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Alantolactone is a eudesmane-type sesquiterpene lactone that exerts various biological effects, including anti-inflammatory activity. In the present study, screening using the RIKEN Natural Products Depository chemical library identified alantolactone derivatives that inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells stimulated with proinflammatory cytokines and Toll-like receptor ligands. In human lung adenocarcinoma A549 cells stimulated with tumor necrosis factor-α (TNF-α), six alantolactone derivatives inhibited ICAM-1 expression in a dose-dependent manner and at IC 50 values of 13-21 μM, whereas that of alantolactone was 5 μM. Alantolactone possesses an α-methylene-γ-lactone moiety, whereas alantolactone derivatives do not. In the nuclear factor κB (NF-κB) signaling pathway, alantolactone prevented the TNF-α-induced phosphorylation and degradation of the inhibitor of NF-κB α (IκBα) protein, and its downstream signaling pathway. In contrast, alantolactone derivatives neither reduced TNF-α-induced IκBα degradation nor the nuclear translocation of the NF-κB subunit RelA, but inhibited the binding of RelA to the ICAM-1 promoter. The inhibitory activities of alantolactone and alantolactone derivatives were attenuated by glutathione. These results indicate that alantolactone derivatives inhibit the TNF-α-induced NF-κB pathway by a different mechanism from alantolactone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A 68-year-old man with small-cell lung cancer developed anti-collapsin response-mediator protein (CRMP)-5 antibody-related paraneoplastic neurological syndrome (PNS) presenting with ataxia and chorea during treatment with durvalumab. As a result of steroid therapy, anti-CRMP-5 antibodies became negative, hyperintense lesions on brain magnetic resonance imaging disappeared, and neurological symptoms improved. After resuming durvalumab, he became unable to walk due to neurological adverse events (nAEs). There have been no reported cases manifesting PNSs and nAEs as a result of the same immune checkpoint inhibitors (ICIs) administered at different times. Resuming ICIs in patients diagnosed with PNSs should be performed with prudence.

Background/aim: To investigate the outcomes of patients with centrally located non-small-cell lung cancer (NSCLC) treated with proton beam therapy (PBT) using moderate hypofractionation., Patients and Methods: Between 2006 and 2019, 34 patients with centrally located T1-T4N0M0 NSCLC who received moderate hypofractionated PBT were retrospectively reviewed., Results: The median follow-up was 50.8 months (range=5.8-100.4 months). The 3-year overall survival, progression-free survival (PFS), and local control rates were 70.4%, 55.5% and 80.5%, respectively. Grade 2 or 3 lung adverse events (AEs) after PBT were observed in five (14.7%) patients; however, grade 3 radiation pneumonitis was observed in one (2.9%) patient. Notably, no grade 4 or higher AEs were observed. Regarding the correlation between the lung dose and proximal bronchial tree maximum dose and grade 2 or higher lung AEs, a weak correlation was observed between the mean lung dose and AEs (p=0.035). Although the clinical target volume (CTV) was a risk factor for poor PFS, no significant correlation was found between the CTV and lung AEs after PBT., Conclusion: Moderate hypofractionated PBT may be a useful radiotherapy method for centrally located cT1-T4N0M0 NSCLC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has been approved as a treatment for ALK-positive lung cancer. This review provides information regarding the pharmacology and clinical features of lorlatinib, including its efficacy and associated adverse events. Pivotal clinical trials are discussed along with the current status of lorlatinib as a treatment for ALK-positive lung cancer and future therapeutic challenges.

Background/aim: To investigate the outcomes of elderly patients with cT1-3N0M0 non-small cell lung cancer (NSCLC) undergoing proton beam therapy (PBT)., Patients and Methods: Between 2009 and 2019, 110 patients receiving hypofractionated PBT for cT1-3N0M0 NSCLC were retrospectively reviewed., Results: The median follow-up was 36.5 months (range=4.9-131.0 months). In the elderly group (80 years or older), the 3-year overall survival and progression-free survival rates were 79.8% and 73.9%, respectively, and the corresponding rates in the younger group were 80.5% and 61.2%, respectively. Grade 3 radiation pneumonitis (RP) was observed in 4.4% patients in the young group, whereas no grade 3 RP was observed in the elderly group. Age was not a risk factor for symptomatic RP. There were no significant differences in the survival and adverse events between the elderly and younger groups., Conclusion: PBT may be a reasonable approach for treating lung cancer in elderly patients with T1-3N0M0 NSCLC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The accelerated development of lung cancer treatments has resulted in a single global study that is sufficient for a new agent and indication to be approved. Not all new treatments predominate globally, and differences in standards of care may influence the efficacy of treatments in the real world., Methods: The results from Japanese domestic trials and global trials that included a subset population of Japanese patients were evaluated for 18 genomic targeted agents and immune therapies approved after 2000. The results were collected from drug applications that were reviewed for treatment approval in Japan., Results: Japan is one of the first countries to approve and fully reimburse new agents around the world. Alectinib and nivolumab, which were first developed by Japanese pharmaceutical companies, were evaluated in an independent domestic trial, which resulted in their early approval. For most other indications, 1.1-15.8% of the patients who participated in pivotal registration studies were Japanese, and their treatment results were comparable to those of the overall population. Overall survival was less likely to be improved by four agents for which the post-protocol therapy might have been different in Japan than in other countries., Conclusions: Overall, a positive result in a global trial was emulated in Japanese patients and led to the approval of a new standard treatment in Japan. Early approvals were attained by either participating in the global registrational study or conducting a domestic phase II study. The higher efficacy of new agents may be an issue in the future, as Japanese patients had early access to the new agent and may receive better treatment after the trial., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 51-year-old male underwent total gastrectomy for esophagogastric junction cancer(T3N0M0, Stage ⅡA). He was diagnosed with an alpha-fetoprotein(AFP) producing tumor and hepatoid adenocarcinoma. One month after radical surgery, computed tomography(CT) showed lung metastasis, and the patient's serum AFP level was high. He underwent chemotherapy( S-1 and wPTX/RAM)and eventually died 4 months after surgery.

A de novo single-nucleotide mutation in the EGFR gene can cause the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are used for clinical treatment of such lung cancers, but acquired resistance often mitigates their efficacy. Accordingly, monitoring of de novo and acquired nucleotide mutations is essential for clinical treatment of lung cancers with EGFR-TKIs. Previously, we reported that oligoribonucleotide interference-PCR (ORNi-PCR) can accurately and cost-effectively detect single-nucleotide mutations. In this study, we applied ORNi-PCR to simultaneous detection of the de novo L858R and acquired T790M mutations in the EGFR gene in lung cancer cells. First, we established optimal experimental conditions for ORNi-PCR to simultaneously detect the two single-nucleotide mutations in genomic DNA from lung cancer cells. The conditions we established could also be used for ORNi-PCR using complementary DNA reverse-transcribed from extracted RNA. We found that ORNi-PCR could detect lung cancer cells possessing both single-nucleotide mutations among a large number of cells harboring wild-type sequences, even when the cancer cells constituted less than ~0.2% of all cells. Our findings demonstrate that ORNi-PCR can simultaneously detect multiple single-nucleotide mutations in a gene of interest and might therefore be useful for simultaneous detection of EGFR mutations in clinical examinations.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real-world practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4- not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.

Pembrolizumab has become the standard first-line treatment for non-small cell lung cancer (NSCLC) patients with high PD-L1expression. MET exon 14 skipping is a rare mutation typically found in older, female, and non-smoking patients with NSCLC. Herein, we report the case of a 71-year-old non-smoking woman who was diagnosed with NSCLC in the left lung. EGFR mutation and ALK fusion were not detected. Because the biopsy specimen showed high PD-L1 expression with a tumor proportion score of 95%, pembrolizumab was introduced as first-line therapy, but resulted in no clinical benefit. The patient was subsequently administered chemotherapy with carboplatin and pemetrexed, leading to remarkable tumor shrinkage. A next-generation sequencing panel analysis revealed a MET exon 14 skipping mutation. Thus, pembrolizumab might not be effective for NSCLC patients with MET exon 14 skipping mutations, even if PD-L1 expression is high., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non-hematologic toxicity. DLT was evaluated during day 1-28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75-87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day.

Background: Despite their broadly recommended use as chemotherapeutic agents, the porphyrogenicity of methotrexate and actinomycin D have not been confirmed. Accordingly, it is not known whether these agents are safe for use in patients with porphyria., Case Presentation: In this report, we present a case of an invasive mole with lung metastasis in a 49-year-old Japanese woman who had previously been diagnosed with acute intermittent porphyria at 27 years of age but had no recent history of acute intermittent porphyria attacks. Her serum human chorionic gonadotropin level was elevated 1 month after hysterectomy, and she was referred to our center for chemotherapy. After she received 100 mg of methotrexate, drug eruptions were observed starting on day 3 and grew progressively worse. Erythema and mucosal erosion spread throughout her body, whereupon she was administered prednisolone. In addition, our patient experienced febrile neutropenia and required granulocyte colony- stimulating factor treatment. No changes in our patient's urinary coproporphyrin or uroporphyrin levels were detected during this entire episode. Methotrexate was replaced by actinomycin D (0.5 mg/body intravenously on days 1-5 every 2 weeks). After five uneventful cycles of actinomycin D, our patient achieved and maintained a normal serum human chorionic gonadotropin level for 3 years., Conclusions: Methotrexate and actinomycin D did not induce acute porphyric attacks in this patient with acute intermittent porphyria; however, severe adverse effects were noted with methotrexate. Although further investigation is required, our data suggest that these agents are nonporphyrinogenic and can therefore be used to treat patients with comorbid porphyria.

An increase in tumor-associated macrophages (TAMs) around the tumor microenvironment has been closely associated with a poor prognosis in patients with cancer, and M2 TAMs promote tumor growth and tumor metastasis by stimulating angiogenesis or lymphangiogenesis in tumors. We herein examined the effects of nine synthetic hydroxystilbenes on M2 macrophage activation and differentiation, and three selected dihydroxystilbenes on vascular endothelial cell growth factor (VEGF)-C-induced tube formation in human lymphatic endothelial cells (HLECs) (in vitro). We also investigated the antitumor and antimetastatic effects of three synthetic dihydroxystilbenes in LM8-bearing mice in vivo. The three selected synthetic stilbenes (at concentrations of 5, 10, 25, and 50 μM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, but promoted that of transforming growth factor-β1. The three dihydroxystilbenes (at concentrations of 10-50 μM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation of M2 macrophages. Furthermore, the 2,3- and 4,4'-dihydroxystilbene inhibited VEGF-C-induced lymphangiogenesis in HLECs. Both 2,3- and 4,4'-dihydroxystilbene (at 10 and 25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung in mice. These results suggested that the antitumor and antimetastatic effects of 2,3- and 4,4'-dihydroxystilbene were partly due to anti-lymphangiogenesis, and the regulation of M2 macrophage activation and differentiation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

A 50-year-old man with a history of smoking of 45 pack-years underwent right lower lobectomy after neoadjuvant chemoradiotherapy for locally advanced non-small cell lung cancer diagnosed on a bronchial biopsy and standard imaging examinations, including chest-abdominal contrast-enhanced computed tomography (CT) and whole-body F-18 fluorodeoxyglucose positron emission tomography/CT. Left orchiectomy was performed simultaneously to treat the slightly swollen left testis, which had remained unchanged for over five years. The thoracic tumor was proven to be in pathological complete remission and the testicular lesion was pathologically diagnosed as an embryonal carcinoma. Furthermore, a pathological reevaluation of the preoperative bronchial biopsy specimen revealed the lung tumor to be a metastatic embryonal carcinoma.

Non-small-cell lung carcinomas do not sufficiently respond to cancer chemotherapeutic drugs. Combination effects of cancer chemotherapy drugs (paclitaxel and carboplatin) with nobiletin or powdered Shiikuwasha extract from Citrus depressa were examined by isobologram and combination index analyses. It was demonstrated that the combination generated a synergistic inhibitory effect against the proliferation of the human non-small-cell lung carcinoma cell lines A549 and H460 and that of the two chemotherapy drugs, paclitaxel was responsible for this synergistic effect. Furthermore, the percentage of apoptotic cells was decreased with increasing rates of nobiletin to paclitaxel and carboplatin. These findings were considered to be attributed to the ability of nobiletin to regulate cells in the G1 phase, which escaped cell death initiated by paclitaxel and carboplatin. An antitumor activity assay showed that this combination significantly suppressed the growth of subcutaneous A549 tumor xenografts in nude mice., (Georg Thieme Verlag KG Stuttgart · New York.)

Calcification and ossification are very rare in primary squamous cell carcinoma of the lung. We report a 55-year-old male with primary squamous cell carcinoma of the lung who on histopathological examination was seen to have extensive calcification and ossification. Squamous carcinoma of the lung rarely presents with osteocartilaginous metaplasia. The case is presented here for its unique presentation.

Intrapulmonary schwannoma is uncommon and preoperative radiological diagnosis is rare. Described is a schwannoma that developed as a pulmonary hilar nodule in a 38-year-old woman. The nodule showed strong (18)F-fluorodeoxyglucose uptake with a maximum standard uptake value of 5.98 on positron emission tomography and had a high apparent diffusion coefficient (2.5 × 10(3) mm(2)/s) on diffusion-weighted magnetic resonance imaging. Combination of these functional imaging techniques warrants further evaluation in radiological diagnosis of intrapulmonary schwannoma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-naïve patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3-43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial.

We conducted a phase II trial to evaluate the safety and efficacy of weekly paclitaxel in patients with resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Thirty-two NSCLC patients at a median age of 58.0 years (range 33-75) were enrolled. The Eastern Cooperative Oncology Group performance status scores (0/1/2) were 18/9/5, respectively. The majority of patients had adenocarcinoma (84%) and stage IV disease (81%). The response rate for the first-line chemotherapy was 28%. Paclitaxel was administered at a dose of 80 mg/m(2) as an intravenous infusion 60 min weekly for 6 consecutive weeks of an 8-week cycle. All patients were assessable for response and toxicity. The median number of cycles administered was two (range 1-8), and the overall response rate was 15.6%. The median survival time (MST) was 10.6 months (95% CI=8.2-12.5), while the 1-year survival rate was 37.5%, and the median progression-free survival was 4.9 months (95% CI=3.0-7.1). Hematological toxicities (grade 3 or 4) were observed in 15 patients (46.9%) with leukopenia, and in 4 (12.5%) with anemia. Non-hematological toxicity was generally mild, though grade 3 anorexia was observed in 3 patients (9.3%). No treatment-related deaths were observed. In conclusion, second-line weekly paclitaxel is effective in NSCLC patients treated with docetaxel plus carboplatin and is associated with a tolerable toxicity profile., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

A 56-year-old man with abnormal chest X-P and stool occult bleeding was admitted. Colonoscopy detected rectal cancer and sigmoid al polyps. The biopsy results suggested that the rectal lesion was well- to moderately-differentiated adenocarcinoma and the sigmoidal polyp contained well -differentiated adenocarcinoma. CT scan revealed multiple lung, liver and lymph node metastasis. We judged the case to be inoperable and decided to start systemic chemotherapy (FOLFOX4). After treatment with chemotherapy, the tumor shrank and metastatic lesions disappeared. Low anterior resection was done, and final pathological examination revealed a complete response of the main tumor by treating with FOLFOX4.

The aim of this study was to evaluate the efficacy and tolerability of gefitinib ('IRESSA') in Japanese patients with previously untreated stage IV non-small-cell lung cancer (NSCLC). This was a multi-institutional phase II study. Thirty-four patients with previously untreated stage IV NSCLC were enrolled between May 2003 and September 2004. Gefitinib was administered orally 250 mg once a day and was continued until there was either disease progression or severe toxicity. Objective tumour response rate was 26.5% (95% confidence interval, 11.7-41.3%). Adverse events were generally mild (National Cancer Institute-Common Toxicity Criteria grade 1 or 2) and consisted mainly of skin rash, fatigue and liver dysfunction. No pulmonary toxicity was observed. The global health status revealed that there was no change in quality of life during the study. This study found that single-agent gefitinib is active and well tolerated in chemo-naive Japanese patients with advanced NSCLC.

A phase I/II study was conducted to determine the maximum-tolerated dose, the safety and tolerability, and the clinical efficacy of carboplatin and docetaxel in combination in patients with stage IV non-small-cell lung cancer. Patients with measurable, previously untreated, good performance status, and stage IV non-small-cell lung cancer were eligible. Increasing doses of docetaxel were given in combination with a fixed dose of carboplatin except at level 5. Cycles were repeated every four weeks. Seventy-seven patients were registered. In phase I, 27 patients were entered at five different dose levels. A docetaxel dose of 60 mg/m(2) and carboplatin area under the concentration time curve 6 was recommended for phase II, and an additional 50 patients were entered at this level for a total of 56 patients. Grade 3/4 neutropenia was the most common adverse event and occurred in 70% of the patients. Two patients had febrile neutropenia. Fifty-six patients were assessable for response; 21 partial responses were observed for an overall response rate of 37.5%. The median time to tumor progression was 4.0 months (range, 1.0-21.0 months), and the median survival was 12.9 months (range, 0.4-51.3 months). The one-year survival rate was 46.4%. The combination of docetaxel 60 mg/m(2) and carboplatin area under the concentration time curve 6 is feasible and effective in patients with stage IV non-small-cell lung cancer.

We previously found that ergosterol isolated from Agaricus blazei inhibited tumor growth through the inhibition of tumor-induced neovascularization. In the present study, we isolated further anti-angiogenic substances (A-1 and A-2) from this fungus using an assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor, and A-1 was identified as sodium pyroglutamate. Next, we examined the antitumor and antimetastatic actions of A-1 using Lewis lung carcinoma (LLC)-bearing mice. A-1 (30, 100 and 300 mg/kg) inhibited tumor growth and metastasis to the lung. The reduction of the numbers of splenic lymphocytes, CD4+ and CD8+ T cells in LLC-bearing mice was inhibited by the oral administration of A-1 (30, 100 and 300 mg/kg). Further, A-1 increased the number of apoptotic cells of tumors and the numbers of CD8+ T and natural killer cells invading the tumors, and inhibited the increase of von Willebrand factor expression (a measure of angiogenesis) in the tumors. These results suggest that the antitumor and antimetastatic actions of A-1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor-induced neovascularization. This is the first report showing that sodium pyroglutamate isolated from A. blazei as an anti-angiogenic substance has potent antitumor and antimetastatic actions, as well as immune-modulatory activity, in tumor-bearing mice.

The roots of Angelica keiskei Koizumi (Umbelliferae) have traditionally been used as a health food considered to have diuretic, laxative, analeptic and lactagogue effects. Recently, it has been thought that the roots and herbs of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. It has been reported that chalcone derivatives, such as xanthoangelol and 4-hydroxyderricin, are isolated as main components from this root. Recently, we reported that the 50 % ethanol extract, the ethyl acetate-soluble fraction and the isolated xanthoangelol, inhibited tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. In the present study, we examined the effects of 4-hydroxyderricin on tumor growth and metastasis to the lung or liver in subcutaneous or intrasplenic LLC-implanted C57BL/6J female mice. 4-Hydroxyderricin at a dose of 50 mg/kg x 2/day orally inhibited the tumor growth in subcutaneous LLC-implanted mice and inhibited the lung metastasis and prolonged the survival time in mice after the removal of subcutaneous tumors by surgical operation. Doxorubicin (5 mg/kg x 2/week, i. p.) inhibited the tumor growth and metastasis to the lung, but it shortened the survival time and reduced the survival rate compared to those in 4-hydroxyderricin-treated mice. 4-Hydroxyderricin inhibited DNA synthesis in LLC cells at a concentration of 100 microM, but it had no effect on the DNA synthesis in human umbilical vein endothelial cells (HUVECs) or on the adherence of LLC cells to HUVECs. 4-Hydroxyderricin inhibited Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 10 to 100 microM. The weights of the spleen and thymus in mice with subcutaneously implanted LLC were maintained close to those of normal mice by orally administered 4-hydroxyderricin. In addition, 4-hydroxyderricin (50 mg/kg x 2/day) inhibited the reduction of the numbers of lymphocytes, CD4+, CD8+ and natural killer (NK)-T cells in the spleen of tumor-removed mice. Doxorubicin reduced the numbers of lymphocytes, CD4+, CD8+ and NK cells compared to those in LLC-removed mice. These results suggest that the antitumor and antimetastatic activities of 4-hydroxyderricin may be modulated by the immune system and the inhibition of angiogenesis.

The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate-soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC-bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the (1)H- and (13)C-NMR spectra. Xanthoangelol inhibited tumor growth in LLC-bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 microM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor-induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 1-100 microM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1-100 microM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor-induced neovascularization through inhibition of the formation of capillary-like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells., (Copyright 2003 Wiley-Liss, Inc.)

Previously, we reported that a methanol extract (500 mg/kg x 2/day) of the heartwood of Cassia garrettiana inhibited the tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. Furthermore, we isolated the two active substances from the methanol extract of C. garrettiana and identified compound 1 as cassigarol A. In the present study, compound 2 was identified as 3, 3', 4, 5'-tetrahydroxy stilbene (piceatannol) based on the 1H-NMR spectral data and products formed by oxidation with potassium permanganate. We examined the active substance (compound 2, piceatannol) and its acetylated derivative on the tumor growth and lung metastasis in LLC-bearing and carcinectomized mice. Piceatannol (50 mg and 100 mg/kg x 2/day) did not affect the tumor growth, while piceatannol acetate (50 mg and 100 mg/kg x 2/day) significantly inhibited the tumor growth. Piceatannol and its derivative piceatannol acetate inhibited the metastasis to the lung dose-dependently in carcinectomized mice. Moreover, piceatannol and piceatannol acetate prolonged the survival time and increased the survival rate in carcinectomized mice. In addition, piceatannol inhibited the formation of capillary-like networks of human umbilical vein endothelial cells (HUVECs) at the concentrations of 10 to 100 microM, but its acetylated derivative did not. Therefore, it is suggested that the antimetastatic activities of piceatannol might be due to the inhibition of tube formation (angiogenesis) of HUVECs.

A methanol extract (500 mg/kg x 2/day) of the heartwood of Cassia garrettiana inhibited the tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. We isolated the two active substances from the methanol extract of C. garrettiana: compound 1 was identified as Cassigarol A and the determination of the structure of compound 2 is now in progress. We examined the effect of the active substance (compound 1, Cassigarol A) on tumor growth and lung metastasis in LLC-bearing and primary tumor-removed mice and found that Cassigarol A (50 mg and 100 mg/kg x 2/day) inhibited the tumor growth and metastasis to the lung. In addition, Cassigarol A inhibited the plasmin activity and the formation of capillary-like networks of human umbilical vein endothelial cells (HUVECs) at concentrations of 10 to 100 microM. Therefore, it is suggested that the antitumor and antimetastatic activities of Cassigarol A might be due to the inhibition of plasmin activity and formation of tubes (angiogenesis) from HUVECs.

We report a case of multiple cavitary pulmonary metastases of gallbladder cancer. Radiologically, every cavity displayed a very thin wall containing only air inside. The postmortem histopathological examination showed that: (1) the cavities were surrounded by normal alveoli; (2) these walls were composed mostly of adenocarcinoma cells; (3) necrotic or mucous substance was sparse in the cavity space; (4) cancer cells infiltrated along the surface of the alveolar septa, and (5) the morphology of the cancer cells of the gallbladder and the lung was the same. It seemed likely that the thin-walled cavities in the lung might result from central breakdown of the tumor and subsequent expectoration of debris through the connected airways.

METHODS. The expression of ABH blood group carbohydrate antigens was examined histochemically in tumors and adjacent nontumorous tissues of 89 cases of human lung carcinoma in which nontumorous tissues expressed blood group carbohydrate antigens compatible with the erythrocyte blood group types. RESULTS AND CONCLUSIONS. Loss of ABH blood group antigens in lung carcinomas correlated with their metastatic potential, especially with the recurrence of hematogenous metastasis. Consequently, patients with tumors that retained compatible ABH blood group antigens showed a better prognosis than patients with tumors of altered antigenic profiles. The loss of blood group B antigen more significantly affected both the hematogenous metastasis and prognosis than that of A and H antigens.

A 45-year-old male with pulmonary blastoma was described. The patient suffered from headache and gait disturbance, and was diagnosed metastatic brain tumor. The histopathology of the removed tumor indicated metastasis from pulmonary blastoma. The pulmonary tumor, which had been detected on the chest x-ray film but misdiagnosed tuberculous lesion, was subsequently diagnosed pulmonary blastoma by TBLB. The patient underwent left upper lobectomy with mediastinal lymph node dissection, but died 12 months after the operation. To our knowledge, only 54 cases with pulmonary blastoma have hitherto been reported in the Japanese literature.

We encountered three patients with synchronous double cancers in the lung and stomach. Although the gastric cancers were resected curatively in all three patients, the lung cancers were resected palliatively because they were too advanced for curative resection. In the Japanese literature we found 25 operated cases of synchronous double cancers and 24 operated cases of metachronous double cancers in the lung and stomach. Early diagnosis and curative resection of both cancers improve the survival rate of these primary double cancers.

Two cases of inflammatory pseudotumor of the lung were reported. Case 1. A 68 year-old man was referred to our hospital because of an abnormal shadow on chest X-ray. He had a history of pneumonia in the right upper lobe five months before. The chest X-ray film revealed a coin lesion in the right upper lung field (S1), the same segment as the previous pneumonia. Although RPF and INH were administered for three months, the shadow did not change, and cough and sputum continued. In order to confirm the diagnosis, open thoracotomy was performed and microscopic findings of the resected tumor showed inflammatory pseudotumor; proliferation of fibrous tissue with infiltration by inflammatory cells (plasma cells, lymphocytes and a few neutrophils). Case 2. A 35 year-old man was admitted to our hospital because of an abnormal shadow on chest X-ray, i.e. a coin lesion with vascular indentation in the left lower lung field (S8). A wedge resection including the mass was performed, and histopathologic examination revealed inflammatory pseudotumor, or plasma cell granuloma; proliferation of fibrous connective tissue with infiltration by predominantly mature plasma cells. Both patients have been doing well after the operation. We also reviewed 46 cases reported in the Japanese literature and discussed various aspects of this disease. Of 10 patients who had a history of previous respiratory tract infection, 8 had histopathologic features with various inflammatory cells, including many lymphocytes, as in our Case 1. Although the common etiology of inflammatory pseudotumor is obscure, we suppose that in some cases the lesion may be a result of post-inflammatory repair process.

During the period from 1973 to 1986, 230 patients with lung cancer were operated on at our Surgical Clinic of Kagoshima University Hospital. There were fourteen patients (6.1%) with lung cancer in the right middle lobe. There were 13 male and 1 female patients. The histological types were adenocarcinoma (10), squamous cell carcinoma (4). Five-year survival rate of 14 patients was 34.9%. Statistically, it was similar to that of the patients with lung cancer in the other lobes. As concerns with the histological type of lung cancer in the right middle lobe, the case of squamous cell carcinoma revealed poorer prognosis than those of adenocarcinoma, because there were many cases of advanced cancer in the former case.

A 68-year-old male, who had advanced rectal cancer with multiple pulmonary metastases, had undergone resection of rectal cancer operatively and was treated with a combination chemotherapy using 5'-DFUR (5'-deoxy-5-fluorouridine) and MMC (mitomycin C) for multiple pulmonary metastases. Nine months from the start of this therapy, pulmonary metastatic lesions disappeared completely on chest X-ray examination and computed tomography. This case corresponded to complete response (CR) according to the response criteria proposed by Koyama-Saitoh. No significant side effects were observed during this chemotherapy. From the results in this case, the combination chemotherapy was considered to be one of the effective antineoplastic therapies available for pulmonary metastasis from large bowel cancer.