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.

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.

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.

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.

Calcium spike electrogenesis and other electrical activity in continuously cultured small cell carcinoma of the lung.

Spike electrogenesis, local depolarizing and hyperpolarizing responses, spontaneous rhythmic firing, and alternating resting potentials were measured in cells from a continuously cultured small cell carcinoma of the lung. Spike generation was blocked by MnCl2. In view of this evidence for calcium-spike electrogenesis and previous evidence of secretory activity in these cells, this cell line (DMS 53) can provide a model for the study of excitation-secretion behavior in human neoplastic cells.

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.

Fast, hungry and unstable: finding the Achilles' heel of small-cell lung cancer.

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.

The cigarette burden (measured by the number of pack-years smoked) negatively impacts the response rate to platinum-based chemotherapy in lung cancer patients.

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.

Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications--a retrospective study of 30 patients from the rare cancer network.

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.

Raised serum urea predicts for early death in small cell lung cancer.

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.

Long-term survival in paraneoplastic opsoclonus-myoclonus syndrome associated with small cell lung cancer.

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.

Diagnosing and managing patients with lung cancer.

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 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.

P-selectin mediates adhesion of platelets to neuroblastoma and small cell lung cancer.

Activated platelets and stimulated endothelial cells express P-selectin, an integral membrane protein receptor that binds monocytes and neutrophils. P-selectin mediates adhesion to glycoproteins with carbohydrate structures containing sialyl-Lewis X. Since many carcinoma cells also express these carbohydrate structures and are known to interact with platelets, we asked whether P-selectin may mediate this interaction. Both small cell lung cancer and neuroblastoma cell lines bound to activated platelets, and this interaction was blocked with inhibitory anti-P-selectin antibodies and by pretreatment of these cancer cells with neuraminidase or trypsin. Platelet binding to the small cell lung cancer cells was not inhibited with anti-GP IIb-IIIa antibody or Arg-Gly-Asp-Ser peptide. Pretreatment of the neuroblastoma cells with inhibitors of N-linked carbohydrate biosynthesis had little effect on binding to P-selectin, indicating that relevant carbohydrate ligand(s) may be O-linked. In addition, lipospheres containing P-selectin specifically bound to cryostat sections derived from a small cell lung tumor and two neuroblastoma tumors, but not to sections of normal lung. These observations demonstrate that P-selectin mediates binding of platelets to small cell lung cancer and to neuroblastoma and suggest a possible role for this lectin in metastasis.

Combination chemotherapy with paclitaxel and ifosfamide as the third-line regimen in patients with heavily pretreated small cell lung cancer.

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.

Sleep disturbances and impaired daytime functioning in outpatients with newly diagnosed lung cancer.

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

Extracellular matrix regulation of drug resistance in small-cell lung cancer.

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.

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.