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Background Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. Methods This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Results Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. Conclusion Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).

Introduction Anti-vascular endothelial growth factor therapy has been shown to be effective in non-small cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE); however, there are no data to suggest that ramucirumab has the same effects. Methods We therefore decided to conduct a phase II study of ramucirumab plus docetaxel for NSCLC patients with MPE. The MPE control rate at eight weeks after the start of treatment will be the primary endpoint, and the objective response rate, progression-free survival, one-year survival rate, overall survival, and toxicity profile will be secondary endpoints. Discussion A previous study indicated that administering chemotherapy in combination with bevacizumab was effective at controlling pleural effusion in patients with NSCLC with carcinomatous pleurisy. It is expected that ramucirumab will have a similar effect to the same group.

Background: Single-agent amrubicin chemotherapy is a key regimen, especially for small cell lung cancer (SCLC), however, it can cause severe myelosuppression. Purpose: The purpose of this study was to determine the real-world incidence of febrile neutropenia (FN) among patients treated with single-agent amrubicin chemotherapy for thoracic malignancies. Patients and methods: The medical records of consecutive patients with thoracic malignancies, including SCLC and non-small cell lung cancer (NSCLC), who were treated with single-agent amrubicin chemotherapy in cycle 1 between January 2010 and March 2020, were retrospectively analyzed. Results: One hundred and fifty-six patients from four institutions were enrolled. Their characteristics were as follows: median age (range): 68 (32–86), male/female: 126/30, performance status (0/1/2): 9/108/39, SCLC/NSCLC/others: 111/30/15, and prior treatment (0/1/2/3-): 1/96/31/28. One hundred and thirty-four (86%) and 97 (62%) patients experienced grade 3/4 and grade 4 neutropenia, respectively. One hundred and twelve patients (72%) required therapeutic G-CSF treatment, and 47 (30%) developed FN. Prophylactic PEG-G-CSF was not used in cycle 1 in any case. The median overall survival of the patients with FN was significantly shorter than that of the patients without FN (7.2 vs. 10.0 months, p = 0.025). Conclusions: The real-world incidence rate of FN among patients with thoracic malignancies that were treated with single-agent amrubicin chemotherapy was 30%. It is suggested that prophylactic G-CSF should be administered during the practical use of single-agent amrubicin chemotherapy for patients who have already received chemotherapy.

BACKGROUND The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination of nedaplatin and amrubicin would be a promising treatment approach for patients with SCC. Therefore, a phase II study of this chemotherapeutic combination was designed to evaluate its efficacy and safety for treatment-naive patients with advanced SCC. METHODS A total of 21 treatment-naive patients with stage IIIB/IV or postoperative recurrent SCC were enrolled from six institutions. Nedaplatin (100 mg/m2 ) on day 1 and amrubicin (25 mg/m2 ) on days 1-3 were administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR), while the secondary endpoints included overall survival (OS), progression-free survival (PFS), and drug toxicities. RESULTS Partial response was observed in seven of 21 cases (ORR, 33.3%; 95% confidence interval [CI], 14.5-52.2). Disease control rate, which includes stable disease, was 71.4%. Median OS and PFS was 14.6 and 4.1 months, respectively. This regimen did not cause any treatment-related deaths. Grade 3/4 neutropenia developed in 8 of 21 cases (38.1%); however, febrile neutropenia developed in only 9.5% of the cases. Grade 3/4 gastrointestinal or neuromuscular toxicities were not observed. CONCLUSION The efficacy of the combination of nedaplatin and amrubicin was comparable to that of other conventional chemotherapeutic regimens for treatment-naive patients with advanced SCC, and no severe gastrointestinal or neuromuscular toxicities were observed. This combination therapy may be an alternative treatment approach, particularly in patients who cannot tolerate gastrointestinal or neuromuscular toxicities.

A 78-year-old man was admitted to our hospital for multiple lung and liver tumors. Initial clinical diagnosis was hepatocellular carcinoma (HCC) with lung metastases because of a high value of serum protein induced by vitamin K absence or antagonist II (PIVKA-II) (6,705 mAU/mL). However, a review of a prior CT showed the lung tumor had existed 6 months before liver tumors were detected. The tumors progressed rapidly and the patient died 37 days after admission. Autopsy revealed that both lung and liver tumors exhibited the histology of large cell neuroendocrine carcinoma (LCNEC). Immunohistochemistry revealed that the tumor cells expressed not only neuroendocrine markers but also PIVKA-II diffusely. Hepatoid differentiation was not detected. Background liver did not show any chronic liver disease. The final diagnosis was PIVKA-II producing LCNEC of the lung with multiple liver metastases. PIVKA-II producing tumors other than HCC are extremely rare. To our best knowledge, this is the first case report of PIVKA-II producing neuroendocrine tumors of the lung.

Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy involving chemotherapy and concurrent thoracic radiotherapy is the standard treatment for limited-disease (LD)-SCLC. This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) for LD-SCLC. Patients that fulfilled the following eligibility criteria were enrolled: being aged ≤ 75 years and chemotherapy-naive and having a performance status (PS) of 0–1, LD-SCLC, and adequate organ function. The patients received escalating doses of amrubicin on days 1, 2, and 3, and a fixed 60-mg/m2 dose of cisplatin on day 1. Four cycles of chemotherapy were administered, with each cycle lasting 4 weeks. TRT involving 2 Gy/day, once daily, commenced on day 2 of the first cycle of chemotherapy. The initial dose of amrubicin was 20 mg/m2 (level 1), and the dose was escalated to 25 mg/m2 (level 2) and then 30 mg/m2 (level 3). Eight patients from three institutions were enrolled at three dose levels. The patients’ characteristics were as follows: male/female: 3/5; median age (range): 68.5 (60–73); PS 0/1: 4/4; stage IIIA/IIIB disease: 3/5. Both level 3 patients experienced DLT (grade 4 neutropenia and/or leukopenia lasting > 4 days). Level 3 was defined as the MTD, and level 2 was recommended as the dose for this regimen. Seven patients exhibited partial responses, and 1 displayed progressive disease (response rate: 88%). The median progression-free survival and overall survival periods were 11.1 and 39.5 months, respectively. No treatment-related deaths occurred. When this regimen was combined with TRT for LD-SCLC, the MTD was 30 mg/m2 for amrubicin and 60 mg/m2 for cisplatin. In addition, neutropenia and leukopenia were DLT, and doses of 25 mg/m2 for amrubicin and 60 mg/m2 for cisplatin are recommended for this regimen.

Background Various polymorphisms have been detected in the UDP-glucuronosyltransferase 1A ( UGT1A ) gene, and UGT1A1 *28 and UGT1A1 *6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose (MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1 *28 or UGT1A1 *6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1 *28 or UGT1A1 *6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28 /− and *6 /−), were aged ≤75 years old, had a performance score of 0–1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1 * 28 or UGT1A1 * 6 gene polymorphism is 60 mg/m2.

We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma., Internal Medicine, 55(19), pp.2849-2853; 2016

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were &ge, 75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9&ndash, 17.5), and the median OS was 22.0 months (95% CI: 16.0 months&ndash, not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3&ndash, 4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were &ge, 75 years old.

Background: S-1, a novel oral fluoropyrimidine, is active in the treatment of non-small cell lung cancer (NSCLC). However, data on S-1 for elderly patients with NSCLC are insufficient. Methods: Eligibility criteria were no prior chemotherapy, stage IIIB or IV NSCLC, performance status 0-1, age >70 years, and adequate hematological, hepatic, and renal functions. Patients received S-1 (40 mg/m2 twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. The primary end point was the tumor response rate. Results: Thirty-two patients were enrolled and 31 patients were evaluable for response. The patients' median age was 80 years (range: 71-88). The response rate was 22.6% (95% CI: 11-38). Neutropenia, anemia, thrombocytopenia, febrile neutropenia, and diarrhea of grade ≥3 occurred in 6, 6, 10, 3, and 3%, respectively. Conclusions: In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity.

It is widely recognized that the risk of secondary neoplasms increases as childhood cancer survivors progress through adulthood. These are mainly hematological malignancies, and recurrent chromosome translocations are commonly detected in such cases. On the other hand, while secondary epithelial malignancies have sometimes been reported, chromosome translocations in these epithelial malignancies have not. A 33-year-old man who had been diagnosed with acute lymphoblastic leukemia and treated with chemotherapy almost 20 years earlier was diagnosed with lung adenocarcinoma. After chromosomal rearrangement of echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene was detected in this adenocarcinoma, he responded to treatment with crizotinib. It was therefore concluded that this echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase gene-positive lung adenocarcinoma was a secondary epithelial malignancy.

Lessons Learned Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients. In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population. Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. Background Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. Methods This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. Results A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%–72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1–82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. Conclusion Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Background: We conducted a phase II trial of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and evaluated the relationship between plasma concentration and efficacy of erlotinib. Methods: Patients who were previously treated but naive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), with advanced NSCLC harboring EGFR mutations, were enrolled. Erlotinib was given at 150 mg once daily until disease progression. The primary end point was objective response rate (ORR). Plasma trough levels of erlotinib were measured on Days 2 (D2) and 8 (D8) by high-performance liquid chromatography. Results: In total, 29 patients were enrolled from September 2008 to January 2011. ORR was 61.5 % (95 % confidence interval [CI] 40.57-79.8) of 26 assessable patients. The median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 16.9 months, respectively. Skin rash was observed in 24 patients, mostly at grade 1 or 2. Grade 2 pneumonitis was observed in one patient. We collected blood samples from 16 patients. The median PFS of the high and low D8/D2 ratio group was 11.2 months and 5.7 months, respectively (p = 0.044, hazard ratio = 0.301, 95 % CI 0.094-0.968). Conclusion: Erlotinib showed an ORR comparable to that seen in previous studies for patients with NSCLC harboring EGFR mutations, although response, the primary end point, did not reach the predetermined threshold level. The D8/D2 ratio of erlotinib plasma trough levels might be a predictive factor for PFS., Cancer Chemotherapy and Pharmacology, 72(6), pp.1299-1304; 2013

Healthcare-associated pneumonia (HCAP) is a new concept of pneumonia, which was proposed in the ATS/IDSA guidelines. The guidelines explain that HCAP patients should be treated with broad-spectrum antimicrobial drugs directed at multidrug-resistant pathogens. However, in Japan, there are many elderly people who received in-home care service. These patients seemed to be consistent with the concept of HCAP, but they did not meet the definition of HCAP. Therefore, the Japanese Respiratory Society modified the definition of HCAP according to the medical environmental in Japan. We retrospectively observed HCAP patients and nursing home and healthcare-associated pneumonia (NHCAP) patients who were hospitalized during 24 months at the Japanese Red Cross Nagasaki Genbaku Hospital (Nagasaki, Japan). Patient background, disease severity, identified pathogens, initial antibiotic regimens, and outcomes were compared. A total of 108 patients (77 HCAP and 31 NHCAP except HCAP patients) were evaluated. Of NHCAP except HCAP patients, 27 (87.1 %) were above 3 in the ECOG PS score. There were almost no significant differences between the two groups in characteristics, pneumonia severity, identified bacteria, initial antibiotic regimens, and response rate of initial antibiotic therapy. Although the in-hospital mortality of HCAP patients and NHCAP except HCAP patients was 9.1 % and 19.4 %, respectively, this difference did not reach statistical significance (P > 0.05). Our study suggested that, in the criteria of HCAP, some Japanese patients, who were consistent with the concept of HCAP, were classified as community-acquired pneumonia (CAP). Therefore, there is a need to change the definition of HCAP according to the medical environment in Japan., Journal of Infection and Chemotherapy, 19(1), pp.70-76; 2013

Background. Superior vena cava syndrome (SVCS is a serious complication of cancer; however intravenous stenting is infrequently performed as treatment for SVCS in Japan because the procedure has not been approved for coverage by the Japanese national health insurance program. Case Report. A 67‑year‑old male undergoing chemotherapy for malignant pleural mesothelioma developed dyspnea and was admitted to our hos‑ pital two years and two months after receiving the cancer diagnosis. On CT the patients right pleural lesion ex‑ hibited enlargement causing stenosis of the SVC right main pulmonary artery and right main bronchus. He pre‑ sented with edema of the upper body including the face and cervical vein swelling and SVCS was diagnosed. The dyspnea increased in severity in spite of a well‑maintained SpO2 value and the patient developed an urgent status; therefore it became difficult to wait for the effects of radiotherapy. After obtaining informed consent from the patient and his family SVC stenting was performed. The patients symptoms immediately improved following treatment and no complications were observed. The SVCS did not recur for three months after which the pa‑ tient moved into home medical care. Conclusion. Our results in this case show that SVC stenting is a useful thera‑ peutic option for treating SVCS caused by malignant mesotheliomas. Furthermore we expect that endovascular treatment for SVCS will be approved for coverage under the Japanese national health insurance program. (JJLC. 2013;53:250‑254

Background As the toxicity associated with the α-GalCer-pulsed dendritic cell (DC) therapy could be considered to be negligible, its addition to postoperative adjuvant chemotherapy would be expected to greatly improve the therapeutic effect, and could result in prolonged survival. The aim of the present study is to compare the therapeutic efficacy of alpha-galactosylceramide-pulsed DC therapy in patients who have undergone a complete resection of stage II–IIIA non-small-cell lung cancer (NSCLC) followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to that in patients who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only). Methods Subsequent to the complete resection of NSCLC, followed by the administration of cisplatin plus vinorelbine dual-agent combination adjuvant chemotherapy, patients who satisfy the inclusion criteria will be randomly allocated to either the α-GalCer-pulsed DC immune therapy group, or the standard treatment group. In total, 56 patients will be included in the study. The primary endpoint is recurrence-free survival, and the secondary endpoints are natural killer T-cell-specific immune response, the frequency of toxic effects and safety, and overall survival. Discussion In order to determine the efficacy of α-GalCer-pulsed DC therapy, the present study compares patients with stage II–III NSCLC who underwent complete surgical resection followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to those who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only). Trial registration UMIN000010386 (R000012145). Registered on 1 April 2013. UMIN-CTR is officially recognized as a registration site which satisfies ICMJE criteria. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2103-4) contains supplementary material, which is available to authorized users.

A 78-year-old man was admitted to our hospital for multiple lung and liver tumors. Initial clinical diagnosis was hepatocellular carcinoma (HCC) with lung metastases because of a high value of serum protein induced by vitamin K absence or antagonist II (PIVKA-II) (6,705 mAU/mL). However, a review of a prior CT showed the lung tumor had existed 6 months before liver tumors were detected. The tumors progressed rapidly and the patient died 37 days after admission. Autopsy revealed that both lung and liver tumors exhibited the histology of large cell neuroendocrine carcinoma (LCNEC). Immunohistochemistry revealed that the tumor cells expressed not only neuroendocrine markers but also PIVKA-II diffusely. Hepatoid differentiation was not detected. Background liver did not show any chronic liver disease. The final diagnosis was PIVKA-II producing LCNEC of the lung with multiple liver metastases. PIVKA-II producing tumors other than HCC are extremely rare. To our best knowledge, this is the first case report of PIVKA-II producing neuroendocrine tumors of the lung.

We consider the problem of online automatic tuning. In this setting, we execute the target program with some tuning parameters N times, where N is given, while optimizing the parameters to minimize some objective function such as the total execution time. Thus we have to choose the parameters for each execution by taking into account the trade-off between exploration and exploitation. The ATMathCoreLib library developed by Suda is a set of software that solves this problem. To model the performance of the target software, ATMathCoreLib uses a linear statistical model, and its basis functions must be provided by the user. In this paper, we investigate how to choose the basis functions appropriately, using the singular value decomposition of a square matrix as an example. We consider three cases, namely, (I) when the performance characteristics of the target problem are well understood by the user, (II) when the tuning parameter has a complicated structure, as occurs in the case of simultaneous selection of an algorithm and its parameter, and (III) when the performance characteristics of the target problem are not known to the user. The results of using ATMathCoreLib with different basis functions for each case are given. They help one understand the tuning by ATMathCoreLib and contribute to the progress of ATMathCoreLib.

Background Various polymorphisms have been detected in the UDP‐glucuronosyltransferase 1A (UGT1A) gene, and UGT1A1 *28 and UGT1A1 *6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose (MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1 *28 or UGT1A1 *6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1 *28 or UGT1A1 *6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28 /− and *6 /−), were aged ≤75 years old, had a performance score of 0–1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1 * 28 or UGT1A1 * 6 gene polymorphism is 60 mg/m2.

The safety and efficacy of platinum-based combination chemotherapy for elderly patients with advanced Non-Small-cell lung cancer (NSCLC) remains unclear. We conducted phase I and phase II trials of a combination of vinorelbine and carboplatin for patients, Clinical Lung Cancer, 13(5), pp.347-351; 2012

PURPOSE: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment. METHODS: We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status, The original publication is available at www.springerlink.com, Cancer Chemotherapy and Pharmacology, 67(2), pp.331-338; 2011

Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC., Journal of Thoracic Oncology, 6(1), pp.121-127; 2011

INTRODUCTION: We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status < or =3, age < or = 80 years, and stages IIIB-IV cancer. Epidermal growth factor receptor mutations in 23 patients were analyzed retrospectively. RESULTS: The median plasma gefitinib values were 662 ng/ml on D3 and 1064 ng/ml on D8, and the D8/D3 ratio was 1.587. The median progression-free survival (PFS) was 71 days, and the median overall survival was 224 days. Adenocarcinoma, never smoking, and high D8/D3 ratio were associated with better PFS. Multivariate analysis showed that PFS was associated with never smoking and high D8/D3 ratio. Never-smokers with a high D8/D3 ratio showed the best PFS. Overall survival was not associated with the D8/D3 ratio. Epidermal growth factor receptor mutation analysis of 23 patients showed that 15 patients had exon 19 deletion and/or exon 21 point mutation. Median PFS was similar between mutation-positive and mutation-negative individuals in the high D8/D3 group, whereas mutation-negative individuals in the low D8/D3 group showed the worst median PFS. CONCLUSIONS: A high D8/D3 ratio was independently associated with better PFS in patients with NSCLC treated with gefitinib. Our findings suggest that the pharmacokinetics of gefitinib may be involved in its antitumor activity., Journal of thoracic oncology, 5(9), pp.1404-1409; 2010

BackgroundAmrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established.PurposeTo determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC.Patients and methodsEligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0–1, age ≤75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m2, and the dose was escalated to 35 and 40 mg/m2.ResultsSixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m2 and AUC 5. A dose of 35 mg/m2 amrubicin and carboplatin AUC 5 was recommended in this regimen.ConclusionsThis regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting.

PURPOSE The treatment strategy for patients with non–small-cell lung cancer (NSCLC) involving ipsilateral mediastinal lymph nodes is still controversial. We performed a phase II feasibility study of induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC. PATIENTS AND METHODS Patients with mediastinoscopy- positive stage IIIA N2 NSCLC received 2 cycles of cisplatin 80 mg/m2, vinorelbine 25 mg/m2, and mitomycin-C 8 mg/m2. Patients without progressive disease underwent thoracotomy and lobectomy with lymph node dissections 2-4 weeks later. RESULTS From January 2000 to July 2004, 24 eligible patients (15 men, 9 women) were enrolled. Induction chemotherapy was completed as planned in 23 patients (95.8%). Hematological toxicity was the primary grade 3/4 toxicity. Twelve (50%) patients achieved a partial response. Twenty-three patients underwent surgical resection, and complete resection was achieved in 22 patients (95.7%). There were no surgery-related deaths. Pathologic complete response in metastatic lymph nodes was achieved in 5 patients. With a median follow-up of 5.4 years (range, 2.88-7.7 years), the estimated 5-year survival was 51.8% (95% CI, 41.3-62.3) and progression-free survival was 46.6% (95% CI, 36–57.2). CONCLUSION Induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC was feasible and associated with high response to lymph node metastasis and good survival.

Purpose: Breast cancer resistance protein (BCRP) confers resistance against topoisomerase I inhibitors in cancer cells. Very recently, we reported that gefitinib reverses BCRP-mediated drug resistance by direct inhibition. However, it remains undetermined how much BCRP contributes to the resistance to topoisomerase I inhibitors in non-small cell lung cancer (NSCLC). The present study was designed to examine whether BCRP levels in NSCLC cells are correlated with the resistance to topoisomerase I inhibitors and the reversal effect by gefitinib. Methods: BCRP levels and its function were evaluated by Western blotting and flowcytometry, respectively. Gefitinib-insensitive NSCLC cells expressed various levels of BCRP, which were closely correlated not only with the IC50 values of SN-38 (r=0.874, P

Purpose: The combination of carboplatin and etoposide is currently considered the most appropriate regimen for treating elderly patients with small-cell lung cancer (SCLC). Previous reports on elderly patients, 70 years or older, found that the recommended dose was close to that of younger patients. Then, we conducted a phase I study of carboplatin and etoposide in elderly patients, 75 years or older, with SCLC. This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Methods: Twenty-six patients fulfilling the eligibility criteria, chemotherapy-naive, performance status (PS) of 0–2, age ≥75, and adequate organ functions were enrolled. Patients’ characteristics were: male/female=21/5; PS 0/1/2=9/11/6; median age (range)=78 (75–82); and limited/extensive stage=16/10. The patients intravenously received carboplatin with a target AUC of 4 or 5 mg min/ml (Chatelut formula) on day 1 and etoposide at 80–120 mg/m2 on days 1, 2 and 3. Therapy was repeated four times in every 4 weeks. Results: The MTD of carboplatin/etoposide was AUC=5/80, 4/110, and 4/120. The DLTs were thrombocytopenia, neutropenia, leukopenia, and febrile neutropenia. Overall, grade 4 thrombocytopenia, neutropenia (≥4 days), leukopenia (≥4 days), and febrile neutropenia occurred in 27, 20, 7, and 13% of cases at MTD levels, respectively, and 0% at other levels. Twenty of 26 patients showed objective responses (2CR, 18PR; RR=77%). Conclusion: A dose of carboplatin of AUC=4 and etoposide of 100 mg/m2 was recommended in this regimen.

We encountered a rare case of the left common iliac artery in a 92-year-old Japanese female cadaver during dissection practice for medical students. The artery entered into the small pelvis without branching to the external iliac artery. There, it went down slightly medially and then turned laterally and passed behind the first sacral nerve. The artery ran anterolaterally further and returned to the greater pelvis and became the external iliac artery, which continued to the femoral artery as usual. During the course in the small pelvis, the artery branched to give rise to each branch of the internal iliac artery. We speculate that in the present case, a communication between the median sacral artery and the superior gluteal artery, passing behind the first sacral nerve, enlarged and compensated the usual common iliac artery.

An anomalous muscle was found in the superficial region of the right popliteal fossa in a 90-year-old Japanese female cadaver during dissection practice for medical students. The muscle ran transversely between the medial head of the gastrocnemius muscle and the tendon of the biceps femoris muscle, covering the nerves, vessels and muscle in the popliteal fossa. The muscle received its nerve supply from the common peroneal nerve. Based on the result of nerve fiber analysis, we speculated that the anomalous muscle might be close to the short head of the biceps femoris muscle in its derivation.

Irinotecan, a topoisomerase I inhibitor, is an effective agent for non-small-cell lung cancer (NSCLC). To determine the efficacy and toxicity of irinotecan and carboplatin, we conducted a phase II study in 61 patients with advanced NSCLC. Every 4 weeks, the patients received irinotecan 50 mg/m2 (days 1, 8 and 15) and carboplatin (day 1) with a target AUC of 5 mg min/ml using the Chatelut formula. All patients were evaluable for toxicity, and of 59 patients evaluable for response, 20 achieved a partial response and 26 showed no change. The overall response rate was 34% (95% confidence interval 23–48%). Grade 3 or 4 anemia, leukopenia, neutropenia, thrombocytopenia and diarrhea occurred in 32%, 32%, 60%, 25%, and 7%, respectively. The median survival time and 1-year, and 2-year survival rates were 10.0 months, 37.6%, and 15.2%, respectively. Irinotecan with carboplatin is effective for advanced NSCLC and safe.

A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1-3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m2 was escalated in 5-mg/m2 increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m2. In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m2 and amrubicin 25 mg/m2 was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC.

There has been no literature which reports a case of interstitial lung disease associated with sorafenib. However, a recent post-marketing survey in Japan revealed that interstitial pneumonia occurred in 4 among approximately 2 000 Japanese patients treated with sorafenib. In this article, we describe a Japanese patient with severe interstitial pneumonia probably caused by sorafenib treatment for metastatic renal cell carcinoma. Oncologists supervising future clinical trials for lung cancer should be alert to the fact that sorafenib can potentially induce serious interstitial lung disease, although this might depend on racial differences.

Incidence data of 22 cranial nonmetric traits were investigated in the Aeneolithic Yayoi people in the northwestern Kyushu area, and compared with those in Yayoi people in the northern Kyushu area, Yayoi people in Yamaguchi and Jomon people. Smith's Mean Measures of Divergence (MMD) were obtained in 8 groups after addition of modern people in the northwestern Kyushu area and others. Based on these data, principal co-ordinate analysis and cluster analysis were performed. The following results were obtained. The characteristics of the Yayoi people in northwestern Kyushu succeeded the characteristics of Neolithic Jomon people, and differ markedly from Yayoi people of continental lineage. Among the 22 traits, the incidences of supraorbital foramen, biasterionic suture vestige, hypoglossal canal bridging, pterygospinous foramen, transverse zygomatic suture vestige and mylohyoid bridging were greatly different between the Yayoi people in northwestern Kyushu and the Yayoi people of continental lineage. In the northwestern Kyushu area, a marked difference in cranial nonmetric traits was found between Yayoi and modern people. Such a difference probably developed because of the hereditary influence of Yayoi people of continental lineage in and after the Protohistoric Kofun period.

Objective: Our goal was to investigate whether the length and lead-time biases of radiologic screening for lung cancers vary according to the histologic type of the tumor. Methods: We analyzed the survival rates and radiographs of 119 cases of adenocarcinomas-large-cell carcinomas (ALC) and 50 peripheral squamous cell carcinomas (PSQ) detected in 205,401 screened individuals. Results: The sensitivity of screening and 5-year survival rates were 84.0% and 48.2% for ALC, and 52.0% and 18.5% for PSQ, respectively. The corrected length bias was 4.3% for ALC and 4.6% for PSQ. Stage III-IV ALC was often identified on 1-year-old films, but stage III-IV PSQ was not. Half of stage I ALC presented 2 or more years before detection, while half of stage I PSQ appeared within 1 year before detection. The survival rate of nonresected cases with stage I ALC was decreased 4 years after detection, while that of nonresected cases with stage I PSQ was decreased just after detection. The period of stage I ALC and PSQ was at least 6 years and 1 year, respectively. Conclusions: Slowly growing ALC had high sensitivity in radiologic screening and a high rate in 5-year survival, but had long lead time and delay in detection. PSQ grew rapidly resulting in low sensitivity in radiologic screening, and short lead time and survival. In both types, the magnitude of corrected length bias was not remarkable. The survival of ALC should be carefully evaluated because of the long lead time.

症例は81歳, 男性.咳, 労作時呼吸困難のため, 近医を受診し胸部X線で両下肺野の網状影および右肺門縦隔リンパ節腫張を指摘され当科に入院した.入院後, 右S9原発の進展型肺小細胞癌 (T4N2M0) と診断した.高齢で肺気腫を伴い, 腎機能もクレアチニンクリアランス31ml/分と低下が認められたが, Chatelut式を用いてAUC=5を目標とした第1日のカルボプラチンと第1-3日のエトポシド75mg/m2による併用化学療法を行った.第1コース目に測定したカルボプラチンのAUCは目標よりやや低い4.42であったが, 血液毒性はG-CSFの併用で耐用可能で4コースが施行され, 効果は70%縮小の有効であった.自覚的な副作用も軽く, 高齢・腎機能低下例においてもChatelut式を用いたこの治療法はG-CSFを併用すれば安全に施行可能なことが示唆された.

To assess the feasibility of treatments for patients with small cell lung cancer (SCLC) showing a poor performance status (PS, Eastern Cooperative Oncology Group; ECOG 3 or 4), we retrospectively reviewed the outcome for 13 SCLC patients showing poor PS treated at the National Cancer Center Hospital between January 1984 and May 1994. The main factors which contributed to poor prognosis were superior vena cava (SVC) syndrome, massive pleural effusion, tracheal stenosis due to lymph node swelling, pericardial effusion and pulmonary fibrosis (causing dyspnea in combination), brain metastasis resulting in neurological disturbance, cachexia, Eaton-Lambert syndrome causing muscle weakness, retroperitoneal lymph node metastasis causing abdominal pain, peritoneal effusion due to abdominal lymph node swelling, vertebral metastasis causing paraplegia, and dermatomyositis/polymyositis (DM/PM) causing muscle weakness. All of the patients received chemotherapy with or without radiotherapy. The PS of 8 patients improved with treatment, but no improvement was seen in 5. We analyzed these 13 patients and considered the treatments for those with poor PS. Chemo-radiotherapy was tolerable in SCLC patients showing PS 3, and improved their PS if severe conditions or combined disease did not arise concurrently. It was further suggested that PS 4 patients with severe conditions or combined disease should not be given the treatments.

To clarify the role of bronchoscopy for endotracheobronchial tuberculosis (EBTB), we performed a prospective study in 45 patients with active pulmonary tuberculosis, in 15 (33%) of whom bronchoscopic findings related to EBTB were seen. The findings were classified into six types: edematous hyperemic, submucosal nodule, ulcerative (shallowand deep), polypoid, cicatrical, and compression type. Each of these types was related to the healing process and outcome after antituberculosis chemotherapy. Serial bronchoscopy revealed that lesions less advanced than the deep ulcerative type responded to chemotherapy; the deep ulcerative and polypoid types progressed to cicatrical bronchostenosis despite chemotherapy. In the follow-up of patients with lesions of the deep ulcerative and polypoid types, serial bronchoscopy after chemotherapy is recommended; these patients also require adjunctive therapy to prevent cicatrical bronchostenosis.(Internal Medicine 35: 698-703, 1996)

Metrical dental characteristics were investigated in the Kofun series in southern Kyushu. The results of t-tests and Penrose's size distances showed that tooth size in the Kofun series in southern Kyushu was larger than those of the Jomon series and the Yayoi series in northwestern Kyushu, except for the buccolingual diameters in males of the Yayoi series, which were almost equal in size, although smaller than that of the Yayoi series in northern Kyushu. As regards Penrose's shape distances, the Kofun series in southern Kyushu was close to the Yayoi series in northern Kyushu as well as the West-Kofun and East-Kofun series. On the basis of bone and dental morphology, the Yayoi people in northwestern Kyushu are considered descendants of the Jomon people. However, the Yayoi people in northern Kyushu are generally thought to have been influenced by immigrants. Matsumura (1990) noted that the dental characteristics of the West-Kofun and East-Kofun series were closely related to the Yayoi immigrant people in general. Over all, the dental characteristics of the Kofun series of southern Kyushu are closer to those of the immigrant population than those of the native population. Therefore, the Kofun people in southern Kyushu should be considered influenced by the immigrant population.

Copolymers of 3-methacryloxypropyl tris(trimethylsiloxy) silane (SiMA) with methacrylate (MMA) and copolymers trimethylsilyl methyl methacrylate (TMSMMA) with vinyl acetate (VAc) were synthesized by radical polymerization. Membranes were cast from their solutions. Gas permeability, 10-1000 Barrer, of SiMA-MMA membranes was higher than that of TMSMMA-Vac membranes because of higher concentration of trimethylsilyl groups. Both apparent activation energies for gas permeability were very small compared to those of ordinary polymeric membranes. Poly(SiMA) is rubbery and poly(TMSMMA) is glassy at an ambient temperature. Copoly(SiMA-MMA) and copoly(TMSMMA-VAc) were shown to be random copolymers by the relationship between gas permeability coefficients and the molar ratio of each monomer. A series of copolymers in this investigation was shown to be a rare case of the polymer of which gas permeability increased in spite of the larger side chain, trimethylsilyl group, being introduced in the polymer chains.

Background: Irinotecan and gemcitabine are effective against non-small cell lung cancer. We conducted a phase I study of the combined use of irinotecan and gemcitabine in previously untreated patients with advanced non-small cell lung cancer to determine doselimiting toxicities and maximum tolerated dose. Methods: Patients were treated with irinotecan followed by gemcitabine on days 1 and 8 every 3 weeks. Gemcitabine dose was fixed at 1000 mg/m 2 , and irinotecan dose was increased from 60 mg/m 2 . Results: A total of 16 patients was enrolled. Maximum tolerated dose of irinotecan was determined up to level 3 (irinotecan 100 mg/m 2 ). In Japan, the maximum approved weekly dose of irinotecan is 100 mg/m 2 , so this was the dose that was used. Only very mild hematological and non-hematological toxicities were noted. Conclusion: Use of 100 mg/m 2 irinotecan followed by 1000 mg/m 2 gemcitabine on days 1 and 8 every 3 weeks warrants a phase II study.

BACKGROUND. The purpose was to determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy (TRT) in locally advanced nonsmall-cell lung cancer. METHODS. Fifty patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naive, good performance status (PS, 0-2), age