Proteasome inhibition paradoxically degrades gain-of-function mutant p53 R273H in NSCLC and could have therapeutic implications.

Lung cancer is the leading cause of cancer mortality. Despite therapeutic advances in recent years, new treatment strategies are needed to improve outcomes of lung cancer patients. Mutant p53 is prevalent in lung cancers and drives several hallmarks of cancer through a gain-of-function oncogenic program, and often predicts a poorer prognosis. The oncogenicity of mutant p53 is related to its stability and accumulation in cells by evading degradation by the proteasome. Therefore, destabilization of mutant p53 has been sought as a therapeutic strategy, but so far without clinical success. In this study, we report that proteasome inhibition results in degradation of mutant p53 in non-small cell lung cancer (NSCLC) cell lines bearing the R273H mutant protein and show evidence that this was mediated by hsp70. NSCLC cell lines with the mutant R273H allele demonstrated increased susceptibility and apoptosis to proteasome inhibitors. These data suggest that proteasome inhibitors could have therapeutic implications in some subsets of TP53 mutated NSCLC.

Rates of Occult Invasive Disease in Patients With Biopsy-Proven Oral Cavity Squamous Cell Carcinoma in Situ.

Importance: The likelihood that an oral cavity lesion harbors occult invasive disease after biopsy demonstrating carcinoma in situ (CIS) is unknown. While de-escalated treatment strategies may be appealing in the setting of CIS, knowing whether occult invasive disease may be present and its association with survival outcomes would lead to more informed management decisions. Objective: To evaluate rate of occult invasive disease and clinical outcomes in patients with oral cavity CIS. Design, Setting, and Participants: This was a retrospective population-based cohort study using the National Cancer Database and included adults with biopsy-proven oral cavity CIS as the first diagnosis of cancer between 2004 and 2020. Data were analyzed from October 10, 2022, to June 25, 2023. Exposures: Surgical resection vs no surgery. Main Outcomes and Measures: Analyses calculated the rate of occult invasive disease identified on resection of a biopsy-proven CIS lesion. Univariate and multivariate logistic regression with odds ratios and 95% CIs were used to identify significant demographic and clinical characteristics associated with risk of occult invasion (age, year of diagnosis, sex, race and ethnicity, oral cavity subsite, and comorbidity status). Kaplan-Meier curves for overall survival (OS) were calculated for both unresected and resected cohorts (stratified by presence of occult invasive disease). Results: A total of 1856 patients with oral cavity CIS were identified, with 122 who did not undergo surgery (median [range] age, 65 [26-90] years; 48 female individuals [39.3%] and 74 male individuals [60.7%]) and 1458 who underwent surgical resection and had documented pathology (median [range] age, 62 [21-90] years; 490 female individuals [33.6%] and 968 male individuals [66.4%]). Of the 1580 patients overall, 52 (3.3%) were Black; 39 (2.5%), Hispanic; 1365 (86.4%), White; and 124 (7.8%), other, not specified. Among those who proceeded with surgery with documented pathology, 408 patients (28.0%) were found to have occult invasive disease. Higher-risk features were present in 45 patients (11.0%) for final margin positivity, 16 patients (3.9%) for lymphovascular invasion, 13 patients (3.2%) for high-grade invasive disease, and 14 patients (3.4%) for nodal involvement. For those patients with occult disease, staging according to the American Joint Committee on Cancer's AJCC Cancer Staging Manual, eighth edition, was pT1 in 341 patients (83.6%), pT2 in 41 (10.0%), and pT3 or pT4 disease in 26 (6.4%). Factors associated with greater odds of occult invasive disease at resection were female sex, Black race, and alveolar ridge, vestibule, and retromolar subsite. With median 66-month follow-up, 5-year OS was 85.9% in patients who proceeded with surgical resection vs 59.7% in patients who did not undergo surgery (difference, 26.2%; 95% CI, 19.0%-33.4%). Conclusions and Relevance: This cohort study assessed the risk of concurrent occult invasion with biopsy-proven CIS of the oral cavity, demonstrating that 28.0% had invasive disease at resection. Reassuringly, even in the setting of occult invasion, high-risk disease features were rare, and 5-year OS was nearly 80% with resection. The findings support the practice of definitive resection if feasible following biopsy demonstrating oral cavity CIS.

Clinical predictors of premature radiotherapy terminations in senior adults with oral cavity and laryngeal carcinoma.

INTRODUCTION: The underlying factors that contribute to early radiotherapy (RT) termination are understudied, especially in the era of hypofractionated treatment regimens. In this retrospective investigation, we examined the characteristics and causes of premature RT terminations in senior adults (>70 years old) with oral cavity (OC) and laryngeal carcinomas. METHODS: Hundred and eighty-eight patients treated with RT ± systemic therapy for OC and laryngeal cancer from 2017 to 2022 were identified. Premature termination was defined as completion of less than 95% of the prescribed RT. Logistic regression analysis was performed to examine factors predictive of premature termination, and survival was determined using the Kaplan-Meier method. RESULTS: Twenty patients (10.6%) experienced premature RT terminations. On regression analysis, ECOG score at initiation of RT was the only covariate studied to be independently associated with premature termination (OR 2.00, 95%CI: [1.21, 3.30], p = 0.007). Three-year overall survival (49.1% vs. 77.3%) was significantly reduced in the termination cohort (p < 0.0001). CONCLUSIONS: This analysis demonstrated over 1 in 10 patients had premature RT termination, which prognosticated inferior survival outcomes. Poor performance status may highlight patients at risk for premature termination and thus identify good candidates for hypofractionated protocols.

Profile of Capmatinib for the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC): Patient Selection and Perspectives.

Aberrant c-MET (Mesenchymal-Epithelial Transition) signaling contributes to cancer cell development, proliferation, and metastases of non-small cell lung cancer (NSCLC). MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. Capmatinib, the focus of this review article, is a highly selective MET inhibitor approved for use in patients with METex14 mutated NSCLC. In this review, we discuss cMET as a target, the pharmacology of capmatinib, key trials of capmatinib in MET-altered lung cancer, and toxicity profile. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.

A multidisciplinary approach to treating a unique case of recurrent metastatic thymic carcinoma: case report.

Thymic carcinoma (TC) is a rare and aggressive malignancy of the thymus associated with less than 25% 5 years survivability. Our case report showcases the successful treatment of advanced metastatic TC using a multidisciplinary approach and the utility of checkpoint inhibitors in treatment of recurrent TC. A 50-year-old man presented with Raynaud's phenomenon and was found to have a stage IVb TC (T3N2M0). Eight months after management with neoadjuvant chemotherapy, surgical resection and adjuvant chemoradiotherapy, patient was diagnosed with metastasis of TC to the liver and a concurrent stage III (T2N1M0) primary sigmoid colon adenocarcinoma. Following complete resection of the colon adenocarcinoma, the patient started palliative-intent treatment for TC with pembrolizumab given PD-L1 tumor proportionate score of 100%. This resulted in a sustained complete response for 38 months. Our patient did have immune-related adverse events involving multiple organs but was able to continue pembrolizumab for a standard treatment duration of 2 years with multidisciplinary care. When recurrent disease was noted in a portocaval lymph node, pembrolizumab was reinitiated and a second complete response was achieved. The patient has maintained that complete response while maintaining an acceptable quality of life, showing that treatment with pembrolizumab is effective in patients after discontinuation with prior immunotherapy.

Fighting Thymic Carcinoma: A Story of Immunotherapy and Multidisciplinary Care Triumph The thymus is a gland located in the chest that plays a major role in the immune system, particularly before adulthood. Thymic carcinoma (TC) is a type of cancer affecting the thymus that is often challenging to treat given its inadequate response to chemotherapy and tendency to spread to other organs. A 50-year-old man was found to have advanced stage thymic carcinoma, which is associated with a less than 25% 5-year survival rate. Eight months after completing a rigorous treatment protocol of chemotherapy, surgery and radiation therapy, his original thymic cancer was found to have metastasized to the liver. Simultaneously, he was diagnosed with stage III sigmoid colon cancer. He underwent curative surgery for colon cancer and was started on pembrolizumab for thymic cancer. Pembrolizumab is an immunotherapy drug that boosts the body's own immune system to fight against the cancer. Inadvertently, it can turn immune cells against healthy tissues, which results in symptoms called immune-related adverse events (irAEs). Indeed, he experienced various irAEs involving multiple organs. These events were effectively managed by involving multiple specialists and initiating medications to calm the immune system and allow him to continue immunotherapy. He had a complete response to treatment and was able to complete the standard treatment course of two years. He retained a complete response for over three years before his tumor recurred. He was restarted on pembrolizumab and achieved a complete response again. This case highlights a unique presentation of metastatic TC and the utility of a multidisciplinary approach for treatment to maintain a high quality of life five years after diagnosis.

Characteristics of Patients With Second Primary Lung Cancer Following Breast Cancer: A Retrospective Descriptive Study.

BACKGROUND: Breast cancer (BC) is the most common noncutaneous malignancy in women and survivors are at an increased risk for secondary malignancy with lung cancer (LC) being the most common. There are few studies that have explored the clinicopathological specifics of LC in BC survivors. METHODS: In this single-institution, retrospective study, we identified BC survivors who subsequently developed LC, examined their breast and LC clinical and pathological characteristics and compared them to the general BC and LC population as published in the literature. RESULTS: In our study, we found the following associations that could be meaningful: an association between receiving radiation (RT) and LC (including a statistically significant P = .03 chance of ipsilateral LC after BC treatment with RT), a higher incidence and amount of smoking and LC, high BRCA positivity (78.9%) in the few patients who had germline testing, and a higher incidence of EGFR mutations in NSCLC after BC (60.9%) as well as an earlier stage of NSCLC disease. CONCLUSION: Treatments such as RT, genetic factors such as BRCA mutations, and tobacco use may increase the risk of developing LC amongst BC survivors. Exploring this further can potentially lead to better risk stratification through modified low-dose CT chest screening protocols to catch LCs earlier and ultimately improve outcomes. Past studies have shown that BC survivors who are subsequently diagnosed with NSCLC may have improved OS compared with primary NSCLC and our study showed a high incidence of EGFR mutated NSCLC, which also suggest both improved prognosis and a different molecular profile of NSCLC, which warrants further investigation. Lastly, BC survivors who subsequently are diagnosed with NSCLC had earlier stage disease in our study, perhaps a result of surveillance, highlighting the importance of close monitoring of BC survivors.

Safety and Efficacy of Immune Checkpoint Inhibitors in Cancer Patients and Preexisting Autoimmune Disease: A Systematic Review and Meta-Analysis in Non-Small-Cell Lung Cancer.

BACKGROUND: Cancer patients with preexisting autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for toxicity. As indications for ICI expand, more data are needed on the safety and efficacy of ICI treatment in cancer patients with AID. METHODS: We systematically searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events. Outcomes of interest include incidence of autoimmune flare, irAE, response rate, and ICI discontinuation. Study data were pooled using random-effects meta-analysis. RESULTS: Data were extracted from 24 cohort studies, consisting of 11,567 cancer patients (3774 NSCLC patients and 1157 with AID). Pooled analysis revealed an AID flare incidence of 36% (95% CI, 27%-46%) in all cancers and 23% (95% CI, 9%-40%) in NSCLC. Preexisting AID was associated with an increased risk of de novo irAE in all cancer patients (RR 1.38, 95% CI, 1.16-1.65) and NSCLC patients (RR 1.51, 95% CI, 1.12-2.03). There was no difference in de novo grade 3 to 4 irAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, preexisting AID was associated with a 2-fold increased risk of de novo grade 3 to 4 irAE (RR 1.95, 95% CI, 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95% CI, 1.19-2.04). CONCLUSIONS: NSCLC patients with AID are at a higher risk of grade 3 to 4 irAE but are more likely to achieve treatment response. Prospective studies focused on optimizing immunotherapeutic strategies are needed to improve outcomes for NSCLC patients with AID.

Harmine loaded Au@MSNs@PEG@Asp6 nano-composites for treatment of spinal metastasis from lung adenocarcinoma by targeting ANXA9 in vivo experiment.

Background: Annexin A9 (ANXA9) has been proved to be concerned with cancer development. However, to explore the clinical consequences of ANXA9 in lung adenocarcinoma (LUAD), especially its correlation to spinal metastasis (SM) has no in-depth study. The study was expected to elucidate the mechanism of ANXA9 in regulating SM of LUAD and create a productive nano-composites delivery system targeting this gene for treatment of SM. Methods: Harmine (HM), a ß-carboline extracted from the traditional Chinese herb Peganum harmala, loaded Au@MSNs@PEG@Asp6 (NPS) nano-composites were synthesized. Bioinformatics analysis and clinical specimens' tests were used to verify the association between ANXA9 and prognosis of LUAD with SM. The immunohistochemistry (IHC) was employed to detect the expression levels of the ANXA9 protein in LUAD tissues with or without SM, and its significance in clinic was also explored. ANXA9­siRNA was applied to investigate the molecular mechanism of ANXA9 in tumor behaviors. The HM release kinetics was detected by high performance liquid chromatography (HPLC) method. The cellular uptake efficiency of nanoparticles by A549 cells was observed by fluorescence microscope. Antitumor effects of nanoparticles were assessed in the nude mouse model of SM. Results: The genomic amplification of ANXA9 was prevalent in LUAD tissues and closely associated with poor outcome and SM (P<0.01). The experimental result manifested that high expression of ANXA9 could lead to wretched prognosis and ANXA9 was an independent risk factor for survival (P<0.05). After impeding expression of ANXA9, the proliferation and metastatic ability of tumor cells obviously decreased, and expression of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9) were considerably downregulated, while the expression of associated oncogene pathway were downregulated (P<0.01) as well. The synthesized HM-loaded NPS nano-composites could target to cancer and response to reactive oxygen species (ROS) to release HM slowly. Notably, in comparison to free HM, the nano-composites showed excellent targeting and anti-tumor effects in the A549 cell-bearing mouse model. Conclusions: ANXA9 may serve as a novel biomarker for predicting poor prognosis in LUAD, and we provided an efficient and targeting drug delivery nano-composites system for precise treatment of SM from LUAD.

Implementing physician education to increase lung cancer screening uptake.

Aim: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. The US Preventive Services Task Force and National Comprehensive Cancer Network recommend annual low-dose computed tomography (LDCT) for eligible adults. We conducted a study to assess physician LDCT referral patterns. Methods: The study was divided into a pre-, intervention, and post-intervention periods. The intervention was a LC screening educational series. We evaluated rates of LDCT screening referrals during pre- and post-intervention periods. Results: In the pre-intervention period, 75 patients fulfilled US Preventive Services Task Force and/or National Comprehensive Cancer Network criteria and 27% underwent LDCT. In the post-intervention period, 135 patients fulfilled either screening criteria of whom 61.5% underwent LDCT. Conclusion: In our study, educational lectures improved compliance significantly and should be used as tool for primary care providers to effectively increase LDCT screening referrals.

Efficacy of ketamine mouthwash in the management of oral and pharyngeal toxicity associated with head and neck chemoradiotherapy: protocol for a phase II, Simon's two-stage trial.

INTRODUCTION: Curative intent treatment of head and neck cancer (HNC) is frequently radiation therapy over 7 weeks with concurrent chemotherapy. This regimen is effective but carries a burden of toxicity leading to severe pain and treatment breaks portending inferior outcomes. Conventional palliation methods include opioids, anticonvulsants and local anaesthetics. Breakthrough toxicities are nevertheless ubiquitous and present an urgent unmet need. Ketamine is an inexpensive drug with mechanisms of analgesia outside the opioid pathway including N-methyl-D-aspartate (NMDA) receptor antagonism and a pharmacologically unique property of opioid desensitisation. Systemic ketamine is validated in randomised controlled trials for efficacy in reducing pain and/or opioid burden in the oncologic setting. Literature supports peripherally administered ketamine for pain control without systemic toxicity. These data support our rationale of using ketamine mouthwash to decrease acute toxicity of curative treatment of HNC, the efficacy of which is our aim to elucidate. METHODS AND ANALYSIS: This is a phase II, Simon's two-stage trial. Patients have pathologically confirmed HNC and an intended regimen of 70 Gy of radiation with concurrent cisplatin. The protocol is initiated on diagnosis of grade 3 mucositis and consists of 2 weeks of 4 times daily (QID) ketamine mouthwash use. The primary endpoint is pain response defined as a combination of pain score and opioid use. 23 subjects will be enrolled in stage 1. If statistical criteria are met, 33 subjects will be enrolled in stage 2. Secondary endpoints include daily pain, daily opioid use, dysphagia at baseline and completion, nightly sleep quality, feeding tube placement and any unscheduled treatment breaks. ETHICS AND DISSEMINATION: All trial data will be stored in an Institutional Review Board (IRB) approved database. The protocol is registered under Northwell IRB registration number #22-0292 and U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) approval has been granted under IND number 161609. Results are intended to be published in an open-source journal and further data, statistics and source documents are available on request. TRIAL REGISTRATION NUMBER: NCT05331131.

Expression patterns and clinical significance of estrogen receptor in non-small cell lung cancer.

BACKGROUND: Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERß expression patterns by gender, cancer cell type, and receptor location in lung cancer. METHODS: We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords "lung cancer," "estrogen receptor," and "immunohistochemistry." We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. RESULTS: We examined 4874 lung cancers from 5011 patients. ERß is the predominant form of ER expressed, mainly found in the nucleus. The ERß positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERß was associated with a better prognosis. CONCLUSION: We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERß with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.

Osteoradionecrosis versus Cancer Recurrence: An Unresolved Clinical Dilemma.

INTRODUCTION: Osteoradionecrosis is a rare and debilitating risk of definitive chemoradiotherapy for head and neck squamous cell carcinoma. It is difficult to distinguish between osteoradionecrosis and recurrent or progressive disease, as clinical and radiologic features may be similar. Our aim was to compare the clinical presentation and radiologic features of osteonecrosis with those of recurrent or progressive cancer. METHODS: We conducted a single-center case series of 19 patients with head and neck squamous cell carcinoma diagnosed between 2011 and 2019 who subsequently developed clinical and/or radiological suspicion of osteoradionecrosis. The population was a referred sample from head and neck cancer physicians at Northwell Health Cancer Institute. Clinician notes and imaging reports were reviewed to assign a final diagnosis of either cancer, osteonecrosis, or indeterminate. RESULTS: No differences were found in the clinical presentation or radiologic features between groups. Median time between treatment and development of symptoms was longer in patients with a final diagnosis of osteoradionecrosis than recurrent or progressive disease (5 vs. 3 months), but this difference was not statistically significant. Radiation dose and type were not associated with diagnosis. Mean standard uptake value maximums on positron emission tomography/computed tomography were significantly higher in the cancer group (median 14.8 vs. 9.1, p < 0.0152). At 1 year after first suspicion of osteoradionecrosis, 100% of osteoradionecrosis patients were alive, versus 28.6% of cancer patients. DISCUSSION/CONCLUSION: There is significant overlap in clinical and radiologic features of osteoradionecrosis and cancer. Standard uptake maximums may be helpful in predicting diagnosis. Occurrence of symptoms within 6 months of completing chemoradiotherapy should raise the concern for malignancy.

One size does not fit all: Evaluating disparities in lung cancer screening eligibility amongst the Hispanic population.

Lung cancer (LC) is the leading cause of cancer death among Hispanic men. We assessed the tendencies for screening eligibility amongst Hispanic prior to LC diagnosis according to the NCCN and The USPSTF guidelines available at the time of diagnosis. We conducted an observational study in patients diagnosed with LC from 2016 to 2019. Charts were reviewed to assess their screening eligibility prior to LC. The chi-square test was used to examine the association between race and ethnicity with each screening criteria. A total of 530 subjects were reviewed, of which 432 were included in the analysis. One hundred fifty-three and 245 subjects were ineligible for screening under NCCN and USPSTF criteria prior to their LC diagnosis. Twenty-eight of the subjects who did not fulfill NCCN criteria identified as AA and 12 as Hispanics. Forty and 20 of the USPSTF screening ineligible subjects identified as AA and Hispanics. There was a significant association between screening eligibility criteria in Hispanics, with 52% Hispanic subjects meeting NCCN criteria compared to only 20% who met USPSTF (p=0.0184). There was also a significant association between ethnicity and USPSTF eligibility criteria (p=0.0166), as 80% of Hispanic subjects were screening ineligible under USPSTF criteria compared to 56% of non-Hispanic or other. In our study, Hispanics had significantly lower tendencies of meeting the USPSTF LC screening eligibility criteria than non-Hispanics or other. Interestingly, a proportionally higher number of Hispanics who were ineligible under USPSTF criteria met NCCN criteria. These findings suggest that leniency in the screening criteria can possibly lead to earlier detection of LC in high-risk individuals. Recently, USPSTF has modified their criteria which may benefit more of these individuals. To improve rates of screening and overall mortality of minorities, organizations should continue to re-evaluate and liberalize their screening guidelines.

Assessing the methodological quality of quality-of-life analyses in first-line non-small cell lung cancer trials: A systematic review.

BACKGROUND: Non-cytotoxic therapy has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients. With unique mechanisms of action, these agents have decidedly improved survival and have demonstrated an improved toxicity profile. However, the real-life experience of the patient, which is commonly assessed by health-related quality of life (HRQoL) measurement, is not clearly established with this new generation of lung cancer treatments. The heterogeneity created by specific patient subgroups and different therapeutics calls for a tailored-approach to analyzing patient-reported outcomes. The objective of this systematic review was to assess the methodological quality of HRQoL analysis in Randomized Clinical Trials (RCTs) involving biologic agents to treat NSCLC. METHODS: A systematic literature search was performed using Medline, Embase, and Web of Science databases to identify NSCLC RCTs published between January 1st, 2000 and January 1st, 2020 reporting HRQoL measures. Only RCTs that both enrolled previously untreated patients with advanced NSCLC and had HRQoL analysis were included. RESULTS: 4203 abstracts were screened, of which only 85 RCTs met inclusion and exclusion criteria for analysis. The most applied HRQoL assessment tools were the EORTC-QLQ-C30 (47, 55.3 %), and EORTC-QLQ-LC13 (35, 41.2 %). The median number of verified CONSORT-PRO Extension criteria in the included trials was 3, and only in 10 (11.8 %) trials were all criteria well-documented. Notably, only 21 (24.7 %) RCTs performed subgroup analyses to specifically evaluate HRQoL in different patient populations. CONCLUSION: QoL reporting in clinical trials is inconsistent and the quality of QoL measures adopted in a majority of trials is suboptimal. Considering the fact that NSCLC is a biologically diverse disease and that the treatments differ based on patient and tumor-specifics, efforts should be pursued to tailor QoL measures for different subsets of this patient population in addition to mandating QoL reporting in clinical trials. We believe that this is necessary to understand the real-life experience of lung cancer patients in the era of personalized medicine.

The Evolving Role of PD-L1 Inhibition in Non-Small Cell Lung Cancer: A Review of Durvalumab and Avelumab.

Non-small cell lung cancer (NSCLC) was traditionally associated with a poor prognosis. Between 2010 and 2016, the 5-years overall survival for all stages combined was about 25 percent. However, the recent use of immunotherapy has led to significant improvements in progression free survival (PFS) and overall survival (OS). Immune check point inhibitors enable the host immune system to mount a lethal response against tumor cells. Both PD-1 (nivolumab, pembrolizumab, cemipilimab) and PD-L1 inhibitors (atezolizumab and durvalumab) have been approved by the FDA for use in NSCLC, either as individual agents or in combination with platinum-based chemotherapy, radiation therapy, or other agents. As the future of immunotherapy for lung cancer continues to evolve, with multiple agents approved or in various stages of clinical research, it is imperative that we understand the mechanism of action, clinical activity, ongoing clinical trials, indications for use and toxicity for individual agents in addition to having general, basic knowledge about this new class of cancer therapeutics. In this review, we focus on two of the newer PD-L1 inhibitors, durvalumab and avelumab.

American Head and Neck Society Endocrine Surgery Section and International Thyroid Oncology Group consensus statement on mutational testing in thyroid cancer: Defining advanced thyroid cancer and its targeted treatment.

BACKGROUND: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence-based statement on the definition of advanced thyroid cancer and its targeted systemic treatment. METHODS: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel. RESULTS: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided. CONCLUSIONS: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted.

Missed Opportunities? An Observational Analysis of Lung Cancer Screening Utilization Amongst Patients With Lung Cancer.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. The U.S. Preventive Services Task Force (USPSTF) and National Comprehensive Cancer Network (NCCN) recommend annual low-dose CT chest (LDCT) for LC screening in high-risk adults who meet appropriate criteria, which primarily focus on age and smoking history. Despite this, screening rates remain low and patients with LC are typically diagnosed at a later stage.We conducted a single-center retrospective analysis of patients with an established diagnosis of lung cancer to evaluate if screening guidelines were appropriately followed before the cancer diagnosis.Patients diagnosed with LC between 2016 and 2019 were included in the analysis. Charts were reviewed for demographics, detailed smoking history, as well as histology and stage of LC. Associations between categorical factors and screening were examined using the chi-square test. Associations between continuous and ordinal factors and screening were examined using the Mann-Whitney test.A total of 530 charts were reviewed, of which 52% met NCCN criteria and 35% met USPSTF criteria. Only 4.0% and 4.8% of patients who met NCCN and USPSTF criteria, respectively, underwent screening. There was a significant association between staging at diagnosis and screening with LDCT. All the patients who had screening CT scans were diagnosed at localized stages of lung cancer in both NCCN and USPSTF groups compared to 49.1% and 48% in eligible subjects that did not undergo screening, respectively.Our study showed that despite established guidelines for LC screening and insurance coverage, a vast majority of screening-eligible LC patients have never had LDCT. We found that patients who underwent screening as per guidelines were diagnosed at earlier stages of the disease. Ongoing efforts to increase awareness and adherence to LC screening guidelines are needed to improve early detection and reduce LC mortality.

Forming the Hematology-Oncology Collaborative Videoconferencing (CO-VID) Learning Initiative: Experiential Lessons Learned From a Novel Trainee-Led Multidisciplinary Virtual Learning Platform.

PURPOSE: COVID-19 challenged medical practice and graduate medical education. Building on previous initiatives, we describe and reflect on the formative process and goals of the Hematology-Oncology Collaborative Videoconferencing Learning Initiative, a trainee-led multi-institutional virtual COVID-19 learning model. METHODS: Clinical fellows and faculty from 13 US training institutions developed consensus needs, goals, and objectives, recruited presenters, and generated a multidisciplinary COVID-19 curriculum. Weekly Zoom conferences consisted of two trainee-led instructional segments and a trainee-moderated faculty Q&A panel. Hematology-oncology training program faculty and trainees were the targeted audience. Leadership evaluations consisted of anonymized baseline and concluding mixed methods surveys. Presenter evaluations consisted of session debriefs and two structured focus groups. Conference evaluations consisted of attendance, demographics, and pre- or postmultiple-choice questions on topic learning objectives. RESULTS: In 6 weeks, the initiative produced five conferences: antivirals, anticoagulation, pulmonology, provider resilience, and resource scarcity ethics. The average attendance was 100 (range 57-185). Among attendees providing both pre- and postconference data, group-level knowledge appeared to increase: antiviral (n = 46) pre-/postcorrect 82.6%/97.8% and incorrect 10.9%/2.2%, anticoagulation (n = 60) pre-/postcorrect 75%/93.3% and incorrect 15%/6.7%, and pulmonary (n = 21) pre-/postcorrect 66.7%/95.2% and incorrect 33.3%/4.8%. Although pulmonary management comfort appeared to increase, comfort managing of antivirals and anticoagulation was unchanged. At the conclusion of the pilot, leadership trainees reported improved self-confidence organizing multi-institutional collaborations, median (interquartile range) 58.5 (50-64) compared with baseline 34 (26-39), but did not report improved confidence in other educational or leadership skills. CONCLUSION: During crisis, trainees built a multi-institutional virtual education platform for the purposes of sharing pandemic experiences and knowledge. Accomplishment of initiative goals was mixed. Lessons learned from the process and goals may improve future disaster educational initiatives.

A real world analysis of first line treatment of advanced EGFR mutated non-small cell lung cancer: A multi-center, retrospective study.

INTRODUCTION: The recently published FLAURA trial demonstrated that osimertinib has remarkable efficacy in front-line setting for non-small cell lung cancer (NSCLC). While this has transformed current practice, there are no effective treatments following progression on osimertinib. The aim of our study was to compare progression-free survival (PFS) and overall survival (OS) between patients initiated on osimertinib to those started on other EGFR TKIs. METHODS: This was a multicenter, retrospective study conducted at two large academic centers. Adult patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received EGFR therapy between 2014 and 2019 were included. Patients were dichotomized based on front-line TKI (osimertinib vs. other). PFS, OS, and time-to-discontinuation were evaluated. RESULTS: One-hundred seventy-two patients were included in the final analysis. Fifty-two (30.2%) patients received osimertinib and 120 (69.8%) patients received another EGFR TKI. The PFS rates at 6, 12, and 18 months were 86.3%, 79.5%, 69.8% in the osimertinib group and 86.6%, 64.2%, 39.3% in the other EGFR TKI group, respectively (p < 0.0036).Estimated OS at 6, 12, and 18 months was similar for both groups: 94.2%, 94.2%, 80.2% and 95.7%, 93.9%, 84.1%, respectively [Adjusted HR = 0.95 (95% CI, 0.37-2.44; p < 0.9128]. CONCLUSION: Osimertinib demonstrated greater 12 and 18 month PFS compared to other EGFR TKIs. This finding is consistent with results of the FLAURA trial. However, unlike FLAURA, there were no differences in estimated OS between the two groups in our study. Further research to evaluate optimal sequencing strategies in the real world of first, second and third generation TKIs is needed.