Salvage surgery following tyrosine kinase inhibitor treatment for advanced non-small cell lung cancer.

BACKGROUND: No standard therapy for non-small lung cancer patients that have acquired resistance to tyrosine kinase inhibitor (TKI) therapy has been established. Some can be effectively treated by salvage surgery, though indications for that procedure remain unclear. Reported here is the clinical course of a patient who experienced early post-operative distant metastases. CASE PRESENTATION: A 48-year-old woman without symptoms was referred to another hospital for abnormal chest radiography findings and diagnosed with adenocarcinoma of the left lower lobe (cT2aN3M1b, stage IVB; TNM staging 7th edition). Gene mutation analysis revealed positive for epidermal growth factor receptor exon 19 deletion. Afatinib treatment was started, resulting in partial response, though regrowth of the main tumor was noted 1.5 years later. Bronchoscopic re-biopsy findings revealed a T790M point mutation and afatinib was switched to osimertinib. At 1.5 years following the start of osimertinib administration, the primary tumor was found to have regrown again and stereotactic radiation therapy was administered. Findings at 3.5 years after osimertinib administration indicated that all lymph nodes and distant metastases, excluding the primary tumor, were well controlled, and the patient was referred to our hospital for salvage surgery. Osimertinib was discontinued, and a left lower lobectomy with a left lingular segmentectomy and pleural biopsy were performed. The patient was discharged following an uneventful postoperative course. Three days after discharge, glossodynia developed and examination findings revealed tongue metastasis. The symptoms improved following re-administration of osimertinib, though right adrenal gland metastasis appeared 8 months after surgery. Radiation therapy was performed for tongue and right adrenal gland metastases, and the patient was alive 1 year after salvage surgery without out-of-control lesion appearing after the radiation therapy under the administration of osimertinib. CONCLUSION: The present patient experienced multiple instances of systemic recurrence after undergoing salvage surgery. Experience with this case indicates that systemic therapy is essential for patients with distant metastatic lung cancer even following salvage surgery for the primary tumor.

A 78-Year-Old Man With Repeated Dyspnea and Neutrophilia in Peripheral Blood and BAL.

CASE PRESENTATION: A 78-year-old man with asthma and COPD presented with shortness of breath, cough, and severe malaise for 4 days. Upon arrival, the patient was conscious and body temperature was 37.5°C. Arterial oxygen saturation (Spo2) was 80% on room air. Laboratory data demonstrated a WBC count of 17,400/µL (89.5% neutrophils) and C-reactive protein of 5.00 mg/dL. CT scan of chest revealed scattered ground-glass in the upper right lobe and thickening of the bronchial wall. Based on these findings, acute bronchopneumonia was diagnosed and antibacterial therapy was started. The day after admission, the patient's general condition and shortness of breath had gradually improved. We treated and observed him carefully for 10 days in the hospital on antibacterial therapy because of his underlying comorbidities (asthma and COPD) and his ongoing hypoxemia. Three days after discharge, the patient re-presented with shortness of breath, hypoxemia, and loss of appetite. The patient was hospitalized for a second time.

Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity.

INTRODUCTION: Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. PATIENTS AND METHODS: Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. RESULTS: The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). CONCLUSION: Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

[A case report of S-1 single effective use as third-line chemotherapy and re-challenge in a recurrent squamous cell lung cancer patient].

CASE: A 72-year-old male had suffered from a recurrent pulmonary squamous cell carcinoma. He had a history of systemic chemotherapy including carboplatin+paclitaxel(CBDCA+PTX)and docetaxel(DOC). As third-line chemotherapy, this patient was treated with 100 mg of S-1 daily for 4 weeks followed by 2 weeks of rest. Maximal effect was acquired 3.5 months after start of S-1 and resulted in partial response. Since tumors re-grew, S-1 was stopped and other chemotherapies including gemcitabine+vinorelbine(GEM+VNR)and gefitinib were tried but proved ineffective. The tumors gradually grew and, subsequently, right total atelectasis occurred. Re-administration of S-1 showed tumor regression and atelectasis improved. Now this patient is continuing treatment with S-1 monotherapy.

Successful multimodal treatment in a patient with thymoma accompanied by hepatic metastasis.

Despite a benign histologic appearance, thymomas have metastatic potential. Here we report a case of a patient with a Masaoka stage IVb thymoma who was successfully treated using a multimodal strategy including systemic chemotherapy, radiofrequency ablation, and thoracic surgery. Despite complete remission after treatment, the patient developed myasthenia gravis with ptosis and neck drop symptoms. Hepatic metastasis of thymoma is a relatively rare occurrence and, to the best of our knowledge, this is the first report about the application of radiofrequency ablation to thymoma.

Preliminary experience with a modified premedication protocol that included intravenous diphenhydramine and calcium bromide for the prophylaxis of paclitaxel-related hypersensitivity reactions.

BACKGROUND: Paclitaxel often causes severe hypersensitivity reactions (HSRs) rapidly after infusion, even in patients given prophylactic therapy. The purpose of this study was to analyze the incidence of paclitaxel-related HSRs in patients with non-small cell lung cancer (NSCLC) retrospectively, and to assess the feasibility of a modified premedication protocol. METHODS: One hundred and seven patients who were pretreated with either a conventional premedication regimen (two doses of dexamethasone) or a short premedication regimen (single dose of dexamethasone with oral diphenhydramine and intravenous ranitidine), prior to paclitaxel infusion were retrospectively analyzed. A modified premedication regimen, consisting of 12.5 ml of Rescalmin (intravenous diphenhydramine 50 mg and calcium bromide 437.5 mg), intravenous ranitidine 100 mg, and intravenous dexamethasone 20 mg, was given 30 min prior to paclitaxel, with oral dexamethasone 8 mg given on the night before the paclitaxel. Patients received paclitaxel intravenously at 175 mg/m(2) over 3 h, followed by carboplatin, AUC 5, over 1 h on day 1 every 3 weeks. RESULTS: In the conventional premedication group, 21 patients had HSRs (32.3%); in 1 of these patients the HSR was considered to be severe (1.5%). In the short premedication group, 19 patients had HSRs (45.2%); in 6 of these patients the HSRs were considered to be severe (14.3%). The incidence of severe HSRs was significantly higher in the short premedication group than in the conventional premedication group (P = 0.027). In the modified premedication protocol study, HSR events were recorded in 14 patients (63.6%); 14 showed flushing, 2 had skin rash, and 1 had tachycardia. No severe HSRs were seen. CONCLUSIONS: The incidence of HSRs in the short premedication group tended to be higher than that in the conventional premedication group. The modified premedication protocol was found to be feasible for preventing paclitaxel-related HSR, but case accumulation is needed.

Gefitinib-sensitive EGFR lacking residues 746-750 exhibits hypophosphorylation at tyrosine residue 1045, hypoubiquitination, and impaired endocytosis.

Gefitinib-sensitive nonsmall cell lung cancers (NSCLC) are characterized by somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR). The mutant EGFR forms are reported to mediate characteristic signal transduction pathways that are different from those mediated by the wild-type EGFR and are involved in transformation in vivo. We have examined signal transduction pathways initiated from a frequently identified gefitinib-sensitizing mutant EGFR lacking residues 746-750 by employing a mouse fibroblast cell line that is free of endogenous EGFR and transiently transfected COS-7 cells. Upon EGF stimulation, the deletion-mutant EGFR mediated prolonged downstream signals. The analysis of the phosphotyrosine patterns of the receptor revealed that the deletion-mutant EGFR lacked phosphorylation at tyrosine residue 1045, which is the major binding site of Cbl. The EGF-induced endocytosis of the deletion-mutant EGFR was impaired. The ubiquitination and downregulation of the deletion-mutant EGFR were also reduced. On the other hand, another mutant, EGFR, possessing a L858R substitution, exhibited phosphorylation at 1045 and its downstream signalings were not prolonged. These data suggest that the signal transduction pathways initiated from these mutant forms are different, and that impaired endocytosis might be responsible for the prolonged signals mediated by the deletion-mutant EGFR.

Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.

Constitutively activated signal transducers and activators of transcription (STAT) are reported to cause uncontrolled transmission of growth signals. In this study, we analyzed the roles of an inhibitor of STAT, protein inhibitor of activated STAT (PIAS) 3, in the development of lung cancer. Treatment with an inhibitor of phosphatidylinositol 3-kinase, LY294002, retarded the growth of human lung cancer cells and rendered them more sensitive to chemotherapeutic agents. However, the inhibition of JAK/STAT by AG490 significantly suppressed cell growth but did not increase drug sensitivity at all. Overexpression of PIAS3 not only significantly inhibited cell growth but also rendered cancer cells up to 12.0-fold more sensitive to the above drugs, which was associated with the suppression of Akt phosphorylation. Inhibition of PIAS3 with small interfering RNA, nevertheless, led cancer cells to accelerate cell proliferation, deteriorate chemosensitivity, and augment Akt phosphorylation. Although the overexpression of suppressors of cytokine signaling 3 in cancer cells also inhibited cell growth and STAT3 phosphorylation, it neither increased sensitivity to chemotherapeutic drugs nor affected the phosphorylation of Akt. These results indicate that PIAS3 may be an attractive candidate for targeting the JAK/STAT and PI3-K/Akt signaling pathways in cancer treatment.

The extracellular domain of p185(c-neu) induces density-dependent inhibition of cell growth in malignant mesothelioma cells and reduces growth of mesothelioma in vivo.

EGFR is involved in the density-dependent inhibition of cell growth, while coexpression of EGFR with erbB2 can render normal cells transformed. In this study, we have examined the effect of a species of p185 that contains the transmembrane domain and the extracellular domain of p185(c-neu), on growth properties of a human malignant mesothelioma cell line that coexpresses EGFR and erbB2. The ectodomain form of p185(c-neu) enhanced density-dependent inhibition of cell growth and we found that p21 induction appeared to be responsible for this inhibitory effect. Previously, the extracellular domain species was shown to suppress the transforming abilities of EGFR and p185(c-neu/erbB2) in a dominant-negative manner. The ability of this subdomain to affect tumor growth is significant, as it reduced in vivo tumor growth. Unexpectedly, we found that the domain did not abrogate all of EGFR functions. We noted that EGFR-induced density-dependent inhibition of cell growth was retained. Tyrosine kinase inhibitors of EGFR did not cause density-dependent inhibition of cell growth of malignant mesothelioma cells. Therefore, simultaneously inhibiting the malignant phenotype and inducing density-dependent inhibition of cell growth in malignant mesothelioma cells by the extracellular domain of p185(c-neu) may represent an important therapeutic advance.

[Clinical efficacy of TS-1 in refractory bone recurrence of a postoperative squamous lung cancer patient].

BACKGROUND: We need more effective treatments for refractory non-small cell lung cancer. CASE: A 61-year-old man had a recurrence in the left ninth rib invading the chestwall 4 years after resection of squamous cell lung cancer. The metastatic lesion grew larger even after 3 different regimens of systemic chemotherapy and local irradiation. Then he started to receive 120 mg of TS-1 daily for 28 days followed by 14 days of rest (1 course). A partial response was achieved after 2 courses of the treatment and continued for 6 weeks. Doses of oxycodone hydrochloride could be reduced to one-sixth of the initial dose according to tumor regression. CONCLUSION: This is the first report to show the effectiveness of TS-1 for a refractory recurrence of lung cancer to the bone.

Phase I study of weekly cisplatin, vinorelbine, and concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer.

BACKGROUND: The combination of chemotherapy and thoracic radiation therapy (TRT) is considered as a standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Although the frequent interaction of anticancer agents and irradiation may produce stronger radio-sensitizing effects, the daily administration of these agents is complicated. We therefore used weekly administration of these agents, and conducted a phase I study of weekly cisplatin, vinorelbine, and concurrent TRT. The purpose of this study was to identify the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the recommended dose of this treatment. METHODS: Patients with locally advanced NSCLC were enrolled in this study. Both cisplatin and vinorelbine were given intravenously on a weekly schedule for 6 weeks, starting on the first day of TRT, i.e., on days 1, 8, 15, 22, 29, and 36. The total dose of TRT was 60 Gy. The dose of cisplatin was fixed at 20 mg/m(2) per week. The starting dose of vinorelbine was 15 mg/m(2) per week (dose level 1). RESULTS: Nine patients were enrolled in this study. All three patients at dose level 1 experienced DLTs. We decreased the dose of vinorelbine to 10 mg/m(2) per week (dose level 0). Two of the six patients at dose level 0 experienced DLTs. Therefore, dose level 1 was considered as the MTD, and dose level 0 as the recommended dose. The DLTs of this treatment were esophagitis, fatigue, infection, and hyponatremia. CONCLUSION: The recommended dose of cisplatin is 20 mg/m(2) per week and that of vinorelbine is 10 mg/m(2) per week with standard TRT. A phase II study of this treatment is warranted.

The gefitinib-sensitizing mutant epidermal growth factor receptor enables transformation of a mouse fibroblast cell line.

A specific inhibitor of the Epidermal Growth Factor Receptor (EGFR), Gefitinib, displays significant antitumor effects against non-small cell lung cancers (NSCLC) that express EGFR with mutations in their tyrosine kinase domain. Although previous reports have already demonstrated that oncogenic transformation can be induced by some mutant EGFR forms, the precise differences between mutant and wild-type EGFR in terms of mechanisms of transformation have not been fully elucidated. We show here that a murine fibroblast cell line, NR6 becomes transformed by an expression level of the mutant EGFR form lacking E746-A750 that is far less than that needed with transfected wild-type EGFR. However, the mutant EGFR was unable to transform NR6 in a ligand-independent manner, as was seen with the wild-type EGFR. The consequent biological features after transformation, including DNA synthesis or cell cycle progression and biochemical characteristics such as MAPK activation mediated by the mutant EGFR are comparable and equivalent to those mediated by wild-type EGFR. These data suggest that the mutant EGFR possesses greater ligand-dependent transformation when compared with wild-type EGFR, although the exact mechanisms to account for this characteristic remain to be defined.

A phase I/II study comparing regimen schedules of gemcitabine and docetaxel in Japanese patients with stage IIIB/IV non-small cell lung cancer.

OBJECTIVE: Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine-docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients. METHODS: In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients. RESULTS: Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6-45.6%] overall and 30.0% (95% CI 16.6-46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study. CONCLUSIONS: Gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.