The prognostic impact of a high number of peritumoral alveolar macrophages in neuroendocrine carcinoma in the lung.

Alveolar macrophages (AMs) are resident macrophages in the lungs; however, whether the number of AMs plays a role in the lung neuroendocrine tumor (NET) prognosis remains unclear. We counted the number of AMs located around the tumor (peritumoral alveolar macrophages [pAMs]) and the number of AMs located apart from the tumor (distant macrophages; dAMs). In 73 cases of neuroendocrine carcinoma (NEC: small cell lung carcinoma and large cell neuroendocrine carcinoma), the group that contained higher pAMs (≥86/µm2 ) revealed shorter recurrent-free survival (RFS) than those with lower pAMs (<86/µm2 ) (p = 0.005). Bivariate analysis showed that the number of pAMs was an independent predictor of a poor RFS. In contrast, in the carcinoid tumor cohort (n = 29), there was no statistically significant correlation between the two groups with high and low numbers of pAMs in RFS (p = 0.113). Furthermore, we examined the correlation between genomic alterations and the number of pAMs in NEC, but no significant correlation was observed. In conclusion, the number of pAMs is a prognostic factor for NEC in the lung and pAMs may contribute to tumor progression within the peritumoral microenvironment.

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

Early specialized palliative care for patients with metastatic lung cancer receiving chemotherapy: a feasibility study of a nurse-led screening-triggered programme.

BACKGROUND: Strategies to implement early specialized palliative care have not yet been established. The present study investigated the feasibility of a nurse-led, screening-triggered early specialized palliative care intervention programme and obtained data to design a randomized controlled trial. METHODS: Patients with metastatic lung cancer undergoing first-line platinum-based chemotherapy were eligible. The intervention consisted of (1) a questionnaire-based screening programme and (2) advanced-level nurse counselling and care coordination with interdisciplinary team approach. The primary endpoint was the completion rate of the assessment questionnaire after the second course of first-line chemotherapy (T2). Secondary endpoints included changes in Functional Assessment of Cancer Therapy-Lung scores, depression and anxiety rates based on the Patient Health Questionnaire 9 and the Hospital Anxiety and Depression Scale, and the contents of specialized palliative care. RESULTS: A total of 50 patients were enrolled between August 2012 and March 2014. Median age was 66 years (range, 40-78 year) and 84% were male. A total of 38 patients had stage IV non-small cell lung carcinoma and 12 had extensive disease small-cell lung carcinoma. The completion rate was 70% (95% confidence interval 56.0-81.0). The median duration between baseline and T2 was 53 days. Improvement from baseline were observed at T2 in Functional Assessment of Cancer Therapy-Lung scores (86.0 ± 18.1 vs 94.9 ± 18.2, P = 0.057), depression (16.0 vs 5.7%; P = 0.26) and anxiety (32.0 vs 22.9%; P = 0.65); however, these results were not statistically significant. CONCLUSIONS: This early specialized palliative care intervention is feasible and could be useful in improving patients' quality of life. The present results justify the initiation of a randomized control trial.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.

Carboplatin, S-1 and concurrent thoracic radiotherapy for elderly patients with locally advanced non-small cell lung cancer: a multicenter Phase I/II study.

OBJECTIVES: We conducted a Phase I/II study of carboplatin, S-1 and concurrent thoracic radiotherapy (TRT) for elderly patients (71 years or older) with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received carboplatin (AUC 3-5) on Day 1 and S-1 (30-40 mg/m2 two times daily) on Days 1-14, every 2 weeks, for up to four cycles, plus concurrent TRT at a total dose of 60 Gy. The primary endpoint for the Phase II study was the 1-year progression-free survival (PFS) rate. RESULTS: Eighteen patients were enrolled in the Phase I study. Febrile neutropenia, a decreased platelet count and esophagitis were dose-limiting toxicities. The recommended doses for the Phase II study were determined to be an AUC of 3 for carboplatin, 40 mg/m2 twice daily for S-1. Twenty-eight patients were evaluated in the Phase II study. The 1-year PFS rate was 57.1% (90% CI 41.6-71.4%), and the median PFS was 16.8 months (95% CI 7.8-not assessable [NA]). The lower limit of the 90% CI for 1-year PFS exceeded the prespecified threshold value of 30%; therefore, the primary endpoint was met. Grades 3-4 toxicities included thrombocytopenia (21%) and hyponatremia (11%). Grade 3 radiation pneumonitis was observed in 18% of patients. No treatment-related deaths were observed. CONCLUSION: Combination chemotherapy consisting of carboplatin plus S-1 and concurrent TRT had a promising efficacy in elderly patients with locally advanced NSCLC; however, radiation pneumonitis was frequently observed.

The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions.

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 1.0).

In Japan, the social (medical) health-care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as "cancer clinical sequencing," which uses a next-generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.

Publication of lung cancer clinical trials in the Japanese Clinical Trial Registry.

INTRODUCTION: Since June 2005, the University Hospital Medical Information Network-Clinical Trial Registry (UMIN-CTR) has been an International Committee of Medical Journal Editors (ICMJE)-approved clinical trial registry in Japan. The number of clinical trials registered in the UMIN-CTR has increased annually. To date, no report exists regarding the publishing of clinical trials registered in the UMIN-CTR. Therefore, we evaluated the publication frequency of clinical trials registered in the UMIN-CTR in Japan. METHODS: We targeted trials that assessed the treatment effect of chemotherapy or molecular targeting drugs for lung cancer. We included trials registered between June 2005 and January 2010, and identified published trials through a computer-based search of MEDLINE and Google Scholar. The cumulative publication rate of the trials was calculated using Kaplan-Meier analysis. RESULTS: In our study, 179 trials met the inclusion criteria. Of these, 46.4% (83/179) trials were published by the end of the cut-off period. With regard to publication, differences existed between the information recorded in the UMIN-CTR database and the actual searched results. The publication rate between groups was insignificantly different; however, whether a clinical study group did or did not conduct a trial differed significantly (53.3% vs. 36.1%; P = 0.024). Phase II studies with positive results were more likely to be published (84.4%); however, the overall publication rate was low (41.8%), which may reflect publication bias. CONCLUSIONS: The UMIN-CTR fundamentally functions as the unique ICMJE-approved clinical trial registry in Japan. However, it seems insufficient to require it as the official clinical database.

Changes in the tumor microenvironment during lymphatic metastasis of lung squamous cell carcinoma.

Metastasis and growth in neoplastic lesions requires the multistep regulation of microenvironmental factors. We aimed to elucidate the microenvironmental changes in the process of lymphatic metastasis of lung squamous cell carcinoma. We examined the morphological characteristics of 102 cases of primary tumor (PT), 50 of intralymphatic tumor (ILT), 51 of lymph node (LN) micrometastasis (LN-Mic; ≤2 mm in size), and 82 of LN macrometastasis (LN-Mac; ≥10 mm in size). Afterwards we evaluated the expression of nine molecules (epidermal growth factor receptor, fibroblast growth factor receptor 2, CD44, aldehyde dehydrogenase 1, Podoplanin, E-cadherin, S100A4, geminin, and ezrin) in matched PT, ILT, LN-Mic, and LN-Mac from 23 of these cases. The number of smooth muscle actin α-positive fibroblasts, CD34-positive microvessels and CD204-positive macrophages were also examined. As a result, the mitotic index of tumor cells was significantly lower in ILT and LN-Mic than PT and LN-Mac (P < 0.001). Moreover, stromal reaction in ILT and LN-Mic was less prominent than in PT and LN-Mac (P < 0.001). Immunohistochemical study revealed that epidermal growth factor receptor expression level and frequency of geminin-positive cells in ILT and LN-Mic were significantly lower than in PT and LN-Mac (P < 0.05). The number of stromal cells indicated by staining of CD34, CD204, and smooth muscle actin α in ILT and LN-Mic was also significantly lower than in PT and LN-Mac (P < 0.05). In lung squamous cell carcinoma, drastic microenvironmental changes (e.g., growth factor receptor expression and proliferative capacity of tumor cells and structural changes in stromal cells) occur during both the process of lymphatic permeation and the progression into macrometastases.

Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma.

Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.

Genomic profiling of small-cell lung cancer: the era of targeted therapies.

The molecular profiling of small-cell lung cancer is challenging because of the difficulty in obtaining suitable tumor samples for integrative genomic analysis. While an urgent need exists for well-defined and effective therapeutic targets in small-cell lung cancer, no significant improvement has been made in treating this disease over the past 30 years. Recently, three reports describing comprehensive genomic analyses of small-cell lung cancer have been published. These reports have provided a framework of biologically relevant genes in small-cell lung cancer and have demonstrated that the genomic landscape of small-cell lung cancer was almost equivalent between Asian and Caucasian populations. Of note, these three comprehensive genomic analyses and other molecular analyses of small-cell lung cancer have contributed to the identification of patient populations that may benefit from promising targeted agents, such as those affecting the PI3K/AKT/mTOR pathway, FGFR1, RET or AURORA kinase inhibitors. Targeting small-cell lung cancer cells with tumor suppressor gene alteration based on synthetic lethality is also promising. The present review provides an overview of the biologically relevant genetic alterations and targeted therapies of small-cell lung cancer focusing on recent discoveries that could impact the management of small-cell lung cancer.

Docetaxel for platinum-refractory advanced thymic carcinoma.

OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm. While platinum-based chemotherapy has been reported to be effective for advanced thymic carcinoma in a first-line setting, little information is available regarding the benefits of salvage chemotherapy for platinum-refractory thymic carcinoma. This study assessed the efficacy and safety profiles of docetaxel monotherapy for platinum-refractory thymic carcinoma. METHODS: A total of 13 thymic carcinoma patients treated with docetaxel monotherapy in a second- or later-line setting between January 2003 and April 2014 were retrospectively reviewed. The median age was 61 years (range, 41-75 years). RESULTS: The overall response rate and disease control rate were 31% [95% confidence interval (CI), 6-56%] and 77% (95% CI, 54-100%), respectively. The median progression-free survival and overall survival after docetaxel monotherapy were 5.5 months (95% CI, 2.3-6.5 months) and 24.0 months (95% CI, 9.4-31.2 months), respectively. The most common Grade ≥3 toxicity was neutropenia (62%). No incidents of febrile neutropenia and no treatment-related deaths were recorded. CONCLUSIONS: This retrospective analysis demonstrated that docetaxel was active against platinum-refractory thymic carcinoma with acceptable toxicities. Docetaxel monotherapy might be a promising therapeutic option for patients with platinum-refractory thymic carcinoma.

Low-dose irinotecan as a second-line chemotherapy for recurrent small cell lung cancer.

OBJECTIVE: Irinotecan is a potent inhibitor of deoxyribonucleic acid topoisomerase 1 and the weekly schedule of 100-125 or 350 mg/m(2) administration on Day 1 every 3 weeks is recommended for recurrent small cell lung cancer. However, severe gastrointestinal toxic effects and myelosuppression are often observed in this dose setting. We conducted a retrospective study to evaluate the efficacy and safety of low-dose irinotecan monotherapy (60 mg/m(2) on Days 1, 8 and 15 every 4 weeks) as second-line chemotherapy for small cell lung cancer. METHODS: The medical charts of small cell lung cancer patients who had received second-line chemotherapy at the National Cancer Center Hospital East between April 2003 and June 2012 were reviewed. Consecutive 57 patients who were treated with low dose of irinotecan (60 mg/m(2) on Days 1, 8 and 15 every 4 weeks) were analyzed in this study. RESULTS: Median age was 70 years (range, 51-83). Fifty-two (91%) were male, 36 (63%) had an Eastern Cooperative Oncology Group performance status 0-1 and 26 (46%) were sensitive relapse. The median number of chemotherapy cycles was 2. The objective response rate was 32% (95% confidence interval: 20-45%).The median progression-free survival and the median overall survival were 2.9 months (95% confidence interval: 1.9-3.4 months) and 5.3 months (95% confidence interval: 3.6-7.6 months), respectively. The incidence of Grade 3/4 neutropenia, diarrhea and nausea/vomiting was 21, 4 and 5%, respectively. CONCLUSIONS: Low-dose irinotecan monotherapy for recurrent small cell lung cancer might be effective with favorable toxicity. Randomized trial of 60 mg/m(2) versus standard dose of irinotecan is warranted.

Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: a retrospective study.

OBJECTIVE: Magnesium supplementation has been reported to have a nephroprotective effect on cisplatin-induced renal dysfunction, but little evidence exists regarding the effect of magnesium preloading before cisplatin administration. We started to include magnesium preloading (8 mEq) in cisplatin-containing treatment regimens in January 2011. The aim of the present study was to evaluate whether magnesium preloading reduces cisplatin-induced nephrotoxicity. METHODS: We retrospectively reviewed 496 thoracic malignancy patients treated with cisplatin (≥60 mg/m²)-containing regimens as a first-time chemotherapy between January 2009 and December 2011. We compared the incidence of Grade ≥2 serum creatinine elevation according to the Common Terminology Criteria for Adverse Events, version 4.0, between magnesium preloading group (n = 161 [32%]) and non-magnesium preloading group (n = 335 [68%]) during the first cycle and all cycles. RESULTS: The median number of administered cycles was four in both groups. The incidence of Grade ≥2 serum creatinine elevation in magnesium preloading group was significantly lower during both the first cycle and all cycles than in the non-magnesium preloading group (4.9 versus 19.1% during the first cycle, and 14.2 versus 39.7% during all the cycles). A multivariate analysis indicated that magnesium preloading significantly reduced cisplatin-induced nephrotoxicity throughout the entire period from after the first administration (odds ratio: 0.262, 95% confidence interval: 0.106-0.596 during the first cycle, and odds ratio: 0.234, 95% confidence interval: 0.129-0.414 during all cycles). CONCLUSIONS: Magnesium preloading before cisplatin administration significantly reduced cisplatin-induced nephrotoxicity.

Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma.

Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis. IMPLICATIONS: SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.

Prognostic value of predominant subtype in pathological stage II-III lung adenocarcinoma with epidermal growth factor receptor mutation.

OBJECTIVES: This study extracted clinicopathological features associated with recurrence and evaluated the tumor microenvironment in consecutive cases with resected pathological stage II-III epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (EGFR-mt). METHODS: Between January 2008 and November 2018, we retrospectively reviewed 387 consecutive patients with pathological stage II-III lung adenocarcinoma who underwent surgical resection. We examined the EGFR mutation status (wild-type or mutant) and the evaluated clinicopathological features of all patients. In addition, tumor-promoting cancer-associated fibroblasts (CAFs), tumor-associated M2 macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment of EGFR-mt cells were evaluated by immunohistochemical analysis. RESULTS: EGFR-mt (n = 124, 32 %) had more lymph node and pulmonary metastases than EGFR-wild-type lung adenocarcinoma (EGFR-wt) despite the smaller invasive component size. The disease-free survival (DFS) of patients with EGFR-mt tended to be shorter than that of patients with EGFR-wt. In the analysis according to the predominant subtype, EGFR-mt with papillary-predominant subtype had a significantly shorter 5-year DFS than that of EGFR-wt with papillary-predominant subtype (15.3 % vs. 44.1 %, p < 0.01). We observed no significant differences among the other subtypes. Multivariate analysis of DFS in patients with EGFR-mt revealed that male sex, pathological stage III, lymph node metastasis, pulmonary metastasis in the same lobe and non-acinar and non-lepidic predominant subtypes (papillary, solid, or micropapillary) were independent poor prognostic factors. Immunohistochemical analysis of EGFR-mt revealed that non-acinar- and non-lepidic-predominant subtypes were associated with a higher frequency of podoplanin-positive CAFs (36 % vs. 13 %, p = 0.01) and a higher median number of CD204-positive TAMs (61 vs. 49, p = 0.07) compared to the acinar- or lepidic-predominant subtypes. CONCLUSIONS: Non-acinar and non-lepidic predominant subtypes were predictors of recurrence and had an aggressive tumor microenvironment in pathological stage II-III EGFR-mt.

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia.

OBJECTIVES: In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. MATERIALS AND METHODS: The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. RESULTS: Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35-3.46]; ICIs vs docetaxel, 1.49 [1.21-1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07-0.64]). CONCLUSIONS: After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

Renal toxicity caused by brand-name versus generic cisplatin: a comparative analysis.

OBJECTIVE: A generic cisplatin formulation has replaced the brand-name formulation since November 2003 in our hospital. We retrospectively assessed the renal toxicity caused by the brand-name and generic cisplatin formulations. METHODS: The medical records of patients with thoracic malignancy who were treated at our hospital between November 2000 and April 2008 were reviewed. In total, 1296 eligible patients received 80 mg/m(2) of cisplatin: 499 patients were treated with the brand-name cisplatin formulation before November 2003 (Group 1) and 797 patients were treated with the generic formulation after November 2003 (Group 2). We compared the maximum serum creatinine level after chemotherapy in the two groups. RESULTS: The patient characteristics, including age, sex and performance status, and pretreatment serum creatinine levels were well balanced between the two groups. More patients received four cycles of chemotherapy in Group 2 (P < 0.0001). The median (range) of the maximum serum creatinine levels during all the chemotherapy cycles were 1.1 (0.5-4.1) mg/dl and 1.1 (0.5-4.4) mg/dl in Groups 1 and 2, respectively (P = 0.0237). The incidence of grade 0 serum creatinine elevations decreased from 47% to 39%, while that of grade 1 serum creatinine elevations increased from 32% to 41% (P = 0.0094). The incidence rates of grade 2 or 3 serum creatinine elevations were similar (21 vs. 20%). The time to serum creatinine elevation was also similar in Groups 1 and 2 (P = 0.161). CONCLUSION: Although grade 1 maximum serum creatinine level was more common in the generic cisplatin formulation group, this was attributed to the larger number of patients receiving four cycles of chemotherapy in this group.