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Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/Δ) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Δ/Δ) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis.

Background: Amrubicin is an active agent for the treatment of small-cell lung cancer (SCLC). However, there have been no reports of long-term amrubicin use., Patients and Methods: Twelve patients with SCLC who were treated with eight or more cycles of amrubicin chemotherapy were retrospectively reviewed., Results: The median number of cycles of amrubicin chemotherapy received by the patients was 12 (range=8-20), and the median cumulative dose of amrubicin was 2076 mg (range=1200-2856 mg). The median survival time of the study patients was 1104 days (range=459-1997 days). The main adverse events observed during amrubicin chemotherapy were leukopenia and neutropenia. The cardiothoracic ratio (CTR), expressed as the mean (standard deviation) of the values measured at the initiation and termination of amrubicin chemotherapy was 46.2 (4.0), and 46.1 (5.1), respectively. The change in CTR did not reach statistical significance (p=0.92)., Conclusion: Long-term amrubicin chemotherapy is a safe and effective treatment that is associated with a good survival prognosis in properly selected patients.

We present two patients with leptomeningeal metastases (LM) from lung adenocarcinoma that progressed or newly developed, respectively, during gefitinib therapy which had exhibited substantial antitumor effects on widespread lesions. In both cases, a switch to erlotinib therapy brought about long-lasting dramatic symptomatic improvement and markedly prolonged survival. The first patient is a 46-year-old female who presented with progressive headache and vomiting. Multiple pulmonary, hepatic and bone metastases immediately shrank in response to gefitinib. However, 1 month after completion of concurrent whole brain radiation, dizziness and urinary retention newly emerged, worsening the symptoms observed at presentation. Magnetic resonance imaging (MRI) demonstrated enlargement of ventricles and new gadolinium (Gd)-enhanced disseminated nodules on the surface of the cerebral cortex, suggesting the existence of uncontrollable LM. Sequential erlotinib therapy resulted in symptomatic improvement with a finding of regression of Gd-enhancement on MRI. The beneficial effect lasted for 10 months, though a follow-up brain MRI showed further enlarged ventricles. She finally died due to LM after surviving for 11 months under erlotinib treatment. The other patient is a 55-year-old female in whom headache and vomiting occurred while gefitinib therapy had maintained shrinkage of all pre-existing tumors in the thorax and bones. Brain MRI strongly suggested occurrence of LM with a finding of Gd-enhanced sulci. A switch to erlotinib therapy relieved the symptoms with disappearance of Gd-enhancement. However, the symptoms recurred with a finding of further enlargement of ventricles on brain MRI after 11 months. Finally, she died due to LM after surviving for 12 months under erlotinib treatment.

Purpose: Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG) is increasingly used in early assessment of tumor response after chemotherapy. We investigated whether a change in [(18)F]FDG uptake at 2 days of gefitinib treatment predicts outcome in patients with lung adenocarcinoma., Experimental Design: Twenty patients were enrolled. [(18)F]FDG-PET/computed tomographic (CT) scan was carried out before and 2 days after gefitinib treatment. Maximum standardized uptake values (SUV) were measured, and post-gefitinib percentage changes in SUV were calculated. Early metabolic response (SUV decline < -25%) was compared with morphologic response evaluated by CT scan and with progression-free survival (PFS)., Results: At 2 days of gefitinib treatment, 10 patients (50%) showed metabolic response, 8 had metabolic stable disease, and 2 had progressive metabolic disease. Percentage changes of SUV at 2 days were correlated with those of tumor size in CT at 1 month (R(2) = 0.496; P = 0.0008). EGFR gene was assessable in 15 patients, and of 12 patients with EGFR mutations, 8 showed metabolic response at 2 days and 6 showed morphologic response at 1 month. None of 3 patients with wild-type EGFR showed metabolic or morphologic response. Metabolic response at 2 days was not statistically associated with PFS (P = 0.095), but when a cutoff value of -20% in SUV decline was used, metabolic responders had longer PFS (P < 0.0001)., Conclusion: Early assessment of [(18)F]FDG tumor uptake with PET at 2 days of gefitinib treatment could be useful to predict clinical outcome earlier than conventional CT evaluation in patients with lung adenocarcinoma., (© 2011 AACR.)

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion-type oncoprotein that exists in approximately 5% of non-small cell lung cancer (NSCLC). It has been demonstrated that NSCLC driven by EML4-ALK is strongly addicted to this fusion-type oncokinase. A clinical trial of crizotinib (PF-02341066) sponsored by Pfizer has proven this oncogene addiction in humans by demonstrating a high response rate to inhibition of ALK kinase activity. In the present study, we report on three cases harboring EML4-ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK-specific tyrosine kinase inhibitor., (© 2011 Japanese Cancer Association.)

Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion-mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion-mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC.

The tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) gefitinib has beneficial effect in some patients with refractory advanced non-small cell lung cancer (NSCLC). However, the majority of responders eventually develop acquired resistance during the course of prolonged continuous treatment. Here we present a case of 76-year-old Japanese female, who had never smoked, with poor performance status from bronchioloalveolar carcinoma (BAC), in whom a brief initial 5-week administration of gefitinib resulted in dramatic antitumor effects that lasted approximately 8.5 months after cessation of the treatment. Furthermore, the relapsed tumor later regressed again by re-treatment with the TKI. She survived 26 months since she first took gefitinib. Unexpectedly, neither sensitizing mutations for EGFR-TKIs nor increased copy numbers were detected in EGFR gene of her BAC cells. This case suggests that, in some patients with NSCLC, even short-term administration of gefitinib may bring about clinical benefits and disease response comparable to the standard long-term daily dosing schedule. Short-term use of gefitinib will also be able to minimize the expensive medical cost of the TKI. The potential role of short-term or pulse-dose therapy with EGFR-TKIs should be clarified in further prospective studies. Moreover, it is urgent to develop better strategies by which we could distinguish responders to the TKIs from nonresponders among patients who do not have any EGFR gene alterations.