A case of hepatoid adenocarcinoma of the lung harboring KRAS G12C responded favorably to sotorasib.

Hepatoid adenocarcinoma of the lung is a rare variant of adenocarcinoma. We describe a case of hepatoid adenocarcinoma of the lung that harbored KRAS G12C and responded favorably to sotorasib. A man in his 70s was found to have an abnormality on his chest X-ray. He underwent right middle lobectomy, and a pathological examination of the surgical specimen showed conventional invasive adenocarcinoma with highly focal hepatoid adenocarcinoma. He received chemoradiotherapy and concurrent radiation, followed by durvalumab for postoperative recurrence. After three doses of durvalumab, he reported feeling short of breath. A computed tomography scan showed emerging broad consolidation in the right lower lobe. Transbronchial lung biopsy specimens from the consolidation showed hepatoid adenocarcinoma harboring KRAS G12C mutation. Therefore, he was started on sotorasib 960 mg daily. Eight days later, a computed tomography scan showed that the area of consolidation had reduced in size. Progressive disease was detected after 42 days of treatment with sotorasib. The patient died 1 month after cessation of sotorasib and 3 months after postoperative recurrence. We have encountered what we believe to be the first case of hepatoid adenocarcinoma of the lung with KRAS G12C mutation that responded favorably to treatment with sotorasib.

Solitary Pure Ground-glass Opacity Suspected of Being the Initial Presentation of Nonfibrotic Hypersensitivity Pneumonitis.

We herein report a rare case of hypersensitivity pneumonitis (HP) that was initially demonstrated as solitary pure ground-glass opacity (GGO) on chest computed tomography (CT). A 51-year-old woman with a history of breast cancer underwent follow-up CT, which revealed solitary pure GGO. The patient developed exertional dyspnea after two years, and CT revealed diffuse centrilobular nodules in addition to GGO, which had increased in size. An antigen avoidance test was performed to diagnose HP, leading to the resolution of CT abnormalities, including the GGO. Our findings suggested that nonfibrotic HP can present as solitary pure GGO.

Deep convolutional neural network for differentiating between sarcoidosis and lymphoma based on [18F]FDG maximum-intensity projection images.

OBJECTIVES: To compare the [18F]FDG PET/CT findings of untreated sarcoidosis and malignant lymphoma (ML) and develop convolutional neural network (CNN) models to differentiate between these diseases using maximum intensity projection (MIP) [18F]FDG PET images. METHODS: We retrospectively collected data on consecutive patients newly diagnosed with sarcoidosis and ML who underwent [18F]FDG PET/CT before treatment. Two nuclear radiologists reviewed the images. CNN models were created using MIP PET images and evaluated with k-fold cross-validation. The points of interest were visualized using gradient-weighted class activation mapping (Grad-CAM). RESULTS: A total of 56 patients with sarcoidosis and 62 patients with ML were included. Patients with sarcoidosis had more prominent FDG accumulation in the mediastinal lymph nodes and lung lesions, while those with ML had more prominent accumulation in the cervical lymph nodes (all p < 0.001). For the mediastinal lymph nodes, sarcoidosis patients had significant FDG accumulation in the level 2, 4, 7, and 10 lymph nodes (all p < 0.01). Otherwise, the accumulation in ML patients tended to be in the level 1 lymph nodes (p = 0.08). The CNN model using frontal and lateral MIP images achieved an average accuracy of 0.890 (95% CI: 0.804-0.977), a sensitivity of 0.898 (95% CI: 0.782-1.000), a specificity of 0.907 (95% CI: 0.799-1.000), and an area under the curve of 0.963 (95% CI: 0.899-1.000). Grad-CAM showed that the model focused on the sites of abnormal FDG accumulation. CONCLUSIONS: CNN models based on differences in FDG accumulation sites archive high performance in differentiating between sarcoidosis and ML. CLINICAL RELEVANCE STATEMENT: We developed a CNN model using MIP images of [18F]FDG PET/CT to distinguish between sarcoidosis and malignant lymphoma. It achieved high performance and could be useful in diagnosing diseases with involvement across organs and lymph nodes. KEY POINTS: • There are differences in FDG distribution when comparing whole-body [18F]FDG PET/CT findings in patients with sarcoidosis and malignant lymphoma before treatment. • Convolutional neural networks, a type of deep learning technique, trained with maximum-intensity projection PET images from two angles showed high performance. • A deep learning model that utilizes differences in FDG distribution may be helpful in differentiating between diseases with lesions that are characteristically widespread among organs and lymph nodes.

Tolerability of sotorasib for KRAS positive lung adenocarcinoma patient with pre-existing interstitial pneumonia; A case report.

A 74-year-old man was referred to our hospital with an abnormal chest shadow. Computed tomography (CT) revealed a mass in the left upper lobe and interstitial pneumonia (IP). The patient underwent CT-guided needle biopsy and was diagnosed as lung adenocarcinoma with cT2aN1M1a Stage IVA (PUL). The patient was administered 6 cycles of CBDCA + nab-paclitaxel as first-line, 3 cycles of atezolizumab as second-line, and 8 cycles of S-1 as third-line treatment but finally showed tumor progression. Because comprehensive genome profiling test revealed KRAS G12C mutation, sotorasib was initiated as fourth-line treatment and showed tumor regression without exacerbation of pre-existing IP.

The possibility of mutations of RAS signaling genes and/or TP53 in combination as a negative prognostic impact on pathological stage I non-small cell lung cancer.

BACKGROUND: The recurrence rate of non-small cell lung cancer (NSCLC) is as high as 30%, even in the cancer with pathological stage I disease. Therefore, identifying factors predictive of high-risk pathological recurrence is important. However, few studies have examined the genetic status of these tumors and its relationship to prognosis. MATERIALS AND METHODS: A cohort of 328 cases of primary lung cancer that underwent complete resection at Tokyo Medical and Dental University (TMDU) was screened for 440 cancer-associated genes using panel testing. Further analyses included 92 cases of pathological stage I NSCLC who did not receive adjuvant chemotherapy. Ridge regression was performed to identify association studies mutational status and postoperative recurrence. These data were then validated using clinical and genetic data from 56 patients in The Cancer Genome Atlas (TCGA). RESULTS: Mutations in TP53, RAS signaling genes KRAS and HRAS, and EGFR were recurrently detected. Ridge regression analysis relevant to recurrence, as well as survival analysis, performed using data from the TMDU cohort revealed significantly shorter relapse-free survival (RFS) for patients with RAS signaling or TP53 gene mutations than for those without (log-rank test, p = 0.00090). This statistical trend was also suggested in the TCGA cohort (log-rank test, p = 0.10). CONCLUSION: Mutations in RAS signaling genes and/or TP53 could be useful for the prediction of shorter RFS of patients with stage I NSCLC.

High density and proximity of CD8+ T cells to tumor cells are correlated with better response to nivolumab treatment in metastatic pleural mesothelioma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. METHODS: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD-L1 positive cells, cell density, and cell-to-cell distance were analyzed by multiplex immunofluorescence. RESULTS: PD-L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. CONCLUSIONS: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma.

A phase II feasibility study of carboplatin and nab-paclitaxel for advanced non-small cell lung cancer patients with interstitial lung disease (YLOG0114).

BACKGROUND: A standard treatment regimen for advanced non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) has not been established since most clinical trials exclude such patients because of the high risk of acute exacerbation of ILD. This study aimed to prospectively investigate the efficacy and safety of carboplatin and nab-paclitaxel as a first-line regimen for NSCLC patients with ILD. METHODS: The enrolled patients had treatment-naïve advanced NSCLC with ILD. The patients received 4-6 cycles of carboplatin (area under the curve = 5) on day 1 and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the completion rate of four or more cycles. Secondary endpoints included toxicity, overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-five patients were enrolled in this study. Nine patients had adenocarcinoma, 11 had squamous cell carcinoma, one had large cell carcinoma, and four had NSCLC, not otherwise specified. The completion rate of ≥4 cycles was 76% (95% confidence interval: 56.2%-88.8%), which met the primary endpoint. The ORR and DCR were 44% and 88%, respectively. The median PFS and OS were 5.8 months and 15.8 months, respectively. Three patients experienced grade ≥2 pneumonitis, and one patient met the acute exacerbation criteria. CONCLUSION: The 4-week modified regimen of carboplatin and nab-paclitaxel showed tolerable toxicity with favorable efficacy in NSCLC patients with ILD. This regimen may be an effective treatment option for patients in real clinical settings.

Profile of metastatic lung cancer patients susceptible to development of thromboembolism during immunotherapy.

BACKGROUND: Thromboembolism (TE) is a serious complication in lung cancer patients; however, risk factors for developing TE during treatment with immuno-oncology (IO) drugs are unclear. MATERIALS AND METHODS: A retrospective study of lung cancer patients hospitalized in Tokyo Medical and Dental University was performed to clarify the association between TE and systemic therapy, especially IOs. Patients were divided into an IO cohort, a chemotherapy cohort (CT cohort), and a control cohort (patients without recurrence after surgery). Association studies of variables relevant to TE were performed. RESULTS: A total of 592 patients were enrolled (IO cohort, 120; CT cohort, 294; control cohort, 178). Eight patients (6.7%) in the IO cohort, seven (2.4%) in the CT cohort, and three (1.7%) in the control cohort developed TE. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis identified IO, a history of TE, poor performance status (PS), and prior anticoagulation therapy as being associated with TE. Subsequent multivariate logistic regression analysis identified a history of TE (odds ratio (OR), 6.03; 95% confidence interval (CI), 2.09-17.40; P = 0.01) and poor PS (OR, 3.84; 95% CI, 1.34-11.00; P < 0.001) as potential risk factors for developing TE. The incidence of TE in the IO cohort patients with both of these characteristics was significantly higher (OR, 52.82; 95% CI, 6.72-506.37; P < 0.001) than that in the control cohort. CONCLUSION: Lung cancer patients with a history of TE and poor PS are at increased risk of TE during treatment with IOs. MICRO ABSTRACT: The profiles of lung cancer patients susceptible to development of thromboembolism (TE) during immunotherapy are unclear, even though TE is associated with a worse prognosis. Here, association studies of variables relevant to TE revealed that patients with a history of TE and poor performance status are at higher risk of developing TE during immunotherapy.

Clinical utility of comprehensive genomic profiling in Japan: Result of PROFILE-F study.

INTRODUCTION: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. RESULTS: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. CONCLUSIONS: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.

Treatment of advanced lung cancer based on genomic profiling using liquid biopsy (plasma): A review of three cases.

Of the 80 solid tumor cases in which liquid biopsy (LB) was performed using Guardant360 in the PROFILE study, nine were lung cancer cases. Here, we review three cases in which LB was useful in diagnosing ALK fusion-positive lung cancer, selecting sequential ALK-tyrosine kinase inhibitors, confirming uncommon EGFR mutations, and receiving biomarker-compatible therapy.

Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) patients with pre-existing interstitial lung disease (ILD) is unclear. MATERIALS AND METHODS: Retrospective medical data from advanced or recurrent NSCLC patients who were treated with nivolumab or pembrolizumab at ten institutions in Japan between January 2016 and September 2018 were analyzed. Eligible patients were divided into two groups according to the presence of pre-existing ILD. RESULTS: A total of 461 NSCLC patients were enrolled, 412 without ILD (Non-ILD group) and 49 with ILD (ILD group). The response rate (RR) and disease control rate (DCR) of the ILD group were not inferior to those of the Non-ILD group [RR: 49.0 % (24/49) vs. 30.1 % (124/412), P < 0.01 and DCR: 69.4 % (34/49) vs. 51.2 % (211/412), P = 0.016, respectively]. Non-inferior outcomes were also observed with respect to progression-free survival (PFS) and overall survival (OS) (median PFS: 5.9 months vs. 3.5 months, P = 0.14 and median OS: 27.8 months vs. 25.2 months, P = 0.74 in the ILD and Non-ILD groups, respectively). Among immune-related adverse effects (irAEs), checkpoint inhibitor pneumonitis (CIP) was more frequently observed among NSCLC patients in the ILD group [30.6 % (15/49) vs. 9.5 % (39/412), P < 0.01]. The frequency of irAEs other than CIP and infusion reactions was not significantly different between the ILD group and the Non-ILD group. CONCLUSION: These results suggest that the clinical outcomes of ICIs are not significantly affected by pre-existing ILD despite the increased frequency of CIP. NSCLC patients with ILD are therefore probable candidates for ICIs.

A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study).

BACKGROUND: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. METHODS: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. RESULTS: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). CONCLUSIONS: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.

MuLBSTA score is a useful tool for predicting COVID-19 disease behavior.

BACKGROUND: The prediction of COVID-19 disease behavior in the early phase of infection is challenging but urgently needed. MuLBSTA score is a scoring system that predicts the mortality of viral pneumonia induced by a variety of viruses, including coronavirus, but the scoring system has not been verified in novel coronavirus pneumonia. The aim of this study was to validate this scoring system for estimating the risk of disease worsening in patients with COVID-19. METHODS: This study included the patients who were treated between April 1 st and March 13 th , 2020. The patients were classified into mild, moderate, and severe groups according to the extent of respiratory failure. MuLBSTA score was applied to estimate the risk of disease worsening in each severity group and we validated the utility of the scoring system. RESULTS: A total of 72 patients were analyzed. Among the 46 patients with mild disease, 17 showed disease progression to moderate or severe disease after admission. The model showed a sensitivity of 100% and a specificity of only 34.5% with a cut-off value of 5 points. Among the 55 patients with mild or moderate disease, 6 deteriorated to severe disease, and the model showed a sensitivity of 83.3% and a specificity of 71.4% with a cut-off value of 11 points. CONCLUSIONS: This study showed that MuLBSTA score is a potentially useful tool for predicting COVID-19 disease behavior. This scoring system may be used as one of the criteria to identify high-risk patients worsening to life-threatening status.

[Clinical Utility of Comprehensive Genome Profiling Using FoundationOne CDx in Japanese Population(PROFILE-F Study)].

BACKGROUND: FoundationOne CDx is a cancer genome profiling test that has already been approved by the FDA, but its clinical utility in Japanese patients is unknown. In this study, we examined the clinical utility of FoundationOne CDx. METHODS: 46 samples from 43 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne CDx between September 2018-January 2019. RESULTS: The median age of 43 patients was 63 years(ranged 18 to 82 years), and among them 24 were males and 19 females. Major cancer types were hepato-biliary and pancreatic(8 cases)and other digestive organs(8 cases). All 27 cases in which genome cancer board had been completed by January 17, 2019 were analyzable, and the number of detected gene mutations(except VUS)was an average of 4.3(ranged 0 to 14)per case. Of the 27 cases, one or more mutations were found in 26 cases(96%), and in all such 26 cases actionable mutations with candidates for therapeutic agents were found. In 4(15%)of them, the treatment corresponding to the gene mutation was performed. Among the cases in which target disease matched and clinical trials of the drug were being conducted in Japan, only one case participated in the trial. The most common reason for not participating in the trial was disease deterioration and PS reduction (33%). CONCLUSIONS: The FoundationOne CDx test showed that it can detect gene mutations in various cancer types in Japanese patients.

Ablation of miR-146b in mice causes hematopoietic malignancy.

Excessive and constitutive activation of nuclear factor-κB (NF-κB) leads to abnormal cell proliferation and differentiation, leading to the development of malignant tumors, including lymphoma. MicroRNA 146a (miR-146a) and miR-146b, both of which carry an identical seed sequence, have been shown to contribute to inflammatory diseases and tumors by suppressing the expression of key molecules required for NF-κB activation. However, the functional and physiological differences between miR-146a and miR-146b in disease onset have not been fully elucidated. In this study, we generated miR-146b-knockout (KO) and miR-146a-KO mice by genome editing and found that both strains developed hematopoietic malignancies such as B-cell lymphoma and acute myeloid leukemia during aging. However, the B-cell lymphomas observed in miR-146a- and miR-146b-KO mice were histologically different in their morphology, and the malignancy rate is lower in miR-146b mice than miR-146a mice. Upon mitogenic stimulation, the expression of miR-146a and miR-146b was increased, but miR-146b expression was lower than that of miR-146a. Using a previously developed screening system for microRNA targets, we observed that miR-146a and miR-146b could target the same mRNAs, including TRAF6, and inhibit subsequent NF-κB activity. Consistent with these findings, both miR-146a- and miR-146b-KO B cells showed a high proliferative capacity. Taken together, sustained NF-κB activation in miR-146b KO mice could lead to the development of hematopoietic malignancy with aging.