Prognostic Implications of Small Cell Lung Cancer Transcriptional Subtyping for CNS Metastases.

PURPOSE: Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). METHODS: Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS: Of 164 patients, most were either A+/N- or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N- (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N- (16% [95% CI, 7.5 to 27.9]) and A-/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N- and A-/N+, had worse OS compared with A+/N+ (A+/N-: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A-/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR). CONCLUSION: To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N- or A-/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

Survival impact of prophylactic cranial irradiation in small-cell lung cancer in the modern era of magnetic resonance imaging staging.

BACKGROUND: In the modern era of magnetic resonance imaging (MRI) staging, the benefit of prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC) has been controversial. This study evaluated the prognostic impact of PCI in patients with limited- or extensive-stage SCLC who had no brain metastases at diagnosis according to MRI. METHODS: Data from newly diagnosed patients in 2014 from the Korean Association for Lung Cancer Registry database were used. Patients with limited- or extensive-stage SCLC who had no brain metastases according to MRI were identified. Univariate and multivariate survival analyses were conducted to assess the prognostic association of PCI. RESULTS: Of 107 and 122 patients with limited- and extensive-stage SCLC, 24% and 14% received PCI, respectively. In the limited-stage SCLC group, the 2-year overall survival (OS) rates of patients who received PCI and those who did not were 50% and 29% (P = 0.018), respectively. However, there was no significant difference in OS for patients with extensive-stage SCLC (P = 0.336). After adjusting for other covariates, PCI was found to be associated with improved OS in the limited-stage SCLC group (P = 0.005). Based on the time-course hazard rate function plots in the limited-stage SCLC group, the OS benefit of PCI was maximized within the first year of follow-up. CONCLUSIONS: In the modern era of MRI staging, PCI might be beneficial for patients with limited-stage SCLC but not for those with extensive-stage SCLC. Further studies with a large sample size are needed to verify the prognostic association of PCI.

Managing Central Nervous System Spread of Lung Cancer: The State of the Art.

Brain metastases (BrM) are common in both non-small-cell lung cancer and small-cell lung cancer. Substantial progress in BrM management has occurred in the past decade related to advances in both radiation and medical oncology. Recent and ongoing radiation trials have focused on increasing the candidacy for focal therapy of BrM with stereotactic radiosurgery; reducing the toxicity and improving patient selection for whole brain radiotherapy; and, in small-cell lung cancer, evaluating brain magnetic resonance imaging surveillance without prophylactic cranial irradiation, hippocampal avoidance in prophylactic cranial irradiation and whole brain radiotherapy, and the role of upfront stereotactic radiosurgery for BrM. In medical oncology, the development of multiple tyrosine kinase inhibitors with encouraging CNS activity and emerging data on the CNS activity of immune checkpoint inhibitors in some patients have opened the door to novel systemic and multidisciplinary treatment strategies for the management of BrM. Future research will focus on more robust characterizations of the CNS activity of targeted therapy and immunotherapies, as well as optimal integration and patient selection for multidisciplinary strategies involving CNS-active drugs, radiation therapy, and CNS surveillance.

Aberrant Alteration of Circulating Lymphocyte Subsets in Small Cell Lung Cancer Patients Treated with Radiotherapy.

Purpose: The role of different circulating lymphocyte subsets, as well as their correlation with clinical characteristics of small cell lung cancer patients have not yet been fully understood. This study aims to evaluate the influence of the fluctuating absolute numbers of lymphocyte subpopulations in peripheral blood of patients with small cell lung cancer. Methods: The absolute counts and percentages of lymphocyte subsets in peripheral blood of 329 patients with small cell lung cancer were retrospectively analyzed. The numbers of CD3+, CD3+CD4+, and CD3+CD8+ T lymphocytes, CD3-CD19+ B lymphocytes, and CD3-CD16+CD56+ NK cells were evaluated by flow cytometry. Their relationship with the patients' clinical characteristics were statistically evaluated. Results: The CD4/CD8 values derived from the absolute number and percentage of CD3+CD4+ cells divided by CD3+CD8+ cells were identical (1.86 ± 0.99). There was no association between any of the lymphocyte subsets levels and age/sex of the 329 patients with small cell lung cancer. The patients with advanced stage had a reduction in CD3+ and CD3+CD4+ T cell counts and a decreased CD4/CD8 ratio. The levels of CD3+CD4+ T cells, CD3-CD19+ B cells, CD3-CD16+CD56+ NK cells, and CD4/CD8 ratio were associated with advanced tumor-node-metastasis stage. Patients who had undergone radiotherapy were characterized by lymphopenia with lower numbers of CD3+, CD3+CD4+, CD3+CD8+ T lymphocyte, B lymphocyte, NK cell, and CD4/CD8 ratio. The evaluation of individual CD4/CD8 ratio should be combined with other clinical parameters. Conclusions: Patients with small cell lung cancer have altered lymphocyte homeostasis. Lymphopenia was a long-lasting feature of the enrolled patients who were treated with radiotherapy. The available lymphocyte subsets levels might be used to manage the clinical treatment scheme.

Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study.

PURPOSE: Radiation dose received by the neural stem cells of the hippocampus during whole-brain radiotherapy has been associated with neurocognitive decline. The key concern using hippocampal avoidance-prophylactic cranial irradiation (HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of brain metastasis within the hippocampal avoidance zone. METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10 fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary end points included other FCSRT scores, quality of life (QoL), evaluation of the incidence and location of brain metastases, and overall survival (OS). Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. RESULTS: Participants' baseline characteristics were well balanced between the two groups. The median follow-up time for living patients was 40.4 months. Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%) compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P = .003). Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months. The incidence of brain metastases, OS, and QoL were not significantly different. CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive function in patients with SCLC. No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI.

Re-evaluation of prophylactic cranial irradiation in limited-stage small cell lung cancer: a propensity score matched analysis.

We attempted to re-evaluate the efficacy of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) with more recent data. A total of 179 patients with LS-SCLC received radical thoracic radiotherapy and chemotherapy at our institution between 1998 and 2018. One hundred twenty-eight patients who achieved complete response (CR), good partial response (PR), and PR without progression for at least for one year after initial therapy were enrolled in this study. These patients were divided into a PCI group (group A, n = 43), and a non-PCI group (group B, n = 85). Survival outcomes were retrospectively evaluated. Because several background factors differed significantly between groups A and B, propensity score (PS) matching was performed as 1:1 match of the two groups. Finally, we analyzed 64 patients (group A/B = 32/32). Median follow-up periods were 53 and 31 months in groups A and B, respectively. There were no significant differences between the groups' backgrounds. Two-year overall survival (OS) rates were 77% in group A and 62% in group B (p = 0.224). Two-year brain metastasis free survival (BMFS) rates were 85% in group A and 57% in group B (p = 0.008). The number of patients who underwent a brain imaging test for confirmation of no brain metastasis (BM) after radical thoracic radiotherapy and chemotherapy (before PCI) was 84 (group A/B = 32/52). A PS matched analysis for cases of pre-PCI brain imaging group, two-year OS rates for group A/B were 73/59% (p = 0.446). Two-year BMFS rates for group A/B were 91/52% (p = 0.021). Retrospectively, PS matched analysis revealed that adding PCI to LS-SCLC patients who achieved good thoracic control significantly improved BMFS, but OS did not improve.

Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry.

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce. PATIENTS AND METHODS: This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. RESULTS: With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8-10.2 months), with an estimated rate of 70.3% (95% CI 67.2-73.4%), 38.9% (95% CI 35.4-42.4%), and 14.8% (95% CI 11.8-17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1-2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. CONCLUSION: This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.

A new nomogram and risk classification system for predicting survival in small cell lung cancer patients diagnosed with brain metastasis: a large population-based study.

BACKGROUND: The prognosis of patients with small cell lung cancer (SCLC) is poor, most of them are in the extensive stage at the time of diagnosis, and are prone to brain metastasis. In this study, we established a nomogram combined with some clinical parameters to predict the survival of SCLC patients with brain metastasis. METHODS: The 3522 eligible patients selected from the SEER database between 2010 and 2015 were randomly divided into training cohort and validation cohort. Univariate and multivariate Cox regression analysis were used to evaluate the ability of each parameter to predict OS. The regression coefficients obtained in multivariate analysis were visualized in the form of nomogram, thus a new nomogram and risk classification system were established. The calibration curves were used to verify the model. And ROC curves were used to evaluate the discrimination ability of the newly constructed nomogram. Survival curves were made by Kaplan-Meier method and compared by Log rank test. RESULTS: Univariate and multivariate analysis showed that age, race, sex, T stage, N stage and marital status were independent prognostic factors and were included in the predictive model. The calibration curves showed that the predicted value of the 1- and 3-year survival rate by the nomogram was in good agreement with the actual observed value of the 1- and 3-year survival rate. And, the ROC curves implied the good discrimination ability of the predictive model. In addition, the results showed that in the total cohort, training cohort, and validation cohort, the prognosis of the low-risk group was better than that of the high-risk group. CONCLUSIONS: We established a nomogram and a corresponding risk classification system to predict OS in SCLC patients with brain metastasis. This model could help clinicians make clinical decisions and stratify treatment for patients.

Role of radiation in extensive stage small cell lung cancer: a National Cancer Database registry analysis.

The role of prophylactic cranial irradiation (PCI) and thoracic radiation therapy (TRT) in extensive-stage small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with extensive-stage small cell lung cancer with no brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive polychemotherapy, had other palliative radiation or had missing information. A propensity score-matched analysis was also performed. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received PCI and 21% received TRT. The addition of PCI and TRT improved median survival and survival at 1 and 2 years (p ≤ 0.05). The propensity score-matched analysis confirmed the same overall survival benefit with both PCI and TRT. This registry-based analysis of >1500 accredited cancer programs shows that PCI and TRT are not commonly utilized for extensive-stage small cell lung cancer patients who are treated with multiagent chemotherapy. The addition of PCI and TRT significantly improves overall survival in this otherwise poor prognostic group. Further research is needed to confirm the role of PCI and TRT, especially in the era of improved systemic therapy.

Lay abstract The role of radiation therapy in patients with metastatic small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with metastatic small cell lung cancer without brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive multiagent chemotherapy, had other palliative radiation or had missing information regarding treatment. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received radiation to the brain and 21% received radiation to their lungs. The addition of brain and lung radiation therapy improved median survival and survival at 1 and 2 years. The addition of prophylactic cranial irradiation and thoracic radiation therapy improves survival in extensive-stage small cell lung cancer. Future research is needed to evaluate the role of radiation in the era of chemoimmunotherapy.

Role of microRNAs in regulating cell proliferation, metastasis and chemoresistance and their applications as cancer biomarkers in small cell lung cancer.

Small cell lung cancer (SCLC), a smoking-related highly aggressive neuroendocrine cancer, is characterized by rapid cell proliferation, early metastatic dissemination, and early relapse due to chemoresistance to first-line platinum-doublet chemotherapy. Genomically, SCLC tumors show nearly universal loss of TP53 and RB1 tumor suppressor genes, while gene expression signature classifies them into 4 distinct subgroups based on the expression patterns of lineage transcription factors - ASCL1/ASH1, NEUROD1, YAP-1, and POU2F3. Due to the lack of targetable molecular alterations and clinically useful diagnostic, prognostic and predictive biomarker, there is insignificant progress in the therapeutic management of SCLC patients. Numerous studies have shown a significant involvement of non-coding RNAs in the regulation of cell proliferation, invasion and migration, apoptosis, metastasis, and chemoresistance in various human cancers. In this review, we comprehensively discuss the role of microRNAs (miRNAs) in regulating the aforementioned biological process in SCLC. For this, we searched the scientific literature and selected studies that have evaluated the role of miRNAs in the disease pathogenesis or as a cancer biomarker in SCLC. Our review suggests that several miRNAs are involved in the pathogenesis of SCLC mainly by regulating cell proliferation, metastasis, and chemoresistance. Few studies have also demonstrated the clinical utility of miRNAs in monitoring response to chemotherapy as well as in predicting survival outcomes. However, more in-depth mechanistic studies utilizing in vivo models and multicentric studies with larger patient cohorts are needed before the applications of miRNAs as therapeutic targets or as biomarkers are translated from the laboratory into clinics.

Differentiation of brain metastases from small and non-small lung cancers using apparent diffusion coefficient (ADC) maps.

BACKGROUND: Brain metastases are particularly common in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC showing a less  aggressive clinical course and lower chemo- and radio sensitivity compared to SCLC. Early adequate therapy is highly desirable and depends on a reliable classification of tumor type. The apparent diffusion coefficient is a noninvasive neuroimaging marker with the potential to differentiate between major histological subtypes. Here we determine the sensitivity and specificity of the apparent diffusion coefficient to distinguish between NSCLC and SCLC. METHODS: We enrolled all NSCLC and SCLC patients diagnosed between 2008 and 2019 at the University Medical Center Göttingen. Cranial MR scans were visually inspected for brain metastases and the ratio of the apparent diffusion coefficient (ADC) was calculated by dividing the ADC measured within the solid part of a metastasis by a reference ADC extracted from an equivalent region in unaffected tissue on the contralateral hemisphere. RESULTS: Out of 411 enrolled patients, we detected 129 patients (83 NSCLC, 46 SCLC) with sufficiently large brain metastases with histologically classified lung cancer and no hemorrhage. We analyzed 185 brain metastases, 84 of SCLC and 101 of NSCLC. SCLC brain metastases showed an ADC ratio of 0.68 ± 0.12 SD, and NSCLC brain metastases showed an ADC ratio of 1.47 ± 0.31 SD. Receiver operating curve statistics differentiated brain metastases of NSCLC from SCLC with an area under the curve of 0.99 and a 95% CI of 0.98 to 1, p < 0.001. Youden's J cut-point is 0.97 at a sensitivity of 0.989 and a specificity of 0.988. CONCLUSIONS: In patients with lung cancer and brain metastases with solid tumor parts, ADC ratio enables an ad hoc differentiation of SCLC and NSCLC, easily achieved during routine neuroradiological examination. Non-invasive MR imaging enables an early-individualized management of brain metastases from lung cancer. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00023016).

miR-31 Displays Subtype Specificity in Lung Cancer.

miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy. SIGNIFICANCE: These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/1942/F1.large.jpg.

Paraneoplastic acquired haemophilia A in extensive-stage small cell lung cancer (ES-SCLC) in the era of immunotherapy.

Small cell lung cancer (SCLC) is a deadly and rapidly progressive disease that can present with various paraneoplastic syndromes on initial workup. Acquired factor VIII (FVIII) deficiency, also known as acquired haemophilia A (AHA), has been identified as a rare paraneoplastic syndrome in SCLC. Here, we present a 61-year-old woman with a massive gastrointestinal bleed and prolonged activated partial thromboplastin time (PTT) in the emergency department. She was diagnosed with rare paraneoplastic AHA secondary to extensive-stage SCLC (ES-SCLC). She was treated with high-dose steroids and factor bypassing agents, which led to the resolution of bleeding and undetectable FVIII inhibitor levels. She was subsequently treated for ES-SCLC with carboplatin, etoposide and atezolizumab. This case report highlights a rare clinical presentation of paraneoplastic AHA that necessitates prompt recognition in patients with SCLC with ongoing bleeding and elevated PTT.

Hyaluronic Acid Correlates With Bone Metastasis and Predicts Poor Prognosis in Small-Cell Lung Cancer Patients.

Background: Hyaluronan (HA) is one of the essential elements of the extracellular matrix (ECM), involved in the onset of metastasis in various tumors. The interaction and binding of the ligand-receptor HA/cluster of differentiation-44 (CD44) regulate the physical and biochemical properties of the ECM, which correlates with an increased propensity toward metastasis and poor survival outcome. Our study aimed to explore HA for predicting metastasis and survival rate in patients with small-cell lung cancer (SCLC). Materials and Methods: This prospective cohort study recruited 72 patients with SCLC. Plasma HA and CD44 levels were assayed by enzyme-linked immunosorbent assay (ELISA) for 72 cases before initial systematic treatment (baseline samples), and plasma HA was detected via after-2-cycle-chemotherapy (A-2-C-CT) in 48 samples. Logistic regression analysis and the Cox proportional risk model were used to determine the independent predictors of distant metastasis and survival rate of patients. Results: Baseline plasma HA was notably associated with bone metastasis (BM) [OR (95% CI = 1.015 (1.006-1.024), p = 0.001]. Multivariate logistic regression analysis showed that baseline plasma HA was chosen as an independent predictor of BM. Either baseline HA or CD44 or both were associated with BM. Dynamic alteration of HA was notably associated with A-2-C-CT clinical efficacy. Multivariate Cox regression analysis in forward likelihood ratio showed that A-2-C-CT HA was an independent predictor of progression-free survival (PFS) and overall survival (OS). Conclusions: HA appears to be used as an independent predictive factor for BM, and the dynamic detection of HA can predict prognosis in SCLC patients. The mechanism of the HA/CD44 axis in BM of SCLC deserves further exploration.

Prognostic immunohistochemical markers for small cell lung cancer: A review.

BACKGROUND: Small Cell Lung Cancer (SCLC) is one of the most aggressive thoracic malignancies and has been very challenging in developing personalized medicine. While immunohistochemistry (IHC) markers have established role in pathology diagnosis of SCLC, it is particularly important to apply early and simple methods to effectively determine the prognosis. This study aimed to review and identify prognostic protein markers that have potential to be incorporated into clinical care for SCLC. METHODS: we systematically reviewed PubMed, Embase, Web of Science and Cochrane Library until October 19th, 2019 that reported prognostic IHC markers in SCLC. In this review, we focused on markers evaluated in at least two independent studies to compile the most forthcoming prognostic markers. RESULTS: According to their function in the tumor, including proliferation-related markers, growth suppression-related markers, invasion- and metastasis-related markers, apoptosis-related markers, angiogenesis-related markers, immune regulation-related markers. Extensive reports into informative tables based on sufficiencies of evidence were summarized as some easy-to-use literature reservoirs for further referring. CONCLUSIONS: Strong evidence supports that the 24 emerging markers or their combinations may be useful in predicting prognosis, helping personalized therapy decision-making for SCLC patients.

First Reported Case of Localized Extra-pulmonary Small Cell Carcinoma (EPSC) of the Esophagus Treated With Triple Therapy.

BACKGROUND/AIM: Early stage extra-pulmonary small cell carcinoma (EPSC) of the esophagus is very rare and is usually treated with chemo-radiation or surgical resection. CASE REPORT: A case of early stage small cell carcinoma of the esophagus that was treated with all three current modalities of chemotherapy, radiation, and surgery. To our best knowledge this is the first case treated with triple therapy. The patient is a 64-year-old male with increasing gastroesophageal reflux disease (GERD) symptoms. EGD biopsy of the mass showed small cell carcinoma. Metastatic work up was negative. Patient was treated with 6 cycles of a platinum-based agents and Etoposide along with radiation. Patient underwent distal esophagectomy. Patient is alive without evidence of recurrent disease at 20 months follow up. CONCLUSION: Currently there are no definite treatment recommendations, but we present a possible future option with good outcomes in patients who can tolerate triple therapy.