Squamous Cancer Research Articles

Bronchial artery chemoembolization with drug-eluting beads versus bronchial artery infusion followed by polyvinyl alcohol particles embolization for advanced squamous cell lung cancer: A retrospective study

PurposeTo analyze the efficacy and safety of bronchial arterial embolization (BACE) with drug-eluting beads (DEB) versus bronchial artery infusion (BAI) followed by polyvinyl alcohol (PVA) particle embolization for the treatment of advanced squamous cell lung cancer after the failure of systemic therapy. MethodThirty-six patients with advanced squamous cell lung cancer who underwent bronchial arterial interventional therapy were included in this retrospective study. The DEB group (n = 20) was treated with nedaplatin and DEB loaded with gemcitabine, and the PVA group (n = 16) BAI with nedaplatin and gemcitabine followed by embolization with PVA particles. The treatment efficacy and complications were analyzed. ResultsThe technical success rate was 100 %. The two groups were followed up for a median period of 8.9 months. The mean overall survival (OS) in the DEB group was 12.6 months (95 % CI:9.99–15.21), which was significantly longer than 8.14 months (95 % CI:6.07–10.2) in the PVA group (p = 0.007). The median progression-free survival (PFS) in the DEB group was 4.3 months (95 % CI:2.33–6.27), significantly longer than 3.2 months (95 % CI:2.55–3.85) in the PVA group (p = 0.030). The objective response rate (ORR) six months after the procedure was 50 % in the DEB group and 12.5 % in the PVA group. In the univariate and multivariate analyses, DEB-BACE was an independent prognostic factor for survival. Only grade 1 adverse events like fever, chest pain, and cough were seen. ConclusionsDEB-BACE may be a good choice for patients with advanced lung squamous cell carcinoma, as it could prolong OS and PFS without increasing adverse events.

Electrochemotherapy with intravenous bleomycin for heavily pre-treated vulvar cancer patients

ObjectiveThe management of vulvar cancer recurrences is complicated by patients’ advanced age and comorbidities. Bleomycin-based electrochemotherapy is a potential treatment option in this setting. However, no data on long-term outcomes...

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Actinic keratosis as a predictor of primary multiple synchronous squamous cell skin cancer: a clinical case

We present a clinical case of a primary multiple synchronous highly differentiated keratinizing squamous cell skin cancer in an 84-year old patient with multiple actinic keratosis and actinic cheilitis. The clinical case is unique for the simultaneous development of primary multiple squamous cell carcinoma of the tip of the nose and the vermilion zone of the lower lip in a patient with a past occupational and solar burden, a light phenotype, and signs of chronic photo injury the skin. Clinical, dermatoscopic and sonographic signs of keratotic actinic keratosis were identified in the patient and confirmed by pathomorphological examination. The risk factors for malignant transformation of actinic keratosis were found, such as multiple efflorescences and a long disease history. The malignant transformation of the actinic areas manifested as rapidly progressive ulceration zones more than 1 cm in diameter, pronounced hyperkeratosis, inflammation and infiltration of the underlying tissues, increased bleeding and pain. It is to be underlined that definitive and differential diagnosis requires pathomorphological assessment of the skin biopsy sample. This clinical case indicates that patients with multiple foci of actinic keratosis should be under a lifelong follow-up by dermatovenereologists, with mandatory treatment and prevention measure.

Common inherited variants of PDCD1, CD274 and HAVCR2 genes differentially modulate the risk and prognosis of adenocarcinoma and squamous cell carcinoma

BackgroundTo investigate the association between single nucleotide polymorphisms (SNPs) of PDCD1, CD274, and HAVCR2 genes with the risk and outcomes of non-small cell lung cancer (NSCLC) subtypes: squamous cell lung cancer (LUSC) and lung adenocarcinoma (LUAD).MethodsTaqMan SNP genotyping assays or polymerase chain reaction-restriction fragment length polymorphism methods were used to determine genotypes of: PDCD1: rs36084323, rs7421861, rs11568821, rs2227981, rs10204525; CD274: rs822335, rs10815225, rs17718883, rs2297136, rs4742098, rs4143815; HAVCR2: rs10057302, rs1036199. Among 383 NSCLC patients, 112 were diagnosed with LUAD and 116 with LUSC. The control group consisted of 433 unrelated, cancer-free subjects.ResultsA CC genotype of rs4143815 and GG genotype of rs4742098 were associated with two times higher risk of developing LUSC (CC vs. GG + GC, OR = 2.31; 95% CI = 1.32, 4.06; P = 0.003; GG vs. AA + AG, OR = 2.26; 95% CI = 1.17, 4.36; P = 0.016, respectively). Moreover, rs4143815 was an independent predictor of the age at diagnosis of LUAD. The carriers of C allele were diagnosed 4.81 years later (95% CI = 1.47, 8.15; P = 0.006) than patients with the GG genotype. The rs10057302 CA genotype was an independent predictor of overall survival in LUSC (adjusted HR = 0.13; 95% CI = 0.02, 0.93; P = 0.043). NSCLC carriers of rs11568821 T allele had almost double the risk of death (adjusted HR = 2.05; 95% CI = 1.28, 3.29; P = 0.003) compared to carriers of CC genotype.ConclusionsOur results provided additional evidence that SNPs of genes for PD-1, PD-L1 and TIM-3 differentially modulate the risk and prognosis of LUSC and LUAD.

Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma.

Cancer is a principal cause of death in the world, and providing a better quality of life and reducing mortality through effective pharmacological treatment remains a challenge. Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 µM, high selectively (SI > 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.

Efficacy and safety of anti-PD-1 antibody plus chemoradiotherapy in locally advanced esophageal squamous cancer.

To compare effects and adverse events of anti-programmed cell death protein 1 (anti-PD-1) antibody combined with chemoradiotherapy (CRT) and CRT alone as the initial treatment in locally advanced esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed locally advanced ESCC patients who received Anti-PD-1+CRT as initial treatment at 3 institutions. Primary outcomes of interest were progression-free survival (PFS) and overall survival (OS); secondary outcomes were objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and treatment-related adverse events (AEs) including immune-related adverse events (irAEs). At data cutoff, 81 patients were included (30 Anti-PD-1+CRT, 51 CRT). Median follow-up was 31.4 months. Anti-PD-1+CRT resulted in significant improvements in PFS (median, 18.6 vs. 11.8 months, HR 0.48 [95% CI, 0.29-0.80], P = 0.008), and OS (median, 27.7 vs. 17.4 months, HR 0.37 [95% CI, 0.22-0.63], P = 0.002), compared with CRT in ESCC. The ORR and DCR of patients treated with Anti-PD-1+CRT were also significantly higher than those treated with CRT (80.0% vs. 56.9%, P = 0.034), (100% vs. 82.4%, P = 0.023), respectively. Anti-PD-1+CRT had better durable response compared with CRT, with DoR (median,17.3 vs. 11.1 months, P = 0.022). Treatment-related adverse event incidence was similar between the two groups (any Grade, 93.3% vs. 92.2%; ≥Grade 3, 50.0% vs. 33.3%). Anti-PD-1 plus chemoradiotherapy demonstrated promising antitumor activity and was well tolerated in locally advanced ESCC.

Sleeve Lobectomy After Neoadjuvant Chemoimmunotherapy Versus Chemotherapy for Squamous Cell Lung Cancer: A Multicenter, Retrospective Study

IntroductionTo analyze the feasibility and efficacy of sleeve lobectomy after neoadjuvant immunotherapy in multicenter patients with squamous cell lung cancer. MethodsWe retrospectively identified patients who received neoadjuvant immunotherapy (n = 14) or chemotherapy alone (n = 33) at five thoracic surgery centers between 2018 and 2020. The primary end point was 30-day major complications. The secondary end point was major pathologic response. Multivariate analysis was performed with a log-binomial regression model adjusting potential risk factors. ResultsAll patients received induction therapy and underwent sleeve lobectomy without 90-day postoperative deaths. The distribution of age, sex, nutrition status, pulmonary and cardiac function, tumor stage, surgical approach, and location of the pulmonary lobe was well balanced between the two cohorts. In the immunotherapy cohort, two patients (14.3%) experienced a pulmonary major complication, whereas nine pulmonary major complications and one cardiac major complication (30.3%) occurred in the chemotherapy cohort (p = 0.302). ConclusionsNeoadjuvant immunotherapy in addition to chemotherapy did not increase 30-day risk of postoperative complications, and immunotherapy is a favorable factor affecting pathologic downstage and response. Therefore, sleeve lobectomy after induction chemoimmunotherapy appears safe and feasible.

Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer

AimsImmune checkpoint inhibitor (ICI) therapy has become a viable treatment strategy in bladder cancer. However, treatment responses vary, and improved biomarkers are needed. Crucially, the characteristics of immune cells remain understudied especially in squamous differentiated bladder cancer (sq-BLCA). Here, we quantitatively analysed the tumour-immune phenotypes of sq-BLCA and correlated them with PD-L1 expression and FGFR3 mutation status.Methods Tissue microarrays (TMA) of n = 68 non-schistosomiasis associated pure squamous cell carcinoma (SCC) and n = 46 mixed urothelial carcinoma with squamous differentiation (MIX) were subjected to immunohistochemistry for CD3, CD4, CD8, CD56, CD68, CD79A, CD163, Ki67, perforin and chloroacetate esterase staining. Quantitative image evaluation was performed via digital image analysis.ResultsImmune infiltration was generally higher in stroma than in tumour regions. B-cells (CD79A) were almost exclusively found in stromal areas (sTILs), T-lymphocytes and macrophages were also present in tumour cell areas (iTILs), while natural killer cells (CD56) were nearly missing in any area. Tumour-immune phenotype distribution differed depending on the immune cell subset, however, hot tumour-immune phenotypes (high density of immune cells in tumour areas) were frequently found for CD8 + T-cells (33%), especially perforin + lymphocytes (52.2%), and CD68 + macrophages (37.6%). Perforin + CD8 lymphocytes predicted improved overall survival in sq-BLCA while high PD-L1 expression (CPS ≥ 10) was significantly associated with higher CD3 + , CD8 + and CD163 + immune cell density and high Ki67 (density) of tumour cells. Furthermore, PD-L1 expression was positively associated with CD3 + /CD4 + , CD3 + /CD8 + and CD68 + /CD163 + hot tumour-immune phenotypes. FGFR3 mutation status was inversely associated with CD8 + , perforin + and CD79A + lymphocyte density.ConclusionsComputer-based image analysis is an efficient tool to analyse immune topographies in squamous bladder cancer. Hot tumour-immune phenotypes with strong PD-L1 expression might pose a promising subgroup for clinically successful ICI therapy in squamous bladder cancer and warrant further investigation.

Immunohistochemical assessment of possible anticancer effect mechanisms of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone in PDX models of lung cancer

Purpose of the study. Evaluation of the expression of immunohistochemical tumor markers Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43 when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in mice with xenographs of squamous cell lung cancer.Materials and methods. Subcutaneous PDX models of human squamous cell lung cancer were created in immunodeficient BALB/c Nude mice. A fragment of the patient’s tumor (3 × 3 × 3 mm) was implanted subcutaneously in the right thigh of a previously anesthetized mouse. 200 μl of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone was administered orally using a probe in 12 doses once every 3 days. All animals were divided into groups depending on the tropolone doses: experimental groups 2–5 with doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively. The control group received 1 % starch gel which was tropolone carrier. The animals were euthanized 36 days after the start of the substance administration, and the tumor tissue was isolated and prepared for the IHC study according to the standard protocol. IHC reactions were performed using antibodies for Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43.Results. Higher tropolone doses were associated with decreased expression of Ki-67, b-catenin, and the Bcl-2 protein, but increased expression of the P53 protein. The dosage of tropolone and expression of connexin 43 were directly proportional.Conclusion. Immunohistochemical analysis of expression of proteins in PDX models of human squamous cell lung cancer when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone showed the changes indicating its antitumor efficacy and suggesting a possible mechanism of action based on the activation of apoptosis.

Probabilistic canonical correlation analysis for sparse count data

Canonical correlation analysis (CCA) is a classical and important multivariate technique for exploring the relationship between two sets of continuous variables. CCA has applications in many fields, such as genomics and neuroimaging. It can extract meaningful features as well as use these features for subsequent analysis. Although some sparse CCA methods have been developed to deal with high-dimensional problems, they are designed specifically for continuous data and do not consider the integer-valued data from next-generation sequencing platforms that exhibit very low counts for some important features. We propose a model-based probabilistic approach for correlation and canonical correlation estimation for two sparse count data sets. Probabilistic sparse CCA (PSCCA) demonstrates that correlations and canonical correlations estimated at the natural parameter level are more appropriate than traditional estimation methods applied to the raw data. We demonstrate through simulation studies that PSCCA outperforms other standard correlation approaches and sparse CCA approaches in estimating the true correlations and canonical correlations at the natural parameter level. We further apply the PSCCA method to study the association of miRNA and mRNA expression data sets from a squamous cell lung cancer study, finding that PSCCA can uncover a large number of strongly correlated pairs than standard correlation and other sparse CCA approaches.
 Journal of Statistical Research 2022, Vol. 56, No. 1, pp. 73-98

Evaluation of PAX1/ST6GALNAC5 methylation as a triage test for cervical intraepithelial neoplasia and cervical cancer.

Aim: To identify DNA methylation markers for triage in a cohort of human papillomavirus-positive (HPV+) women. Methods: The methylation markers were identified and evaluated for the detection of cervical high-grade squamous intraepithelial lesions (HSILs) or cervical cancer (collectively referred to as 'HSIL+') in HPV+ women (n=692). Results: Combined PAX1/ST6GALNAC5 methylation testing yielded HSIL+ sensitivity of 0.838 and 0.818, with a specificity of 0.827 and 0.810, in the training and test sets, respectively. For cervical cancer, the specificity and sensitivity were 0.969 and 1.000 in the training set and 0.967 and 0.875 in the test set. Moreover, the combined marker methylation test (0.86; 77/90) was more sensitive than the cytology (0.31; 28/90) for HSIL+. Conclusion: The combined PAX1/ST6GALNAC5 marker may have clinical application for detecting HSIL+ in HPV+ women undergoing screening.

A Phase I/II Study of Necitumumab Plus Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non–Small Cell Lung Cancer Study: (NEJ048A/NEXUS)

BackgroundPlatinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non–small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin–bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC. Patients and MethodsIn phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II. ConclusionThis is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

Comparison of lymph node metastasis pattern from esophagogastric junction adenocarcinoma versus very low thoracic esophageal squamous cancer: a propensity-matched analysis.

The anatomical locations of esophagogastric junction adenocarcinoma (AEG) and very low thoracic esophageal squamous cell carcinoma (ESCC) are similar. This study aimed to evaluate the difference in lymph node metastasis (LNM) distribution between AEG and very low thoracic ESCC. Data from 156 Siewert I-II AEG patients and 120 ESCC patients with proximal edges located within 5 cm of the esophagogastric junction (EGJ) and underwent curative surgery from 2010 to 2015 were retrospectively analyzed using propensity score matching (PSM). Five or six baseline variables were included in PSM separately. All patients underwent curative transthoracic surgery and systematic lymphadenectomy. After PSM, LNM rates of major stations were compared using the chi-squared test or Fisher's exact test. After PSM was performed with covariates (age, sex, T stage, grade, tumor length), 60 pairs of patients were included. The lower mediastinal and total thoracic LNM rates of ESCC were significantly higher than those of AEG (18.3% vs. 3.3%, P=0.019; 25% vs. 3.3%, P=0.002). After further addition of the N stage as a variant to the previous PSM model, we found that the paracardial LNM distribution was significantly different between ESCC and AEG patients (36.1% vs. 19.7%, P=0.043). Among all tumor characteristics, only the T stage was positively correlated with paracardial LNM in ESCC (P=0.010), but not in AEG. In AEG, the median survival was poor for patients with thoracic LNM. Patients with very low thoracic ESCC exhibit stronger metastatic ability in the lower mediastinal and paracardial nodes than Siewert I-II AEG. However, the pathological metastasis of AEG in thoracic nodes was associated with poor survival outcomes.

Multistate Pharmacometric Model to Define the Impact of Second-Line Immunotherapies on the Survival Outcome of the IMpower131 Study.

Overall survival is defined as the time since randomization into the clinical trial to event of death or censor (end of trial or follow-up), and is considered to be the most reliable cancer end point. However, the introduction of second-line treatment after disease progression could influence survival and be considered a confounding factor. The aim of the current study was to set up a multistate model framework, using data from the IMpower131 study, to investigate the influence of second-line immunotherapies on overall survival analysis. The model adequately described the transitions between different states in patients with advanced squamous non-small cell lung cancer treated with or without atezolizumab plus nab-paclitaxel and carboplatin, and characterized the survival data. High PD-L1 expression at baseline was associated with a decreased hazard of progression, while the presence of liver metastasis at baseline was indicative of a high risk of disease progression after initial response. The hazard of death after progression was lower for participants who had longer treatment response, i.e., longer time to progression. The simulations based on the final multistate model showed that the addition of atezolizumab to the nab-paclitaxel and carboplatin regimen had significant improvement in the patients' survival (hazard ratio=0.75, 95% prediction interval: 0.61-0.90 favoring the atezolizumab + nab-paclitaxel and carboplatin arm). The developed modeling approach can be applied to other cancer types and therapies to provide a better understanding of efficacy of drug and characterizing different states, and investigate the benefit of primary therapy in survival while accounting for the switch to alternative treatment in the case of disease progression.

PP01.10 A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory (R/R) NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)

PP01.10 A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory (R/R) NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)

Role of the XPC Gene Expression in the Prevention of Oxidative and DNA Damage to Lung Squamous Carcinoma Cells

Background and Hypothesis: Xeroderma pigmentosum group C (XPC) is a DNA repair protein involved in the detection and repair of DNA damage caused by oxidative lesions through global genomic repair. Carcinogens, chemotherapeutics, and UV-lesions require repair of DNA by XPC. Exposure to one environmental toxin, cigarette smoke (CS), leads to cancer development and can worsen outcomes of those with cancer, however, the precise mechanisms and why susceptibility varies individually remains poorly understood. This study examines the role of XPC in cell survival in human lung squamous cancer cells (H520), and hypothesizes that XPC protects against DNA damage and cell death after exposure to cigarette smoke extracts (CSE).
 Methods: Lentiviral vector transduction for XPC knock-down (XPCKD) was completed in H520 cells. Transfection efficiency was measured by green fluorescence protein to determine multiplicity of infection (MOI); puromycin resistance was measured by CCK. XPC was targeted at two sites (Mission shRNA 118 and 119, Sigma), and gene knock-down efficiency determined by qRT-PCR. Survival of unmodified and H520-XPCKD cells to CSE exposure was determined by CCK and clonogenic survival assays.
 Results: Lentiviral knock-down decreased XPC gene expression by 68-78% in H520-XPCKD as measured by RT-qPCR, with protein knock-down confirmed by Western blot. There was increased susceptibility of H520-XPCKD to CSE with decreased cell survival in XPCKD compared to non-transduced H520 cells.
 Conclusion: XPC protects H520 cells against cell death due to exposure to cigarette smoke. Future studies will be performed to confirm the degree of protection and to determine the mechanism of XPC protective effect. These findings could be important for the discussion of risk factors with patients to understand the risks of smoking in patients with lung cancer and help physicians determine patient specific susceptibility.

Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT3

Squamous cell lung cancer maintains its growth through elevated glucose consumption, but selective glucose consumption inhibitors are lacking. Here, we discovered using a high-throughput screen new compounds that block glucose consumption in three squamous cell lung cancer cell lines and identified 79 compounds that block glucose consumption in one or more of these cell lines. Based on its ability to block glucose consumption in all three cell lines, pacritinib, an inhibitor of FMS Related Receptor Tyrosine Kinase 3 (FLT3) and Janus Kinase 2 (JAK2), was further studied. Pacritinib decreased glucose consumption in squamous cell lung cancer cells in cell culture and in vivo without affecting glucose consumption in healthy tissues. Pacritinib blocked hexokinase activity, and Hexokinase 1 and 2 mRNA and protein expression. Overexpression of Hexokinase 1 blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Overexpression of FLT3 but not JAK2 significantly increased glucose consumption and blocked the ability of pacritinib to inhibit glucose consumption in squamous cell lung cancer cells. Additional FLT3 inhibitors blocked glucose consumption in squamous cell lung cancer cells. Our study identifies FLT3 inhibitors as a new class of inhibitors that can block glucose consumption in squamous cell lung cancer.

Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells.

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RARγ is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RARγ antagonist inhibition of the action of RARγ led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RARγ, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells.

Contemporary outcomes of esophageal and gastroesophageal junction neuroendocrine tumors.

Adenocarcinoma and squamous cell esophageal cancers have been extensively studied in the literature. Esophageal neuroendocrine (NET)/carcinoid tumors are less commonly studied and have only been described in small series. The purpose of this study was to describe the demographics and natural history of esophageal NETs, as well as optimal treatments. We hypothesized that surgical resection would be the best treatment of esophageal NETs. The National Cancer Database was used to identify adult patients with esophageal or gastroesophageal junction (GEJ) cancer from 2004 to 2018. Patients were characterized as carcinoid/NET, adenocarcinoma, or squamous cell cancer. Clinical and demographic characteristics were compared between the histology groups. The primary outcome was overall survival, which was assessed by multivariable Cox analysis. Multivariable Cox analysis was also used to analyze factors associated with survival among NET patients who underwent surgery. Among 206,321 patients with esophageal cancer, 1,563 were NETs (<0.01%). Relative to the other two histologies, NETs were associated with younger age, female sex, and advanced clinical stage at diagnosis. Multivariate analysis suggested that NETs were less likely to be treated with surgical resection (OR 0.51, P<0.001). Nonetheless, surgical resection was associated with improved survival (HR 0.64, P=0.003). Among patients with NETs who received surgery, neoadjuvant therapy was associated with improved overall survival (HR 0.38, P=0.013). NET of the esophagus presents with more advanced disease than other common histologies. Among patients with nonmetastatic cancer, surgical resection appears to be the best treatment. Neoadjuvant systemic therapy may offer survival benefit, but future studies are necessary.