Metastatic Lung Carcinoma Research Articles

Lichen spinulosus in a patient undergoing Atezolizumab therapy for metastatic squamous cell lung carcinoma

Lichen spinulosus in a patient undergoing Atezolizumab therapy for metastatic squamous cell lung carcinoma

8248 Glucocorticoid Induced Adrenal Crisis Masked By Metastatic Lung Carcinoma

Abstract Disclosure: N. Abrahimi: None. A. Abrahimi: None. Background: Chronic glucocorticoid use of three weeks or longer can cause hypothalamic-pituitary-adrenal axis inhibition by negative feedback, causing adrenal suppression. (1) Adrenal crisis is diagnosed by an acute clinical decompensation, persistent hypotension that resolves with high dose steroid administration. (2) Adrenal crisis is precipitated by several causes such as illness, dehydration, trauma, emotional distress and sometimes due to no identifiable cause. (2) Clinical Case: 64-year-old male past medical history of lung carcinoma metastatic to mediastinum who presented to the hospital with tachycardia. On presentation, patient was tachycardic, tachypneic, and hypotensive. Labs significant for WBC 22, Na+ 129, K+ 3.2, Cr 3.4. Patient received 2.5 L bolus of NS and was given one dose of azithromycin due to concern for sepsis. After fluid resuscitation, hypotension and tachycardia resolved. Presenting symptoms included ongoing nausea, decreased appetite and malaise for several weeks. Repeat labs post fluid resuscitation showed resolution of leukocytosis, improvement of AKI, and repletion of electrolytes. CT chest abdomen pelvis showed questionable pneumonia, however, consolidations were difficult to distinguish from known malignant masses. Clinical picture was not consistent with pneumonia and so additional antibiotics were held. Several hours later, blood pressure decreased, and patient began requiring vasopressors. Cefepime was started given concern for septic shock. Nearly 48 hours after initiation of broad-spectrum antibiotics hypotension persisted and patient remained on vasopressors. Given clinical decline, etiology of shock was reconsidered. Patient reported daily prednisone use over the last several months for COPD management. Given high clinical suspicion of adrenal crisis in setting of chronic steroid use and glucocorticoid withdrawal, patient was started on hydrocortisone 100 mg every 8 hours. Shortly after initiation of stress dosed steroids, the patient was successfully weaned off vasopressors with complete resolution of hypotension. Conclusion: Presentation and symptoms of adrenal insufficiency and crisis including nausea, anorexia, fatigue, malaise, hypotension and electrolyte abnormalities are nonspecific, can go unrecognized and be masked by other disease processes, such as metastatic cancer. (1) Adrenal crisis is life threatening and must be diagnosed and treated early to prevent mortality. (2) Therefore, adrenal crisis should always be on the differential in patients who present with shock.

P1.09B.02 Double Lung Transplantation in Patients with Metastatic Lung-limited Non-Small Cell Lung Carcinoma (NSCLC)

P1.09B.02 Double Lung Transplantation in Patients with Metastatic Lung-limited Non-Small Cell Lung Carcinoma (NSCLC)

1274P Osimertinib versus first/second generation tyrosine kinase inhibitors as first-line therapy for metastatic EGFR-mutated non-small cell lung carcinoma: Overall survival using real-world data from TriNetX platform

1274P Osimertinib versus first/second generation tyrosine kinase inhibitors as first-line therapy for metastatic EGFR-mutated non-small cell lung carcinoma: Overall survival using real-world data from TriNetX platform

1368P Correlation between depth of response at 6 months and survival in patients (pts) with metastatic non-small cell lung carcinoma (mNSCLC): SPORE trial

1368P Correlation between depth of response at 6 months and survival in patients (pts) with metastatic non-small cell lung carcinoma (mNSCLC): SPORE trial

Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study

BackgroundCheckpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel.MethodsMEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a “significant IrAE” (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs.DiscussionThe pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment.Trial RegistrationThe study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

Unlikely Cohabitants: A Collision Tumor of Metastatic Small Cell Lung Carcinoma and Adrenal Adenoma

Unlikely Cohabitants: A Collision Tumor of Metastatic Small Cell Lung Carcinoma and Adrenal Adenoma

Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.

3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p<0.001) and PFS (fold change 3.395, p<0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]

Double lung transplantation in patients with metastatic lung-limited non-small cell lung carcinoma (NSCLC): A case series.

8643 Background: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. Double lung transplantation (DLT) may offer curative treatment for metastatic lung-limited NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 02/2024 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study cohort A (NCT05671887). Exclusion criteria includes presence of extrapulmonary disease. Results: Six patients with stage IVA NSCLC who underwent lung transplantation were included. Five (83.3%) patients underwent double lung, and one (16.7%) patient single lung transplantation. Four (66.7%) patients had invasive mucinous, and two (33.3%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-71; one (16.7%) was Asian, five (83.3%) were White, four (66.7%) were male, and three (50%) had a history of smoking. One (16.7%) patient had a past medical history of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). The median pretransplant treatment lines were 2 (1-5). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C > T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 28, 18, 8, 8, 5, and 4-month posttransplant follow-up. Conclusions: Six patients underwent DLT successfully without significant complications. All patients were alive and in good health. Ongoing DREAM study will continue to investigate the role of DLT in metastatic lung-limited NSCLC patients (especially in pN0). Clinical trial information: NCT05671887 .

#2108 Secondary amyloidosis in a cancer patient on pembrolizumab—an unusual finding

Abstract Background and Aims With the widening horizon of ICPIs in the management of oncological disorders, we require to remain vigilant of the possible iRAEs. We present a case report of secondary amyloidosis in at metastatic non-small cell lung carcinoma (NSCLC) patient treated with Pembrolizumab. We aim to describe the clinic-biological & histopathological characteristics of ICPI-related kidney injury which may be beyond interstitial nephritis & its response to treatment & the role of kidney biopsy to define ICPI-related kidney injury. Treatment is challenging due to a paucity of relevant data, implicating further studies. Treatment with colchicine and steroids, tocilizumab in the setting of elevated interleukin-6 (IL6) levels have been reported in case series; unfortunately no appreciable renal benefit were noted. Method 77 year male, diabetic & hypertensive on regular medication for >15 yr, reformed smoker (≈50 pack-years of cigarette) diagnosed with NSCLC (EGFR–wild type, PDL1–70%), received Pembrolizumab (13 cycles) & Paclitaxel + Carboplatin & was in remission. Follow up PET showed partial response—new lesions in brain. Gemcitabine added to the treatment & had received 2 cycles, till hospitalization with febrile episode, decreased oral intake & progressive edema. Clinical evaluation was non-contributory. Hematology & biochemical evaluation (Table 1) showed raised serum creatinine 1.1 mg/dL (baseline 1 mg/dL), urinalysis—2+ protein, quantification showed 2.9295 g/24 h → 6.38 g/24 h (baseline uPCR-0.19 g/g). Abdominal ultrasound & ECHO finding were not conclusive. Fundoscopy showed no evidence of proliferative diabetic or hypertensive retinopathy. Results Kidney Biopsy (Figure) was done. LM showed, few of 8 gloms with mild segmental mesangial expansion due to amorphous extracellular deposits which was PAS & silver negative but showed congophilia (Fig. A,B,C,D). If negative for albumin, IgG, IgA, C3, C1q & had 1+ granularity in the mesangium on IgM staining & showed no light chain restriction in glomeruli & tubular cast for kappa & lambda. IHC (Fig. E) was positive for serum amyloid associated proteins. EM revealed minimal subendothelial & mesangial expansion due to extracellular material organized into randomly arranged fine fibrils, & no significant foot process effacement, electron dense deposits along the capillary basement membrane or within mesangium, glomerular basement membrane, thereby excluding possibility of light chain deposition disease. Conclusion Secondary amyloidosis with ICPI use has uncommonly & with Pembrolizumab rarely been reported. Treatment is challenging due to paucity of literature. Hassan Izzedine et al. in their case series, on Pembrolizumab treated cancer patient [N = 676], showed 12 patients (7 men) (Incidence 1.77%) developed AKI (n = 10) &/or Proteinuria (n = 2), median duration of use 9 months. All (n = 12) underwent renal biopsy, which showed AIN in 4, ATI in 5, MCD in 2. Recovery happened with withdrawal of drug coupled with corticosteroid. Reintroduction resulted in more severe recurrence of AIN in 1 patient only. Lapman et al. reported 1 case of secondary amyloidosis in cancer patients treated with Pembrolizumab. 42yr male Caucasian, had no reported chronic illness, except Asthma. Similarly developed significant proteinuria (Urine Pro 3+) & AKI (Sr. Creat 1.58 mg/dl; Baseline 1.0 mg/dl) after 90 days of Pembrolizumab therapy. Under went 2 Kidney Biopsy–1st Biopsy revealed AA amyloid. AA amyloidosis was attributed to Pembrolizumab as repeat Bx revealed progressive deposits despite remission of malignancy, but his kidney disease progressed, and had to be initiation on maintenance hemodialysis. Stopping Pembrolizumab & corticosteroids led to resolution of proteinuria in our patient too.

Antibody-Drug Conjugates as Novel Therapeutic Agents for Non-Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers.

KRAS as a Prognostic and Predictive Marker in Metastatic Non-Small Cell Lung Carcinoma: A Systematic Review.

Metastatic non-small cell lung cancer (NSCLC) poses a significant clinical challenge, prompting a focused investigation into the role of KRAS mutations in prognosis and treatment response. Targeted therapies offer promising avenues for intervention, motivating a comprehensive analysis of existing evidence. Conducted in June 2023, our review delved into MEDLINE (Medical Literature Analysis and Retrieval System Online), Embase, Scopus, and the Cochrane Register of Controlled Trials. Rigorous inclusion and exclusion criteria guided the selection of 12 articles, comprising two randomized controlled trials (RCTs) and 10 observational studies. Multiple investigators independently executed data extraction, evaluating prognostic factors (overall and progression-free survival) and predictive outcomes (treatment and objective response). The Newcastle-Ottawa Scale (NOS) and modified Jadad scores were used for study quality assessment of observational studies and RCTs, respectively. From an initial pool of 120 articles, the 12 selected studies, spanning 2013 to 2022, encompassed 2,845 metastatic NSCLC patients. KRAS mutations, particularly the G12C variant, emerged as a pivotal factor influencing treatment response. Notably, KRAS wild type patients displayed enhanced responses to platinum-based chemotherapy, while those with KRAS mutations exhibited favourable outcomes with immune checkpoint inhibitors (ICIs). The role of KRAS mutations as prognostic indicators in metastatic NSCLC is underscored by this systematic review, with implications for both survival and treatment response. The discernment between KRAS wild type and mutant patients offers insights into tailored therapeutic strategies, with platinum-based chemotherapy and immune checkpoint inhibitors emerging as context-dependent options. Nevertheless, more research is required to solidify the predictive role of KRAS and explore the efficacy of KRAS inhibitors and other targeted therapies, paving the way for refined and personalized interventions in the management of metastatic NSCLC.

Effects of reprogrammed splenic CD8+ T-cells in vitro and in mice with spontaneous metastatic Lewis lung carcinoma

BackgroundMetastatic disease is a major and difficult-to-treat complication of lung cancer. Considering insufficient effectiveness of existing therapies and taking into account the current problem of lung cancer chemoresistance, it is necessary to continue the development of new treatments.MethodsPreviously, we have demonstrated the antitumor effects of reprogrammed CD8+ T-cells (rCD8+ T-cells) from the spleen in mice with orthotopic lung carcinoma. Reprogramming was conducted by inhibiting the MAPK/ERK signalling pathway through MEKi and the immune checkpoint PD-1/PD-L1. Concurrently, CD8+ T-cells were trained in Lewis lung carcinoma (LLC) cells. We suggested that rCD8+ T-cells isolated from the spleen might impede the development of metastatic disease.ResultsThe present study has indicated that the reprogramming procedure enhances the survival and cytotoxicity of splenic CD8+ T-cells in LLC culture. In an LLC model of spontaneous metastasis, splenic rCD8 + T-cell therapy augmented the numbers of CD8+ T-cells and CD4+ T-cells in the lungs of mice. These changes can account for the partial reduction of tumors in the lungs and the mitigation of metastatic activity.ConclusionsOur proposed reprogramming method enhances the antitumor activity of CD8+ T-cells isolated from the spleen and could be valuable in formulating an approach to treating metastatic disease in patients with lung cancer.

Mutational Profiling by Next-Generation Sequencing in Patients with Metastatic Non-Small Cell Lung Carcinoma: Our Experience

Introduction According to GLOBOCAN 2020, overall lung cancer is the second most common cancer in both sexes (11.4%) accounting for highest cancer-related mortality (18%).1 Adenocarcinoma subtype of non-small cell lung cancer (NSCLC) is the most common subtype and is divided into further molecular subtypes based on oncogenic driver mutations. Overall survival in these patients is poor with the use of conventional platinum-based double chemotherapy and various recent studies on targeted therapy studies have showed improved survival. Therefore, broad panel-based testing like next-generation sequencing (NGS) is strongly recommended to identify these targetable driver mutations. Aims and Objectives The aim of this study was to evaluate the mutational profile in patients with metastatic NSCLC (mNSCLC) by NGS method. Materials and Methods A hospital-based prospective observational study done on 88 patients under the Department of Medical Oncology, State Cancer Institute during a period of 1 year. All patients above 18 years of age diagnosed as mNSCLC having Eastern Cooperative Oncology Group performance status 0 to 2 and evaluated for mutational profiling by NGS method were included. Five gene panel tests including endothelial growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK), BRAF, mesenchymal epithelial transition (MET), and ROS proto-oncogene 1 (ROS1) were used. Results and Observations Majority of mNSCLC cases were in the age group of 41 to 50 years (n = 30, 34.1%) with average age at presentation being 53.74 years. Male: female ratio was 1.14:1 and most patients were nonsmokers. Adenocarcinoma subtype of mNSCLC cases had the highest mutational burden (n = 55, 62.5%). EGFR (n = 32, 56.14%) was the most common mutation followed by EML4-ALK (n = 19, 33.33%). Most common EGFR mutation was in Exon 19. Other rare mutations were ROS1 (n = 4), BRAF V600E (n = 1), and MET (n = 1). Skeleton was the most common site of metastasis across all driver mutations. Conclusion EGFR and EML4-ALK were the commonest targetable mutations detected in the study. As there is very limited data from North Eastern region of India regarding mutational status in mNSCLC, this study opens up possibilities for further studies targeting multiple mutations to give us more comprehensive understanding of the mutational landscape of mNSCLC in this era of precision medicine.

Influence of allogeneic mesenchymal stem cells of red bone marrow culture on the development of Lewis lung epidermoid carcinoma in vivo

The relevance of this study is conditioned by the widespread use of stem cells in veterinary medicine, a wide range of studies and ambiguous data on the oncoprotective properties of stem cells of different origins. In this regard, the purpose of this study was to investigate the course of the tumour process in Lewis lung carcinoma and the specific features of the effect of allogeneic mesenchymal stem cells of red bone marrow culture on it. The leading approach to investigating this problem was the method of modelling Lewis lung carcinoma in C57BL6 mice and the use of stem cells. The use of allogeneic mesenchymal stem cells from the bone marrow culture of C57BL6 mice with transplanted epidermoid metastatic carcinoma of the Lewis lung contributed to the activation of the tumour process. Under the influence of allogeneic mesenchymal stem cells of red bone marrow culture from Day 14 to Day 24 of the study, the body weight of mice decreased by 7.0-12.1% (P < 0.05) compared to the control, the diameter of the primary tumour increased by 1.43-1.51 times (P < 0.05), which is conditioned by the activation of primary tumour growth. The number of lymphocytes as producers of vascular growth factor in primary tumour tissue under the influence of allogeneic mesenchymal stem cells of red bone marrow culture significantly increased by 1.47 and 1.52 times on Day 18 of the experiment compared to animals of the control group and placebo (P < 0.05), respectively. This promoted angiogenesis in the primary tumour node and metastasis through the circulatory system. After administration allogeneic mesenchymal cells of red bone marrow culture to mice, a larger volume of lung metastases was recorded, which was 41.52±7.9 mm3 compared to the values in the control and placebo groups, respectively, 17.94±6.59 and 16.43±5.32 mm3 . The morphological picture of the histological sections of the primary tumour of Lewis lung carcinoma confirms all the signs of qualitative and quantitative indicators of its progression. The findings obtained are of both theoretical and practical value for clinical veterinary medicine on the use of allogeneic bone marrow mesenchymal stem cells in tumour processes

Abstract 2030: N-cadherin-mediated activation of PI3K/Akt pathway following application of tumor treating fields (TTFields)

Abstract Introduction: Tumor Treating Fields (TTFields) therapy is FDA-approved for the treatment of glioblastoma and unresectable pleural mesothelioma, and has recently demonstrated benefit (together with an immune checkpoint inhibitor) for the treatment of metastatic non-small cell lung carcinoma (NSCLC) progressing on or after platinum-based therapy. The current study aimed to uncover cellular response mechanisms to TTFields. Methods: A2780 ovarian cancer cells and H1299 NSCLC cells were treated with TTFields for 72 h (200 and 150 kHz, respectively; 1.7 V/cm RMS). Changes in signaling pathways were analyzed using the Luminex multiplex assay and validated by protein expression. Fluorescence microscopy, calcium switch assay, antibody neutralization assay, and immunoprecipitation were employed to investigate the mechanism of action. The efficacy of concomitant treatment with TTFields and a potential inhibitor was tested in cell lines (cytotoxic and clonogenic effects) and two orthotopic mouse models: MOSE-L-FFL ovarian cancer and LL/2 lung cancer. Immunohistochemistry was performed on tumor sections from both models. Results: Increased AKT phosphorylation was observed in the cancer cells treated with TTFields. N-cadherin, known to be involved in the activation of the PI3K/AKT pathway, was elevated in the membranes of cells treated with TTFields. Elimination of calcium ions required for N-cadherin homophilic ligation abrogated TTFields-induced AKT phosphorylation, whereas calcium supplementation restored AKT phosphorylation. Inhibition of N-cadherin-mediated cell-cell contacts by neutralizing antibody resulted in a significant reduction in TTFields-induced AKT phosphorylation. Pull-down assays with an anti-N-cadherin antibody demonstrated increased recruitment of the p85 regulatory subunit of PI3K to N-cadherin complexes following TTFields application. TTFields-induced activation of AKT could be mitigated in cell cultures as well as in animal models by application of the PI3K inhibitor alpelisib. Co-treatment with alpelisib also enhanced the effectiveness of TTFields in vitro and in vivo. Conclusions: The PI3K/AKT signaling pathway, activated via cell-cell N-cadherin interactions, plays a role in the cancer cell response to TTFields treatment. Inhibiting the PI3K/AKT pathway may potentially sensitize tumors to TTFields. Citation Format: Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer-Tov, Rom Paz, Lilach Koren, Kerem Wainer-Katsir, Alexandra Volodin, Bella Koltun, Boris Brant, Yiftah Barsheshet, Tal Kan, Cfir David, Tharwat Haj Khalil, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. N-cadherin-mediated activation of PI3K/Akt pathway following application of tumor treating fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2030.

KRT13 and UPK1B for differential diagnosis between metastatic lung carcinoma from oral squamous cell carcinoma and lung squamous cell carcinoma

Oral squamous cell carcinomas unusually show distant metastasis to the lung after primary treatment, which can be difficult to differentiate from primary squamous cell carcinoma of the lung. While the location and number of tumor nodules is helpful in diagnosing cases, differential diagnosis may be difficult even with histopathological examination. Therefore, we attempted to identify molecules that can facilitate accurate differential diagnosis. First, we performed a comprehensive gene expression analysis using microarray data for OSCC-LM and LSCC, and searched for genes showing significantly different expression levels. We then identified KRT13, UPK1B, and nuclear receptor subfamily 0, group B, member 1 (NR0B1) as genes that were significantly upregulated in LSCC and quantified the expression levels of these genes by real-time quantitative RT-PCR. The expression of KRT13 and UPK1B proteins were then examined by immunohistochemical staining. While OSCC-LM showed no KRT13 and UPK1B expression, some tumor cells of LSCC showed KRT13 and UPK1B expression in 10 of 12 cases (83.3%). All LSCC cases were positive for at least one of these markers. Thus, KRT13 and UPK1B might contribute in differentiating OSCC-LM from LSCC.

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

Metastatic micropapillary cervical adenocarcinoma presenting as a cystic neck mass: a diagnostic pitfall that can be mistaken with metastatic papillary thyroid carcinoma

Abstract Introduction/Objective Micropapillary endocervical adenocarcinoma is a rare aggressive variant of cervical adenocarcinoma with a high propensity for lymphovascular spread and poor outcomes. A 69-year-old woman presented with bilateral neck masses for 6 months. Imaging showed multiple multilocular cystic lateral neck masses. Fine needle aspiration was non-diagnostic. A core biopsy showed a papillary adenocarcinoma positive for TTF-1, Napsin-A, and PAX-8 immunostains, and negative for thyroglobulin, interpreted as metastatic papillary carcinoma of possible lung or thyroid origin. Further imaging of the head, neck, and thorax did not reveal a clear primary, but there was extensive involvement of the neck and mediastinal lymph nodes. Given the disease distribution and prominent cystic change in the nodal metastases, the patient underwent total thyroidectomy, bilateral neck, and mediastinal dissections for a presumed thyroid primary. No tumor was found in the thyroid gland. On follow-up the patient was noted to have normal serum thyroglobulin and retroperitoneal lymphadenopathy on PET/CT scan, prompting the search for a pelvic source. Additional immunostains performed in existing samples showed strong estrogen and progesterone receptor expression suggesting a gynecologic primary. At reevaluation, it was found that the patient had postmenopausal bleeding for a year. The colposcopy examination was normal, but a pap smear showed adenocarcinoma. An endocervical biopsy confirmed a micropapillary variant of endocervical adenocarcinoma. Methods/Case Report case report Results (if a Case Study enter NA) NA Conclusion Micropapillary carcinomas occur at multiple sites and are associated with the prominent lymphovascular spread and poor outcomes. The association of prominent neck and mediastinal lymphadenopathy, papillary architecture, cystic metastases, and coexpression of TTF-1, Napsin-A, and PAX-8 led to an erroneous presumption of a thyroid primary. This case highlights how overlapping immunomorphological features between thyroid and gynecologic tumors with papillary architecture, anchoring and confirmation biases, and suboptimal anamnesis can lead to an erroneous diagnosis.

Abstract 18533: Exploring the Rising Incidence of Myocarditis and Other Cardiovascular Adverse Events of Nivolumab and Ipilimumab: Analysis of FDA Adverse Event Reporting System Database

Introduction: Nivolumab and Ipilimumab are human monoclonal antibodies that target cell surface PD1 and anti-CTLA-4 receptors respectively. Nivolumab and ipilimumab combination is used for metastatic small cell lung carcinoma, advanced renal cell carcinoma and metastatic melanoma. The pre-approval CHECKMATE trials have underestimated the occurrence of cardiovascular adverse events (AEs). In contradiction, post-marketing studies have demonstrated a higher incidence of cardiac AEs, particularly myocarditis.Therefore, it is important to establish a post-marketing safety profile of these medications. Methods: We investigated the cardiovascular AEs of nivolumab and ipilimumab using U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Healthcare professionals (HCPs) reported 79.73% and 80.92% of AEs until March 2023 for nivolumab and ipilimumab respectively. We conducted further subgroup analysis of cardiovascular AEs in male, females as well as in three age groups: 18-64, 65-85 and >85 years. Results: Amongst the cardiovascular AEs reported by HCPs, myocarditis was reported in 905 (1.55 %) in nivolumab vs 445 (1.72%) in ipilimumab group. There were higher reports of other cardiovascular AEs including heart failure (1.15% vs 0.74%), pericarditis/pericardial effusion (1.19% vs 0.6% ), myocardial infarction (0.18% vs 0.71%), cardiomyopathy (0.36% vs 0.29%), cardiac arrest (0.41% vs 0.53%) and cardiac death (0.01% vs 0.02%) in nivolumab vs ipilimumab. On sub-group analysis, we observed higher incidence of myocarditis in females (1.54% vs 1.6%) males (1.73% vs. 1.84%) and in patient with age 18-65 years (1.17% vs 1.15%) in both nivolumab vs ipilimumab group as compared to previous studies. Conclusions: The reported events of myocarditis were significantly higher in FAERS reporting as compared to the CHECKMATE trials (<1%) in both nivolumab and ipilimumab groups. Clinicians need to be vigilant in detecting immune-mediated myocarditis, as it often manifests with nonspecific symptoms, with early onset and rapid progression. Given the growing utilization of these medications, it is imperative to conduct additional randomized controlled trials to gain a better understanding of their cardiovascular safety profile.