Search

Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas., (© 2021 Norton et al.; Published by Cold Spring Harbor Laboratory Press.)

Primary small cell carcinoma (SCC) of the pancreas is a rare disease with poor prognosis. Very few cases have been reported in the literature. It is a type of poorly differentiated variety of neuroendocrine tumours of the pancreas with specific immunohistochemical markers. Imaging is not diagnostic for disease, and diagnosis is mainly by biopsy. We report a rare case of SCC of the pancreas who presented with features of obstructive jaundice without any paraneoplastic features. The patient is planned for palliative chemotherapy because of metastasis and is under regular follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Composite tumor of larynx, a recently included entity in the current WHO classification, is often a difficult pathological diagnosis, especially in small biopsies. We report a case of laryngeal composite tumor, initially misdiagnosed as squamous cell carcinoma, which later turned out to be composite in nature, with associated neuroendocrine (small cell carcinoma) component. This report emphasizes the need for obtaining deeper biopsies and their thorough pathological examination to improve the diagnostic accuracy. Keywords: combined small cell carcinoma; composite tumor; larynx; small cell carcinoma; squamous cell carcinoma.

Rationale: Small cell carcinoma (SCC) occurs mostly in the lung, and small cell lung cancer accounts for 13% of newly diagnosed lung cancers. Only 2.5% of SCC occurs in extrapulmonary sites, and SCC of pleural origin is especially very uncommon., Patient Concerns: An 85-year-old man presenting with progressive dyspnea for more than 7 days., Diagnoses: Computed tomography scan of the chest showed massive pleural effusion and diffuse nodular thickening of the pleura on the right chest. Sonography-guided needle biopsy of the pleural mass was performed and histologic and immunohistochemical findings revealed SCC. Since no parenchymal lung lesion was observed, the patient was finally diagnosed with SCC of the pleura (SCCP)., Interventions: Due to the patient's old age and poor performance status, chemotherapy was not performed and only drainage of pleural effusion was conducted for symptom relief., Outcomes: Dyspnea improved after pleural effusion drainage. The patient was discharged and transferred to a local medical center for hospice care., Lessons: Although primary SCCP is extremely rare, SCCP should also be considered as well as mesothelioma in case of presence of a pleural-based mass with massive pleural effusion.

Rationale: Endometrial neuroendocrine carcinoma is a rare histological subtype of endometrial cancer, divided into low-grade neuroendocrine carcinoma (carcinoid) and high-grade neuroendocrine carcinoma (small cell and large cell neuroendocrine carcinoma). It is characterized by high invasiveness and poor prognosis. L/SCNEC is an extremely rare pathological type of endometrial carcinoma, and the number of reports on this condition is few globally., Patient Concerns: A 54-year-old Chinese female presented with vaginal bleeding., Diagnoses: Outpatient hysteroscopy and endometrial biopsy were performed, and the pathological examination revealed that cervix was invaded by endometrial malignancy. The patient underwent a laparoscopic radical hysterectomy was diagnosed with the mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the endometrium combined with serous carcinoma III C2 (FIGO2009)., Interventions: Chemotherapy-radiotherapy-chemotherapy "sandwich" treatment was performed as postoperative therapy., Outcomes: After three chemotherapy circles, the patient showed no evidence of further disease progression., Lessons: L/SCNEC is a rare and invasive disease. Once diagnosed, comprehensive treatments including surgery, radiotherapy, and chemotherapy can prolong the survival of patients and improve the prognosis.

Seesaw nystagmus is characterized by the rhythmic combination of vertical and torsional dysconjugate oscillations where one eye moves up and inward while the other moves down and outward. Common association of seesaw nystagmus with accessory optic track lesions lead to traditional hypothesis that it is due to the mismatch in the vision and vestibular systems. Here we propose a novel mechanism for seesaw nystagmus. We hypothesize that reverberations due to abnormal increases in the excitability of the reciprocally innervating circuit of excitatory burst neuron in the midbrain interstitial nucleus of Cajal causes the seesaw nystagmus. Analogous oscillations of the brainstem burst generators may be responsible for generation of saccadic oscillations or opsoclonus. The key difference is that the interstitial nucleus of Cajal lacks inhibitory burst neurons, hence the lack of post-inhibitory rebound, and relatively lower frequency of the oscillatory cycles causing pendular seesaw nystagmus. In contrast the brainstem burst generator, with reciprocally innervating excitatory and inhibitory burst neurons, and further inhibitory influence of the omnipause neurons results in the post-inhibitory rebound at the burst neurons, hence high oscillation frequency. This novel concept is supported by a unique observation in a patient with antineuronal nuclear autoantibody type 2 due to breast cancer who had combined seesaw nystagmus and superimposed saccadic oscillations. The patient neither had cerebellar deficits typically thought to cause paraneoplastic opsoclonus nor visual deficits that are known cause of seesaw nystagmus. We propose that hyperexcitability of the burst neurons in the interstitial nucleus of Cajal due to paraneoplastic antibody caused pendular seesaw nystagmus. On the other hand, increased excitability of brainstem burst generators and reduced efficacy of the omnipause neurons caused saccadic oscillations., (Published by Elsevier B.V.)

The diagnosis of autoimmune gastrointestinal dysmotility requires a high level of clinical suspicion when standard work-up is unrevealing. We report the case of a 56-year-old male patient with history of tobacco use and a subacute presentation of weight loss, vomiting and cerebellar ataxia. The discovery of paraneoplastic type 1 antineuronal nuclear antibodies and neuronal acetylcholine receptor antibodies led to further directed imaging and diagnostic studies in spite of prior negative chest imaging. Bronchoscopy with endobronchial ultrasound was used to confirm a diagnosis of small cell lung cancer and paraneoplastic syndrome as the cause of the presenting upper gastrointestinal symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Case Presentation: An African American man in his late 30s was referred to the pulmonary clinic for evaluation of a persistent cough of several weeks' duration. Cough was productive of mucopurulent sputum mixed with blood. He also noted generalized weakness and dyspnea with minimal exertion., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Sonic Hedgehog (Shh) pathway is physiologically activated during embryogenesis and development. It plays a role in idiopathic lung fibrosis and is also activated in several solid cancers., State of the Art: Shh pathway is reactivated in thoracic cancers, as small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma. Shh pathway is associated with cancer stem cells and seems to have a crucial role in tumor proliferation, aggressiveness and chemoresistance in these cancers. This review describes the activation mode of Shh pathway in thoracic cancers and its role in small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma, using in vitro and in vivo models. Notably, data from literature show that inhibition of Shh pathway has an antitumor action and sensitizes to chemotherapy., Perspectives: These results incite to develop targeted therapies against Shh pathway in the treatment of thoracic cancers., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Small cell neuroendocrine carcinoma (SNEC) of the paranasal sinuses is an extremely rare and distinctive tumor with aggressive clinical behavior. Moreover, SNECs originating in the head and neck region have been reported to be highly aggressive and to have a poor prognosis. This report describes a patient with a maxillary sinus SNEC who was successfully treated with induction chemotherapy using cisplatin and etoposide followed by concurrent chemoradiation therapy with cisplatin and etoposide as radiosensitizers. The patient has remained free of recurrence during 7 years of follow-up. To the authors' knowledge, this is the first case report describing long-term survival in a patient with a resolved primary SNEC of the maxilla that was successfully treated with neoadjuvant chemotherapy and concurrent chemoradiotherapy. The clinical and pathologic features of the tumor and the optimal treatment of this patient are discussed., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular synapse. About half of LEMS patients have an associated small cell lung carcinoma (SCLC), which is usually detected after diagnosis of LEMS. This short review summarizes clinical and serological markers shown to predict the presence of SCLC in LEMS patients. SOX1 antibodies are a specific marker for SCLC-LEMS but they are also found in SCLC patients without paraneoplastic neurological syndromes. No relation to any clinical characteristic or survival effect has been found for SOX1-positive patients. Several clinical markers also discriminate between SCLC-LEMS and nontumor LEMS. Detailed analysis of these clinical and demographic characteristics from two independent patient cohorts has led to development of the DELTA-P score. This prediction model has provided for a simple clinical tool to indicate the presence of SCLC early in the course of the disease. The DELTA-P score can be used to guide tumor screening in individual patients., (© 2012 New York Academy of Sciences.)

Introduction: We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy., Methods: This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate., Results: Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%)., Conclusion: Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Aims: The aim of this study is to investigate the activity and toxicity of etoposide with AUC 6 doses of carboplatin in patients with previously untreated extensive disease - small-cell lung cancer (SCLC)., Materials and Methods: 88 eligible patients were treated with chemotherapy comprised of carboplatin AUC of 6, IV day 1 and etoposide 100 mg/m 2 , IV day 1-3. This schedule was repeated every 21 days for maximum of six cycles., Results: Patients characteristics: Median age, 62 years; 84 male; ECOG PS 0-1 in 73 patients, PS 2-3 in 15 patients. A total of 431 cycles were administered (median, 6.0). The complete and partial response rates were 23.9% and 45.5%, respectively. Median overall survival (OS) was 9.0 months (95% confidence interval [CI], 8.09 - 9.90 m); 84 patients died. The 1- and 2-year survival probabilities were 33.6% and 5.3%, respectively. The median progression-free survival in patients of 65 was 7.2 months (95% CI, 5.81 - 8.58), 12-month PFS rate was 10%. The median OS was 11.6 months (95% CI, 8.52 - 14.67 m) and 7.5 months (95% CI, 5.61 - 9.38 m) in patients with non-liver and liver metastasis, respectively (P = 0.024). The median OS was 9.3 months (95% CI, 7.83 - 10.76 m) and 7.5 months (95% CI, 5.58 - 9.44 m) in patients with single and multiple distant metastasis, respectively (P = 0.02). Grade 3-4 neutropenia, thrombocytopenia, and anemia were detected in 57.9%, 15.9%, and 11.4% of patients, respectively. Febrile neutropenia was developed in 12 patients., Conclusion: Etoposide with AUC 6 doses of carboplatin is active and tolerable in patients with extensive disease - SCLC.

Introduction: Topoisomerase inhibitors are active agents in small cell lung cancer (SCLC), and preclinical models indicate that sequential administration of a topoisomerase I inhibitor followed by a topoisomerase II inhibitor can result in enhanced cytotoxicity., Patients and Methods: In this phase II study, patients with extensive SCLC were treated with two sequential topoisomerase-based regimens: irinotecan (150 mg/m(2))/oxaliplatin (85 mg/m(2)) [regimen A] on day 1 followed by etoposide (100 mg/m(2)×3)/carboplatin (AUC 6) [regimen B] on day 15. Regimen A was repeated 3 weeks later. The primary objective was objective response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and exploratory correlative analysis of the tumor expression of the excision repair cross complementing (ERCC1) and topoisomerase II-α. Patients received a maximum of 5 cycles of sequential therapy of regimen A→B., Results: The overall response rate was 96%, the 6-month PFS was 76.9%, the median PFS was 8.95 months, and OS was 12.9 months in 26 evaluable patients. Grade 4 neutropenia (23%) and thrombocytopenia (58%) were observed with regimen B; and grade 2/3 nausea-vomiting (54%) and diarrhea (46%) with regimen A. Seven patients required dose reductions in regimen A and 19 patients in regimen B. The dose intensity, delivered during the first three cycles was 89%. No significant correlations were observed between the tumor expression of the ERCC1 and topoisomerase II-α and clinical outcomes (PFS or OS)., Conclusions: Although cross-study comparisons are difficult to make, our data suggests that sequential topoisomerase-targeting regimens may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients (Clinical Trial Registration Number, 9 NCT00240097; Clinical Trials.gov number, NCT00240097)., (Published by Elsevier Ireland Ltd.)

Background: Recent reports have suggested the efficacy of amrubicin (AMR) for relapsed small-cell lung cancer (SCLC). However, doses of AMR in these reports were 40 mg/m(2) or 45 mg/m(2), and severe and frequent myelosuppression were observed. Such side effects are occasionally intolerable, as serious myelosuppression may induce fatal infections. To overcome this clinical problem, we investigated whether 35 mg/m(2) of AMR administration with routine prophylactic use of granulocyte-colony stimulating factor (G-CSF) can reduce myelosuppression, while maintaining efficacy., Methods: Between July 2003 and November 2008, 30 relapsed SCLC patients receiving 35 mg/m(2)/day of AMR were evaluated. Amrubicin was administered on days 1-3 every 3 or 4 weeks. Routine prophylactic use of G-CSF was performed beginning on day 8 and continuing for at least 5 consecutive days or until neutrophils recovered to the normal level., Results: The median number of treatment cycles was four (range 1-9). No complete responses and 13 partial responses were observed, with response rates of: overall 43% (95% confidence interval [CI]: 26-63%); sensitive cases 33% (95% CI: 10-65%); and refractory cases 50% (95% CI: 26-74%) (p=0.4651). The disease control rate (partial response and stable disease) was 80% (95% CI: 61-92%). The progression-free survival times were: overall 4.2 months (95% CI: 3.2-5.2 months); sensitive cases 4.7 months (95% CI: 2.6-5.4 months); and refractory cases 3.5 months (95% CI: 2.6-5.2 months) (p=0.7124). The median OS times were: overall 9.6 months (95% CI: 7.2-12.5 months); sensitive cases 8.4 months (95% CI: 4.6-13.4 months); and refractory cases 11.0 months (95% CI: 6.5-12.6 months) (p=0.9315). The 1-year survival rate was 33%. Regarding grade 3/4 hematological toxicities: leukopenia (47%); neutropenia (50%); anemia (30%); and thrombocytopenia (33%) were observed. Febrile neutropenia occurred in three patients (10%). Transfusions of red blood cells and platelets were performed for eight (27%) and one (3%) patients, respectively. Treatment-related deaths and grade 3/4 non-hematological toxicities were not observed at all., Conclusions: Considering both safety and efficacy, AMR at a dose of 35 mg/m(2) with routine prophylactic use of G-CSF may be more desirable for the treatment of relapsed SCLC in clinical practice., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival., Patients and Methods: Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy)., Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed., Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Mina53, a novel target gene product of c-Myc, is overexpressed in various malignancies. We previously demonstrated that Mina53 is overexpressed in lung cancer patients from the early clinical stages. In this paper, the association between disease prognosis and Mina53 expression in lung cancer patients is analyzed; we found that overexpression of Mina53 in lung cancer patients is associated with favorable prognosis. Statistical analysis using the Kaplan-Meier method showed that patients with negative staining for Mina53 had significantly shorter survival than patients with positive staining for Mina53, especially in stage I or with squamous cell carcinoma. Because the major cause of death in lung cancer patients after surgery is distant metastasis, the effect on cancer cell invasiveness was analyzed for the mechanisms involved in the association with favorable outcome. Overexpression of Mina53 in H226B, a lung squamous cell carcinoma cell line, inhibited cancer cell invasion. Transfection with mina53 shRNA increased the number of invading cells. These results suggest that Mina53 immunostaining is a useful prognostic marker--especially in the early stage of lung cancer--and that Mina53 negative patients should be managed particularly carefully after surgery., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Rbp9 is a Drosophila RNA-binding protein that shares a high level of sequence similarity with Drosophila elav and human Hu proteins. Loss of function alleles of elav are embryonic lethal causing abnormal central nervous system (CNS) development, and Hu is implicated in the development of paraneoplastic neurological syndrome associated with small cell lung cancer. To elucidate the role of Rbp9, we generated Rbp9 mutant flies and examined them for symptoms related to paraneoplastic encephalomyelitis. Although Rbp9 proteins begin to appear from the middle of the pupal period in the cortex of the CNS, the Rbp9 mutants showed no apparent defects in development. However, as the mutant adult flies grew older, they showed reduced locomotor activities and lived only one-half of the life expectancy of wild-type flies. To understand the molecular mechanism underlying this symptom, gene expression profiles in Rbp9 mutants were analyzed and potential target genes were further characterized. Reduced expression of cell adhesion molecules was detected, and defects in the blood-brain barrier (BBB) of Rbp9 mutant brains could be seen. Putative Rbp9-binding sites were found in introns of genes that function in cell adhesion. Therefore, Rbp9 may regulate the splicing of cell adhesion molecules, critical for the formation of the BBB.

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, malignant neoplasm usually present with the widespread abdominal serosal involvement and affects mainly adolescents and young adults. When presenting within visceral organs, as kidney, the diagnosis of DSRCT imposes significant difficulties. We present a case of primary DSRCT of the kidney in a 10-year-old boy mimicking clinically and pathologically Wilms tumor. The tumor showed morphologic and immunohistochemical features of DSRCT and the presence of the Ewing sarcoma and Wilm tumor 1 fusion transcripts resulting from the t(11;22) (p13;q12) reciprocal translocation. DSRCT should be considered in the differential diagnosis of Wilm tumor and other small blue-round cell tumors of the kidney.

Within the framework of the Rare Cancer Network Study, we examined 30 patients suffering from small cell neuroendocrine prostate cancer, either in an early/localized or an advanced/metastatic stage. Patients were treated with cisplatin-based chemotherapy, with or without pelvic radiotherapy. Two patients with early disease achieved complete remission for a duration of 19 and 22 months. Three patients with advanced disease achieved complete remission for 6, 7, and 54 months, respectively. Twenty-five patients succumbed to massive local and/or distant failure. No patient presented with brain metastases as the initial site of relapse. Small cell neuroendocrine prostate carcinoma is a very aggressive disease with a poor prognosis, even in its localized form. Despite initial response, the common cisplatin-based chemotherapy plus radiotherapy failed to improve outcome markedly. Improvement will come from understanding the biology of the disease and integrating new targeted therapies into the treatment of this rare and aggressive tumor.

Aims: Previous studies have defined prognostic factors predicting a favourable response to treatment and long-term survival in small cell lung cancer (SCLC) patients. Here we sought specific pre-treatment features predicting early death in SCLC., Materials and Methods: An exploratory cohort of 62 patients with poor prognosis SCLC and a separate confirmatory independent cohort of 152 unselected SCLC patients were identified to determine risk factors for early death, defined as within 8 weeks of diagnosis., Results: In an exploratory cohort of patients with poor prognosis SCLC, 46 received chemotherapy and 16 patients received no chemotherapy. Multivariate analysis of chemotherapy patients showed a raised serum urea to be predictive of early death - increasing the risk by 13-fold (odds ratio 13.3, 95% confidence interval=2.8-64). In a separate cohort of 152 unselected SCLC patients, 123 received chemotherapy and 29 did not. Logistic regression analysis of treated patients showed that performance status >2 (P=0.009), urea>upper limit of normal (P=0.01), neutrophil count >10 (P=0.024) and weight loss >10% (P=0.03) significantly contributed to the risk of early death. Of note, raised serum urea increased the risk of early death by 12-fold (odds ratio 11.8, 95% confidence interval=1.8-76.9)., Conclusion: We have shown that pre-treatment raised serum urea is a significant predictor of early death. This readily available information will be useful for assessing SCLC patients at the bedside and discussing the risks of chemotherapy with them.

Purpose: To evaluate the impact of the cigarette burden (CB) on the response rate to platinum-based chemotherapy (CT) in patients with lung cancer (LC)., Methods: Retrospective study of patients with LC treated by CT from 2000 to 2005, in a tertiary referral center in Brazil. The CB was measured by the number of pack-years smoked (PY). To evaluate the response (by RECIST), it was necessary to accomplish two cycles of CT. The relevant variables were studied by univariate and multivariate statistical techniques., Results: Two hundred and eighty-five patients (203 men) were studied (mean age=60.6+/-10.1 years, mean PY=58.3+/-35.4). 62.8% were current smokers, 26.7% were former smokers, and 10.5% were non-smokers. 63.2% had non-small-cell lung cancer (NSCLC), and 36.8% had small-cell lung cancer (SCLC). The treatment intent was palliative in 63.9% and curative in 36.1%. All 285 patients received platinum-based CT (etoposide/cisplatin in 68.8% and etoposide/carboplatin in 31.2%). Of these, 155 patients (54.4%) received RT (median dose=50.0 Gy; range=45.0-80.0). The 94 patients (33.0%) who responded to treatment had a mean PY of 38.7+/-27.1, and the 191 patients (67.0%) who did not respond had a mean PY of 67.8+/-35.1, p<0.001. In the multivariate analysis, the main independent negative predictor was CB>or=40 PY (adjusted OR=10.42; 95% CI=5.13-21.28). The others independent negative predictors were: CT (no. of cycles=2-4) (adjusted OR=4.86; 95% CI=2.44-9.68), treatment regimen with CT alone (adjusted OR=3.38; 95% CI=1.67-6.84), and NSCLC histology (adjusted OR=2.75; 95% CI=1.12-6.76)., Conclusion: Patients with CB>or=40 PY have a worse response to platinum-based CT compared to those who have a CB<40 PY.

Lung cancer is the second most common cancer in the UK, however it is responsible for the highest number of cancer deaths. In the past decade advances have been made in lung cancer diagnosis, and the treatment and management of associated problems but the impact on survival and quality of life has been minimal. Understanding how patients are diagnosed with lung cancer, the treatments available and how to manage related concerns and issues will enable nurses to improve the care they provide to lung cancer patients and their families.

Paraneoplastic opsoclonus-myoclonus syndrome (OMS) is associated with small cell lung cancer (SCLC) in adults. Without appropriate treatment for SCLC, all reported patients with SCLC and OMS have died of complications of OMS within 3 months of diagnosis. With appropriate treatment, about half of reported patients have had improvement in neurologic function, and several have become long-term survivors (6-84 months). We report a patient with SCLC who presented with OMS and was refractory to immunosuppressive therapy but responded rapidly to antineoplastic therapy and remains alive with no sign of SCLC recurrence and minimal residual neurologic deficits 30 months after diagnosis. In patients presenting with OMS, early recognition and treatment of the underlying malignancy probably improve the chances for recovery from the OMS with minimal deficit and ultimate survival.

Background: Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy., Methods: To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of beta-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10)., Results: Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic beta-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2., Conclusions: These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes that are required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic beta-cell differentiation is involved in NE differentiation of prostate cancer., ((c) 2007 Wiley-Liss, Inc.)

Purpose: Mitochondrial dysfunction has been attributed a critical role in the etiology and pathogenesis of numerous diseases, and is manifested by alterations of the organelle's membrane potential (Deltapsi(m)). This suggests that Deltapsi(m) measurement can be highly useful for diagnostic purposes. In the current study, we characterized the capability of the novel PET agent (18)F-fluorobenzyl triphenylphosphonium ((18)F-FBnTP) to assess Deltapsi(m), compared with the well-established voltage sensor (3)H-tetraphenylphosphonium ((3)H-TPP)., Methods: (18)F-FBnTP and (3)H-TPP uptake under conditions known to alter Deltapsi(m) and plasma membrane potential (Deltapsi(p)) was assayed in the H345 lung carcinoma cell line. (18)F-FBnTP biodistribution was assessed in CD1 mice using dynamic PET and ex vivo gamma well counting., Results: (18)F-FBnTP and (3)H-TPP demonstrated similar uptake kinetics and plateau concentrations in H345 cells. Stepwise membrane depolarization resulted in a linear decrease in (18)F-FBnTP cellular uptake, with a slope (-0.58+/-0.06) and correlation coefficient (0.94+/-0.07) similar (p>0.17) to those measured for (3)H-TPP (-0.63+/-0.06 and 0.96+/-0.05, respectively). Selective collapse of Deltapsi(m) caused a substantial decrease in cellular uptake for (18)F-FBnTP (81.6+/-8.1%) and (3)H-TPP (85.4+/-6.7%), compared with control. Exposure to the proapoptotic staurosporine, known to collapse Deltapsi(m), resulted in a decrease of 68.7+/-10.1% and 71.5+/-8.4% in (18)F-FBnTP and (3)H-TPP cellular uptake, respectively. (18)F-FBnTP accumulated mainly in kidney, heart and liver., Conclusion: (18)F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of (3)H-TPP. (18)F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.

Purpose: Lung cancer is the leading cause of cancer deaths in the developed world. Small cell lung cancer (SCLC) has the worst prognosis due to the emergence of resistance to chemotherapy. This article will review recent work that has defined mechanisms of chemo-resistance focusing on the role of integrins., Results: SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) and high levels of expression correlate with poor prognosis. ECM protects SCLC cells against chemotherapy-induced cell death by activating beta1 integrins leading to activation of phosphoinositide-3-OH kinase (PI3-kinase), which prevents etoposide-induced caspase-3 activation and subsequent apoptosis. Engagement of ECM prevents etoposide and radiation induced G2/M cell cycle arrest in SCLC cells by blocking the up-regulation of p21Cip1/WAF1 and p27Kip1 and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signalling., Conclusions: Thus, ECM via beta1 integrin-mediated PI3-kinase activation allows SCLC cells to survive treatment induced cell cycle arrest and apoptosis with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance. Novel therapeutic strategies may therefore be directed at inhibiting integrin-mediated cell survival signals improving response rates and cure in this devastating cancer.

Objective: Patient Symptom Assessment in Lung Cancer (PSALC) is a symptom scale developed for use in patients with small cell lung cancer (SCLC) to assess nine lung cancer symptoms (shortness of breath, cough, chest pain, hemoptysis, appetite loss, sleep interference, hoarseness, fatigue, interference with daily activities) scored from 1 (not at all) to 4 (very much). This study aims to retrospectively evaluate the psychometric properties of PSALC using clinical trial data., Methods: Data were analyzed from a randomized, open-label, multicenter trial with 211 patients with SCLC receiving i.v. topotecan versus cyclophosphamide, doxorubicin, and vincristine. PSALC was evaluated at baseline and at 3-week intervals. Internal consistency, reliability, construct validity, and responsiveness were evaluated., Results: Factor analysis indicated that one factor could represent all symptom items, so a PSALC total score (PSALC-TS) was used for psychometric validation. Internal consistency was supported by Cronbach's alpha of 0.74. Reliability of PSALC was supported by an intraclass correlation coefficient of 0.61 and concordance correlation coefficient of 0.72. Construct validity was supported by associations of lower PSALC-TS (less severe symptoms) with better ECOG performance status (p < 0.0001), and of PSALC-TS changes with clinical response. PSALC-TS was responsive to tumor progression (responsiveness statistic = 0.64)., Limitations: The validation was performed retrospectively and was limited by small sample sizes at later assessment timepoints due to disease progression., Conclusions: A retrospective analysis suggests that the PSALC is a reliable, valid, and responsive instrument for measuring SCLC symptoms. If feasible in this population, a prospective validation study could be used to further evaluate these findings.

The efficacy of salvage regimens for small cell lung cancer remains to be established. We evaluated the efficacy and safety of the paclitaxel and ifosfamide (PI) combination chemotherapy salvage regimen in heavily pretreated small cell lung cancer (SCLC) patients. Thirty-five patients who had received more than two prior chemotherapy regimens were treated with PI chemotherapy. Paclitaxel (175 mg/m(2)) was administered on day 1 and ifosfamide (2500 mg/m(2)) on day 1-2 every 3 weeks. Thirty-three patients were available for treatment response evaluation. Median age was 63 years (range, 40-78) and Eastern Cooperative Oncology Group (ECOG) performance scores of 0/1/2 were 29.4%, 61.8%, and 11.8%, respectively. A median of 2 cycles (range, 1-6) of chemotherapy were administered. The overall response rate (RR) in the intent-to-treat population was 20.0% (95% Confidence Interval (CI), 6.7-33.3%) with 7 partial responses (PR) and no complete response (CR). Patients who responded to previous chemotherapy just before PI showed significantly higher RR than non-responders (RR, 57.1% versus 10.7%, P=.023). After a median follow-up of 8.8 months (range, 1.6-14.7), the median time to progression was 3.3 months (95% CI, 2.3-4.4) and the median overall survival was 7.6 months (95% CI, 6.7-8.5). The most common toxicity observed was mild nausea/vomiting and grade 3/4 adverse events were observed in 4 (11.4%) patients. There were no treatment-related deaths in the study. Our findings suggest that salvage PI chemotherapy is a feasible and well tolerated regimen for previously treated SCLC patients. Further studies are warranted to define the effects of PI chemotherapy on quality of life and survival benefits.

Background: Clinical experience suggests that lung cancer (LC) is associated with sleep disturbances that may contribute to impaired daytime functioning and quality of life. Using questionnaires and home actigraphic recordings, we tried to determine whether sleep quality and daytime alertness are impaired in patients with newly diagnosed LC., Patients and Methods: Twenty-nine outpatients with newly diagnosed LC and an Eastern Cooperative Oncology Group performance status

Background: The specific volatile organic compounds (VOCs) exhaled by lung cancer cells in the microenvironment are the source biomarkers of lung cancer and also serve as direct evidence that the diagnosis of lung cancer by breath is possible. However, to the authors' knowledge, few articles published to date have provided accurate VOCs in the microenvironment, thereby leading to different points of view with regard to searching for biomarkers in the breath from lung cancer patients In this article, an innovative pathologic analysis method of lung cancer and the early diagnosis of lung cancer at the cellular level were introduced for this purpose., Methods: Solid-phase microextraction combined with gas chromatography is used as the detection system to determine the VOCs in the culture medium of several target cells, including different kinds of lung cancer cells, bronchial epithelial cells, tastebud cells, osteogenic cells, and lipocytes. As a result, each kind of cells has a unique chromatogram. There are 4 special VOCs that were found to exist in all culture mediums of lung cancer cells, which are the metabolic products of lung cancer cells and can be viewed as markers of lung cancer., Results: The authors were able to determine a correlation between VOCs in the metabolic products of lung cancer cells and VOCs in the breath of lung cancer patients, some of whom had stage I and II disease, and eventually hope to certify the biomarkers in the breath of lung cancer patients., Conclusions: This research is significant and provides the basis for the noninvasive detection and the breath diagnosis of lung cancer using an electronic nose.

Small-cell lung cancer is an aggressive form of lung cancer that, overall, remains the most common cause of cancer death in the US. Some advances have been made in the treatment of small-cell lung cancer using cytotoxic chemotherapeutic agents but no truly targeted therapies are available as of yet. At present, research is focused on finding therapies that can target the specific molecular mechanisms responsible for the survival, growth and metastasis of the tumor thereby improving responses to chemotherapy and minimizing toxicity. Several new agents, such as angiogenesis inhibitors and regulators of apoptosis, have reached clinical testing and multiple others are in preclinical trials. Some of these will be discussed in this review.

Background: Response shift has gained increasing attention in the measurement of health-related quality of life (QoL) as it may explain counter-intuitive findings as a result of adaptation to deteriorating health., Objective: To search for response shift type explanations to account for counter-intuitive findings in QoL measurement., Methods: Qualitative investigation of the response behaviour of small-cell lung cancer (SCLC) patients (n = 23) in the measurement of fatigue with The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) question 'were you tired'. Interviews were conducted at four points during 1st line chemotherapy: at the start of chemotherapy, 4 weeks later, at the end of chemotherapy, and 6 weeks later. Patients were asked to 'think aloud' when filling in the questionnaire., Results: Fifteen patients showed discrepancies between their answer to the EORTC question 'were you tired' and their level of fatigue spontaneously reported during the interview. These patients chose the response options 'not at all' or 'a little' and explained their answers in various ways. In patients with and without discrepancies, we found indications of recalibration response shift (e.g. using a different comparison standard over time) and of change in perspective (e.g. change towards a more optimistic perspective). Patients in the discrepancy group reported spontaneously how they dealt with diagnosis and treatment, i.e. by adopting protective and assertive behaviour and by fighting the stigma. They distanced themselves from the image of the stereotypical cancer patient and presented themselves as not suffering and accepting fatigue as consequence of treatment., Conclusion: In addition to response shift, this study suggests that 'self-presentation' might be an important mechanism affecting QoL measurement, particularly during phases when a new equilibrium needs to be found.

Molecular genetic studies of lung cancer have revealed that clinically evident lung cancers have multiple genetic and epigenetic abnormalities, including DNA sequence alterations, copy number changes, and aberrant promoter hypermethylation. Together, these abnormalities result in the activation of oncogenes and inactivation of tumor-suppressor genes. In many cases these abnormalities can be found in premalignant lesions and in histologically normal lung bronchial epithelial cells. Findings suggest that lung cancer develops through a stepwise process from normal lung epithelial cells towards frank malignancy, which usually occurs as a result of cigarette smoking. Lung cancer has a high morbidity because it is difficult to detect early and is frequently resistant to available chemotherapy and radiotherapy. New, rationally designed early detection, chemoprevention, and therapeutic strategies based on the growing understanding of the molecular changes important to lung cancer are under investigation. For example, methylated tumor DNA sequences in sputum or blood are being investigated for early detection screening, and new treatments that specifically target molecules such as vascular endothelial growth factor and the epidermal growth factor receptor are becoming available. Meanwhile, global gene expression signatures from individual tumors are showing potential as prognostic and therapeutic indicators, such that molecular typing of individual tumors for therapy selection is not far away. Finally, the recent development of a model system of immortalized human bronchial epithelial cells, along with a paradigm shift in the conception of cancer stem cells, promises to improve the situation for patients with lung cancer. These advances highlight the translation of molecular discoveries on lung cancer pathogenesis from the laboratory to the clinic.

Over 95% of patients with small-cell lung cancer (SCLC) die within five years of diagnosis. The standard of care and the dismal prognosis for this disease have not changed significantly over the past 25 years. Some of the characteristics of SCLC that have defined it as a particularly virulent form of cancer -- rapid proliferation, excessive metabolic and angiogenic dependence, apoptotic imbalance and genetic instability -- are now being pursued as tumor-specific targets for intervention both in preclinical and early phase clinical studies. Here, we summarize areas of ongoing anti-cancer drug development, including classes of agents that target essential pathways regulating proliferation, angiogenesis, apoptotic resistance, chromosomal and protein stability, and cell-cell and cell-matrix interaction.

Purpose: The predicted postoperative forced exspiratory volume in one second (FEV (1)) is an important functional factor for predicting the operability of patients with bronchial carcinoma. A software tool that uses a preoperative chest MSCT and pulmonary function test (PFT) for largely automated prediction of the FEV (1) was evaluated., Materials and Methods: Fifteen patients with surgically treated lung cancer were examined with a preoperative chest MSCT (1.25 mm slice thickness, 0.8 mm reconstruction increment) and PFT before and after surgery. CT scans were analyzed by the prototype software MeVisPulmo (MeVis gGmbH, Bremen) that predicted the postoperative FEV (1) as a percentage of the preoperative values measured by PFT. The automated segmentation and volumetry of lung lobes were performed either without or with minimal user interaction. Patients underwent lobectomy in twelve cases (6 upper lobes, 1 middle lobe, 5 lower lobes) and pneumectomy in three cases. The predicted FEV (1) values were compared to the observed postoperative values as a standard of reference. The additional functional parameters "total lung capacity" (TLC) and "forced vital capacity" (FVC) were compared to the FEV (1) results., Results: Automated calculation of predicted postoperative lung function was successful in all cases. Due to an implausible PFT, two of the 15 patients were excluded from the collective. A mean postoperative FEV (1) value of 75 % (SD +/- 12 %) of the preoperative FEV (1) was calculated and 74 % (SD +/- 12 %) was actually measured. The deviations of the predicted value from the measured postoperative FEV (1) ranged between - 289 ml (-12 % of the measured postoperative FEV (1)) and + 294 ml (+ 15 % of the postoperative FEV (1)). The mean deviation (absolute value) was 137 +/- 77 ml/s. This corresponds to 7 +/- 3 % of the measured postoperative FEV (1). Bland-Altman-Statistics showed the 95 % "limits of agreement" for the predicted FEV (1) values to be between - 341 ml and + 301 ml, corresponding to - 17.5 % and + 15.8 of the measured postoperative FEV (1) value. Analysis of the TLC and FVC yielded similar results., Conclusion: In the present pilot study the software-assisted prediction of the postoperative FEV (1) using a preoperative MSCT and pulmonary function test corresponded satisfactorily with the observed postoperative values. The introduced approach may make it possible to obtain additional information for the prediction of functional operability prior to performing lung cancer surgery.

Although adenocarcinoma represents the vast majority of neoplasms of the large intestine, small cell undifferentiated carcinoma (SCUC) also arises from the colorectum. SCUC of the colorectum is highly malignant and shares the similarities in histologic characteristics, behavior, and histochemistry with SCUC of the lung. We report herein a case of SCUC in the ascending colon with rapid enlargement after resection. A 70-year-old male, who presented to a nearby physician with chief complaints of pain in the right lower quadrant, was referred to our hospital. We found a tumor mass that was approximately 15 cm in size in the right lower quadrant. Computed tomography (CT) images showed an irregularly shaped tumor, located inferior to the lower border of the right kidney and in the area of the ascending colon. By colonoscopy, we found a circumferential tumor of the ascending colon. A biopsy indicated it to be SCUC. The patient underwent right hemicolectomy. Two weeks after the resection, we palpated a tumor mass in the same area. The abdominal CT images showed a tumor mass that was approximately 10 cm in size. The tumor rapidly enlarged, and the patient died of multiple organ failure. SCUC is a tumor with a high malignant potential. Radical treatment cannot be achieved by surgical therapy alone and hence further studies of effective adjuvant therapy would be required.

The molecular mechanism(s) for prostate cancer progression to androgen independence are poorly understood. We have recently shown that Foxa1 and Foxa2 proteins are differentially expressed in epithelial cells during murine prostate development, growth, and adult function. Currently, the role of Foxa proteins in prostate cancer development and progression is unknown. Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis. In vitro transient transfection, studies were performed to investigate Foxa/prostate-specific gene regulation. Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models. Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice. Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas. Foxa proteins were also differentially expressed in three prostate cancer cell lines. Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner. These results suggest that Foxa proteins are important in prostate carcinogenesis. In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence. As such, Foxa proteins may represent novel targets for therapeutic intervention., (Copyright 2005 Wiley-Liss, Inc.)

Study Design: We conducted a retrospective study to identify prognostic factors of patients with spinal metastases from lung cancer., Objective: To provide clinical data with strong association to the prognosis and to propose criteria determining indication of operation for spinal metastases., Summary of Background Data: To make a proper selection of patients for whom surgery is indicated, forecasting short-time survival after spinal metastases is very important. In the past, there has been no report of prognostic factors of patients with such metastases from this cancer., Methods: This study included 114 patients with spinal metastases of lung cancer. Tumors were histologically categorized as non-small cell lung cancer (NSCLC) in 94 patients and small cell lung cancer (SCLC) in 20 patients. We investigated prognostic factors after spinal metastases using Cox comparative hazard model and a preoperative prognostic score proposed by Tokuhashi. We also investigated the patients who underwent operation for spinal metastases from lung cancer in our hospital., Results: Multivariate analysis showed that the significant prognostic factors for survival after spinal metastases from NSCLC were performance status (PS), Ca, Alb. Among SCLC patients, Ca, Alb, and a history of chemotherapy were significant (P < 0.05) in univariate analysis. The score of Tokuhashi was not correlative to the survival period. Among the operated patients, postoperative PS was significant for the period of postoperative survival., Conclusion: PS, Ca, and Alb in NSCLC and Ca, Alb, and a history of chemotherapy in SCLC are useful for determining an indication of operation for spinal metastases from lung cancer.

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. The recent progress of scientific research has notably increased knowledge about biological events involved in lung cancer pathogenesis and progression, thanks to the use of molecular biology and immunohistochemistry techniques. Lots of the genetic alteration found in small cells lung cancer (SCLC) and in not small cells lung cancer (NSCLC) concern the expression of cell cycle genes, actually recognized as onco-suppressor genes and the lack of equilibrium between oncogenes and oncosuppressor genes. The present review of literature widely describes the cell cycle control, the lung cancer molecular pathogenesis, the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors, on the basis of the various hystological types too. Such data suggest the potential use of this knowledges in clinical practice both as prognostic factors and innovative therapeutic possibilities and they impose the necessity of new studies about cell cycle control and lung carcinogenesis.

From December 2004 until November 2005, 15 cases of endobronchial cancer presenting with 22 episodes of mechanical obstruction of the airway, difficulty in breathing, hemoptysis, severe coughing, obstructive pneumonia and identified recurrent atelectasis of the lungs. The cancer was removed rapidly, effectively and without complication by a technique of fiberoptic bronchoscopic electrocautery.

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Wide ranging experimental evidence suggests that human small-cell lung cancer (SCLC) has a number of molecular and subcellular characteristics normally associated with neurones. This review outlines and discusses these characteristics in the light of recent developments in the field. Emphasis is placed upon neuronal cell adhesion molecules, neurone-restrictive silencer factor, neurotransmitters/peptides and voltage-gated ion, especially Na(+) channels. The hypothesis is put forward that acquisition of such characteristics and the membrane 'excitability' that would follow can accelerate metastatic progression. The clinical potential of the neuronal characteristics of SCLC, in particular ion channel expression/activity, is discussed in relation to possible novel diagnostic and therapeutic modalities.

Small-cell lung cancer (SCLC) is a tobacco-related malignancy that usually presents in an extensive and therefore incurable stage. Although initially sensitive to platinum agent-based therapy, SCLC rapidly becomes refractory to chemotherapy, leading to disease recurrence and ultimately patient death. Treatment options following failure of first-line platinum agent-based therapy are limited. Small-cell lung cancer is characterized by molecular aberrancies such as overexpression of the antiapoptotic protein Bcl-2, which is regulated in part by the inhibitory IkappaB, a target of the ubiquitin-proteasome degradative pathway. Bortezomib is a proteasome inhibitor that can decrease Bcl-2 expression through diminished IkappaB degradation. Efforts to promote apoptosis in SCLC through the integration of bortezomib into therapy are under way.

The treatment of lung cancer--small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)--is a significant challenge in oncology. The best reported median survival remains near 1 year in advanced NSCLC despite several decades of steady improvement and extensive research with traditional chemotherapy drugs and novel compounds targeted to different aspects of tumor cell growth and function (such as the epidermal growth factor receptor). Extensive-stage SCLC survival is only slightly better. Novel "targeted" therapeutic agents hold promise, but cytotoxic therapy remains the backbone of treatment. Many new cytotoxic agents are currently in development. In this review, we will focus on 2 classes of cytotoxins: epothilones and topoisomerase I inhibitors. Epothilones are microtubule stabilizers with a mechanism of action similar to that of the taxanes, with preclinical activity superior to that of the taxanes. Phase I trials have been completed for patupilone and ixabepilone, and there are encouraging phase II data with ixabepilone in NSCLC. A phase II trial of patupilone is ongoing. The camptothecins, which are topoisomerase I inhibitors, have a long history in the treatment of lung cancer, but the currently available drugs, topotecan and irinotecan, have limitations. Gimatecan and other novel camptothecins have superior preclinical activity and promising phase I/II data in NSCLC and SCLC.