Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas.

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.

Small cell carcinoma of the pancreas: a rare neuroendocrine tumour.

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.

Composite tumor of the larynx: A Case Report.

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.

Pleural small cell carcinoma with massive pleural effusion: A case report.

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.

Mixed large and small cell neuroendocrine carcinoma of the endometrium with serous carcinoma: A case report and literature review.

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.

Paraneoplastic seesaw nystagmus and opsoclonus provides evidence for hyperexcitable reciprocally innervating mesencephalic network.

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.

Autoimmune gastrointestinal dysmotility due to small cell lung cancer.

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.

An African American Man in His Late 30s With Lung Cancer Presenting With Persistent Cough and Hemoptysis.

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.

[Role of the Sonic Hedgehog pathway in thoracic cancers]. / Rôle de la voie Sonic Hedgehog dans les cancers thoraciques.

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.

Long-term survival of a patient with primary small cell neuroendocrine carcinoma of the maxillary sinus: a case report.

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.

SOX1 antibodies in Lambert-Eaton myasthenic syndrome and screening for small cell lung carcinoma.

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.

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer.

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.

Prior lung disease and lung cancer risk in an occupational-based cohort in Yunnan, China.

We used the data from a prospective cohort study among tin miners in Yunnan, China to investigate whether prior lung disease is a risk factor for lung cancer. Information on prior lung disease was obtained from baseline questionnaires. The Cox proportional hazards model was used to examine the relationship between prior lung disease and lung cancer risk. From 1992 to 2001, a total of 502 lung cancer cases were confirmed among 9295 cohort participants. Prior chronic bronchitis was associated with an increase in lung cancer risk with an adjusted HR of 1.50 (95% CI: 1.24-1.81). There was an increased risk of developing squamous cell carcinoma in the setting of prior chronic bronchitis and small cell carcinoma in association with asthma with an adjusted HRs of 1.57 (95% CI: 1.19-2.09) and 2.56 (95% CI: 1.38-4.75), respectively. This prospective study provides further evidence that prior chronic bronchitis correlates with increased lung cancer risk, especially for squamous cell carcinoma. Asthma is associated with increased risk of small cell lung carcinoma.

Phase II study of dose-intense chemotherapy with sequential topoisomerase-targeting regimens with irinotecan/oxaliplatin followed by etoposide/carboplatin in chemotherapy naive patients with extensive small cell lung cancer.

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).

Amrubicin at a lower-dose with routine prophylactic use of granulocyte-colony stimulating factor for relapsed small-cell lung cancer.

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.

Carboplatin plus etoposide for extensive stage small-cell lung cancer: an experience with AUC 6 doses of carboplatin.

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.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: results from 2 phase I studies.

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.

Blood-brain barrier defects associated with Rbp9 mutation.

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.

Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer.

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.