Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B.

High-level MET amplification (METamp) is a primary driver in ∼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).

Clinical outcomes of hyperprogression based on volumetry in non-small cell lung cancer after immune checkpoint inhibitor treatment.

BACKGROUND: Hyperprogressive disease (HPD) is a novel pattern of the treatment course after immune checkpoint inhibitor (ICI) therapy in patients with non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics, outcomes, and associated factors of HPD using a semiautomatic volume measurement. METHODS: This retrospective study enrolled patients with recurrent and/or metastatic NSCLC treated with ICIs between January 2015 and August 2019 at eight tertiary centers in Korea. HPD was defined according to the tumor growth kinetics and time to treatment failure. Tumor volume was measured using a semiautomatic software. RESULTS: A total of 219 NSCLC patients with 35 HPD by volumetric measurement (HPDv) (15.9%) were enrolled. The median duration of overall survival (OS) and OS after ICI treatment (ICI-OS) were 34.5 and 18.4 months, respectively. HPDv patients had significantly worse progression-free survival (PFS) than progressive disease patients without HPDv (1.16 vs. 1.82 months, p-value <0.001). ICI-OS did not significantly differ between patients with HPDv and those without HPDv (2.66 vs. 5.4 months, p = 0.105). PD-L1 expression lower than 50%, more than three metastatic sites, neutrophil-to-lymphocyte ratio equal to or higher than 3.3, and hemoglobin level lower than 10 were found to be associated with HPDv. CONCLUSIONS: There is no standardized definition of HPD. However, defining HPD in NSCLC patients treated with ICI using a semiautomatic volume measurement software is feasible.

Prognostic Factors of Second-line Immune Checkpoint Inhibitors in Patients With Advanced-stage Non-Small Cell Lung Cancer: A Multicenter, Retrospective Study.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor-1 and its ligand have achieved impressive success in treating patients with advanced-stage non-small cell lung cancer (NSCLC) after failed first-line cytotoxic chemotherapy. However, knowledge on clinical biomarkers that could help select patients who will respond well to second-line ICI therapy is limited. PATIENTS AND METHODS: Medical records of patients with NSCLC treated with first-line platinum-based chemotherapy and subsequent second-line ICI were collected from 6 medical centers between January 2018 and June 2020. Clinical information, pathologic variables, and radiologic findings of the data collected were reviewed. The patients were followed up until the date of the last visit, the death of any cause, or the end of data recording (December 31, 2020). RESULTS: A total of 181 patients with NSCLC were treated with second-line ICI following first-line platinum-based doublet chemotherapy. The median progression-free survival was 2.0 months (interquartile range, 1.0 to 5.5 mo), and the median overall survival was 12.0 months (interquartile range, 6.0 to 20.0 mo). Low body mass index (BMI) was independently associated with progression-free survival (odds ratio [OR], 0.826; 95% confidence interval [CI], 0.723-0.945; P=0.005). Similarly, a low BMI (OR, 0.839; 95% CI, 0.740-0.952; P=0.005) and a high number of metastatic organs (OR, 1.682; 95% CI, 1.156-2.448; P=0.007) were independently associated with the overall survival after second-line ICI therapy. CONCLUSION: BMI and the number of metastatic sites were significantly associated with second-line ICI therapy outcomes in patients with NSCLC receiving first-line platinum-based chemotherapy.

rhEGF Treatment Improves EGFR Inhibitor-Induced Skin Barrier and Immune Defects.

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF's positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1α, IL-8, and TNF-α was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients' tissue evaluation, compared with controls, patients' Ki-67 and EGFR expression were decreased (p = 0.015, p = 0.001). Patients' IL-17 and TNF-α expression intensity was higher than that of the control group (p = 0.038, p = 0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely, patients' proportions of IL-17 and TNF-α were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.

A Randomized Controlled Trial of Epidermal Growth Factor Ointment for Treating Epidermal Growth Factor Receptor Inhibitor-Induced Skin Toxicities.

BACKGROUND: The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor-related skin adverse events (ERSEs). MATERIALS AND METHODS: This placebo-controlled, double-blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily. RESULTS: Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex-16 after treatment were significantly different among arms (mean ± SD: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and - 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm. CONCLUSION: EGF ointment is effective for managing ERSEs. It can also improve patients' QoL compared with placebo. Clinical trial identification number. NCT02284139 IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor-related skin adverse events.

Loss of Med1/TRAP220 promotes the invasion and metastasis of human non-small-cell lung cancer cells by modulating the expression of metastasis-related genes.

Med1/TRAP220 is an essential component of the TRAP/Mediator complex. In this study, we present a novel function of Med1 in human non-small-cell lung cancer (NSCLC) progression. We found that the loss of Med1 expression was strongly associated with increased rates of invasion and metastasis in NSCLC patients. Consistent with lung cancer patient data, the knockdown of Med1 in NSCLC cell lines led to an increase in cell migration and invasion. Med1-depleted cells displayed an increase in metastasis in a xenograft tumor model and in an in vivo metastasis assay. Moreover, a microarray analysis revealed that the mRNA levels of the metastasis-related genes uPAR, ID2, ID4, PTP4A1, PKP3, TGM2, PLD1, TIMP2, RGS2, and HOXA4 were altered upon Med1 knockdown. Collectively, these results suggest that the loss of Med1 increases the invasive potential of human NSCLC cells by modulating the expression of metastasis-related genes.

Liver cirrhosis as a delayed complication of Stevens-Johnson syndrome.

A 26-year-old woman was referred to our department due to fever and skin rash after having taken medication for a common cold. Physical examination revealed erythematous skin changes on her body associated with mucosal involvement in her eyes and oral cavity. Peripheral blood examination revealed leukopenia and thrombocytopenia. Liver function test showed hyperbilirubinemia. She was managed with high dose intravenous immunoglobulin (IVIG) at 1.0 gm/kg of body weight infused for 5 consecutive days. Although the patient's skin lesion improved dramatically with IVIG therapy, her hyperbilirubinemia aggravated progressively. Eighteen months after her presentation, liver cirrhosis was diagnosed by ultrasonography, laboratory and liver biopsy findings.

Absence of hyper-responsiveness to methacholine after specific bronchial provocation tests in a worker with hydroxyapatite-induced occupational asthma.

Hydroxyapatite is commonly used as a filler to replace amputated bone or as a coating to promote bone ingrowth into prosthetic implants. Many modern implants, such as hip replacements and dental implants, are coated with hydroxyapatite. We report a patient with occupational asthma due to hydroxyapatite, proven by a specific inhalation challenge, who experienced an early asthmatic reaction after exposure to hydroxyapatite, without increased airway responsiveness to methacholine despite an increased eosinophil count in the peripheral blood. A 38-year-old male dental implant worker visited our allergy department for the evaluation of occupational asthma. He had treated dental implant titanium surfaces with hydroxyapatite for 1.5 years. One year after starting his employment, he noticed symptoms of rhinorrhea, paroxysmal cough, and chest tightness. His symptoms were aggravated during and shortly after work and subsided several hours after work. When he stopped working for 2 months because of his chest symptoms, he became asymptomatic. After restarting his work, his symptoms reappeared and were aggravated. A methacholine bronchial challenge test had a negative response. The following day, a specific bronchial provocation test with wheat powder was negative. On the third day, a specific bronchial provocation test with hydroxyapatite powder produced an early asthmatic response. On the fourth day, a methacholine bronchial challenge test was negative. Further studies are needed to evaluate the exact pathogenetic mechanism of hydroxyapatite-induced occupational asthma.

A different TRAP220 expression in distinct histologic subtypes of lung adenocarcinoma and the prognostic significance.

Adenocarcinomas are a very heterogeneous subgroup of lung cancers, in which oncogenesis is linked to different molecular events. Recent evidence suggests that the hormonal status may contribute to the pathogenesis of lung adenocarcinoma. TRAP220 is the main subunit of the TRAP/Mediator complex and it binds to nuclear hormone receptors in the presence of their cognate ligand, as a cofactor of the transcription machinery. Since TRAP220 is an essential coactivator that interacts directly with estrogen receptor ß (ERß), we examined the expression of TRAP220 protein to investigate its role in lung adenocarcinoma, with particular attention being paid to its different histologic subtypes and the ERß expression. We performed immunohistochemical detection of TRAP220 and ERß protein in eighty-seven tissue samples from lung adenocarcinoma patients by using a tissue microarray, and Western blotting was then done to confirm the immunohistochemical observations. TRAP220 immunoreactivity was observed in 27 (31.0%) of the 87 adenocarcinoma cases. Analysis of the TRAP220 expression by Western blotting confirmed the immunohistochemical results. The TRAP220 expression was more frequently positive in the non-solid subtypes (bronchioloalveolar, acinar, and papillary patterns) than that in the solid subtype (P=0.027) and the TRAP220 expression was more frequently positive in the well-differentiated adenocarcinomas than that in the moderately or poorly differentiated adenocarcinomas (P=0.005). The tumors with a negative TRAP220 expression were larger in size (P=0.048) and they more frequently showed lymph node metastasis (P=0.002), pleural invasion (P=0.026) and an advanced TNM stage (P=0.012). The frequency of the TRAP220 expression in the cases with an ERß expression was significantly higher than that in those cases without an ERß expression (P=0.003). The Kaplan-Meier survival curves demonstrated that the patients with a positive TRAP220 expression had a significantly longer survival time than those patients with a negative TRAP220 expression (P=0.014). The multivariate analysis revealed that a TRAP220 expression was an independent good prognostic factor (P=0.049). Our data may be useful to understand the different biologic basis for the development and progression of the subtypes of lung adenocarcinoma.

Catamenial hemoptysis: a nationwide analysis in Korea.

BACKGROUND: Hemoptysis is a potentially serious clinical problem. However, there is no consensus on the clinical characteristics, treatment and patient outcome of catamenial hemoptysis. OBJECTIVE: Clinical characteristics, treatments and outcome in patients of catamenial hemoptysis were evaluated. METHODS: We conducted a retrospective nationwide observational analysis of Korean patients with catamenial hemoptysis. RESULTS: Nineteen patients with catamenial hemoptysis were evaluated from 13 tertiary-care hospitals in Korea. The median age of the patients was 25 years; 8 (42%) were ever-smokers. Eight patients were pathologically diagnosed; 11 were diagnosed by clinical criteria. Sixteen (84%) patients had a history of obstetric or gynecological procedures before developing hemoptysis. The mean amount of hemoptysis (mean +/- SD) was 58.3 +/- 71.3 for surgery, 46.4 +/- 33.2 for hormonal and 29.1 +/- 26.3 for conservative treatment groups. Hemoptysis did not recur in 8 (89%) of 9 patients after surgery. None of the patients in the hormonal or conservative treatment groups had persistent hemoptysis. There was an excellent outcome (complete remission and partial responses) in all patients with conservative treatment, suggesting that endometrial cells implanted into the lung may have a benign course. CONCLUSION: Patients without massive hemoptysis can be treated conservatively or with hormonal agents.

Forkhead box M1 expression in pulmonary squamous cell carcinoma: correlation with clinicopathologic features and its prognostic significance.

Forkhead box M1 (FoxM1) transcription factor has been shown to play important roles in regulating the expression of genes that are involved in cell proliferation, differentiation, and transformation by promoting both G(1)/S and G(2)/M transition. Although it has been reported that the FoxM1 signaling network is frequently deregulated with an up-regulated FoxM1 expression in human malignancies, the role of FoxM1 in lung cancer remains to be determined. We performed immunohistochemical detection of FoxM1 protein in 69 tissue samples from patients with primary pulmonary squamous cell carcinoma using a tissue microarray, and Western blotting was done to confirm the immunohistochemical observations. FoxM1 immunoreactivity was observed in 26 (37.7%) of the 69 squamous cell carcinoma cases. Analysis of the FoxM1 expression in 12 squamous cell carcinoma tissues and 2 normal lung tissues by Western blotting confirmed the immunohistochemical results. A FoxM1 expression was more frequently detected in the moderately or poorly differentiated squamous cell carcinomas than in the well-differentiated squamous cell carcinomas (P = .008). The tumors with a positive FoxM1 expression more frequently showed lymph node metastasis (P = .027) and an advanced American Joint Committee on Cancer stage (P = .049). The Kaplan-Meier survival curves demonstrated that patients with a positive FoxM1 expression had a significantly shorter survival time than those patients with a negative FoxM1 expression (P = .003). The multivariate analysis revealed that the FoxM1 expression was an independent poor prognostic factor (P = .018). A subset of pulmonary squamous cell carcinoma with a FoxM1 expression was associated with progressive pathologic features and an aggressive clinical course.

Epigenetic silencing of human T (brachyury homologue) gene in non-small-cell lung cancer.

Early detection of lung cancer is challenging due to a lack of adequate biomarkers. To discover novel tumor suppressor genes (TSGs) silenced by aberrant promoter methylation, we analyzed the gene expression profiles of two lung adenocarcinoma cell lines using pharmacologic-unmasking and subsequent microarray-analysis. Among 617 genes upregulated, we selected 30 genes and investigated the methylation status of their promoters by bisulfite sequencing analysis. Aberrant methylation was detected in four genes (CRABP2, NOEY2, T, MAP2K3) in at least one lung adenocarcinoma cell lines. Furthermore, the T promoter was methylated in 60% of primary lung adenocarcinomas versus 13% of non-malignant lung tissues. Conversely, RT-PCR analysis revealed T expression was low in lung tumors, while high in normal tissues. In addition, no non-synonymous mutations related to gene silencing were found. While further analysis is warranted, our results suggest that T has the potential to be a novel candidate TSG in lung cancer.

Fascin immunoreactivity for preoperatively predicting lymph node metastases in peripheral adenocarcinoma of the lung 3 cm or less in diameter.

OBJECTIVE: Fascin is an actin-bundling protein that induces cell membrane protrusions and increases the motility of normal and transformed epithelial cells. We evaluated the expression of fascin by performing immunohistochemistry to determine its role in the progression of small-size peripheral lung adenocarcinomas and to elucidate its utility as a preoperative novel therapeutic option. METHODS: Immunohistochemistry for fascin was performed in 49 peripheral adenocarcinomas of 25% (high grade). RESULTS: Overall, fascin immunoreactivity was detected in 30 (61.2%) out of the total 49 cases. The tumors with high-grade fascin immunoreacivity tended to more frequently show lymph node metastasis (P = 0.0007), lymphovascular invasion (P = 0.0084) and a higher stage (P = 0.05). There was no significant association with age, gender, tumor size and the histological subtype. The 2mm-sized TMA cores, which were considered as a substitute for percutaneous needle biopsy sample in this study, showed concordant results with the CWT section (kappa = 0.836). CONCLUSIONS: We suggest that fascin immunoreactivity may identify the subsets of peripheral adenocarcinomas of the lung 3 cm or less in diameter that have a different potential to metastasize to the regional lymph nodes. The evaluation of fascin immunoreactivity on the preoperative biopsy sample could be a novel therapeutic strategy for selecting the most appropriate therapy for small-size pulmonary adenocarcinomas.

Diffuse alveolar hemorrhage associated with antineutrophil cytoplasmic antibody levels in a pregnant woman taking propylthiouracil.

Propylthiouracil (PTU) is known to be a potential cause of antineutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis, resulting in glomerulonephritis and diffuse alveolar hemorrhage (DAH). Herein, we describe a 25-year-old pregnant woman who developed a perinulcear ANCA (p-ANCA) and myeloperoxidase ANCA (MPO-ANCA) positive DAH during PTU therapy. The patient improved after corticosteroid therapy and discontinuation of the PTU. Methimazole was prescribed in spite of the risk of recurrence of DAH because of the pregnancy. The patient is currently free from pulmonary problems. Our case shows that the alternative agent, methimazole, can be used to treat hyperthyroidism in a pregnant patient with PTU associated DAH.

Gene Expression Profiling of Non-Small Cell Lung Cancer.

PURPOSE: cDNA microarray provided a powerful alternative, with an unprecedented view scope, in monitoring gene expression levels, and led to the discovery of regulatory pathways involved in complicated biological processes. This study was performed to gain better understanding of the molecular mechanisms underlying the carcinogenesis and progression of lung cancer. MATERIALS AND METHODS: Using a cDNA microarray, representing 4, 600 cDNA clusters, we studied the expression profiles in 10 non-small cell lung cancer (NSCLC) samples and the adjacent noncancerous lung tissues form the same patients. The alterations in the levels of gene expression were confirmed by reverse-transcription PCR in 10 randomly selected genes. RESULTS: Genes that were differently expressed in the cancerous and noncancerous tissues were identified. One hundred and nine genes (of which 68 were known) and 69 cDNAs (of which 32 were known) were up- and down-regulated in>70% of the NSCLC samples, respectively. In the cancerous tissues, the genes related to the cell cycle, metabolism, cell structure and signal transduction, were mostly up-regulated. Furthermore, we identified a few putative tumor suppressor genes that had previously been proposed by other workers. CONCLUSION: S: These results provide, not only a new molecular basis for understanding the biological properties of NSCLC, but also useful resources for the future development of diagnostic markers and therapeutic targets for NSCLC.