Case Report: Durable therapy response to Osimertinib in rare EGFR Exon 18 mutated NSCLC.

Up to 20% of all non-small cell lung cancer patients harbor tumor specific driver mutations that are effectively treated with tyrosine kinase inhibitors. However, for the rare EGFR deletion-insertion mutation of exon 18, there is very little evidence regarding the effectiveness of tyrosine kinase inhibitors. A particular challenge for clinicians in applying tyrosine kinase inhibitors is not only diagnosing a mutation but also interpreting rare mutations with unclear therapeutic significance. Thus, we present the case of a 65-year-old Caucasian male lung adenocarcinoma patient with an EGFR Exon 18 p.Glu709_Thr710delinsAsp mutation of uncertain therapeutic relevance. This patient initially received two cycles of standard platinum-based chemotherapy without any therapeutic response. After administration of Osimertinib as second line therapy, the patient showed a lasting partial remission for 12 months. Therapy related toxicities were limited to mild thrombocytopenia, which ceased after dose reduction of Osimertinib. To our knowledge, this is the first report of effective treatment of this particular mutation with Osimertinib. Hence, we would like to discuss Osimertinib as a viable treatment option in EGFR Exon 18 p.Glu709_Thr710delinsAsp mutated lung adenocarcinoma.

Long-term response to pimitespib in postoperative recurrent gastrointestinal stromal tumors with PDGFRA D842V mutation: a case report.

BACKGROUND: Exon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation. CASE PRESENTATION: A 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation. CONCLUSIONS: We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.

Exon-18-EGFR Mutated Transformed Small-Cell Lung Cancer: A Case Report and Literature Review.

Small-cell lung cancer (SCLC) transformation from EGFR mutant adenocarcinoma is a rare entity that is considered to be a new phenotype of SCLC. While transformation from adenocarcinoma (ADC) with EGFR exon 19 deletions and exon 21 L858R point mutations has been described, to our knowledge, no cases of transformation to SCLC from exon-18-mutated ADC have been reported. We reported a clinical case of a patient with exon-18-EGFR-transformed SCLC, and we performed a systematic review of the literature.

Real-life comparison of afatinib and erlotinib in non-small cell lung cancer with rare EGFR exon 18 and exon 20 mutations: a Turkish Oncology Group (TOG) study.

OBJECTIVES: To compare the survival of first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with rare EGFR exon 18 and exon 20 mutation-positive non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively evaluated survival characteristics of 125 patients with EGFR exon 18 and exon 20 mutated NSCLC who received erlotinib or afatinib as first line treatment between 2012 and 2021 from 34 oncology centres. Since exon 20 insertion is associated with TKI resistance, these 18 patients were excluded from the study. RESULTS: EGFR exon 18 mutations were seen in 60%, exon 20 mutations in 16%, and complex mutations in 24% of the patients with NSCLC who were evaluated for the study. There were 75 patients in erlotinib treated arm and 50 patients in afatinib arm. Patients treated with erlotinib had progression-free survival time (PFS) of 8.0 months and PFS was 7.0 months in the afatinib arm (p = 0.869), while overall survival time (OS) was 20.0 vs 24.8 months, respectively (p = 0.190). PFS of exon 18 mutated arm was 7.0 months, exon 20 mutated arm was 4.3 months, and complex mutation positive group was 17.3 months, and this was statistically significant (p = 0.036). The longest OS was 32.5 months, seen in the complex mutations group, which was not statistically different than exon 18 and in exon 20 mutated groups (21.0 and 21.2 months, respectively) (p = 0.323). CONCLUSION: In this patient group, especially patients with complex mutations are as sensitive to EGFR TKI treatment similar to classical mutations, and in patients with rare exon 18 and exon 20 EGFR mutation both first- and second-generation EGFR-TKIs should be considered, especially as first- and second-line options.

Efficacy of EGFR-Tyrosine Kinase Inhibitors for advanced non-small cell lung cancer patients harboring rare EGFR mutations of exon 18 E709X.

EGFR-tyrosine kinase inhibitors (TKIs) show efficacy against lung cancer, and afatinib has been used as a standard therapy for patients with non-small cell lung cancer (NSCLC) with EGFR rare mutations such as S768I, G719X, and L861Q. However, the efficacy of EGFR-TKIs against NSCLC with EGFR rare mutations of exon 18 E709X has been less studied. The present study aimed to analyze the efficacy and safety of EGFR-TKIs in NSCLC patients with rare mutations. Our study enrolled 15 NSCLC patients with exon 18 E709X mutation who were admitted to Zhejiang Cancer Hospital. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were analyzed. The ORR of the entire cohort of patients was 33.3%. The PFS of all patients with exon 18 E709X mutations was 10.9 months. The OS was not reached. The PFS of patients with exon 18 E709-T710delinsD and E709A/G/K mutations showed no significant difference (5.3 vs. 13.5 months, P = 0.238). A significant difference in OS was observed between patients with exon 18 E709-T710delinsD mutation and those with E709A/G/K mutation (12.2 months vs. not reached, P = 0.029). No significant difference in efficacy was observed between second- and third-generation TKIs for NSCLC patients with exon 18 E709X mutations (PFS: 13.5 vs. 10.9 months, P = 0.774; OS: 17.1 months vs. not reached, P = 0.072). New treatment-related adverse events were not observed. NSCLC patients with exon 18 E709X mutations may benefit from treatment with second- or third-generation EGFR-TKIs.

Successful sequential tyrosine kinase inhibitors to overcome a rare compound of EGFR exon 18-18 and EGFR amplification: A case report.

Background: New mutational detection techniques like next-generation sequencing have resulted in an increased number of cases with uncommon mutation and compound mutations [3%-14% of all epidermal growth factor receptor (EGFR) mutations]. In rare exon 18 mutations (3%-6%), G719X and E709X represent the majority, but CMut associating these exon 18 points mutations are even rarer, making the understanding of the impact of epidermal growth factor receptor tyrosine kinase inhibitors still limited. Three generations of EGFR tyrosine kinase inhibitors (TKIs) are available to target EGFR mutations, but according to the types of mutations, the sensitivity to TKI is different. Afatinib, osimertinib, and neratinib have showed some effectiveness in single exon 18, but no report has precisely described their efficiency and acquired mechanism of resistance in a CMut of exon 18-18 (G719A and E709A). Case presentation: We report a case of a 26-year-old woman with bilateral advanced adenocarcinoma of the lung harboring a compound mutation associating G719A and E709A in exon 18, who developed an EGFR amplification as resistance mechanism to osimertinib. She presented a significant clinical and morphological response under sequential TKIs treatment (afatinib, osimertinib, and then neratinib). Conclusion: A non-small cell lung cancer (NSCLC) with rare compound mutation exon 18-exon 18 (G719A and E709A) and EGFR amplification can be overcome with adapted sequential second- and third-generation TKIs. This report has potential implications in guiding decisions for the treatment of these rare EGFR mutations.

L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment.

Osimertinib, a mutant-specific third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is emerging as the preferred first-line of treatment for EGFR-mutant lung cancer. However, osimertinib resistance inevitably develops among patients treated with the drug. The modal resistance mechanisms of osimertinib include the occurrence of epithelial transition factor (c-MET) amplification and C797S mutation, whereas rare mutations are presented as case reports. Recently, the L718Q/V mutation in exon 18 of EGFR has been reported to contribute to one of the possible mechanisms of resistance. The clinical features and subsequent treatment strategies for this mutation require further research. This study retrospectively enrolled NSCLC patients with the L718Q/V mutation from 2017 to 2021 at the Cancer Hospital of the University of the Chinese Academy of Sciences (Zhejiang Cancer Hospital), as well as additional patients with the same mutation from PubMed literature, to summarize the clinical features of the mutation. The association between the detection of L718Q/V and resistance to osimertinib, as well as impacts on the therapeutic process and outcome, was analyzed. We included a total of two patients diagnosed at Zhejiang Cancer Hospital and twelve patients from the literature. Of the fourteen total patients, 64.3% were male and 35.7% were female. The average age of the group was 60.2 years (range 45-72). A history of tobacco use was common among the group. In all of the cases we considered, the L718Q/V mutation was secondary to the L858R mutation. The second-generation TKI afatinib was found to provide a high disease control rate (DCR) (85.7%, 6/7) and relatively low objective response rate (ORR) (42/9%, 3/7). The median progression free survival (mPFS) for this treatment reached 2 months (1-6 months). The patients failed to benefit from chemotherapy combined with immunotherapy or other TKI medications. Due to the limited number of cases considered in this study, future studies should explore drugs that more precisely target the L718Q/V mutation of EGFR exon 18.

Epidermal Growth Factor Receptor immunohistochemical expression in hepatocellular carcinoma without Epidermal Growth Factor Receptor exons 18-21 mutations.

Introduction: EGFR targeted therapies, have been proved beneficial for patients with HCC, nevertheless additional research on EGFR immunoexpresion and EGFR mutations is still needed, especially in population in which it has not been done yet. The aim of this study is to evaluate EGFR immunoexpression in HCC without EGFR exons 18-21 mutations and to evaluate its influence on survival in HCC patients in North Macedonia. Methods: We studied 31 cases of HCC for EGFR immunohistochemical expression and EGFR exons 18-21 mutations. The following clinical parameters were analyzed: Hepatitis B and C virus infection, presence of cirrhosis, tumor size, enlarged lymph nodes, metastases, alpha fetoprotein level and overall survival. Presence of the EGFR immunosignal (membranous and cytoplasmic) and the percentage of positive tumor cells in the entire tumor tissue specimen were semi-quantitatively determined. Results: Hepatitis B and C virus infection, tumor size, metastatic disease and EGFR immunoexpression have influence on patient's survival. No EGFR exons 18-21 mutations were detected in this group of HCCs. EGFR expression of 61%-80% in tumor tissue significantly influenced survival of the patients (p < 0.01). Multiple Cox regression confirmed tumor size of 5-10 cm (p < 0.05), tumor size > 10 cm (p < 0.01) and EGFR expression in range of 61% to 80% (p < 0.05) as independent survival predictors in patients with HCC. Conclusion: EGFR overexpression in range of 61% to 80% was an independent survival predictor in patients with HCC, implying that these patients could benefit from EGFR inhibition. However, the absence of EGFR mutations in exons 18-21 in any of the cases of this study suggest that single drug EGFR targeted therapy in patients with HCC may be insufficient.

Complete Response to Afatinib of an EGFR Exon 18 delE709_T710insD-Mutated Stage IV Lung Adenocarcinoma.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are frequently found in patients with lung adenocarcinomas, 90% being deletions in exon 19 or point mutation in exon 21. Three generations of tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are available and have changed patient prognosis but less data is available on exon 18 mutations and their sensitivity to TKI therapy. Exon 18 delE709_T710insD accounts for 0.06% (16/27,294) of all EGFR mutations and is an oncogenic driver. Several partial responses to afatinib have been described. CASE DESCRIPTION: We report the first case, to the best of our knowledge, of the complete response to afatinib of a 57-year-old patient with stage IV lung adenocarcinoma with a delE709_T710insD mutation in the EGFR gene detected by next-generation sequencing. Oral afatinib was prescribed and despite treatment interruptions and dosage tapering due to cutaneous adverse events, a complete response was achieved 12 months after treatment initiation and is currently maintained at 17 months. CONCLUSION: When EGFR mutation is suspected, complete DNA sequencing of exons 18 to 21 should be carried out and we suggest that afatinib should be the first-line treatment for exon 18 delE709_T710insD-mutated advanced lung adenocarcinomas. LEARNING POINTS: Rare EGFR gene mutations are not detected by standard diagnostic kits.DNA sequencing is required to diagnose rare mutations of the EGFR gene.delE709_T710insD-mutated stage IV lung adenocarcinomas respond to afatinib.

Efficacy of tyrosine kinase inhibitors against lung cancer with EGFR exon 18 deletion: Case report and pooled analysis.

BACKGROUND: Within the exon 18 of EGFR, a complex, in-frame deletion-delE709_T710ins-has been described among pulmonary adenocarcinomas with an estimated prevalence of 0.3%. Available evidences suggest that some EGFR tyrosine kinase inhibitors (TKI) have activity against this cancer. However, due to the rarity of this mutation, it remains unclear which TKI is the most effective. METHODS: We reported our experience using afatinib followed by osimertinib in a patient with this mutation. We performed a systematic review of literature and conducted a pooled analysis to compare the outcomes of treatment with first generation TKIs vs. afatinib. Cases with compound mutations were excluded. RESULTS: Our patient achieved a partial response to afatinib with a progression-free survival of 11 months. Upon disease progression, osimertinib failed to control the disease. Literature review identified 14 cases being reported: 8 received first generation TKI and 6 received afatinib. Among those with tumor response assessed, partial response occurred in 2 out of 7 patients (28.6%) treated with first generation TKI compared with 6 out of 6 patients (100%) treated with afatinib, p = 0.03. The median progression-free survival (PFS) was 3.1 months vs. 7.0 months, respectively, p = 0.005. Insufficient evidences were available to assess for the efficacy of osimertinib. CONCLUSION: Based on currently available data, afatinib was associated with a greater tumor response rate and a longer PFS than the first generation TKIs.

A Lung Adenocarcinoma Patient With a Rare EGFR E709_T710delinsD Mutation Showed a Good Response to Afatinib Treatment: A Case Report and Literature Review.

For advanced lung adenocarcinoma patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies, and achieve favorable responses. However, for the rare EGFR deletion-insertion mutation of exon 18, there is no evidence of the efficacy of EGFR TKIs. Herein, we report a lung adenocarcinoma patient harboring a rare EGFR E709_T710delinsD mutation who was treated with afatinib as the first-line therapy and achieved a progression-free survival of 23 months. After the disease progressed, the patient received almonertinib treatment and exhibited a stable disease. This case indicated that non-small cell lung cancer patients harboring the EGFR E709_T710delinsD mutation could benefit from afatinib treatment, followed with almonertinib treatment, as a potential therapeutic strategy.

Successful treatment of an osimertinib-resistant lung adenocarcinoma with an exon 18 EGFR mutation (G719S) with afatinib plus bevacizumab.

Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.

Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size.

BACKGROUND: Platelet derived growth factor receptor alpha (PDGFRα) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFRα protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction. METHODS: Our study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFRα expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls. RESULTS: PDGFRα staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFRα overexpression. This overexpression was significantly associated with mutations in exon 18 (P = 0.024), RAS wild type status (P < 10-3), tumor diameter (P = 0.048), whereas there was no association with tumor side (P = 0.13) and other clinicopathological features. CONCLUSION: Overexpression of PDGFRα in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFRα overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.

Phenotypic and Genotypic Characterization of von Willebrand Factor Gene (Exon 18 and 20) in Saudi Healthy Individuals.

INTRODUCTION: Von Willebrand disease (VWD) is an autosomal congenital bleeding syndrome that was described as being the most widespread genetic condition among men. In Saudi Arabia, the genotyping of the VWF gene is necessary to establish a diagnosis procedure for VWD. AIM: The current research, however, attempted to evaluate the phenotypic-genotypic association of the Von Willebrand factor (exon 18 and 20) gene in healthy subjects to establish effective molecular diagnostic strategies. METHODS: This was a cross-sectional retrospective included 100 healthy people who have been chosen from King Fahad University Hospital. Whole blood samples were collected from all individuals, as well as the laboratory analysis was done using automatic analyzers for; platelet count, ABO blood group and coagulation parameters. DNA Sanger sequencing has been used to sequestrate the full exons 18 and 20. RESULTS: In exon 18 of healthy people, three unusual sequence variations (1 missense and 2 synonymous; rs775479826, rs1286572448 and rs369828268) compared to other recorded VWF variations (3 missense and 1 synonymous; c.2365A > G, c.2385T > C, c.2344C > T and c.2340C > G). But in exon 20 only 1 synonymous novel (rs113240752) 1 registered VWF variations in missense (c.2555G > A) were identified. CONCLUSION: The present variants found on those participates could be a realistic approach to detect mutation in the VWF gene to illustrating the relationship of phenotypic and genetic abnormalities variables may lead to determining the functional effect in mutations specific to the Saudi people that can be used to develop a diagnostic tool for VWD in KSA.

Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation.

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

Activity of EGFR TKIs in Caucasian Patients With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations.

BACKGROUND: Molecular characterization of non-small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting. PATIENTS AND METHODS: We collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups. RESULTS: Eighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations. CONCLUSION: Our study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations.

Osimertinib Treatment Was Unsuccessful for Lung Adenocarcinoma with G719S, S768I, and T790M Mutations.

Epidermal growth factor receptor (EGFR) T790M mutations are the most frequent mechanism of resistance to first- and second-generation tyrosine kinase inhibitors, and osimertinib is an effective treatment for patients with both EGFR-activating mutations and T790M resistance mutations. We describe the case of a 68-year-old woman with lung adenocarcinoma with G719S, S768I, and T790M mutations in which osimertinib treatment was unsuccessful. The patient died of disease progression one month after discontinuing osimertinib treatment. This case suggests that osimertinib may be ineffective for treating patients with uncommon mutations such as G719S when the patient has also acquired a T790M resistance mutation.

The 180 splice variant of NCAM-containing exon 18-is specifically expressed in small cell lung cancer cells.

BACKGROUND: The Neural Cell Adhesion Molecule (NCAM) is a glycoprotein expressed as 120, 140 and/or 180 kDa isoforms, all derived through alternative splicing of a single gene. NCAM 120 contains no intracellular domain, whereas NCAM 140 and 180 have different intracellular domains determined by alternative splicing of exon 18. NCAM has been described as a biomarker to discriminate small cell lung cancer (SCLC) from non-SCLC (NSCLC). However, peripheral blood mononuclear cells (PBMC) also express NCAM. We studied the expression of NCAM splice variants in cell lines, tumor tissues and control cells. METHODS: Using reverse transcriptase-PCR we evaluated the expression of NCAM exon 18 splice variants in lung cancers cell lines, control cell lines, PBMC of healthy controls and SCLC tissue. In addition we studied the expression of the NCAM exon 18 encoded protein (E18) in SCLC by immunocytochemistry and flow cytometry using an E18-specific monoclonal antibody obtained by hybridoma fusion of E18-immunized mouse spleen cells. Finally we looked at immune responses to E18 in mice. RESULTS: We found expression of RNA encoding the NCAM 180 variant in all SCLC cell lines. NCAM exon 18 was not expressed in 23/28 (82%) of the other tumor and leukemia cell lines tested and PBMC. Next, we also evaluated the expression of NCAM exon 18 in human SCLC tissue. Expression of NCAM exon 18 in 8 of the 10 (80%) SCLC biopsy samples was found. The newly raised E18-specific antibodies stained NCAM at the adherent junctions between adjacent cells in SCLC cell lines. The data demonstrate the intracellular location of E18 in SCLC. Furthermore, a specific cytotoxic T cell (CTL) response and significant antibody titers were found in mice upon immunization with recombinant E18 and its encoding DNA. CONCLUSIONS: The results of this study can be applied in the diagnosis and immunotherapy of SCLC. A larger study investigating E18 as a marker for SCLC is indicated.