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A 44-year-old woman underwent contrast-enhanced CT with iopamidol because of a suspected sinusitis. After 10 min, she developed dyspnoea and nausea. Intravenous administration of hydrocortisone 500 mg and metoclopramide 10 mg did not improve her symptoms. One hour later, her percutaneous oxygen

Primary malignant pericardial mesothelioma is an extremely rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. A 67-year-old male patient, an ex-smoker, complaining of progressive lethargy was referred to a hospital for investigation of persistent pericardial effusion. The pericardial fluid cytology was categorized as class Ⅲ. Thereafter, he was referred to our hospital for further evaluation. Fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed FDG accumulation in the pericardium and mediastinal lymph node. Surgical biopsy of the pericardium was performed through a subxiphoid approach for a definitive diagnosis. Histopathological examination revealed diffuse infiltration of the pericardium by a malignant tumor consisting of epithelioid cells with large round nuclei and prominent nucleoli, arranged in a tubular papillary pattern. Finally, the patient was diagnosed with primary malignant pericardial mesothelioma of epithelioid type. The patient died 6 weeks after admission. This diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and FDG PET to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit.

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. Methods COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. Results A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. Conclusions The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. Trial registration Clinicaltrials.jp number: JapicCTI-205238. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00517-4.

The overall effect of lifestyle habits, such as alcohol consumption, on general health remains controversial and it is important to clarify how such habits affect aging-related health impairments. To discover novel impacts of lifestyle on general health, we employed a mathematical approach to perform a comprehensive, unbiased, cross-sectional analysis of data from 6036 subjects who participated in a Japanese health checkup. Notably, we found that moderate alcohol consumption was positively correlated with lung function, muscle mass, and strength. Health checkup data were collected periodically from the same subjects. These people were light to moderate drinkers who had high health awareness and were basically free of major underlying diseases. We next analyzed 5 years of data from 1765 of these subjects. We found that higher baseline alcohol consumption, as well as increased alcohol intake over 5 years attenuated time-related deterioration of forced vital capacity without affecting total lung volume. This effect was independent of smoking. Our study suggests a possible protective effect of moderate amounts of alcohol on lung function, due to increased muscle mass/strength and forced vital capacity.

Background: Both advanced cancer patients and their family caregivers experience distress and have a range of concerns after cancer diagnosis. However, longitudinal studies on this topic have been lacking. Aim: To investigate concerns in both patients with advanced lung cancer and their family caregivers longitudinally from diagnosis. Design: A multi-center prospective questionnaire-based study. Setting/participants: We recruited patients with newly diagnosed advanced lung cancer and their family caregivers at 16 hospitals in Japan. We prospectively assessed the prevalence of their concerns using the Concerns Checklist and investigated the associations between their concerns and mental status as well as quality of life until 24 months after diagnosis. Results: A total of 248 patients and their 232 family caregivers were enrolled. The prevalence of serious concerns was highest at diagnosis (patients: 68.3%, family caregivers: 65.3%). The most common serious concern was concern about the future in both groups at diagnosis (38.2% and 40.5%, respectively) and this remained high in prevalence over time, while the high prevalence of concern about lack of information improved 3 months after diagnosis in both groups. Approximately one-third of patient-family caregiver dyads had discrepant reports of serious concerns. The presence of serious concerns was significantly associated with anxiety and depression continuously in both groups. Conclusions: The majority of advanced lung cancer patients and their family caregivers have serious concerns from diagnosis, which is associated with their psychological distress. The spectrum of concerns alters over the disease trajectory, warranting efficient tailored care and support for both groups immediately after diagnosis.

The development of molecular targeted therapy has improved clinical outcomes in patients with life-threatening advanced lung cancers with driver oncogenes. However, selective treatment for KRAS-mutant lung cancer remains underdeveloped. We have successfully characterised specific molecular and pathological features of KRAS-mutant lung cancer utilising newly developed cell line models that can elucidate the differences in driver oncogenes among tissues with identical genetic backgrounds. Among these KRAS-mutation-associated specific features, we focused on the IGF2-IGF1R pathway, which has been implicated in the drug resistance mechanisms to AMG 510, a recently developed selective inhibitor of KRAS G12C lung cancer. Experimental data derived from our cell line model can be used as a tool for clinical treatment strategy development through understanding of the biology of lung cancer. The model developed in this paper may help understand the mechanism of anticancer drug resistance in KRAS-mutated lung cancer and help develop new targeted therapies to treat patients with this disease.

EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level. Implications: Using comprehensive protein phosphorylation array and patient-derived lung cancer cells, we found that IGF2 autocrine-mediated IGF1R pathway activation is a clinically relevant and common mechanism of acquired resistance to osimertinib.

Background Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time. Materials and Methods We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being. Results The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p = .010 and p = .014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer–specific symptom burden at 3 months (p = .008 and p = .005, respectively) and lower emotional well-being at 6 months (p = .006). Conclusion Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately. Implications for Practice This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.

A 56-year-old woman presented with repeated swelling of the lips and face. She had a history of childhood asthma; she had a recurrence of asthma when she was 54 years old and was taking inhaled corticosteroids, and other antiasthma drugs. The swelling of her lips and face improved temporarily with oral corticosteroids (OCS), but recurred soon after discontinuing OCS. Her peripheral blood eosinophil count was 632/μL (9.3%), and her serum was negative for myeloperoxidase-anti-neutrophil cytoplasmic antibody and serine proteinase3-anti-neutrophil cytoplasmic antibody. Hematoxylin and eosin staining of her back skin revealed abundant eosinophilic infiltrate around the vascular area of the shallow dermis layer, but no evidence of vasculitis and we diagnosed her as eosinophilic annular erythema (EAE). Punctate staining of galectin-10, chromatolytic eosinophils, and net-like DNA was also evident in close proximity to the free granules, indicating extracellular vesicles and eosinophil extracellular traps (ETosis). We started daily OCS to control her asthma and skin eruption/oedema. Three months after administering daily OCS, benralizumab was initiated for withdrawal from OCS dependence and treatment of severe asthma. After initiation of benralizumab, her skin and subcutaneous tissue symptoms promptly improved. OCS was discontinued, and no edematous erythema has been observed since then. Bronchial asthma has also been well-controlled. This is the first report on the evidence of eosinophil ETosis in the dermis of EAE patients and the efficacy of benralizumab in a patient with EAE. Benralizumab may be a useful drug for treating refractory EAE with severe eosinophilic asthma.

Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC. Significance: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

BackgroundNot all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.MethodsNSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.ResultsTwenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.ConclusionsAlthough autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration numberUMIN000006128

EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); however, treatment with EGFR–TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR–TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR–TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR–TKIs and that SHOC2 affects the sensitivity to EGFR–TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations. Implications: This study showed that SHOC2 works as a modulator of sensitivity to EGFR–TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR–TKIs.

ABT‐263 (Navitoclax) is a BH3‐mimetic drugs targeting anti‐apoptotic B‐cell lymphoma‐2 (BCL‐2) family proteins, including BCL‐2, BCL‐xL, and BCL‐w, thereby inducing apoptosis. In small‐cell lung cancer (SCLC) cells, the response to ABT‐263 is associated with the expression of myeloid cell leukemia‐1 (MCL‐1) protein, however the efficacy of ABT‐263 in non‐small‐cell lung cancer (NSCLC) has not been thoroughly evaluated. There are currently no established biomarkers for predicting the efficacy of ABT‐263 treatment in NSCLC. We screened a panel of different NSCLC cell lines and found that ABT‐263 inhibited cell proliferation and induced apoptosis in Calu‐1, Calu‐3, and BID007 cells. Inconsistent with previous reports on SCLC, low levels of MCL‐1 did not predict the response to ABT‐263 in NSCLC cells, however we found that intracellular levels of reactive oxygen species (ROS) in cancer cells were associated with sensitivity to ABT‐263 in NSCLC cells. We also showed that increasing the level of intracellular ROS could enhance the sensitivity to ABT‐263 in NSCLC cells. In summary, we propose that the intracellular levels of ROS could be used as a potential novel biomarker for predicting a response to ABT‐263 in NSCLC. Furthermore, we show some evidence supporting the further assessment of ABT‐263 as a new therapeutic strategy in patients with NSCLC combined with agents regulating ROS levels. We believe that our findings and follow‐up studies on this matter would lead to novel diagnostic and treatment strategies in patients with NSCLC., This article clarified the potential relationship between intracellular ROS and sensitivity to BH3‐mimetic drug, ABT‐263 in non‐small‐cell lung cancer.

Background Prognostic understanding in advanced cancer patients and their caregivers may have an impact on the delivery of effective care. The aims of this study were to explore prognostic understanding at diagnosis in both patients with advanced lung cancer and their caregivers and to investigate correlates of their understanding. Subjects, Materials, and Methods A total of 193 patients with newly diagnosed advanced lung cancer and their 167 caregivers were enrolled at 16 hospitals in Japan. We assessed their perceptions of prognosis and goals of therapy and examined their associations with their sociodemographic characteristics, clinical status, quality of life, mood symptoms, and the status of disclosure of information by their treating physicians. Results One fifth of patients and caregivers (21.7% and 17.6%, respectively) mistakenly believed that the patients’ cancer was “completely curable.” Substantial proportions of them (16.9% and 10.3%, respectively) mistakenly believed that the primary goal of therapy was to remove all the cancer. Levels of anxiety and depression in both patients and caregivers were significantly higher among those who had accurate understanding of prognosis. In multivariate analyses, inaccurate perceptions of prognosis in patients were associated with sex, better emotional well-being, and lower lung cancer-specific symptom burden. Caregivers’ inaccurate perceptions of patients’ prognoses were associated with better performance status and better emotional well-being of patients. Conclusion Substantial proportions of advanced lung cancer patients and their caregivers misunderstood their prognosis. Interventions to improve their accurate prognostic understanding should be developed with careful attention paid to its associated factors. Implications for Practice This study demonstrated that substantial proportions of patients with newly diagnosed advanced lung cancer and their caregivers had misunderstandings about their prognosis. Accurate perceptions of prognosis, which are indispensable in the delivery of effective care, were associated with elevated levels of anxiety and depression in both patients and caregivers, warranting psychosocial care and support for them immediately after diagnosis. Inaccurate perceptions of prognosis in patients were associated with better emotional well-being and lower lung cancer-specific symptom burden. Illness understanding in caregivers was associated with patients’ physical and mental status. Those findings provide insight into how they obtain accurate illness understanding.

Background Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor, exerts remarkable effects against EGFR T790M resistance mutation-positive non-small cell lung cancer. Identifying T790M mutation by re-biopsy is essential before prescribing osimertinib. Tissue biopsy is the golden standard for this purpose, but several factors limit its success rate. The liquid biopsy with blood, using circulating tumor DNA, has been an alternative method. However, the true biological meaning and equivalence of liquid biopsy and tumor biopsy are still under investigation. Especially, the usefulness of serum samples to detect T790M mutation is not yet been known. Patients and methods We prospectively evaluated the sensitivity, specificity, and parallelism of the detection of EGFR mutations in tissue re-biopsy and liquid biopsy (plasma and serum), simultaneously, from June 2016 to May 2017. EGFR mutations in tumor re-biopsy were evaluated by COBAS ver2 and PNA-LNA PCR clamp method, and those in liquid biopsy were evaluated with COBAS ver2. Results Fifteen patients were enrolled. In 10 patients whose EGFR mutation was detected in liquid biopsy, the original EGFR mutation (exon 19 del or L858R) was detected in all patients. Detection of EGFR mutation by COBAS ver2 and by PNA-LNA method was almost the same in tissue re-biopsy. The detection rate of T790M was lower than that of the original EGFR mutation in liquid biopsy compared to that in tissue re-biopsy. The detection of T790M in serum exhibited a higher specificity (67%) and positive predictive value (50%) than that in plasma (50% and 40%, respectively). The detection sensitivity was similar in plasma and serum. Conclusion Plasma, serum, and tissue genotyping can have complementary roles for detecting EGFR-T790M using COBAS ver2. Repeated tests with different samples and different methods may improve accuracy of T790M detection and will lead to the maximum benefit for the patient.

A 69-year-old man with post-operative recurrence of lung adenocarcinoma was treated with multiple chemotherapies, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A second biopsy revealed an EGFR T790M mutation. As 10th-line chemotherapy, osimertinib was initiated. After 24 weeks, chest computed tomography (CT) revealed asymptomatic ground-glass opacities in both lobes. After four weeks of osimertinib discontinuation, imaging revealed rapid lung cancer progression. Osimertinib was resumed. After 11 weeks, CT revealed decreased lung nodules with no exacerbation of interstitial lung disease. We describe a patient who experienced transient asymptomatic pulmonary opacities during treatment with osimertinib, which was successfully managed by a "stop-and-go" approach.

IntroductionThe rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale.Methods and analysisIn this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives.Ethics and disseminationThis trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

Vemurafenib improves survival of melanoma patients. However, cutaneous side-effects commonly occur in them. Nivolumab and ipilimumab are monoclonal antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4, both of which regulate excessive T-cell activation. Although these agents induce antitumor immunity against melanoma, the modified immune condition may result in an unexpected adverse reaction which has not been observed previously. Herein, we report a case who manifested severe erythema multiforme-like eruption with mucosal involvement associated with vemurafenib following nivolumab. The patient also subsequently suffered from ipilimumab-induced interstitial pneumonia with refractory course. Such a case has never been reported. This case suggested that dermatologists should pay special attention to unexpected adverse events of these drugs, and carefully observe cutaneous and respiratory status of patients during the treatment of melanoma.

Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKI) have become the first line treatment for patients with EGFR mutated non-small cell lung cancer (NSCLC) as a result of multiple clinical trials demonstrating superior response and less toxicity as compared to conventional cytotoxic agents. However, despite the clinical experience among nearly two decades, it is well known that EGFR-TKI monotherapy cannot cure EGFR mutation-positive lung cancer patients due to the occurrence of drug resistance. While dramatic initial tumor shrinkage is shown in most patients with EGFR-TKI treatment, therapeutic resistance is often observed in 1-2 years. This is likely caused by the outgrowth of rare pre-existing resistant clones and/or small fraction of drug tolerant persister cells (DTPs) which survive and acquire resistance to EGFR-TKIs. Several previous studies have clarified the acquired resistance mechanisms to EGFR-TKIs, but little is known how the DTPs survive during the initial phase of drug exposure and rapidly adapt to EGFR-TKIs. Utilizing the genome wide CRISPR/Cas9 screening, we have previously reported that DTPs were capable to exploit endoplasmic reticulum stress to survive EGFR-TKI exposure (Terai, et al, Cancer Research 2018). Further analysis of this data identified multiple genes which could affect the initial drug response to EGFR-TKIs, including the scaffold protein coding gene, SHOC2. In our present study we focused on this unique protein and revealed its critical function as a modulator of drug response to EGFR-TKIs in lung cancer cells. We confirmed that depletion/overexpression of SHOC2 in PC9 cells, an EGFR-dependent NSCLC cell line, renders the cells sensitive/resistant to all 1st to 3rd generation EGFR-TKIs. We have also confirmed similar findings with another EGFR dependent NSCLC cell line named H1975. Reduction of phosphorylation levels of ERK1/2 induced by EGFR-TKIs were stronger in PC9 or H1975 cells with SHOC2 knockout, indicating that SHOC2 can facilitate ERK1/2 reactivation during EGFR-TKI treatment. The above data indicate that SHOC2 is essential for DTPs and its function is correlated with MAPK-ERK pathway activity. Celastrol, a candidate SHOC2 inhibitor, inhibited the emergence of DTPs and synergized with EGFR-TKIs. Additionally, we showed that SHOC2 depletion enhanced the growth inhibitory effect of osimertinib in vivo. Lastly, we confirmed the increased expression of SHOC2 in clinical human samples which experienced EGFR-TKI failure. Our findings could offer a new treatment strategy for NSCLC patients with EGFR mutation leading to the increase of the degree and duration of EGFR TKIs response. Citation Format: Hideki Terai, Junko Hamamoto, Tadashi Manabe, Katsura Emoto, Takeshi Masuda, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga. SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3081.

In non-small cell lung cancer (NSCLC), several somatic mutations such as EGFR and EML4-ALK have been identified in a significant subgroup of patients. Multiple clinical trials involving tyrosine kinase inhibitors (TKIs) have demonstrated significant improvement in the prognosis of lung cancer patients with these mutations. However, in clinic, lung cancer cells gradually acquire resistance to these inhibitors in a span of approximately 1 - 2 years. In TKI resistant lung cancer patients, next-generation sequencing of clinical samples from individual patients enables the detection of genetic alterations that contribute to drug resistance, such as EGFR T790M and EGFR C797S mutations. However, it does not always offer an appropriate treatment strategy for patients with acquired resistance. In contrast, the presence of living cancer cells allows researchers to biologically evaluate the roles of mutations or bypass pathways. For a thorough clarification of resistance mechanisms, living cancer cells, in addition to genomic information, are essential. In our report, we have established six patient-derived cancer cells (PDCs) from NSCLC patients who were treated with various TKIs and thereafter experienced disease progression. The success rate for PDCs was as high as 50% (6/12). Upon the established cell lines, 2 cases had EML4-ALK and the rest had EGFR mutation as an oncogene. After establishing the PDCs, TKI resistance was confirmed by MTS cell proliferation assay and 5 of 6 cases showed matched TKI resistance referring to the clinical background. To elucidate the adaptive resistant mechanisms in PDCs, Sanger sequence was performed and none of the gene mutations that have been previously reported to contribute to resistance to TKIs was detected. Next, to investigate the bypass pathway activation in these cell lines, we performed phospho-receptor tyrosine kinase (RTK) array screening. Interestingly, 4 of 5 cases showed activation of bypass RTK signaling and 3 of 4 cases obtained combined effectiveness with the additional RTK inhibitor. Furthermore, we have performed western blotting in 3 PDCs and detected that combination treatment attenuated the phosphorylation of the downstream molecules. In conclusion, by using PDCs, we have clarified the mechanism of acquired resistance and detected the treatment strategy to overcome these resistances. The findings suggest that PDCs may help develop precision medicine for TKI resistant patients. Citation Format: Tadashi Manabe, Hiroyuki Yasuda, Hideki Terai, Junko Hamamoto, Toshiki Ebisudani, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima. Establishment of patient-derived cancer cell lines to elucidate the resistant mechanism of tyrosine kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2991.

Lung cancer is the leading cause of cancer-associated deaths worldwide. Metabolic reprogramming facilitates the growth advantage of cancer cells and is a hallmark of cancer. Although multiple studies have investigated the cancer-specific metabolic status of lung cancer, it remains unclear. Aberrant fucosylation, which results from the deficiency or overexpression of fucosyltransferases, is also associated with a variety of cancers, including lung cancer. However, the role and regulatory mechanism(s) of fucosylation in lung cancer remain largely unknown. In order to elucidate the specific metabolic status of human lung cancer tissues, we performed metabolomics profiling of paired tumor and normal tissues from patients with non-small cell lung cancer (NSCLC) using both capillary electrophoresis mass-spectrometry (CE-MS) and imaging mass-spectrometry (I-MS). We used principle component analysis (PCA) to confirm that human lung cancer has distinctive metabolic patterns. We revealed upregulation of the GDP-L-fucose de novo pathway, which regulates the level of fucosylated glycoproteins, in lung cancer tissues compared to the adjacent non-malignant lung tissues. In order to elucidate the mechanisms by which fucosylation is increased in lung cancer tissues, gene expression of fucosyltransferases (FUT1-9) were evaluated. We confirmed that fucosyltransferase 3 (FUT3) expression was increased in a significant proportion of human primary lung adenocarcinoma samples and was correlated with sLeX expression. A fucosylation inhibitor, 6-alkynyl-fucose, inhibited the proliferation and invasion of lung cancer cell lines with high endogenous FUT3 expression in vitro. Exogenous FUT3-overexpressing lung cancer cells did not show increased proliferation, but showed significantly increased invasion and adhesion activities in vitro. In order to confirm whether FUT3 promoted metastasis of A549 cells in an experimental lung metastatic mouse model, A549 lung cancer cells expressing EGFP (A549-EGFP) and A549 lung cancer cells overexpressing FUT3 (A549-FUT3) were intravenously administered to BALB/C nude mice and the numbers of metastatic nodules in the lungs were counted after 8 weeks. In concordance with our observations in vitro, there was no significant difference in tumor growth between the A549-EGFP and A549-FUT3 treatments in vivo. Interestingly, injection of A549-FUT3 resulted in an increase in the number of lung metastases compared to the injection of A549-EGFP, suggesting that FUT3 is a positive regulator of cancer invasion and metastasis. Furthermore, high expression of FUT3 in lung cancer tissues predicted a poorer prognosis for patients with lung adenocarcinoma. These findings highlight the important roles of protein fucosylation in lung cancer progression and provide the preclinical rationale to target this pathway in lung cancer treatment. Citation Format: Keita Masuzawa, Hiroyuki Yasuda, Atsushi Matsuda, Hideki Terai, Yuki Sugiura, Junko Hamamoto, Daisuke Arai, Shizuko Kagawa, Katsura Emoto, Shinnosuke Ikemura, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga. The role of protein fucosylation in lung cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 365.

Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4-10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations.The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH.We observed a mild but significant (P 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P 0.05) tumor growth inhibition without significant body weight loss or skin rash.The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.

Objective: Targeted therapy-induced facial skin toxicities may reduce overall quality of life (QoL) in cancer patients. We investigated whether facial skin toxicities affect QoL and attempted to identify factors related to QoL in patients with advanced/recurrent cancer. Methods: We performed a cross-sectional study in 34 outpatients with advanced/recurrent cancer showing targeted therapy-induced facial skin toxicities in Japan between November 2016 and February 2017. For measurement, we used the Kessler Psychological Distress Scale (K6), Mental Adjustment to Cancer (MAC) Scale, and Dermatology Life Quality Index (DLQI). Data were analyzed using Spearman's rank correlation coefficient. Results: Mean DLQI score in 34 patients was 4.59 (standard deviation ± 4.70), which was interpreted as a small effect on a patient's life. Acneiform rash was the most common skin condition noted, followed by xerosis, pruritus, and erythema. Analysis of DLQI scores revealed that symptoms and feelings was the domain most commonly affected among different domains constituting the DLQI. MAC analysis revealed that the fighting spirit score was the highest among MAC scales. We found that age, K6, and fatalism construct in MAC were significantly correlated with total DLQI scores (age: Spearman's ρ= −0.48, P = 0.004; K6: ρ= 0.58, P < 0.001; fatalism; ρ= −0.39, P = 0.025). Conclusions: This is the first study investigating targeted therapy-induced facial skin toxicities in cancer patients. Our results suggest potential negative effects of facial skin toxicities on overall QoL in patients with advanced/recurrent cancer in middle and early old age.

Stereotactic radiosurgery (SRS) using the Gamma Knife (GK) is now being increasingly utilized for the treatment of brain metastases. However, there are a few reported cases of SRS-induced brain neoplasms. We herein report the case of a Japanese woman with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR)-mutations who was treated four times with a GK for brain metastases. She developed glioblastoma 5.7 years after the initial GK surgery. Radiation-induced secondary neoplasms generally appear after a latency period of several years. Advances in cancer therapy have improved the survival of patients with NSCLC, providing enough time for secondary neoplasms to appear after SRS.

This Phase II study was conducted to evaluate the efficacy and safety of S-1 and irinotecan combination therapy as a second-line treatment in patients with advanced non-small cell lung cancer.Irinotecan was administered at 60 mg/m(2) on Days 1 and 8. Oral S-1 was administered on Days 1-14 every 3 weeks at 80 mg/day for patients with a body surface area of1.25 m(2), 100 mg/day for patients with a body surface area of 1.25-1.5 m(2) and 120 mg/day for patients with a body surface area of1.5 m(2). The primary endpoint was response rate, while the secondary endpoints were progression-free survival, overall survival and safety.Thirty-one patients were enrolled in this study. The response and disease control rates were 6.5 and 58.1%, respectively. Progression-free survival and median survival time were 2.8 and 12.6 months, respectively. Grade 3-4 adverse events were reported for 29.0% of the patients. Hematological toxicities of Grade 3 or 4 included leukopenia (9.7%), neutropenia (9.7%), febrile neutropenia (3.2%), thrombopenia (3.2%) and anemia (6.5%). Non-hematological toxicities of Grade 3 or 4 included pneumonitis (6.5%), diarrhea, colitis, dyspnea, rash, oral mucositis, anorexia and pulmonary thromboembolism/deep vein thrombosis (3.2% each).S-1 and irinotecan combination therapy at the present dose and schedule exhibited only modest efficacy with mild toxicities in previously treated patients with non-small cell lung cancer. No further clinical investigation with current dose and schedules is warranted for patients with non-small cell lung cancer who failed first-line platinum-based doublet chemotherapy.

The number of elderly patients with advanced non-small cell lung cancer (NSCLC) is increasing. Although several studies have suggested the benefit of chemotherapy with a platinum doublet for elderly patients with advanced NSCLC, this treatment is still controversial in this age group. To evaluate the efficacy and tolerability of combination chemotherapy with biweekly paclitaxel and carboplatin for elderly patients with advanced NSCLC, we conducted a multicenter, non-randomized, open label, phase II trial. We recruited patients aged ≥70 years with clinical stage IIIB and IV NSCLC and ECOG performance status (PS) of 0–2. Patients received paclitaxel (90 mg/m2) and carboplatin (AUC = 2.5) on day 1 and 15, every 4 weeks. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Sixty-five patients (median age 79 years; range 70–87 years) were enrolled. Forty-nine patients were men, and 48 were stage IV. The PS was 0, 1, and 2 in 28, 33, and 4 patients, respectively. The histological type of NSCLC was non-squamous in 69.3 % and squamous cell carcinoma in 30.7 % of patients. The median number of treatment cycles was 3 (range 1–6). The response rate was 29.4 % (95 % CI 18.7–43.0), and the disease control rate was 78.0 % (95 % CI 64.8–87.2). Median PFS and OS were 3.8 months (95 % CI 1.9–5.3) and 17.3 months (95 % CI 10.4–25.1), respectively. The most common grade 3 or 4 toxicities were neutropenia (27 %), leukopenia (15 %), infection (10 %), and anemia (8 %). The combination of biweekly paclitaxel and carboplatin was effective and well tolerated in elderly patients with advanced NSCLC.

Key Clinical Message Cytomegalovirus superinfection is associated with a poor prognosis in non‐HIV Pneumocystis pneumonia (PCP) and can cause deterioration of PCP not only simultaneously but also after initiating PCP treatment. Cytomegalovirus pneumonia should be considered in cases with deterioration after initiating PCP treatment; multiple nodular lesions are useful findings for the diagnosis.

Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy.A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test.The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P .05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029). Previous radiotherapy also had a positive association with the treatment response (P = .012).The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged ≥70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged

Rationale: Histoplasmosis occurs most commonly in Northern and Central America and Southeast Asia. Increased international travel in Japan has led to a few annual reports of imported histoplasmosis. Healed sites of histoplasmosis lung infection may remain as nodules and are often accompanied by calcification. Previous studies in endemic areas supported the hypothesis that new infection/reinfection, rather than reactivation, is the main etiology of symptomatic histoplasmosis. No previous reports have presented clinical evidence of reactivation. Patient concerns: An 83-year-old Japanese man was hospitalized with general fatigue and high fever. He had been treated with prednisolone at 13 mg/d for 7 years because of an eczematous skin disease. He had a history of travel to Los Angeles, Egypt, and Malaysia 10 to 15 years prior to admission. Five years earlier, computed tomography (CT) identified a solitary calcified nodule in the left lingual lung segment. The nodule size remained unchanged throughout a 5-year observation period. Upon admission, his respiratory condition remained stable while breathing room air. CT revealed small, randomly distributed nodular shadows in the bilateral lungs, in addition to the solitary nodule. Diagnosis: Disseminated histoplasmosis, based on fungal staining and cultures of autopsy specimens. Interventions: The patient's fever continued despite several days of treatment with meropenem, minocycline, and micafungin. Although he refused bone marrow aspiration, isoniazid, rifampicin, ethambutol, and prednisolone were administered for a tentative diagnosis of miliary tuberculosis. Outcomes: His fever persisted, and a laboratory examination indicated severe thrombocytopenia with disseminated intravascular coagulation. He died on day 43 postadmission. During autopsy, the fungal burden was noted to be higher in the calcified nodule than in the disseminated nodules of the lung, suggesting a pathogenesis involving endogenous reactivation of the nodule and subsequent hematogenous and lymphatic spread. Lessons: Physicians should consider histoplasmosis in patients with calcified nodules because the infection may reactivate during long-term corticosteroid therapy.

Purpose Bronchoscopic microsampling (BMS) is a novel and direct method with which to obtain epithelial lining fluid (ELF) from the lungs. Analysis of DNA hypermethylation of tumor suppressor genes (TSGs) is expected to be a sensitive tool for the early detection of lung cancer. It has been reported that the existence of EGFR mutations and EML4-ALK gene rearrangements are related to the sensitivity of corresponding kinase inhibitors. We aimed to evaluate the suitability of ELF as a sample for analyzing molecular changes specific for lung cancer. Patients and methods We collected ELF from 61 lung cancer patients by BMS from the airway close to the peripheral lung nodule and purified the nucleic acids. We performed methylation specific PCR in each ELF as well as matched serum and tumor tissue for TSGs for DNA methylation analysis. We also examined EGFR mutations and EML4-ALK rearrangement. Results The sensitivity for detecting DNA hypermethylation in ELF vs serum was 74.1% vs 18.5%. We found 60.1% of patients had at least one hypermethylation in ELF, while only 27.9% had it in serum. Of note, DNA hypermethylation was detected even in stage I patients (60.0%) and the detection rate was almost the same level in each stage. We also found the sensitivity for detecting EGFR mutation in ELF vs serum was 58.3% vs 8.3%. We detected an EML4-ALK fusion gene using ELF in one patient. Conclusions BMS is an alternative method to detect cancer specific genetic and epigenetic alterations and will be a useful complementary diagnostic tool for lung cancer. Summary Investigation of genetic and epigenetic changes associated with lung cancer has clinical importance for its diagnosis and management. The clinical usefulness of bronchoscopic microsampling (BMS) in lung cancer has not yet been evaluated. This study demonstrates that BMS could be useful for detecting lung cancer specific molecular changes and valuable for early diagnosis and determination of treatment options for lung cancer.

Introduction Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small cell lung cancers (NSCLCs). Currently available methods of EGFR mutation detection rely on direct sequencing. Here, we describe the use of an alternative way to screen EGFR mutations. Methods A total of 109 frozen tumor specimens from NSCLC patients were obtained. For mutational analysis of EGFR exons 18, 19, and 21, reverse transcription-polymerase chain reaction was performed on the cDNA using original primers designed for restriction fragment length polymorphism (RFLP). Results EGFR mutations were detected in 37 patients (34%) by both RFLP and direct sequencing except one case in which it was detected only by RFLP. EGFR mutations were more frequently observed to be significant by multivariate analysis in patients with adenocarcinoma (OR = 5.56), no-smoking history (OR = 4.34), and 65-year-old or younger (OR = 2.64), but not in women (OR = 1.14). Among 37 patients, 18 were treated with gefitinib and 9 responded to the treatment. One patient without any mutation responded. Conclusion RFLP is a useful method for screening EGFR mutations and can also be applied to predicting the sensitivity of NSCLC patients to EGFR-tyrosine kinase inhibitors.

// Toshiyuki Hirano 1, * , Hiroyuki Yasuda 1 , Tetsuo Tani 1, * , Junko Hamamoto 1 , Ayano Oashi 1 , Kota Ishioka 1 , Daisuke Arai 1 , Shigenari Nukaga 1 , Masayoshi Miyawaki 1 , Ichiro Kawada 1 , Katsuhiko Naoki 2 , Daniel B. Costa 3 , Susumu S. Kobayashi 3 , Tomoko Betsuyaku 1 , Kenzo Soejima 1 1 Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 2 Keio Cancer Center, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Hiroyuki Yasuda, e-mail: hiroyukiyasuda@a8.keio.jp Kenzo Soejima, e-mail: ksoejima@cpnet.med.keio.ac.jp Keywords: EGFR mutation, EGFR tyrosine kinase inhibitors, EGFR exon 20 insertion mutations, in vitro modeling, lung cancer Received: August 18, 2015 Accepted: October 03, 2015 Published: October 15, 2015 ABSTRACT EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the “therapeutic window” of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1 st (erlotinib), 2 nd (afatinib) and 3 rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR . An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1 st and 2 nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

Introduction Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense 18F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. Case presentation A 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense 18F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. Conclusion This is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.

e20577 Background: Nivolumab, an immune checkpoint inhibitor, is now approved as standard treatment for pre-treated advanced non-small cell lung cancer (NSCLC) based on the results from mega clinical trials with carefully selected patients. We sought to clarify the real-world efficacy and safety of nivolumab and to identify the clinical factors influencing the efficacy. Methods: This study enrolled 142 patients with pre-treated advanced NSCLC who had been administered nivolumab (3mg/kg, Q2W) from January to July 2016 at Keio University and affiliated hospitals in Japan. We retrospectively evaluated objective responses, adverse events (AEs), and analysed clinical factors associated with the response. Results: The overall response rate and disease control rate were 17% and 62%, respectively. The rate of any grade AEs was 45%, while the rate of grade 3-4 AEs was 13%. Among patient’s clinical factors such as age, gender, ECOG performance status, types of carcinoma, epidermal growth factor receptor ( EGFR)/ anaplastic lymphoma receptor tyrosine kinase (ALK) mutation status, smoking status, number of previous treatment lines, presence of central nervous system (CNS) metastasis and presence of prior radiotherapy, “ EGFR/ALK mutation negative” and “administration of prior radiotherapy” were independently associated with the good response to nivolumab treatment by multivariate logistic regression analysis (OR NA/ p < 0.01, OR 5.4/ p < 0.01, respectively). None of the 19 EGFR/ALK mutation positive patients showed response. Although a significant difference was not recognized between “current, former smokers” and “never smokers” (chi-square test, p = 0.1), a subsequent analysis showed smoking pack years (PY) was significantly higher in responders than in non-responders ( t-test, p = 0.035). Conclusions: The objective responses and the profiles of AEs confirmed in our study were similar to those observed in Checkmate 057/017 trials. We can use nivolumab safely regardless of age or number of treatment lines. EGFR/ALK mutation and presence of prior radiotherapy were key clinical factors statistically associated with the nivolumab efficacy.

A 76-year-old woman, diagnosed 5 years previously with an asymptomatic mediastinal bronchogenic cyst, was referred to our department as the mass had grown slightly larger. Contrast-enhanced computed tomography and magnetic resonance imaging scans revealed an azygous vein aneurysm with a pulmonary arterial thromboembolism. The patient was treated with heparin for 5 days, and anticoagulation therapy with edoxaban was continued for 12 months. The thrombus resolved, and the aneurysm remained unchanged. An azygous vein aneurysm is a very rare condition that causes pulmonary arterial thromboembolism. Although surgical resection is indicated for patients with azygous vein aneurysms with a risk of rupture and pulmonary embolism, we chose anticoagulation therapy because of the patient's advanced age. This case suggests that the azygous vein aneurysm is one of the differential diagnoses for a mediastinal mass and that anticoagulation therapy can be the treatment of choice for pulmonary arterial thromboembolism with an azygous vein aneurysm.

Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non–small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potent MET/RON dual kinase inhibitor LY2801653 in this setting. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. Using the PamGene platform, we found that inhibition of MET and RON was associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of the MET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small-molecule modality to treat NSCLC. Cancer Res; 74(3); 884–95. ©2013 AACR.

症例は55歳の女性. 平成7年5月頃より喀痰, 咳嗽が出現し, 次第に労作時呼吸困難が増強することから近医を受診した. 胸部単純写真で右上・中肺野に広範な浸潤影を指摘され, TBLBにて肺腺癌と診断された. 化学療法は無効であったが, 経過とともに増加する多量の喀痰に対してインドメタシン吸入 (75rng/日) を開始したところ, 数日のうちに著明な喀痰の減少が認められた. 患者は肺癌の進行により死亡したが, これらの薬剤は患者のQOL改善に非常に有効であった.

A 62-year-old man was seen at the hospital because of dysphagia. Upper gastrointestinal series and endoscopic examination showed a type 2 lesion at the cardia and a Borrmann type 5 lesion in the stomach. Biopsy specimens demonstrated squamous cell carcinoma and signet ring cell carcinoma, respectively. A collision tumor was strongly suspected. The resected material showed the type 2 lesion measuring 6.0×5.0cm and the Borrmann type 5 lesion measuring 8.5×5.5cm which located close to each other at the cardia. Histologically, the esophageal squamous cell carcinoma and the gastric signet ring cell carcinoma were separated only by a thin fibrous tissue, and there was no histological transition between two lesions. With respect to metastatic sites, only one component from each tumor was seen.

Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo , a mouse flank xenograft tumor model was utilized. Results: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

A 72-year-old man with refractory anemia with an excess of blasts developed overt leukemia with leukothrombocytosis. Hematological and physical findings closely resembled those of an accelerated or blastic phase of chronic myelocytic leukemia. The cytogenetic anomaly of i(17q) was observed during the course. The present case is suggestive of the diversities of myelodysplastic syndromes (MDS), including relationships between MDS and myeloproliferative disorders (MPD) and acute leukemia.