Investigation of age and smoking in NSCLC patients with uncommon EGFR mutations.

Introduction: In addition to the two common epidermal growth factor receptor (EGFR) mutations, there are many uncommon mutations. Due to the high number of uncommon types, as well as the rarity of patients, there is lack of information regarding patient demographics, especially age distribution and smoking status. Against this background, we conducted an analysis to clarify the background of patients with uncommon EGFR mutations, especially considering their age distribution and smoking status. Materials and Methods: We retrospectively reviewed the medical records of non-small cell lung cancer (NSCLC) patients diagnosed in a multicenter clinical practice from 2002 to 2023. Patients included all cases of non-advanced and advanced NSCLC with uncommon EGFR mutations. Result: Information on 158 patients with uncommon EGFR mutation was collected. Median age was 72 years, with the age distribution showing that most patients were in their 70s. There was a significant difference between the proportion of patients aged up to 59 years and the proportion aged 75 years or older. In 88 patients with a smoking habit history, a significant correlation was found between smoking index and age. Among non-smokers, there was a peak between ages 70 and 74, which was older than the peak among smokers. Conclusions: Even in elderly patients and NSCLC patients with a history of smoking, although it is unclear whether EGFR mutation is common or uncommon, EGFR gene testing should be performed considering the possibility of these patients being EGFR-positive.

Real Clinical Practice of Combined Atezolizumab Plus Chemotherapy in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival. PATIENTS AND METHODS: This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities. RESULTS: In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%). CONCLUSION: Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.

Patient Age and EGFR-positive Non-small Cell Lung Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: The median age of subjects in many clinical trials of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor conducted to date has been approximately 60 years. However, it is not uncommon to encounter EGFR gene-positive patients in their 70s or 80s. Based on information obtained from these clinical trials, EGFR gene-positive non-small cell lung cancer (NSCLC) patients are considered to be younger than EGFR-negative patients. In this study, we analyzed clinical data to identify whether this assumption is true. PATIENTS AND METHODS: We retrospectively reviewed the medical records of NSCLC patients diagnosed in a multicenter clinical practice from 2009 to 2023. Patients included all cases of non-advanced and advanced NSCLC. RESULTS: Information on 2,540 patients, including 605 EGFR gene-positive patients, was collected. The median age of EGFR-positive and EGFR-negative patients was 72 years and 71 years, respectively, and there was no significant difference in the age of patients between these two groups (p=0.7887). The most common age in these two groups was 70 years. Among the EGFR gene subtypes, the frequency of exon 19 deletion decreased with age, whereas that of EGFR L858R increased. CONCLUSION: Patients in their 70s and 80s with non-small cell lung cancer were relatively frequently EGFR gene-positive. To avoid missing out on treatment opportunities, EGFR gene testing should also be performed on patients in this age group.

Long­term control in a patient with lung adenocarcinoma, nonbacterial thrombotic endocarditis and multiple systemic emboli: A case report.

Systemic emboli are not uncommon in patients with advanced non-small cell lung cancer. The present study describes a rare case of long-term control in a patient with lung adenocarcinoma, nonbacterial thrombotic endocarditis and multiple systemic emboli. Briefly, a 56-year-old man was diagnosed with metastatic lung adenocarcinoma and was treated with pembrolizumab, which was discontinued due to the appearance of a pulmonary immune-related adverse event. During the clinical course, the patient developed pseudo-progression of a brain tumor, repeated thromboembolism in multiple organs and a small vegetation attached to the aortic valve. These lesions were controlled with apixaban after heparin therapy for >3 years. Lung cancer was subsequently treated with pemetrexed and bevacizumab; however, this treatment was terminated due to a complete response and the patient's request to discontinue treatment. More than 3 years have passed since the diagnosis of lung adenocarcinoma, and the patient has been followed up at the hospital without signs of cancer recurrence. Although unusual, the patient's course may provide useful suggestions for the treatment of other patients with a similar evolution.

Rapidly Growing Chest Wall Lipoma: Case Report and Calculating Volume Doubling Time.

Chest wall lipoma is a rare disease that might be asymptomatic and discovered incidentally. Chest wall lipomas are presumed to grow slowly, but no reports have evaluated the tumor volume doubling time (TVDT). The present study herein reports the case of a 35-year-old female patient with a relatively fast-growing chest wall lipoma. Lipomas have their characteristic shape and grow very slowly, so they are rarely completely resected, even though they are monitored and repeated imaging studies are performed. Homogeneous very low density, clear margins, and no invasion to the surrounding structure are characteristic finding on imaging, but some patients without these characteristics here have been reported here. As there has been no report of TVDT for chest wall lipoma, comparison was not possible, but TDVT for lipoma in this patient ranged from 235-412 days. Compared with reports that patients with non-small cell lung cancer showed TVDT of less than 450 days, TVDT in the patient described here did not appear to be slow. Accumulation of knowledge about this rare disease will help to elucidate it further.

EGFR Mutated Non-Small Cell Lung Cancer Complicated by Cancer Associated Ischemic Stroke.

We describe herein two patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) who developed cancer-associated ischemic stroke (CAIS), infarction caused by thromboembolism in the central nervous system. Case 1 was a 63-year-old man with Exon 19 deletion type EGFR mutated lung adenocarcinoma presenting with CAIS. Case 2 was a 71-year-old woman with Exon 21 L858R type EGFR mutated lung adenocarcinoma who developed CAIS during chemotherapy after EGFR-tyrosine kinase inhibitor (TKI) resistance. Although there was no recurrence of CAIS in these patients, anticancer therapy could be hampered by the comorbidity of CAIS. This can develop anytime from before clinical manifestations of NSCLC to the next treatment after EGFR-TKI resistance. The development of CAIS should be noted in patients with EGFR mutated NSCLC, who have a promising long-term prognosis. Anticancer and anticoagulant therapies as well as rehabilitation are important for patients who develop CAIS. Establishment of measurement tests to detect CAIS before onset is desired.

Atezolizumab for EGFR-mutated Non-small Cell Lung Cancer Patients: An Observation Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab, an anti-programed death-ligand 1 monoclonal antibody, targets programed death-ligand 1 expressed on cancer cells and antigen-presenting cells and is now commonly used in combination with chemotherapy. We conducted a study to clarify the efficacy of atezolizumab in epidermal growth factor receptor (EGFR)-mutated patients who are considered less responsive to immune checkpoint inhibitors. PATIENTS AND METHODS: A retrospective review of patients with advanced non-small cell lung cancer (NSCLC) who received atezolizumab-containing therapy at 11 hospitals from April 2018 to March 2023 was performed. RESULTS: Median progression-free survival and overall survival in 33 EGFR-mutated patients treated with atezolizumab monotherapy were 2.0 and 9.0 months, respectively, and those in 19 patients who received combined atezolizumab plus chemotherapy were 12.0 and 17.0 months, respectively. When comparing EGFR-mutated and EGFR-negative patients after propensity score matching, there were no significant differences in progression-free survival and overall survival between the two groups, whether atezolizumab monotherapy or combined atezolizumab plus chemotherapy. Among EGFR-mutated patients, being male was a significant favorable factor in both atezolizumab treatment groups. None of the EGFR-mutated patients had grade 5 immune-related adverse events. CONCLUSION: Efficacy of atezolizumab in EGFR-mutated NSCLC patients could be comparable to that for EGFR-negative patients. To prolong the survival of EGFR-mutated NSCLC patients, appropriate selection and sequencing of EGFR for tyrosine kinase inhibitors, as well as immune checkpoint inhibitors, anti-tumor agents, and anti-angiogenic agents are important.

Atezolizumab Monotherapy for Non-small Cell Lung Cancer Patients: An Observational Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab is a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) expressed on cancer cells derived from various organs and antigen-presenting cells and is currently commonly used in combination with chemotherapy. We conducted a study to clarify the current status of response to atezolizumab monotherapy in clinical practice and clarify the factors that contribute to long-term response and survival. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy from April 2018 to March 2023 at 11 Hospitals. RESULTS: The 147 patients evaluated had a progression-free survival (PFS) of 3.0 months and an overall survival of 7.0 months. Immune-related adverse events of any grade were observed in 13 patients (8.8%), grade 3 or higher in nine patients (6.1%), and grade 5 with pulmonary toxicity in one patient (0.7%). Favorable factors related to PFS were 'types of NSCLC other than adenocarcinoma'. Favorable factors for overall survival were 'performance status 0-1' and 'treatment lines up to 3'. There were 16 patients (10.9%) with PFS >1 year. No characteristic clinical findings were found in these 16 patients compared to the remaining 131 patients. CONCLUSION: Efficacy and immune-related adverse events of NSCLC patients associated with atezolizumab monotherapy were comparable to those of previous clinical trial results. Knowledge of characteristics of patients who are most likely to benefit from atezolizumab monotherapy is a crucial step towards implementing appropriate prescribing.

Long-term Progression-free Survival With Pemetrexed Plus Bevacizumab in NSCLC Patients.

BACKGROUND/AIM: Pemetrexed (PEM) and bevacizumab (BEV) are commonly used in combination as second or subsequent line regimens and maintenance therapy after platinum + PEM + BEV therapy for advanced non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) for PEM + BEV has been reported to be less than six months in both clinical trials and clinical practice, but in clinical practice, we found that some patients demonstrate long-term PFS. Furthermore, there is a paucity of clinical practice data on whether long-term administration of PEM + BEV causes renal dysfunction. This study aimed to clarify these aspects in clinical practice. PATIENTS AND METHODS: A retrospective review of patients with advanced NSCLC treated with PEM + BEV between September 2011 and June 2022 at four hospitals was conducted. Long-term PFS in PEM + BEV therapy was defined as ≥12 months. RESULTS: During the study period, 109 patients received PEM + BEV treatment. Of them, 42 (38.5%) achieved long-term PFS ≥12 months. No significant differences in patient characteristics were found between patients with PFS ≥12 months and <12 months, except for 'relapse after resection'. Univariate and multivariate analysis showed that the favorable factor for PFS was 'relapse after resection'. With regard to influence on renal function of PEM + BEV therapy, no significant difference was found before and after PEM+BEV therapy between these two groups. CONCLUSION: NSCLC patients commonly achieved long-term PFS with PEM + BEV therapy with no observed effects on renal function.

Discontinuation of Immune Checkpoint Inhibitor due to irAEs in NSCLC Patients With EGFR Mutation.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small cell lung cancer (NSCLC) treatment. Even patients with epidermal growth factor receptor (EGFR)-mutated NSCLC may choose an ICI after failure of EGFR-tyrosine kinase inhibitor treatment. ICI-mediated immune-related adverse events (irAEs) may prompt NSCLC patients to discontinue their treatment. This study evaluated the effect of ICI treatment discontinuation on the prognosis of patients with EGFR-mutated NSCLC. PATIENTS AND METHODS: We performed a retrospective study that reviewed the clinical courses of patients with EGFR-mutated NSCLC treated with ICI therapy from February 2016 to February 2022. 'Discontinuation' was defined as failure to receive at least two treatment courses of ICI due to grade 2 irAEs (grade 1 in the lung) or higher in patients responding to ICI. RESULTS: During the study period, 13 of 31 patients discontinued ICI therapy due to irAEs. Survival from the initiation of ICI therapy was significantly longer in patients who discontinued ICI therapy compared with those who did not discontinue. In uni- and multivariate analyses, 'discontinuation' was a favourable factor. There was no significant difference in survival from ICI initiation between patients with grade 3 or higher irAEs and those with grade 2 or lower irAEs. CONCLUSION: In this patient cohort, discontinuation of ICI therapy due to irAEs did not adversely affect prognosis in patients with EGFR-mutant NSCLC. Our results suggest that when treating patients with EGFR-mutant NSCLC with ICIs, chest physicians should consider discontinuing ICI with close monitoring.

NSCLC Patients Achieving Long-term Progression-free Survival With Docetaxel Plus Ramucirumab: A Retrospective Study.

BACKGROUND/AIM: The antineoplastic drug docetaxel (DOC) and the antivascular endothelial growth factor inhibitor ramucirumab (RAM) are widely used in combination for second or later-line regimens for advanced non-small cell lung cancer (NSCLC). While the median progression-free survival (PFS) of DOC+RAM has been reported to be less than six months in both clinical trials and clinical practice, there appear to be some patients with long-term PFS. This study aimed to clarify the existence and characteristics of these patients. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced NSCLC treated with DOC+RAM between April 2009 and June 2022 at our three hospitals. There was no established definition of long-term PFS, thus in this study, a PFS of 12 months or longer was defined as long-term PFS. RESULTS: During the study period, 91 patients received DOC+RAM treatment. Of these, 14 (15.4%) achieved long-term PFS. There were no significant differences in patient characteristics between patients with PFS ≥12 months and those with PFS <12 months, except for 'clinical stage IIIA-C' at DOC+RAM initiation and 'post-surgical recurrence'. In uni- and multivariate analyses, favorable factors for PFS were 'Stage III at the start of DOC+RAM' in driver gene-negative patients, and 'under 70 years old' in driver gene-positive patients. CONCLUSION: Many patients in this study achieved long-term PFS with DOC+RAM treatment. In the future, it is expected that long-term PFS will be defined, and the background of patients who achieve such PFS will become clearer.

Relationship Between TTF-1 Expression and PFS of Pemetrexed-containing Chemotherapy in Non-squamous-NSCLC Patients With and Without Driver Genes.

BACKGROUND/AIM: We performed a retrospective study too clarify whether the presence or absence of driver genes affects the relationship between thyroid transcription factor-1 (TTF-1) expression and response to pemetrexed (PEM) in non-squamous non-small cell lung cancer (non-sq-NSCLC) patients. PATIENTS AND METHODS: We reviewed the medical charts of patients treated with PEM-containing chemotherapy during the period from February 2016 to February 2022 at Mito Medical Center-University of Tsukuba, Ryugasaki Saiseikai General Hospital, and University of Tsukuba Hospital. RESULTS: During the period of the study, 185 driver gene-negative patients negative, and 65 driver gene-positive patients were evaluated. Among the 165 driver gene-negative patients, progression free survival (PFS) of TTF-1-expressing patients treated with PEM-containing chemotherapy was significantly longer compared to that of TTF-1-negative patients. In the analysis of 65 driver gene-positive patients, the PFS of TTF-1-positive patients treated with PEM-containing chemotherapy did not differ significantly from that of TTF-1-negative patients. There was no significant difference in PFS between driver gene-negative and driver gene-positive patients treated with PEM-containing chemotherapy. Comparison between four groups defined according to the presence of driver gene and TTF-1 expression indicated shorter PFS only in 'driver gene-negative and TTF-1-negative' patients. CONCLUSION: In driver gene-positive non-sq NSCLC patients, expression of TTF does not affect the survival outcome of PEM-containing-chemotherapy. In other words, in these patients, second-line or later-line PEM-containing chemotherapy after development of resistance for specific-tyrosine kinase inhibitor could be expected to have the same level of efficacy as first-line PEM containing chemotherapy in driver gene-negative, TTF-1-positive non-sq NSCLC patients.

Mesalazine-Induced Diffuse Lung Injury in a Patient Without Respiratory Signs and Symptoms.

Mesalazine is a drug used to treat ulcerative colitis and Crohn's disease, and is known to rarely cause lung injury. We show herein a unique case who developed this drug-induced injury. A 17-year-old boy presented with fever and anorexia after administration of mesalazine. Computed tomography showed extensive ground-glass opacities with peripheral distribution in both lungs. He had general weakness, but had no respiratory symptoms such as cough and dyspnea. With prednisolone, which is primarily aimed at controlling ulcerative colitis, the extensive opacity in both lungs were improved. All patients with this drug-induced lung injury reported to date have had respiratory symptoms, but this patient had no subjective respiratory symptoms and had no abnormalities in respiratory rate and oxyhaemoglobin saturation. Although very rare, we do believe that this clinical course will provide some suggestive information on treatment for patients with similar course in the future.

Octogenarians With Anaplastic Lymphoma Kinase-rearranged Non-small-cell Lung Cancer: A Case Series.

BACKGROUND/AIM: Anaplastic lymphoma kinase (ALK) rearrangements define a distinct group of patients with non-small-cell lung cancer (NSCLC), mainly represented by never-smoking young individuals. However, we also encounter elderly patients with ALK-rearranged NSCLC over the age of 80 years. We report herein three cases of these patients that we have experienced. CASE REPORT: Three patients with ALK-rearranged NSCLC aged 80 years or older received therapy with the ALK-tyrosine kinase, alectinib. Of them, one was male and two had a history of smoking. Comorbidities, especially heart diseases, were prominent. Long-term survival was achieved with alectinib treatment in two patients. CONCLUSION: ALK-rearranged mutations should be evaluated even in octogenarians with NSCLC, regardless of sex and smoking history. Even if they have comorbid diseases, long-term control might be achieved with alectinib therapy in cooperation with physicians other than chest physicians and medical oncologists.

A Malignant Tumor Developed Seven Years After Small Cell Lung Cancer Treated With Etoposide-containing Chemotherapy.

BACKGROUND/AIM: Long-term survival of patients with small cell lung cancer (SCLC) is rare, and, to the best of our knowledge, there has been no SCLC patient who developed second malignancy after long-term survival. CASE REPORT: A 66-year-old woman with a history of smoking was admitted to our hospital with a nodule in her right lung. She was diagnosed with cT2aN3M0 localized-SCLC. Chest irradiation and chemotherapy including etoposide was performed. A new nodule appeared in the right lung more than 7 years after the end of treatment for SCLC. A specimen obtained by bronchoscopic biopsy was pathologically confirmed to be a non-SCLC malignancy. CONCLUSION: There is a possibility of tumor development associated with etoposide, which is known to be carcinogenic, or residual tumor development from combined type SCLC. We could not confirm whether it was second malignancy or recurrence after long-term interval. The number of long-term survivors of SCLC is likely to increase in the future. The clinical course of this patient is interesting from the perspective of long-term survival of SCLC patients and might have implications for the treatment of patients with similar clinical course in the future.

Five-year Disease Control With Alectinib in a Patient With Metastatic ALK-rearranged Lung Adenocarcinoma.

BACKGROUND/AIM: Therapy with alectinib could achieve prolonged progression-free and overall survival in patients with anaplastic lymphoma kinase gene (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, a large proportion of the patients discontinue alectinib treatment due to recurrence. CASE REPORT: A 41-year-old male patient presented with cellulitis of the right upper extremity that had developed in the past 3 weeks. Chest radiograph at the time of admission incidentally revealed a nodule in the right lung. At diagnosis, the patient had spinal bone metastases and thrombosis in the common jugular vein subclavian veins. Therefore, in addition to warfarin therapy and irradiation to the bone metastases, chemotherapy was started. After identifying the presence of the ALK rearranged gene, alectinib therapy was initiated. Since then, alectinib treatment has been continued for more than 5 years. CONCLUSION: Although very rare, there are patients who might be able to maintain a long-term response to alectinib. It is important for chest physicians to manage such patients so that the effects of alectinib can be maintained for a long time.

Distant organ metastasis patterns in lung cancer patients with pancreatic metastasis - a cluster analysis.

Introduction: Pancreatic metastasis of lung cancer is rare, but the narrowing or obstruction of the biliary tract from pancreatic metastases limits the choice of antitumour agents. Lung cancer patients with pancreatic metastasis often have metastasis of other organs. For these patients, however, no studies have been conducted to evaluate distant metastasis sites as metastasis patterns. This study aims to assess whether these patients have specific metastasis patterns at the time of diagnosis of lung cancer. Material and methods: Data were collected from consecutive lung cancer patients with pancreatic metastasis between April 2012 and March 2022. Metastatic patterns were analysed using cluster analysis in patients with lung cancer. Results: During the study period, 33 (2.0%) of 1659 patients were diagnosed as having pancreatic metastasis. Of the 33 patients, 28 (84.8%) were male. Eighteen, 14, and one patient had small cell lung cancer (SCLC), lung adenocarcinoma, and large cell neuroendocrine carcinoma, respectively. They were divided into 3 groups by cluster analysis. A statistically significant difference in metastasis frequency was confirmed among these 3 groups (χ2 test, p = 0.001). Conclusions: In lung cancer patients with pancreatic metastasis, knowledge of the metastatic patterns might be useful for clinical practice in the foreseeable future because it enables more efficient detection of metastatic disease through imaging, and more effective treatment at predicted metastatic sites.

Long-term response in a patient with adenocarcinoma harboring both common and uncommon EGFR mutations.

Recently, we read a paper "Dacomitinib overcomes afatinib-refractory carcinomatous meningitis in a lung cancer patient harbouring EGFR Ex.19 deletion and G724S mutation" published in Investigational New Drugs. Their patient had a very rare compound EGFR mutation. To share our experience, we present a case of 58-year-old man with a long-term response to afatinib in a patient with previously unreported compound EGFR mutation. In patients with rare compound EGFR mutations, afatinib might be one of the treatment option.

Myasthenia gravis that has developed long after radical resection of lung cancer: A case report.

Myasthenia gravis (MG) is the most common disorder of neuromuscular transmission and is a heterogeneous disorder generally caused by auto-antibody to the nicotinic acetylcholine receptor. The current study presented a rare case of MG that occurred a long time after surgical resection of lung cancer. A 58-year-old man with lung adenocarcinoma underwent upper lobectomy and mediastinal lymph node dissection. Severe myasthenic symptoms began 7 years after the operation, and emergent mechanical ventilation was needed because of myasthenic crises. Levels of serum anti-acetylcholine receptor antibody were high and typical decremental responses to repetitive stimulation on electromyography were observed. Appropriate therapies for a severe acute condition were performed, and MG has been controlled for 6 years since then. There is no recurrence of lung cancer or appearance of thymoma. In conclusion, although very rare, physicians should be aware of MG as a potential comorbidity developing in patients with a history of lung cancer.