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Small Cell Lung Cancer

Small cell lung cancer (SCLC) is so called because under the microscope the cancer cells look small; it is also called oat cell cancer. SCLC accounts for just under approximately a 6th of all lung cancers and is usually caused by smoking. Incidence has been declining in countries where there have been reductions in the number of people who smoke.

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Lung Cancer

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Abe Y, Tanaka N
The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy.
Biomed Res Int. 2016; 2016:7969286 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

Ao Z, Yu S, Qian P, et al.
Tumor angiogenesis of SCLC inhibited by decreased expression of FMOD via downregulating angiogenic factors of endothelial cells.
Biomed Pharmacother. 2017; 87:539-547 [PubMed] Related Publications
Fibromodulin (FMOD), an ECM small leucine-rich proteoglycan (SLRP), was reported to promote angiogenesis not only during wound healing, but also in optical and cutaneous angiogenesis-dependent diseases. However, whether it plays important roles in tumor angiogenesis remains unclear. To explore the role of FMOD in tumor angiogenesis of human small cell lung cancer (SCLC), initially the study analyzed the relationship of FMOD expression in cancer tissues of SCLC with clinical characteristics. The analysis revealed that the positive FMOD expression was significantly associated with extensive stage of SCLC and higher vascular density. In mouse models, xenograft tumors developed with FMOD-silenced H446 cells (H446-shFMOD) exhibited slowed growth rate, decreased microvessel density, and reduced blood perfusion related to that of controls (H446-shCON). Additionally, compared with that of controls, the decreased secretion of FMOD in conditioned medium (CM) from H446-shFMOD inhibited proliferation, migration, and invasion of human umbilical vessel endothelial cells (HUVECs). Moreover, the decreased secretion of FMOD downregulated the expression of VEGF, TGF-β1, FGF-2, and PDGF-B in HUVECs. The findings strongly suggested that the autocrine FMOD of cancer cells may promote tumor angiogenesis of SCLC by upregulating the expression of angiogenic factors that act in concert to facilitate the angiogenic phenotype of endothelial cells as a proangiogenic factor. Therefore, silencing FMOD may be a potentially clinical therapy for repressing tumor angiogenesis.

Chang SM, Christian W, Wu MH, et al.
Novel indolizino[8,7-b]indole hybrids as anti-small cell lung cancer agents: Regioselective modulation of topoisomerase II inhibitory and DNA crosslinking activities.
Eur J Med Chem. 2017; 127:235-249 [PubMed] Related Publications
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Intriguingly, the substituent at N(11) (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N(11)-Me derivatives predispose to induce DNA crosslinks, whereas N(11)-H derivatives potently inhibit Topo II. Computational analysis implicates that N(11)-Me restrict the torsion angles of the two adjacent OH on pyrrole resulting in a favorable of DNA cross-linking. Among these hybrids, compound 17a with N(11)-H is more effective than cisplatin and etoposide, but as potent as irinotecan, against the growth of SCLC H526 cells in xenograft model.

Zheng Y, Li X, Jiang Y, et al.
Promoter hypermethylation of Wnt inhibitory factor-1 in patients with lung cancer: A systematic meta-analysis.
Medicine (Baltimore). 2016; 95(49):e5433 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Promoter hypermethylation of Wnt inhibitory factor-1 (WIF-1)-a tumor suppressor gene-has been detected in several types of human tumors. However, the association between WIF-1 promoter hypermethylation and lung cancer remains to be elucidated. Therefore, we conducted this study to evaluate the clinical significance of WIF-1 promoter hypermethylation in lung cancer.
METHODS: A comprehensive literature search was conducted to obtain eligible studies. The combined odds ratios (ORs) or hazard ratios and 95% confidence intervals were used to estimate the strength of associations.
RESULTS: A total of 8 eligible publications with 626 cases and 512 controls were included in our study. The combined ORs revealed that WIF-1 promoter hypermethylation was significantly higher in lung cancer than in controls (OR 10.53, P < 0.001). Moreover, WIF-1 promoter hypermethylation was significantly associated with smoking behavior (OR 1.88, P = 0.002). No significant correlation was found between WIF-1 promoter hypermethylation and sex status, age status, tumor stage, and pathological types in cancer. Multivariate analysis results indicated the absence of correlation between WIF-1 promoter hypermethylation and with relapse-free survival and overall survival. Subgroup analysis by sample type demonstrated that promoter hypermethylation of WIF-1 was significantly associated with an increased risk of lung cancer in the tissue (OR 7.89, P < 0.001), blood (OR 21.83, P = 0.034), and pleural effusion subgroups (OR 157.43, P = 0.001).
CONCLUSIONS: Promoter hypermethylation of WIF-1 may play a crucial role in lung cancer carcinogenesis. It may be a noninvasive biomarker using blood or pleural effusion detection. WIF-1 promoter hypermethylation is correlated with smoking behavior, but not with sex status, age status, tumor stage, pathological types, and the prognosis of lung cancer patients in terms of relapse-free survival and overall survival. More investigations, including a larger number of subjects, are required to further confirm the findings of our analysis.

Lee D, Rho JY, Kang S, et al.
CT findings of small cell lung carcinoma: Can recognizable features be found?
Medicine (Baltimore). 2016; 95(47):e5426 [PubMed] Free Access to Full Article Related Publications
The purpose of this study was to clarify the recognizable computed tomography (CT) features of small cell lung carcinoma (SCLC).Contrast enhanced CT scans were reviewed retrospectively for mass location, mediastinal extension, and other concomitant findings in 142 patients with pathologically proven SCLC. SCLC was classified into hilar mass only (type I), hilar mass with ipsilateral mediastinal extension (type II), hilar mass with bilateral mediastinal extension (type III), and peripheral mass (type IV). When mediastinal lymphadenopathy (m-LAP) was indistinguishable from a hilar mass, we defined it as a mediastinal conglomerate mass (m-CM). Type IIa or IIIa had ipsilateral or bilateral m-LAP and type IIb, IIIb or IIIc had ipsilateral or bilateral m-CM.Type I (n = 8, 5.6%), type II (n = 58, 40.8%), type III (n = 55, 38.8%), and type IV (n = 21, 14.8%) were manifested. The combination of a hilar mass and m-CM was found in 68 patients (47.9%). Type IV masses showed lobulation in 11, microlobulation in 4, both lobulated and irregular margins in 4, and spiculation in 2. A total of 120 patients (84.5%) had a bronchial stenosis/obstruction; single (n = 52) and 2 or more (n = 68). Ninety-five patients (67.0%) had vascular invasion including main/lobar pulmonary artery and superior vena cava, and 55 (38.7%) had pleural effusion and/or pleural nodules. Concomitant parenchymal findings (n = 92, 64.8%) were noted: contiguous consolidation/nodule (n = 45), hematogeneous spread (n = 32), lymphangitic spread (n = 21), obstructive pneumonia (n = 22), and obstructive atelectasis (n = 14).In conclusion, the recognizable CT features of SCLC were a hilar mass with m-CM. Most of the hilar masses showed 2 or more bronchial stenoses/obstructions. Most cases of peripheral SCLC manifested as a lobulated mass rather than a spiculated mass. Vascular invasion and concomitant parenchymal findings were observed commonly.

Luo Y, Tong L, Meng H, et al.
MiR-335 regulates the chemo-radioresistance of small cell lung cancer cells by targeting PARP-1.
Gene. 2017; 600:9-15 [PubMed] Related Publications
The role of miR-335 in the regulation of chemosensitivity and radiosensitivity of small cell lung cancer (SCLC) was investigated. miR-335 was significantly downregulated in multi-drug-resistant SCLC H69AR and H446DDP cells compared with parental cells as detected by qRT-PCR. Then, we demonstrated the negative correlation between miR-335 expression and the chemo-radiosensitivity of SCLC cells, including cell proliferation, cell clonality and cell apoptosis. In addition, miR-335 overexpression inhibited cell migration in vitro and tumor growth in vivo, whereas inhibition of miR-335 promoted cell migration and tumor growth. The underlying mechanism was further studied. Poly [ADP-ribose] polymerase 1 (PARP-1) was identified as a direct target gene of miR-335 in SCLC by bioinformatics analysis and validated via luciferase reporter assay. Overexpression of miR-335 decreased the expression of PARP-1 mRNA and protein, and NF-κB protein levels were correspondingly downregulated, thus regulating the chemo-radiosensitivity of SCLC. Taken together, these findings indicate that miR-335 may serve as a critical regulator of chemo-radiotherapy resistance in SCLC and a new potential therapeutic target.

Inomata M, Hayashi R, Tokui K, et al.
Lactate dehydrogenase and body mass index are prognostic factors in patients with recurrent small cell lung cancer receiving amrubicin.
Tumori. 2016; 102(6):606-609 [PubMed] Related Publications
AIMS AND BACKGROUND: Amrubicin monotherapy can be an effective treatment option for patients with recurrent small cell lung cancer (SCLC). We conducted this retrospective study to investigate the prognostic factors in patients with recurrent SCLC receiving amrubicin monotherapy.
METHODS: The associations between survival and clinical data, including the performance status, body mass index (BMI), plasma lactate dehydrogenase (LDH) level, and plasma neuron-specific enolase level, were evaluated in patients with recurrent SCLC, and a subset analysis of patients with platinum-resistant disease was conducted.
RESULTS: In all, 37 patients were evaluated. The median survival from the date of initiation of amrubicin monotherapy was 9.1 months (95% confidence interval 4.7-12.0 months). Multivariate analysis using a Cox proportional hazard model identified the plasma LDH level (p = 0.049), BMI (p = 0.031), and platinum resistance (p = 0.032) as independent factors associated with survival. The same associations were also observed in the subset of patients with platinum-resistant disease.
CONCLUSIONS: Our findings suggest that the plasma LDH level and BMI may be useful prognostic factors in patients with SCLC receiving amrubicin monotherapy, including patients with platinum-resistant disease.

Ito T, Kudoh S, Ichimura T, et al.
Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1.
Hum Cell. 2017; 30(1):1-10 [PubMed] Related Publications
Small cell lung cancer (SCLC) is one of the most malignant neoplasms in common human cancers. The tumor is composed of small immature-looking cells with a round or fusiform shape, which possesses weak adhesion features among them, suggesting that SCLC shows the morphological characteristics of epithelial to mesenchymal transition (EMT). SCLC is characterized by high metastatic and recurrent rates, sensitivity to the initial chemotherapy, and easy acquirement of chemoresistance afterwards. These characters may be related to the EMT phenotype of SCLC. Notch signaling is an important signaling pathway, and could have roles in regulating neuroendocrine differentiation, proliferation, cell adhesion, EMT, and chemoresistance. Notch1 is usually absent in SCLC in vivo, but could appear after chemotherapy. Notch1 can enhance cell adhesion by induction of E-cadherin in SCLC, which indicates mesenchymal to epithelial transition. On the other hand, achaete-scute complex homologue 1 (ASCL1), negatively regulated by Notch signaling, is a lineage-specific gene of SCLC, and functions to promote neuroendocrine differentiation as well as EMT. ASCL1-transfected adenocarcinoma cell lines induced neuroendocrine phenotypes and lost epithelial cell features. SCLC is characterized by neuroendocrine differentiation and EMT-like features, which could be produced by inactive Notch signaling and ASCL1 expression. In addition, chemical and radiation treatments can activate Notch signaling, which suppress neuroendocrine differentiation and induces chemoradioresistance, accompanied by secession from EMT. Thus, the status of Notch signaling and ASCL1 expression may determine the cell behaviors of SCLC partly through modifying EMT phenotypes.

Peng J, Wang Q, Liu H, et al.
EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway.
Tumour Biol. 2016; 37(9):11959-11971 [PubMed] Free Access to Full Article Related Publications
Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC. We observed that overexpression of EPHA3 in SCLC cells decreased chemoresistance by increasing apoptosis and inducing G0/G1 arrest, accompanied by reduced phosphorylation of PI3K/BMX/STAT3 signaling pathway. Knockdown of EPHA3 expression generated a resistant phenotype of SCLC, as a result of decreased apoptosis and induced G2/M phase arrest. And re-expression of EPHA3 in these cells reversed the resistant phenotype. Meanwhile, increased phosphorylation of PI3K/BMX/STAT3 signaling pathway was observed in these cells with EPHA3 deficiency. Notably, both PI3K inhibitor (LY294002) and BMX inhibitor (LFM-A13) impaired the chemoresistance enhanced by EPHA3 deficiency in SCLC cell lines. Furthermore, EPHA3 inhibited growth of SCLC cells in vivo and was correlated with longer overall survival of SCLC patients. Thus, we first provide the evidences that EPHA3 is involved in regulating the MDR of SCLC via PI3K/BMX/STAT3 signaling and may be a new therapeutic target in SCLC.

Rossetti C, Levernæs MC, Reubsaet L, Halvorsen TG
Evaluation of affinity-based serum clean-up in mass spectrometric analysis: Plastic vs monoclonal antibodies.
J Chromatogr A. 2016; 1471:19-26 [PubMed] Related Publications
Mass spectrometric assays are now of great relevance for trace compound analysis in complex matrices such as serum and plasma samples. Especially in the quantification of low abundant protein-biomarkers, the choice of the sample preparation is crucial. In the present paper immunocapture and Molecular Imprinted Polymers (MIPs) have been applied in the determination of pro-gastrin-releasing peptide, a Small Cell Lung Cancer marker. These affinity-based techniques were compared in terms of matrix effect, limits of detection, repeatability and extraction specificity. In addition, protein precipitation was included for comparison as it is a typical sample preparation method of biological matrices. The results highlighted differences in the methods' performance and specificity, strongly affecting the outcome of the mass spectrometric determination. Plastic and monoclonal antibodies confirmed to be sensitive and specific sample preparations able to determine ProGRP at clinical relevant concentration, although only the use of monoclonal antibodies allowed the reliable quantification of ProGRP at reference levels (8pM). In addition better insight in the specificity of the three sample preparation techniques was gained. This might also be of interest for other biological applications.

Masel EK, Schur S, Nemecek R, et al.
Palliative care units in lung cancer in the real-world setting: a single institution's experience and its implications.
Ann Palliat Med. 2017; 6(1):6-13 [PubMed] Related Publications
OBJECTIVE: Palliative care plays a crucial role in the overall management of patients with advanced lung cancer and was shown to lead to clinically meaningful improvement in quality of life, less aggressive endof-life care, and potentially prolonged survival. Here we summarize our single institution experience on palliative care in patients with lung cancer.
METHODS: The data of patients with lung cancer treated at the palliative care unit of the Medical University of Vienna between June 2010 and March 2013 were retrospectively reviewed. Patient characteristics, reasons for admissions, treatment as well as interventions during hospitalization, and clinical outcomes were determined.
RESULTS: The study enrolled 91 lung cancer patients, who represented 19.8% of the 460 patients admitted to the palliative care unit. They had the following clinical characteristics: 39% females, 61% males; median age 62 years; median Karnofsky performance status 50%, 92% metastatic disease, 74% non-small cell lung cancer (NSCLC), 19% small-cell lung cancer (SCLC), 7% neuroendocrine carcinomas of the lung. Primary reasons for admission were deterioration of performance status in 40%, uncontrolled cancer-related pain in 38%, dyspnea in 13%, and psychosocial factors in 8% of the patients. Median duration of hospitalization was 16 days (range, 1-101 days). Improvement or stabilisation of tumor-related symptoms was achieved in 25% of the patients. Seventy-five percent of all patients died during their first admission. Their median survival from primary diagnosis until death was 16 months (95% confidence interval, 13.7-18.3 months).
CONCLUSIONS: Patients with lung cancer admitted to the palliative care unit had late-stage disease. In order to provide early palliative care, the management of lung cancer patients should guarantee access to ambulatory care, inpatient care and home care as well as cooperation and communication between oncologists and palliative care physicians.

Tong L, Luo Y, Wei T, et al.
KH-type splicing regulatory protein (KHSRP) contributes to tumorigenesis by promoting miR-26a maturation in small cell lung cancer.
Mol Cell Biochem. 2016; 422(1-2):61-74 [PubMed] Related Publications
KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein that has a role in tumorigenesis of small cell lung cancer. The KHSRP protein level was shown to be significantly increased in small cell lung cancer (SCLC) tumor tissues compared with normal lung tissues by immunohistochemical staining. Moreover, KHSRP protein levels were strongly associated with T stage in patients with SCLC. Using in vitro assays, we found that knockdown of the KHSRP gene inhibited cell proliferation and increased cell apoptosis but had no effect on cell migration and invasion. We also showed that down-regulation of the KHSRP gene suppressed tumor growth in vivo. Further analyses indicated that KHSRP was involved in miR-26a maturation and inhibited the expression of PTEN in SCLC cells. Taken together, these findings suggested that KHSRP plays an important role in SCLC tumorigenesis and could be a potential novel therapeutic target for SCLC treatment.

Han N, Cheng QY, Chen B, et al.
PIK3CA Mutations in Resected Small Cell Lung Cancer.
Adv Clin Exp Med. 2016 May-Jun; 25(3):397-402 [PubMed] Related Publications
BACKGROUND: Despite advances in chemotherapy and radiotherapy in recent decades, the prognosis for small cell lung cancer (SCLC) patients is still poor. Targeted therapies in SCLC must be applied systemically to target not only the primary tumor but also metastases. The phosphatidylinositol 3-kinase (PI3K)/AKT pathways play a key regulatory function in the survival, proliferation, energy metabolism and cellular architecture advantages of malignant cells. The phosphatidylinositol 3-kinase catalytic α (PIK3CA) gene, which encodes the p110α catalytic subunit, plays a key role in the activation of AKT downstream signaling and mammary tumor progression. More than 75% of PIK3CA mutations are clustered in the helical (exon 9) and catalytic domains (exon 20). There have been very few studies reporting the PIK3CA mutations status of patients with SCLC who have undergone surgical treatment in mainland China.
OBJECTIVES: The aim of the study was to investigate the PIK3CA mutation in SCLC.
MATERIAL AND METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing technology was used to detect the PIK3CA mutation in 14 cases of retrospectively collected SCLC patients who underwent surgical treatment at Zhejiang Cancer Hospital, Hangzhou, PRC, between 2002 and 2010.
RESULTS: The research revealed no mutations in exons 9 and 20 of the PIK3CA gene. A nucleotide alteration of A1634C (E545A) of exon 9 turned out to be a pseudogene-positive, because the mutation disappeared when near-duplicate detection was employed.
CONCLUSIONS: The incidence of PIK3CA mutation is low in SCLC patients, and the pseudogene-positive alteration of A1634C is prone to occur in exon 9 of PIK3CA mutations in human cancers.

Horie M, Saito A, Ohshima M, et al.
YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer.
Cancer Sci. 2016; 107(12):1755-1766 [PubMed] Free Access to Full Article Related Publications
Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter-individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network-defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete-scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.

Lee JH, Jeong JS, Kim SR, Lee YC
Small cell carcinoma of the pyriform sinus successfully treated with concurrent chemo-radiotherapy: A case report.
Medicine (Baltimore). 2016; 95(36):e4759 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary small cell carcinomas (SCCs) are uncommon in extrapulmonary sites and account for only 2.5% to 5.0% of all SCCs. SCCs in the pyriform sinus are rare and there is little information regarding this disease, especially on therapeutics. Herein, we present a case of successfully treated SCC in the right pyriform sinus that occurred in a patient with small cell lung carcinoma (SCLC) that completely resolved 4 years prior.
METHODS: A 1.5 × 1.5-cm mass in the right pyriform sinus was detected on imaging studies in a 71-year-old male at a regular check-up visit after being in remission from SCLC.
RESULTS: Based on histologic examination and immunohistochemistry, the tumor in the right pyriform sinus was diagnosed as an extrapulmonary SCC. Chemo-radiotherapy was applied to the SCC of the pyriform sinus with a regimen of etoposide and cisplatin. The patient exhibited complete response to treatment and has been disease free for 11 months.
CONCLUSION: This interesting case shows that chemotherapy with concurrent radiation may be an effective therapeutic modality for localized extrapulmonary SCC similar to localized SCLC, which is treated with concurrent chemo-radiotherapy as the standard therapeutic option.

Waheed W, Boyd J, Khan F, et al.
Double trouble: para-neoplastic anti-PCA-2 and CRMP-5-mediated small fibre neuropathy followed by chorea associated with small cell lung cancer and evolving radiological features.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Patients with Purkinje cell cytoplasmic autoantibody type 2 (PCA-2) and collapsin response-mediator protein-5 (CRMP-5) autoantibody can present with multifocal elements of encephalomyeloneuropathy. Except for an anecdotal report, case descriptions of paraneoplastic small fibre neuropathy are lacking. We report paraneoplastic small fibre neuropathy followed by chorea associated with small cell lung cancer. A man aged 57 years with a 35 pack-year smoking history presented with painless subacute paresthesia and weight fluctuation. A non-length-dependent small fibre neuropathy was confirmed by skin biopsy. Further testing revealed positive serum PCA-2 and CRMP-5 autoantibodies, which after positron emission tomography-CT led to histological confirmation of a small cell lung cancer. Initially, abnormal MRI and cerebrospinal fluid studies suggested central nervous system (CNS) involvement which was subclinical; however, 6 months later during antitumour therapy, the patient became symptomatic with choreoathetosis. After combined chemoradiation as well as immunosuppressive and symptomatic therapies, the clinical course stabilised, although residual neurological deficits remained at follow-up a year later. Coexistent PCA-2 and CRMP-5 autoantibodies may occur in the setting of small fibre peripheral neuropathy and choreoathetosis and predict cancer type. Two paraneoplastic syndromes can present successively over months; subclinical CNS involvement with evolving basal ganglia abnormalities can be a paraneoplastic manifestation. In the appropriate clinical setting, paraneoplastic testing should be considered in patients presenting with small fibre neuropathy.

Halvorsen TO, Sundstrøm S, Fløtten Ø, et al.
Comorbidity and outcomes of concurrent chemo- and radiotherapy in limited disease small cell lung cancer.
Acta Oncol. 2016; 55(11):1349-1354 [PubMed] Related Publications
BACKGROUND: Many patients with limited disease small cell lung cancer (LD SCLC) suffer from comorbidity. Not all patients with comorbidity are offered standard treatment, though there is little evidence for such a policy. The aim of this study was to investigate whether patients with comorbidity had inferior outcomes in a LD SCLC cohort.
MATERIAL AND METHODS: We analyzed patients from a randomized study comparing two three-week schedules of thoracic radiotherapy (TRT) plus standard chemotherapy in LD SCLC. Patients were to receive four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders received prophylactic cranial irradiation (PCI). Comorbidity was assessed using the Charlson Comorbidity Index (CCI), which rates conditions with increased one-year mortality.
RESULTS: In total 157 patients were enrolled between May 2005 and January 2011. Median age was 63 years, 52% were men, 16% had performance status 2, and 72% stage III disease. Forty percent had no comorbidity; 34% had CCI-score 1; 15% CCI 2; and 11% CCI 3-5. There were no significant differences in completion rates of chemotherapy, TRT or PCI across CCI-scores; or any significant differences in the frequency of grade 3-5 toxicity (p = 0.49), treatment-related deaths (p = 0.36), response rates (p = 0.20), progression-free survival (p = 0.18) or overall survival (p = 0.09) between the CCI categories.
CONCLUSION: Patients with comorbidity completed and tolerated chemo-radiotherapy as well as other patients. There were no significant differences in response rates, progression-free survival or overall survival - suggesting that comorbidity alone is not a reason to withhold standard therapy in LD SCLC.

Chen S, Wu H, Lv N, et al.
LncRNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer.
Biomed Pharmacother. 2016; 82:583-8 [PubMed] Related Publications
LncRNA colon cancer-associated transcript 2 (CCAT2) was firstly discovered and found overexpressed in colorectal cancer, and identified as is oncogenic lncRNA. However, the significance of CCAT2 in small cell lung cancer (SCLC) remains unclear. The expression of CCAT2 in SCLC tissues and cell lines was detected, and the association between CCAT2 expression and clinicopathological factors was analyzed. Cell proliferation and invasion assays were conducted by using SCLC cell lines transfected with CCAT2-siRNA or NC-siRNA. In our results, CCAT2 expression was elevated in SCLC tissues and cell lines, and correlated with malignant status and poor prognosis of SCLC patients. Furthermore, knockdown of CCAT2 expression effectively suppressed SCLC cell growth and metastasis in vitro. In conclusion, CCAT2 serves as an oncogenic lncRNA, and an independent unfavorable prognostic factor in SCLC patients.

Toyokawa G, Takada K, Haratake N, et al.
Favorable Disease-free Survival Associated with Programmed Death Ligand 1 Expression in Patients with Surgically Resected Small-cell Lung Cancer.
Anticancer Res. 2016; 36(8):4329-36 [PubMed] Related Publications
BACKGROUND: The prognostic significance of programmed death ligand 1 (PD-L1) has been reported in non-small cell lung cancer; however, the significance of PD-L1 expression in patients with resected small-cell lung cancer (SCLC) remains to be clarified.
MATERIALS AND METHODS: Forty patients with SCLC whose resected specimens were available for immunohistochemistry for PD-L1 were evaluated to determine the association between its expression and the clinicopathological factors and prognosis.
RESULTS: Among 40 patients, PD-L1 was expressed in tumor cells (TCs) of six (15%), tumor-infiltrating cells (ICs) of 16 (40%), and TCs and/or ICs cells of 18 (45%) patients. Patients with PD-L1-positve ICs and TCs and/or ICs exhibited significantly longer disease-free survival than those without PD-L1-expression (hazard ratio (HR)=0.268; 95% confidence interval (CI)=0.100-0.645; p=0.003 and HR=0.301; 95% CI=0.118-0.702; p=0.005, respectively).
CONCLUSION: This study provides important evidence on the prognostic value of the PD-L1 expression in resected SCLC patients.

Käsmann L, Janssen S, Rades D
Karnofsky Performance Score, Radiation Dose and Nodal Status Predict Survival of Elderly Patients Irradiated for Limited-disease Small-cell Lung Cancer.
Anticancer Res. 2016; 36(8):4177-80 [PubMed] Related Publications
AIM: Elderly patients require special consideration in oncology treatment. Small-cell lung cancer (SCLC) is a highly aggressive tumour with dismal prognosis. The present study focused on prognostic factors in elderly patients irradiated for limited-disease SCLC.
PATIENTS AND METHODS: In 36 patients aged ≥65 years, 11 factors were evaluated for the impact on survival, namely gender, Karnofsky performance score, body mass index, T-category, N-category, tobacco consumption, time from SCLC diagnosis to irradiation, smoking during irradiation, simultaneous chemotherapy, radiation dose and prophylactic cranial irradiation.
RESULTS: On multivariate analysis, Karnofsky performance score of >70 (p<0.001), N-category 0-2 (p≤0.001) and total radiation dose of >52 Gy (p=0.011) were significantly associated with better survival.
CONCLUSION: Significant predictors of survival in elderly patients irradiated for limited-disease SCLC were identified. A radiation dose of >52 Gy resulted in improved survival when compared to lower doses.

Alberts P, Olmane E, Brokāne L, et al.
Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports.
APMIS. 2016; 124(10):896-904 [PubMed] Related Publications
Oncolytic virotherapy is a recent addition to cancer treatment. Here, we describe positive treatment outcomes in three patients using Rigvir virotherapy. One of the patients is diagnosed with melanoma stage IV M1c, one with small cell lung cancer stage IIIA, and one with histiocytic sarcoma stage IV. The diagnoses of all patients are verified by histology or cytology. All patients started Rigvir treatment within a few months after being diagnosed and are currently continuing Rigvir treatment. The degree of regression of the disease has been determined by computed tomography. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 1 during Rigvir(®) treatment. Using current standard treatments, the survival of patients with the present diagnoses is low. In contrast, the patients described here were diagnosed 3.5, 7.0, and 6.6 years ago, and their condition has improved and been stabile for over 1.5, 6.5, and 4 years, respectively. These observations suggest that virotherapy using Rigvir can successfully be used in long-term treatment of patients with melanoma stage IV M1c, small cell lung cancer stage IIIA, and histiocytic sarcoma stage IV and therefore could be included in prospective clinical studies.

Nicholls L, Keir GJ, Murphy MA, et al.
Prophylactic cranial irradiation in small cell lung cancer: A single institution experience.
Asia Pac J Clin Oncol. 2016; 12(4):415-420 [PubMed] Related Publications
AIM: To compare patient demographics, prophylactic cranial irradiation (PCI) utilization and overall survival (OS) of patients with small cell lung cancer (SCLC) referred to a large tertiary center with those reported in large clinical trials.
PATIENTS AND METHODS: A retrospective review was conducted of consecutive patients with limited stage (LS) and extensive stage (ES) SCLC diagnosed at the Princess Alexandra Hospital between January 2008 and December 2013.
RESULTS: Two hundred and three patients with a mean age of 65.4 (±10.7) years were followed for a median duration of 7.6 months (range 0.5-76.5). At diagnosis, 129 (64%) patients had ES-SCLC, including 39 (19.2%) with cerebral metastases. Median OS in LS-SCLC patients receiving PCI was 18.8 months (0.9-69.4), compared with 8.2 months (0.1-34.4) in patients who did not receive PCI (P < 0.001). Median OS in the ES-SCLC cohort receiving PCI was 13.6 months (5.2-37.5) compared to 5.6 months (0.1-73.6) in patients who did not receive the therapy (P < 0.001). There was a significant improvement in intracranial disease-free survival of 7.1 months in patients with ES-SCLC who received PCI. Forty-two LS-SCLC patients (57%) did not receive PCI due to patient suitability.
CONCLUSIONS: In our SCLC cohort, median OS following PCI in LS-SCLC and ES-SCLC is comparable to published data. PCI use at our institution was lower than utilization rates in large meta-analyses, predominately due to poor chemotherapy tolerance and patient suitability. This may be more representative of patients treated in clinical practice rather than those recruited into large phase III trials.

Goel K, Ateeli H, Ampel NM, L'heureux D
Patient with Small Cell Lung Carcinoma and Suspected Right Upper Lobe Abscess Presenting with a Purulent Pericardial Effusion.
Am J Case Rep. 2016; 17:523-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Cardiac tamponade caused by pericardial effusion has a high mortality rate; thus, it is important to diagnose and treat this condition immediately. Specifically, bacterial pericarditis, although now very rare, is often fatal because of its fulminant process. CASE REPORT We present a case of a 61-year-old man with metastatic small cell lung cancer undergoing chemotherapy who presented with fatigue, poor appetite, and altered mental status. He was found to have a large-volume pericardial effusion with tamponade physiology. He underwent emergent pericardiocentesis. The pericardial effusion was nonmalignant, with cultures growing Streptococcus pneumoniae. It was only after his emergent pericardiocentesis that previous imaging from one month prior was able to be reviewed, which showed possible right upper lobe abscess. CONCLUSIONS Most pericardial effusions in cancer patients are related to their malignancy, either due to direct metastasis or secondary physiologic effects. This case is a unique example of a lung cancer patient presenting with a pneumococcal pericardial effusion, which in itself is a rare phenomenon. This case report demonstrates the importance of considering early antibiotic therapy in patients presenting with pericardial effusion, especially given the high mortality rates of infectious pericardial effusions.

Mahmoud O, Kwon D, Greenfield B, et al.
Intrathoracic extensive-stage small cell lung cancer: assessment of the benefit of thoracic and brain radiotherapy using the SEER database.
Int J Clin Oncol. 2016; 21(6):1062-1070 [PubMed] Related Publications
BACKGROUND: Extensive-stage small cell lung cancer (ESCLC) includes metastatic disease and locally advanced disease confined to the thorax that cannot be encompassed in a typical radiation portal. We assessed and then compared the benefits of thoracic radiotherapy (TRT) and/or brain radiotherapy (BRT) on overall survival (OS) between the intrathoracic (T-ESCLC) and metastatic (M-ESCLC) groups using the Surveillance Epidemiology and End Results database.
METHODS: TRT and BRT data were available for 10150 patients treated from 1988-1997. The T-ESCLC group included 1774 patients. The Kaplan-Meier method was used to estimate OS and the proportional hazards model was used to estimate OS hazard ratios for prognostic factors including age, gender, race, tumor size, T/N stage, TRT, and BRT.
RESULTS: The 2-year OS for T-ESCLC was 7.8 % compared to 3 % in the M-ESCLC group (p < 0.001). In the T-ESCLC group, TRT and BRT were delivered to 750 and 102 patients, respectively. The 2-year OS was 13 % in the TRT group compared to 4.1 % in the no-TRT group (p ≤ 0.001) and 22.5 % in the BRT group compared to 7 % in the no-BRT group (p < 0.001). In the M-ESCLC group, TRT and BRT were delivered to 3093 and 1887 patients, respectively. The 2-year OS was 4.4 % in the TRT group compared to 2.8 % in the no-TRT group (p < 0.001) and 4.3 % in the BRT compared to 2.6 % in the no-BRT group (p < 0.001). Age, gender, TRT and BRT were significant OS prognostic factors in both groups.
CONCLUSIONS: Our study suggests that T-ESCLC is a disease entity distinct from M-ESCLC. Prospective studies to determine whether TRT should be recommended for the thoracic-only subgroup are warranted.

Fernandez-Cuesta L, Perdomo S, Avogbe PH, et al.
Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer.
EBioMedicine. 2016; 10:117-23 [PubMed] Free Access to Full Article Related Publications
Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.

Denny SK, Yang D, Chuang CH, et al.
Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.
Cell. 2016; 166(2):328-42 [PubMed] Article available free on PMC after 14/07/2017 Related Publications
Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

Jamaati H, Baghaei P, Sharifianfard M, et al.
Risk Factors for Lung Cancer Mortality in a Referral Center.
Asian Pac J Cancer Prev. 2016; 17(6):2877-81 [PubMed] Related Publications
BACKGROUND: Lung cancer is one of the most common causes of death that is rising in many countries including Iran. This study aimed to determine the impact of factors on survival of lung cancer patients at a referral center of lung diseases in Tehran, Iran.
MATERIALS AND METHODS: A retrospective study was conducted on adult lung cancer cases admitted to a referral center for lung diseases from 2011 to 2015. Multivariate analysis was performed to determine the risk factors for all-cause mortality.
RESULTS: Of a total 933 patients with lung cancer, 53.4% died, 49.3% of them at the hospital. Overall median follow-up time was 7 months. The most common histological type of cancer was adenocarcinoma with a 13 month median survival time. Age ≥55 and smoking remained significant for all-cause mortality on Cox analysis, whereas gender was not.
CONCLUSIONS: The survival of lung cancer patients is poor and the patients with history of smoking and age ≥55 are at increased risk of death. Having a large hospital-based registry provides a good measurement of prognostic statistics for lung cancer. Further investigations are necessary to establish reasons for mortality.

Käsmann L, Janssen S, Rades D
Prognostic Factors Including the Expression of Thyroid Transcription Factor 1 (TTF1) in Patients Irradiated for Limited-disease Small Cell Lung Cancer.
Anticancer Res. 2016; 36(7):3499-503 [PubMed] Related Publications
AIM: To investigate the impact of tumor-cell expression of thyroid transcription factor 1 (TTF1) on outcomes after irradiation of limited-disease small cell lung cancer (LD-SCLC).
PATIENTS AND METHODS: TTF1 expression plus eight factors were evaluated in 32 patients for locoregional recurrence-free survival (LRFS), metastases-free survival (MFS) and overall survival (OS). These factors included age, gender, Karnofsky performance score (KPS), T- and N-category, respiratory insufficiency, smoking during radiotherapy and hemoglobin levels.
RESULTS: On univariate analysis of LRFS, no factor achieved significance. Improved MFS was associated with KPS >70 (p=0.029), N0-2 (p=0.003), no respiratory insufficiency (p=0.029) and non-smoking states (p<0.001) on univariate analysis, and N-category (p=0.015) and non-smoking (p<0.001) on multivariate analysis. On univariate analysis, OS was associated with KPS >70 (p<0.001), N0-2 (p=0.002), no respiratory insufficiency (p=0.008) and non-smoking (p=0.022). On multivariate analysis, KPS (p=0.008) and N-category (p=0.018) remained significant.
CONCLUSION: In contrast to other factors, TTF1-expression had no significant impact on outcomes after irradiation of LD-SCLC.

Takada K, Toyokawa G, Okamoto T, et al.
An Immunohistochemical Analysis of PD-L1 Protein Expression in Surgically Resected Small Cell Lung Cancer Using Different Antibodies and Criteria.
Anticancer Res. 2016; 36(7):3409-12 [PubMed] Related Publications
BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression in lung cancer appears to be important in immunotherapy, as its expression can predict responses to programmed cell death-1 (PD-1)-blocking antibodies. However, a definitive antibody and cut-off value for PD-L1 expression are urgently needed.
MATERIALS AND METHODS: The PD-L1 expression in 40 surgically resected small cell lung cancer (SCLC) specimens was evaluated by immunohistochemistry (IHC) with three different antibodies: clones E1L3N, 28-8, and SP142, and using three different evaluations: the Allred score, 1% cut-off, and 5% cut-off.
RESULTS: The percentage of tumors with positive PD-L1 expression was inconsistent in the IHC evaluations using the Allred score and 1% cut-off. However, the IHC evaluations using the 5% cut-off showed similar rates of expression using the three different antibodies.
CONCLUSION: The results of this study provided detailed evidence on the frequency of PD-L1 expression in surgically resected SCLC, which may be a useful reference for identifying patients with PD-L1-expressing SCLC.

Bourgeois S, Van Den Berghe I, De Geeter F
Incidental finding of silent appendicitis on (18)F-FDG PET/CT in a patient with small cell lung adenocarcinoma.
Hell J Nucl Med. 2016 May-Aug; 19(2):164-6 [PubMed] Related Publications
We report the incidental diagnosis of acute asymptomatic appendicitis on a fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET/CT) performed for staging of a non small cell lung carcinoma. The patient was asymptomatic and laboratory tests were normal. The case illustrates: a) the possibility to diagnose appendicitis on (18)F-FDG PET/CT and b) the possibility of silent acute appendicitis, although this is a rare occurrence.

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