A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).

Spontaneous biloma as a complication of small cell lung cancer.

Biloma is an extraductular collection of bile within a defined capsular space. Prior reports have documented an association between biloma and abdominal trauma, and between biloma and iatrogenic injury resulting from abdominal surgery, percutaneous catheter drainage, or transhepatic cholangiogram. To our knowledge, bilomas have not previously been associated with lung cancer. We report a case of spontaneous biloma that developed as a complication of small cell lung cancer.

Double high-dose chemotherapy supported by autologous transplantation of peripheral blood stem cells for treatment of an elderly patient with small-cell lung cancer.

We report a 62-year-old male with extensive disease small-cell lung cancer (SCLC) who was successfully treated with double high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (auto-PBSCT). This patient achieved a partial response with 3 cycles of induction chemotherapy. After the peripheral blood stem cell mobilization, two cycles of high-dose ICE regimen (ifosfamide 3,000 mg/m2 at days 1 to 5, carboplatin 400 mg/m2 at days 1, 3, 5, and etoposide 500 mg/m2 at days 1, 3, 5) could be given with further regression of the tumor and acceptable toxicities. This successful case suggests the feasibility of double high-dose ICE with auto-PBSCT in elderly patients with SCLC.

Very young patient with peculiar squamous cell carcinoma of the lung.

A 20-year-old man with squamous cell carcinoma of the lung is described. Histology of the open lung biopsy specimen revealed squamous cell carcinoma with definite keratinization. Interestingly, the tumor cells were characterized by partial expression of CD34 antigen and neuroendocrine differentiation. The diagnosis was delayed in this case because of his young age. This delayed diagnosis resulted in rapid progression and short survival time. In our review of 667 cases of lung cancers at Okayama University Hospital, only 3 (0.4%) of them were under 30 years of age and also showed advanced stage and very poor prognosis. It is important to take note of lung cancer as a differential diagnosis to detect early-stage lung cancer in young patients when they present with abnormal shadow on chest radiograph.

[A case of chronic hypersensitivity pneumonitis induced by shiitake mushroom spores].

A 73-year-old woman was admitted to our hospital with a low-grade fever, dry cough and dyspnea on exertion as the chief complaints. She had been a professional shiitake mushroom grower for 50 years. Three years before visiting our hospital, she had been suspected of having hypersensitivity pneumonitis as a result of chest X-ray examination, bronchoalveolar lavage and transbronchial lung biopsy performed at another clinic. No antigens were identified at that time, but prednisolone was administered. On admission to our hospital, chest radiography and chest computed tomography revealed an interstitial shadow with subpleural honey-combing in both lower lung fields. After steroid pulse therapy, dyspnea on exertion and hypoxia improved moderately. Because of recurrence of the dyspnea, however, she was admitted on four separate occasions. On the second admission, an increase in lymphocytes was found by bronchoalveolar lavage, and septal lymphocytic infiltration accompanying fibrosis was demonstrated by transbronchial lung biopsy. On the fourth admission, a detailed immunological examination and an environmental survey were performed. The environmental provocation test yielded clinical symptoms similar to those experienced at the mushroom farm. Furthermore, tests of precipitation and lymphocyte proliferation in response to shiitake mushroom extracts were positive. Finally a diagnosis of chronic hypersensitivity pneumonitis induced by shiitake mushrooms was confirmed.

[Characteristics of bronchial asthma in the elderly].

To characterize asthma in the elderly, we compared asthma in patients aged over 70 without chronic obstructive pulmonary disease with that in patients in their twenties. In the elderly, 65.5% of the patients had developed asthma after they were fifty years old. The mean duration from onset of asthma was 21.4 years. Of cases in the elderly, 42.1% were severe, and 93.0% were chronic type. IgE was significantly lower in the elderly than in those in their twenties. Among the patients in their twenties, the severe cases had early onset and long duration. In the elderly, however, there were no correlations between severity and age at onset or duration. Severe cases in their twenties had more obstructive ventilatory dysfunction in the stable state than the mild cases. In the elderly, however, the mild cases had the same level of obstructive ventilatory dysfunction as the severe cases. The elderly patients who had more than twenty years duration had lower V50 and V25 than those who had a less than twenty-year history. Small airway obstruction was observed in long-standing cases. As asthma in the elderly causes obstructive ventilatory dysfunction in the stable state, elderly patients might easily develop respiratory failure, even during mild attacks.

Endothelial Gi protein in human coronary arteries.

Endothelium-dependent relaxations mediated by Gi protein are prominently impaired in atherosclerotic coronary arteries. However, it remains to be determined whether the expression of endothelial Gi protein per se is reduced in coronary atherosclerosis. Thus, in the present study the expression of endothelial Gi protein was examined by immunohistochemical staining using a specific antibody against human Gi protein (alpha-subunits of Gi-1 and Gi-2 proteins) in the proximal segment of the left anterior descending coronary arteries (segment 6) from 40 consecutive autopsy cases. The immunoreactive level of the Gi protein was semi-quantitated in four grades (none, 0; slight, +; moderate, +2; high, +3) and the mean value of the ratings of all endothelial cells was used as an index of the endothelial Gi protein expression of the artery. The immunoreactive level of the Gi protein in human coronary arteries was significantly reduced with ageing and extent of coronary atherosclerosis (both P < 0.05), and was lower in patients with than in those without hypertension (P < 0.01) or hyperlipidaemia (P < 0.05). In addition, the level was significantly lower in the eccentric portions than in the concentric ones in each atherosclerotic coronary artery (P < 0.0001). These alterations in the immunoreactive level of endothelial Gi protein in human coronary arteries may explain, in part, why Gi protein-mediated, endothelium-dependent relaxations are prominently impaired in atherosclerosis.

Endothelial Gi protein expression is markedly low in human coronary microvessels.

Gi protein functionally mediates endothelium-dependent relaxations in large epicardial coronary arteries but not in small coronary arteries, which suggests a different involvement of Gi protein in the endothelium-dependent relaxations between large and small coronary arteries. We previously showed that endothelial Gi protein is present in human epicardial coronary artery. In the present study, we examined the expression of endothelial Gi protein in human coronary microvessels. Immunohistochemical staining with a specific antibody against human Gi protein was performed in intramyocardial coronary microvessels and vasa vasorum from 34 autopsy cases. The immunoreactive levels of the endothelial Gi protein were semiquantitated into four grades (none, 0; slight, +1; moderate, +2; high, +3), and the mean value of the ratings of all endothelial cells was then used as an index of the endothelial Gi protein expression of the vessel. The immunoreactive levels of the endothelial Gi protein were extremely low in intramyocardial coronary microvessels and in vasa vasorum, irrespective of the age of the patients, the presence or absence of coronary risk factors, or the influence of medical treatments. These results may therefore explain in part why endothelium-dependent relaxations in coronary microvessels are not functionally mediated by Gi protein.