensitivity, specificity, and reproducibility were 100%, 100%, and 96%, respectively. Following the validation, 14 cases and 10 controls were run and analyzed using OGM at three outside laboratories showing reproducibility of 96.4%. OGM found more clinically relevant SVs compared to SOC testing due to its ability to detect all classes of SVs at higher resolution. The results of this validation study demonstrate the superiority of OGM over traditional SOC methods for the detection of SVs for the accurate diagnosis of various hematological malignancies.

Screening for renal cell carcinoma in renal transplant recipients: a single-centre retrospective study.

OBJECTIVES: The primary objective of our study was to evaluate the effectiveness of renal cell carcinoma (RCC) screening in renal transplant (RT) recipients. DESIGN: Single-centre retrospective study. SETTING AND PARTICIPANTS: 1998 RT recipients who underwent RT at Memorial Hermann Hospital (MHH) Texas Medical Center (TMC) between 1 January 1999 and 31 December 2019 were included and we identified 16 patients (0.8%) with RCC. An additional four patients with RCC who underwent RT elsewhere but received follow-up at MHH TMC were also included. Subject races included white (20%), black (50%), Hispanic (20%) and Asian (10%). OUTCOME MEASURES: The RCC stage at diagnosis and outcomes were compared between patients who were screening versus those who were not. RESULTS: We identified a total of 20 patients with post-RT RCC, 75% of whom were men. The median age at diagnosis was 56 years. RCC histologies included clear cell (75%), papillary (20%) and chromophobe (5%). Patients with post-RT RCC who had screening (n=12) underwent ultrasound or CT annually or every 2 years, whereas eight patients had no screening. All 12 patients who had screening had early-stage disease at diagnosis (stage I (n=11) or stage II (n=1)) and were cured by nephrectomy (n=10) or cryotherapy (n=2). In patients who had no screening, three (37.5%) had stage IV RCC at diagnosis and all of whom died of metastatic disease. There was a statistically significant difference in RCC-specific survival in patients who were screened (p=0.01) compared with those who were not screened. CONCLUSION: All RT recipients who had RCC diagnosed based on screening had early-stage disease and there were no RCC-related deaths. Screening is an effective intervention in RT recipients to reduce RCC-related mortality.

Genomic profiling and sites of metastasis in non-small cell lung cancer.

Background: We investigated the biological predisposition to site of metastasis in patients with NSCLC based on their molecular profiling and program death ligand PD-L1 status. We sought to identify any association between metastatic site and molecular profile in NSCLC patients. Methods: This was a retrospective analysis of patients with stage IV NSCLC who were newly diagnosed from January 2014 to June 2022. Clinical characteristics, pathology, molecular reports, and imaging were retrieved and analyzed. Results: A total of 143 patients were included in the study. Median age was 65 years, with an equal number of men (n=71) and women (n=72). The most common histology was adenocarcinoma (81.8%). At least one genetic mutation was discovered in 100 patients. Mutations with a targetable drug were found in 86 patients. The most common mutations were TP53 (25.2%), EGFR (24.5%), KRAS/NRAS (20.3%), and CDKN2A/2B (7.7%). Patients with any mutation were significantly more likely to have metastatic disease to the brain (57% vs. 37%, p=0.03), but there was no difference in metastatic disease to bone (34% vs. 26%, p=0.32). Patients without a discoverable mutation were significantly more likely to have metastatic disease to other sites (e.g., adrenal gland 91% vs. liver 66%, p=0.002). There was no difference in progression-free survival (PFS) or overall survival (OS) between those with versus without mutations. Median PFS and OS were significantly longer in patients with an EGFR mutation than those with KRAS/NRAS or TP53 mutations. Patients with PD-L1 >1% or TP53 were significantly more likely to have metastatic disease to organs other than bone or brain (p=0.047 and p=0.023, respectively). We identified four prognostic groups in metastatic NSCLC. Patients with PD-L1 <1% and no actionable mutations have the poorest prognosis, with median survival of around 20 months. Conclusion: Patients with mutations discoverable on NGS are more likely to have metastatic disease to the brain. KRAS/NRAS in particular has a predilection to metastasize to the brain and bone. PD-L1 expression and a TP53 mutation, on the other hand, tend to lead to metastasis of NSCLC to organs other than brain or bone. These results need to be corroborated in larger prospective studies.

The Democratization of Hematology-Oncology Medical Education during the COVID-19 Pandemic.

Like many other aspects of hematology-oncology training, medical education experienced rapid changes throughout the COVID-19 pandemic that continue until today. We discuss some of the most transformative areas within medical education, including, but not limited to, educational philosophy; use of virtual resources; inter-institutional connections, shifts in clinical training; changes in recruitment practice; and attention to equity and diversity. Moreover, we add our own experiences to complement the limited literature addressing these topics. We conclude by highlighting some of the benefits of this unprecedented transformation in democratizing medical education that we hope endure beyond the pandemic.

Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity but Not Cardiomyocyte Proliferation.

BACKGROUND: Identifying genetic variants that affect the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity after permanent coronary artery ligation compared with infarcted DBA/2J (D2J) mice. METHODS: Cardiomyocyte cell cycle activity after infarction was monitored in D2J, (D2J×B6N)-F1, and (D2J×B6N)-F1×D2J backcross mice by means of bromodeoxyuridine or 5-ethynyl-2'-deoxyuridine incorporation using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus analysis, fine scale genetic mapping, whole exome sequencing, and RNA sequencing analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. RESULTS: (D2J×B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar compared with D2J mice (0.798±0.09% versus 0.056±0.004%; P<0.001). Quantitative trait locus analysis of (D2J×B6N)-F1×D2J backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of chromosome 3 (logarithm of the odds score=6.38; P<0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, Tnni3k (troponin I-interacting kinase) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of TNNI3K in a D2J genetic background results in elevated cardiomyocyte S-phase activity after injury. Cardiomyocyte S-phase activity in both Tnni3k-expressing and Tnni3k-nonexpressing mice results in the formation of polyploid nuclei. CONCLUSIONS: These data indicate that Tnni3k expression increases the level of cardiomyocyte S-phase activity after injury.

Lung Cancer Treatment Advances in 2022.

The therapeutic landscape of lung cancer treatment is changing rapidly, and new data was presented at the recently concluded American Society of Clinical Oncology 2022 (ASCO22) meeting. We highlight studies of clinical relevance that represent significant updates in the current management of non-small cell lung cancer (SCLC) and small cell lung cancer (NSCLC). We summarize the updates in early-stage NSCLC, mutated and non-mutated advanced NSCLC as well as small cell lung cancer (SCLC), and discuss these advances in the context of the current clinical standard of care.

Glutamic acid decarboxylase (GAD) antibody-positive paraneoplastic stiff person syndrome associated with mediastinal liposarcoma.

Stiff person syndrome (SPS) is a rare, debilitating neurological illness characterised by rigidity and spasms of the axial muscles, causing severe restrictions to mobility. SPS can be classic, partial or paraneoplastic. We report a case of a young woman who presented with seizures and painful spasms of the thoracolumbar muscles who was subsequently diagnosed with SPS. Serological work revealed glutamic acid decarboxylase (GAD) antibodies and imaging showed a large mediastinal mass. The patient underwent surgical resection of the mediastinal mass and final pathology revealed well-differentiated mediastinal liposarcoma. She received five sessions of plasma exchange and her neurological symptoms gradually improved after surgery. This case highlights a rare case of GAD antibody-positive paraneoplastic SPS associated with mediastinal liposarcoma.

Severe pulmonary toxicity related to carfilzomib use: a rare but serious side effect.

Carfilzomib is a selective proteosome inhibitor that is commonly used in the treatment of relapsed or refractory multiple myeloma. Carfilzomib has been commonly associated with respiratory side effects. It can rarely also cause fatal pulmonary toxicity. We present a case of a man in his 50s with plasma cell leukaemia who was initiated on treatment with carfilzomib and dexamethasone. He developed severe pneumonitis requiring oxygen via a high-flow nasal cannula. After an extensive workup, a temporal relationship between the carfilzomib use and exacerbation of the pulmonary symptoms was found. Carfilzomib was permanently discontinued, and the patient was started promptly on methyl prednisolone with complete resolution of his symptoms. Due to the associated risk of mortality if not detected early, we wish to highlight this rare but serious pulmonary toxicity associated with carfilzomib that was managed with high-dose glucocorticoids.

Durable remission with Bruton's tyrosine kinase inhibitor therapy in a patient with leptomeningeal disease secondary to relapsed mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin's lymphoma with a variable clinical course. Central nervous system (CNS) involvement is a rare and dreaded complication in MCL. We report a case of leptomeningeal relapse of MCL that was successfully treated with a single-agent Bruton's tyrosine kinase inhibitor. A man in his 50s with MCL was treated with six cycles of bendamustine-rituximab, achieving a complete remission (CR) and was subsequently placed on rituximab maintenance for 2 years. Four years later, he was hospitalised with symptoms of organic brain syndrome. Brain MRI and cerebrospinal fluid analysis confirmed CNS relapse of MCL. He was treated with dexamethasone, ibrutinib 560 mg/day and intrathecal cytarabine with improvement in neurological symptoms, and a follow-up MRI showed CR. The patient was later switched to acalabrutinib due to intolerance to ibrutinib. The patient is tolerating this regimen well, remaining in CR 3 years later.

Synchronous Diagnosis of Squamous Cell Carcinoma of the Lung and Mixed Cellularity Hodgkin Lymphoma of the Nasopharynx.

Hodgkin lymphoma (HL) is a highly curable B cell lymphoproliferative neoplasm with a bimodal age distribution. Lung cancer is the leading cause of cancer-related deaths in both sexes. We present a rare case of synchronous squamous cell carcinoma (SCC) of the lung and mixed cellularity HL of the nasopharynx. A gentleman in his 70s presented with right-sided chest pain and shortness of breath. CT of the chest showed a peripheral lung mass, and a biopsy confirmed SCC of the lung. The patient underwent a positron emission tomography/computed tomography (PET/CT) for staging that revealed an 18F-fluorodeoxyglucose (FDG)-avid mass in the nasopharynx. Flexible nasal endoscopy and biopsy of the nasopharyngeal mass revealed mixed cellularity classical HL. The patient was started on chemoimmunotherapy for lung cancer. Unfortunately, two months after initiation of treatment, the patient died from COVID-19 pneumonia and multiorgan failure.

Use of MASCC score in the inpatient management of febrile neutropenia: a single-center retrospective study.

PURPOSE: The Multinational Association for Supportive Care in Cancer (MASCC) score is used to risk stratify outpatients with febrile neutropenia (FN). However, it is rarely used in hospital settings. We aimed to describe management, use of MASCC score, and outcomes among hospitalized patients with FN. METHODS: We conducted a retrospective cohort study of patients with cancer and FN. We collected patient demographics, cancer characteristics, microbiological profile, MASCC score, utilization of critical care therapies, documentation of goals of care (GOC), and inpatient deaths. Outcomes associated with low- (≥ 21) versus high-risk (< 21) MASCC scores are presented as absolute differences. RESULTS: Of 193 patients, few (2%, n = 3) had MASCC scores documented, but when calculated, 52% (n = 101) had a high-risk score (< 21). GOC were discussed in 12% (n = 24) of patients. Twenty one percent (n = 40) required intermediate/ICU level of care, and 12% (n = 23) died in the hospital. Those with a low-risk score were 33% less likely to require intermediate/ICU care (95% CI 23 to 44%) and 19% less likely to die in the hospital (95% CI 10% to 27%) compared to those with high-risk score. CONCLUSIONS: MASCC score was rarely used for hospitalized patients with FN, but high-risk score was associated with worse outcomes. Education efforts to incorporate MASCC score into the workflow may help identify patients at high risk for complications and help clinicians admit these patients to a higher level of care (e.g., intermediate/ICU care) or guide them to initiate earlier GOC discussions.

Recurrent copy number variants associated with bronchopulmonary dysplasia.

BACKGROUND: Variability in the incidence and severity of bronchopulmonary dysplasia (BPD) among premature infants suggests that genetic susceptibility plays a role in pathogenesis. An assessment of copy number variants (CNV) in BPD subjects may help to identify loci that harbor genetic susceptibility factors. METHODS: We conducted a retrospective analysis of clinical DNA microarray data from our institution. We identified 19 BPD subjects, and 2 controls groups (full-term and preterm) with no lung-related disease. We reanalyzed raw data from each of these subjects to identify recurrent CNV loci in BPD subjects. RESULTS: We identified three loci (at 11q13.2, 16p13.3, and 22q11.23-q12.1) with recurrent CNV in BPD subjects. The frequency of these CNV was significantly higher in BPD subjects when compared with at least one control group. We interrogated 21 genes residing within the recurrent CNV regions for development-associated changes in expression. Fifteen genes demonstrated significant changes in expression between the pseudoglandular and canalicular stage in human lungs, a time commensurate with birth at highest risk for BPD. We also identified pathways represented by the genes present within the recurrent loci. CONCLUSION: These data identify novel loci that may harbor genes contributing to the genetic susceptibility of BPD.