Tetsuhiko Asao

Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy.

BACKGROUNDS To understand the clinical impact of PD-1/L1 expression in thymoma (TM) and thymic carcinoma (TC), we evaluated the frequency of PD-1/L1 expression in pre/post chemotherapy specimens and the correlation with the treatment efficacy. METHODS The expression of PD-1/L1 was evaluated using immunohistochemistry in patients with TM or TC treated with chemotherapy between 2000 and 2014. Using formalin-fixed, paraffin-embedded tissue samples and a PD-L1 antibody, the expression of PD-L1 in the TM and TC specimens was reported in terms of the H-score (0-300), with a score ≥1 being defined as positive. The PD-1 expression in the tumor-infiltrating immune cells was evaluated based on the intensity (0-3) of staining using a PD-1 antibody. The objective response rate, progression-free survival, and the difference in PD-1/L1 expression between the pre/post chemotherapy were evaluated. RESULTS Thirty patients (TM/TC 12/18) were evaluated. PD-L1 positivity were TM/TC 67%/41%. Within the PD-L1 positive/negative populations, the objective response rates were 50%/0% for TM and 14%/20% for TC. No significant differences in progression-free survival were seen according to the PD-L1 expression status. Increases in both the PD-L1 and PD-1 scores were observed after chemotherapy in six serial pre/post chemotherapy TM specimens, with a mean PD-L1 score and a median PD-1 intensity of 42/93, and 0/2.5, respectively. CONCLUSIONS The substantially high expression of PD-L1 and the increase in PD-L1 and PD-1 expression after chemotherapy supports anti-PD-1/L1 drugs therapy for TM and TC as well as the development of a strategy for its sequential use after chemotherapy.

Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease.

BackgroundNon-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established.MethodWe investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed.ResultsTwenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity.ConclusionWe found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs.

Phase II study of amrubicin at a dose of 45 mg/m2 in patients with previously treated small-cell lung cancer

OBJECTIVE Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer. METHODS Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate. RESULTS From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia. CONCLUSIONS While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited.

Comparison of Amrubicin and Weekly Cisplatin/Etoposide/Irinotecan in Patients With Relapsed Small-cell Lung Cancer

Background Although several agents have been introduced for the treatment of relapsed small‐cell lung cancer (SCLC), there is still only limited evidence regarding second‐ and later‐line chemotherapies for these patients. Patients and Methods Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients’ characteristics and treatments to explore factors associated with the survival outcomes were reviewed. Results A total of 580 patients diagnosed as having SCLC received first‐line chemotherapy/chemoradiotherapy, of which 343 (59%) received second‐line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second‐line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression‐free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first‐line treatment (vs. refractory relapse) (P = .007) and AMR as second‐line treatment (vs. PEI) (P = .005) as independent favorable prognostic factors for survival. Conclusion AMR showed a favorable trend compared with PEI in terms of the progression‐free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted. Micro‐Abstract Limited evidence is available for relapsed small‐cell lung cancer (SCLC). Five hundred eighty consecutive patients with relapsed SCLC treated at our institute were analyzed. Multivariate analysis identified sensitive relapse and amrubicin treatment as independent favorable prognostic factors for survival. Amrubicin showed a favorable trend compared with cisplatin/etoposide/irinotecan in terms of the progression‐free survival and feasibility in SCLC patients with relapsed disease.

Expression levels of UL16 binding protein 1 and natural killer group 2 member D affect overall survival in patients with gastric cancer following gastrectomy

UL16 binding protein 1 (ULBP1) expressed on the tumor cell surface binds to the natural killer group 2 member D (NKG2D) receptor presenting on natural killer (NK), cluster of differentiation (CD)8+ T, and γ δ T cells. However, the roles of ULBP1 and NKG2D expression and associated immune responses in gastric cancer are unclear. The present study investigated the associations between ULBP1 and NKG2D expression and clinical outcomes in patients with gastric cancer. The levels of ULBP1 and NKG2D expression were examined in human gastric cancer cell lines and gastric cancer tissues from 98 patients who underwent surgery from 2004 to 2008. MKN-74 cells expressed ULBP1 with ULBP2, −5, or −6. NKG2D was expressed at a higher level following activation of T cells and NK cells. Among the tissue sections positive for NKG2D expression, 6 patients were positive for CD8 and CD56. In all tissues, NKG2D-expressing cells were typically aCD8+ T cells. Patients with NKG2D expression in tumors exhibited significantly longer overall survival (OS) compared with patients without NKG2D expression in tumors (P=0.0217). The longest OS was observed in patients positive for ULBP1 and NKG2D, whereas the shortest OS was observed in patients negative for ULBP1 and NKG2D. The interaction between ULBP1 and NKG2D may improve OS in patients with gastric cancer, and may have applications in immunotherapy for the induction of adaptive immunity in patients with cancer. Additionally, ULBP1 and NKG2D may be useful as prognostic biomarkers in gastric cancer.

Medical treatment involving investigational drugs and genetic profile of thymic carcinoma

BACKGROUND Thymic carcinoma is a rare neoplasm of the thymus, and information regarding its genetic profile and optimal medical treatment is limited. We sought to characterize the genetic profile of thymic carcinoma and to evaluate the efficacy of various medical treatments, including treatment with tyrosine kinase inhibitors (TKIs), cytotoxic agents, and immune checkpoint inhibitors. METHODS We retrospectively reviewed medical records of 64 consecutive patients with thymic carcinoma at the National Cancer Center Hospital between April 1973 and March 2014. We analyzed treatment course of patients who underwent medical treatment involving investigational drugs. For patients with available tissue samples, targeted sequencing of 50 cancer-related genes using next-generation sequencing was performed. RESULTS Thirty-six patients had received chemotherapy. Median progression-free survival in patients receiving first-line chemotherapy was 7.07 months (95% confidence interval, 5.67-8.93). Median survival time was 32.6 months (95% confidence interval, 23.2-43.4). As second- or later-line chemotherapy, a total of 13 patients were treated with 24 investigational drugs, including 8 multi-targeted TKIs, 5 cytotoxic agents, and 2 immune checkpoint inhibitors. Six (24%) of the patients treated with investigational drugs maintained disease control for at least 6 months. Tissue samples of 52 patients (81.3%) were available for targeted sequencing, consisting of 52 formalin-fixed, paraffin-embedded (FFPE) and 16 fresh frozen tissue samples. The genetic alterations of TP53, KRAS, FBXW7, and NRAS were detected in 7 patients (13.5%), and no KIT mutations were noted. CONCLUSIONS Multi-targeted TKIs exhibited potential clinical efficacy for previously-treated thymic carcinoma. The frequency of genetic alterations in this study was low, with no apparent relationship with the efficacy of chemotherapy.

Protein-losing Enteropathy Caused by Intestinal or Colonic Lymphangiectasia Complicated by Sporadic Lymphangioleiomyomatosis: A Report of Two Cases

This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.

Comparison of Radiotherapy and Chemoradiotherapy for Locoregional Recurrence of Non–small-cell Lung Cancer Developing After Surgery

Background The optimal treatment strategy for locoregional recurrences developing after surgical resection in patients with non–small‐cell lung cancer (NSCLC) is yet to be clearly established. Patients and Methods To investigate the efficacy and safety of radiotherapy (RT) and chemoradiotherapy (CRT), we reviewed the consecutive data of patients with NSCLC with postoperative locoregional recurrences treated at the National Cancer Center Hospital between January 2000 and April 2010. Results We reviewed the data of 74 patients (including 56 who received RT alone and 18 who received CRT) according to our study criteria. The median age was lower and the N factor at the recurrence site was higher in the CRT group compared with the RT group. Most patients received 60 Gy/30 Fr RT in both groups. The 2‐year progression‐free survival (PFS) rate, median PFS, and overall survival (OS) were 44.4%, 19.0 months (95% confidence interval [CI], 0‐41.9 months), and 79.6 months (95% CI, 8.2‐151.0 months), respectively, in the CRT group, although those were 25.0%, 10.6 months (95% CI, 8.7‐12.9 months), and 33.1 months (95% CI, 17.9‐48.3 months), respectively, in the RT group. The adverse event profile was acceptable, with no treatment‐related death in either group. Multivariate analysis identified CRT as being significantly associated with a longer PFS and OS. Conclusion CRT tended to yield better results than RT in terms of the survival outcomes, with acceptable safety profiles of both. We consider that a randomized study comparing RT and CRT is warranted to identify the optimal treatment strategy for patients with NSCLC with postoperative locoregional recurrences. Micro‐Abstract There is little evidence on treatment strategy for postoperative locoregional relapsed non–small‐cell lung cancer. Seventy‐four consecutive patients with non–small‐cell lung cancer with postoperative locoregional recurrences who received chemoradiotherapy (CRT) or radiotherapy at our institute were analyzed. Multivariate analysis identified CRT as a significant survival factor. CRT showed favorable survival outcomes with acceptable feasibility of both CRT and radiotherapy.

Resistance to molecularly targeted therapy in non-small-cell lung cancer

The discovery of oncogenic driver gene mutations, including epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, and ret proto-oncogene (RET) fusion, has led to the development of molecularly targeted therapy for non-small-cell lung cancer (NSCLC). This therapy has changed the standard of care for NSCLC. Despite the dramatic response to molecularly targeted therapy, almost all patients ultimately develop resistance to the drugs. To understand the mechanisms of resistance to molecularly targeted agents, it is essential to understand the molecular pathways of NSCLC. Here, we review the mechanisms of resistance to molecularly targeted therapy and discuss strategies to overcome drug resistance.

Sequential Use of Anaplastic Lymphoma Kinase Inhibitors in Japanese Patients With ALK-Rearranged Non–Small-Cell Lung Cancer: A Retrospective Analysis

Background Second‐generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK‐rearranged non–small‐cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice. Patients and Methods Patients with ALK‐rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively. Results Fifty‐nine patients with ALK‐rearranged NSCLC had been treated and 37 cases were assessable. Twenty‐six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression‐free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%‐80.9%) and 38.4% (95% CI, 12.0%‐64.9%), and 10.7 (95% CI, 5.3‐14.7) months and 16.6 (95% CI, 2.9‐not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months‐not calculable). The 5‐year survival rate of ALK‐rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%‐94.0%). Conclusion The combined PFS and 5‐year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK‐rearranged NSCLC. Micro‐Abstract Sequential anaplastic lymphoma kinase (ALK) inhibitors for ALK‐rearranged non–small‐cell lung cancer (NSCLC) in Japanese patients were retrospectively reviewed. Thirteen patients received crizotinib followed by alectinib. The combined median progression‐free survival and 5‐year survival rates of patients who received sequential ALK inhibitors were 35.2 months and 77.8%. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK‐rearranged NSCLC.