Adenocarcinoma Squamous Cell Carcinoma Research Articles

Determination of esophageal squamous cell carcinoma and gastric adenocarcinoma on raw tissue using Raman spectroscopy

Cancer detection is a global research focus, and novel, rapid, and label-free techniques are being developed for routine clinical practice. This has led to the development of new tools and techniques from the bench side to routine clinical practice. In this study, we present a method that uses Raman spectroscopy (RS) to detect cancer in unstained formalin-fixed, resected specimens of the esophagus and stomach. Our method can record a clear Raman-scattered light spectrum in these specimens, confirming that the Raman-scattered light spectrum changes because of the histological differences in the mucosal tissue.To evaluate the use of Raman-scattered light spectrum for detecting endoscop-ically resected specimens of esophageal squamous cell carcinoma (SCC) and gastric adenocarcinoma (AC).We created a Raman device that is suitable for observing living tissues, and attempted to acquire Raman-scattered light spectra in endoscopically resected specimens of six esophageal tissues and 12 gastric tissues. We evaluated formalin-fixed tissues using this technique and captured shifts at multiple locations based on feasibility, ranging from six to 19 locations 200 microns apart in the vertical and horizontal directions. Furthermore, a correlation between the obtained Raman scattered light spectra and histopathological diagnosis was performed.We successfully obtained Raman scattered light spectra from all six esophageal and 12 gastric specimens. After data capture, the tissue specimens were sent for histopathological analysis for further processing because RS is a label-free methodology that does not cause tissue destruction or alterations. Based on data analysis of molecular-level substrates, we established cut-off values for the diagnosis of esophageal SCC and gastric AC. By analyzing specific Raman shifts, we developed an algorithm to identify the range of esophageal SCC and gastric AC with an accuracy close to that of histopathological diagnoses.Our technique provides qualitative information for real-time morphological diagnosis. However, further in vivo evaluations require an excitation light source with low human toxicity and large amounts of data for validation.

Chemopreventive Properties of Black Raspberries and Strawberries in Esophageal Cancer Review.

Esophageal cancer is one of the most fetal malignancies in the world. Esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC) are two main types of esophageal cancer and each with distinct epidemiological, etiological and histopathological characteristics. The continued global prevalence of tobacco use and alcohol consumption, coupled with limited intake of fresh fruits and vegetables, ensures that esophageal cancer will remain one of the major health threats. In addition to promoting quitting smoking and alcohol abuse, one of the strategies of cancer prevention is to identify foods, food components, or dietary patterns that can prevent or delay the onset of esophageal cancer. A food-based approach has the advantage of a complex of mixtures of bioactive components simultaneously targeting multiple processes in carcinogenesis. We have employed a preclinical rodent model of esophageal SCC to assess the effects of black raspberries (BRB) and strawberries. Our investigations demonstrate that BRB and strawberries are potent inhibitors of esophageal cancer. To prepare for this review, a literature search was performed to screen BRB and strawberries against esophageal cancer using electronic databases from PubMed, Science Direct and Google Scholar. Search was conducted covering the period from January 2000 to June 2022. Our present review has provided a systematic review about chemopreventive effects of BRB and strawberries in esophageal cancer by collecting and compiling diverse research findings from the above sources. In this review, we discussed the anti-tumor potentials of BRB and strawberries in esophageal SCC and esophageal AC separately. For each cancer type, we discuss animal models and research findings from both animal bioassays and human clinical studies. We also discuss the potential mechanisms of action of berries and their key bioactive components.

Neoadjuvant versus definitive chemoradiation in locally advanced esophageal cancer for patients of advanced age or significant comorbidities.

The addition of surgery to chemoradiation for esophageal cancer has not shown a survival benefit in randomized trials. Patients with more comorbidities or advanced age are more likely to be given definitive chemoradiation due to surgical risk. We aimed to identify subsets of patients in whom the addition of surgery to chemoradiation does not provide an overall survival (OS) benefit. The National Cancer Database was queried for patients with locally advanced esophageal cancer who received either definitive chemoradiation or neoadjuvant chemoradiation followed by surgery. Bivariate analysis was used to assess the association between patient characteristics and treatment groups. Log-rank tests and Cox proportional hazards models were performed to assess for differences in survival. A total of 15,090 with adenocarcinoma and 5,356 with squamous cell carcinoma met the inclusion criteria. Patients treated with neoadjuvant chemoradiation and surgery had significantly improved survival by Cox proportional hazards model regardless of histology if <50, 50-60, 61-70, or 71-80years old. There was no significant benefit or detriment in patients 81-90years old. Survival advantage was also significant with a Charlson/Deyo comorbidity condition score of 0, 1, 2, and ≥3 in adenocarcinoma squamous cell carcinoma with scores of 2 or ≥3 had no significant benefit or detriment. Patients 81-90years old or with squamous cell carcinoma and a Charlson/Deyo comorbidity score ≥ 2 lacked an OS benefit from neoadjuvant chemoradiation followed by surgery compared with definitive chemoradiation. Careful consideration of esophagectomy-specific surgical risks should be used when recommending treatment for these patients.

The Prognostic Significance of PD1 and PDL1 Gene Expression in Lung Cancer: A Meta-Analysis.

BackgroundImmune checkpoint blockade therapy represents an extraordinary advance in lung cancer treatment. It is important to determine the expression of immune checkpoint genes, such as programmed cell death 1 (PD1) and programmed cell death-ligand 1 (PDL1), to develop immunotherapeutic strategies. The aim of this study was to explore the association between PD1 and PDL1 gene expression and prognoses and outcomes in lung cancer.MethodsThis meta-analysis analyzed 1,251 patients from eight different microarray gene expression datasets and were evaluated for their prognostic implications and verified using another independent research.ResultsThe mean expression levels of PDL1 in adenocarcinoma (AD) and squamous cell carcinoma (SC) were significantly higher in patients who died than in patients who did not. There was a trend toward incremental increases in PD1 and PDL1 expression significantly decreasing the risk of relapse and death among AD patients (HR = 0.69; 95% CI = 0.53 ~ 0.91; HR = 0.68; 95% CI = 0.54 ~ 0.84, respectively) and SC patients (HR = 0.53; 95% CI = 0.32 ~ 0.89; HR = 0.78; 95% CI = 0.57 ~ 1.00 respectively), as early-stage patients in this study were more likely to have high expression of both PD1 and PDL1 than late-stage patients (P-trend < 0.05). In contrast, late-stage SC patients expressing one or more of the genes at a high level had a significantly elevated risk of relapse (HR = 1.51; 95% CI = 1.07 ~ 2.11) and death (HR = 1.41; 95% CI = 1.08 ~ 1.84). This result was consistent with the validation data set.ConclusionThese findings indicate that high expression of PD1 and PDL1 is associated with superior outcome in early-stage lung cancer but an adverse outcome in late-stage lung cancer. The expression levels of PD1 and PDL1 individually or jointly are potential prognostic factors for predicting patient outcomes in lung cancer.

Monitoring of spontaneous neoplasy distribution in dogs in the conditions of Lviv and in the suburban area of the regional center

The article deals with the results of monitoring searches on the spread of cancer in dogs and conducted the analysis of incidence rates of animals depending on breed, gender and age. Research were performed during the 2016-2019 years on 2015 dogs, who came to the educational research clinics of the Department of Surgery and Diseases of Small Animals named after Stepan Gzhytskyj LNUVMB. Cancer patients sick dogs (n = 259) of diff erent breeds and genders, aged from 4 months to 16 years, were the subject of research. It was installed, that in the structure of surgical diseases of dogs the share of neoplasia averages 12.85% (10.2-14.9% by years of observation). Among neoplasms, breast neoplasia (35.1%) and skin tumors (29.8%) were most commonly reported, less frequently - tumor lesions of the organs of the reproductive system (13.9%), neoplasia of the internal organs (10.5%), neoplasms in the head and neck (6.6%). Neoplastic lesions of hematopoietic and lymphoid tissues (2.3%) and tumors of bones and joints (1.9%) were characterized by sporadic cases. In 20% of dogs, there was a simultaneous tumor lesion of diff erent nosological forms; most often there are skin and breast tumors, less often skin and tumors in the head and neck. It was also installed, that among 259 dog cancer patients, 23.2% of the animals were outbred and 76.8% were purebred (with more than 40 breeds); males accounted for 48.2% and females for 51.8%. The highest incidence of neoplasia was found in animals between 7 and 12 years of age; the median incidence was 8.5 years, and fashion (the highest number of diseased animals) was 9.5 years. It is found out that the dynamic growth of oncological diseases during 2016-2019 occurred, for the most part, by increasing the number of animals with skin tumors and, to a lesser extent, internal organs. Skin tumors were characterized by a wide variety of nosological forms and were diagnosed in dogs of all ages, as well as diff erent breeds and genders. According to the results of histological verifi cation, 42 or 54.7% of animals had benign tumors of the skin and malignancies in 35 or 45.5% of cases. It was also installed, that benign tumors were mostly represented by papilloma (26.0%), less frequently - lipoma (13.0%), dermatofi broma (10.3%), trichoepithelioma (5.2%). Malignancies are distributed as follows: mastocytoma (18.2%), squamous cell carcinoma adenocarcinoma (2.6 %), spindle cell sarcoma (2.6%) fi brosarcoma (1.3%). Therefore, the reported prevalence of spontaneous neoplasia in dogs in our region certify that skin tumors are currently the most important and promising area for further research. Key words: dogs, neoplasms, spread, clinical classifi cation of tumors, skin neoplasia, histological type of tumors.

PINK1 Expression Is Associated with Poor Prognosis in Lung Adenocarcinoma.

PTEN-induced putative kinase protein 1 (PINK1) is a serine/threonine-protein kinase that phosphorylates mitochondrial proteins and is involved in mitophagy. Thus, PINK1 may protect cancer cells against mitochondrial dysfunction during cellular stress. However, the role of PINK1 in lung cancer was rarely explored. In this study, we immunohistochemically analyzed the expression of PINK1 in 256 patients with non-small-cell lung cancer, consisting of 137 patients with adenocarcinoma (AC) and 119 patients with squamous cell carcinoma (SCC). In particular, we focused on the difference in diagnostic or prognostic value of PINK1 expression between AC patients and SCC patients. The patients with AC or SCC were divided into high or low PINK1 expression group, according to the immunohistochemical score that was based on the percentage of PINK1 positive cells and staining intensity. Among the 137 AC specimens, 52 specimens (37.96%) were judged as high PINK1 expression, and likewise, among 119 SCC specimens, 42 specimens (35.29%) were judged as high PINK1 expression. Importantly, high PINK1 expression was significantly associated with postoperative chemoresistance of AC, but not in case of SCC. Moreover, high PINK1 expression was identified as a poor prognostic factor for AC, but not for SCC. These results may reflect the biological difference between AC and SCC. In conclusion, high PINK1 expression is correlated with poor response to chemotherapy and is an independent prognostic factor for AC, but not for SCC. Our findings suggest that PINK1 detection could help stratify patients who may have poor response to chemotherapy and guide the individual treatment.

Small suitability of the DLEC1, MLH1 and TUSC4 mRNA expression analysis as potential prognostic or differentiating markers for NSCLC patients in the Polish population.

According to the latest data, lung cancer is one of the most common cancer worldwide, men contributing nearly 21.2% and women 8.6% of all diagnosed cancers. Late detection of tumour drastically reduces the chance for a cure. Thus, it is important to search for candidate biomarkers for screening of early stage nonsmall cell lung carcinoma (NSCLC). Tumour suppressor genes, DLEC1, TUSC4 and MLH1, localized on 3p21 are recognized to play a role in NSCLC carcinogenesis. The aim of this study was to assess the relationship between the DLEC1, TUSC4 and MLH1 mRNA expression, and clinical features of NSCLC patients, tobacco addiction, and tumour histopathological characteristics. The DLEC1, TUSC4 and MLH1 expression was analysed in lung tumour tissue samples obtained from 69 patients diagnosed with NSCLC: squamous cell carcinoma (n = 34), adenocarcinoma (n = 24), large cell carcinoma (n = 5), carcinoma adenosquamosum (n = 5). A decreased gene expression (RQ < 0.7) was observed for DLEC1 in 60.9% of tumour samples, for MLH1 in 50.7% and for TUSC4 in 26% of NSCLC samples. DLEC1 was decreased in more aggressive subtypes: large cell carcinoma and adenocarcinoma-squamous cell carcinoma. The simultaneous downregulation of two of the studied genes, DLEC1 andMLH1,was observed in 30.4% of NSCLCsamples, highlighting the importance of these two genes in lung carcinogenesis. We found no correlation between the DLEC1, TUSC4 and MLH1 gene expression and NSCLC patient characteristics (gender, age and smoking) or cancer histopathology. No significant differences in the gene expression among NSCLC subtypes indicate the weakness of DLEC1, TUSC4 and MLH1 expression analysis as potential differentiating markers of NSCLC subtypes in the Polish population.

Analysis of clinicopathological characteristics and prognosis on 42 patients with primary gastric adenosquamous cell carcinoma

To investigate the clinicopathological characteristics, diagnosis, treatment and prognosis of patients with primary gastric adenosquamous cell carcinoma. A total of 5 562 patients with gastric neoplasm were admitted in Tianjin Medical University Cancer Institute and Hospital from January 2001 to January 2011. Among them 42 patients were diagnosed as primary gastric adenosquamous cell carcinoma, accounting for 0.76% of all the patients. The clinicopathological and follow-up data of these 42 patients with primary gastric adenosquamous cell carcinoma were retrospectively analyzed, and Cox proportional hazard model was used to analyze the prognostic factors of gastric adenocarcinoma squamous cell carcinoma. Among above 42 patients, 32 were male and 10 were female, with a male-to-female ratio of 3.2/1.0 and the average age was 63 years (range: 46 to 77 years). Five patients (11.9%) were confirmed as adenosquamous cell carcinoma by preoperative pathological examination, while other 37 patients were diagnosed as adenocarcinoma preoperatively. According to the 7th edition AJCC TNM classification system for gastric adenocarcinoma, 5 patients (11.9%) were in stage II(, 30 patients (71.4%) in stage III( and 7 patients (16.7%) in stage IIII(. The maximum tumor diameter was > 5 cm in 18 patients (42.9%). Borrmann type III(-IIII( was found in 29 patients (69.0%), and poorly differentiated (or undifferentiated) tumor was found in 32 patients (76.2%). Radical operations were performed in 31 patients (73.8%), the reasons of non radical operations included infiltration of pancreas in 3 patients, infiltration of radices mesocili transvers in 1 patient and classification of stage IIII( in 7 patients. Lymph node dissection was performed in 37 patients, 83.8% of them (31/37) was found with lymphatic metastases. Twenty-five patients received adjuvant chemotherapy except for 7 patients in stage IIII( and 10 patients who refused adjuvant chemotherapy. All the patients had an average survival time of 36.4 months and median survival time of 28.0 months, and the overall 1-, 3- and 5-year survival rates were 82.2%, 42.3% and 18.2% respectively. Univariate analysis revealed that tumor size (χ2=4.039, P=0.044), Borrmann type (χ2=18.728, P=0.000), tumor differentiation (χ2=19.612, P=0.000), radical gastectomy (χ2=41.452, P=0.000), lymph node metastasis (χ2=9.689, P=0.002) and clinical stage (χ2=26.277, P=0.000) were associated with postoperative survival. Multivariate analysis revealed that tumor differentiation (HR=10.560, 95%CI:2.263-49.281, P=0.003), radical gastrectomy (HR=4.309, 95%CI:1.311-14.168, P=0.016) and clinical stage (HR=2.392, 95%CI:1.022-5.600, P=0.044) were independent prognosis factors. Primary gastric adenosquamous cell carcinoma is rare with poor prognosis. Radical gastrectomy is recommended. Tumor differentiation, radical gastrectomy and clinical stage are important indicators to evaluate prognosis of primary gastric adenosquamous cell carcinoma.

Adenosquamous cell carcinoma derived from intraductal papillary mucinous neoplasm of the pancreas confirmed by genetic analysis.

275 Background: Adenosquamous cell carcinoma (ASC) is an uncommon histologic variant of pancreatic cancer, representing only 1-4 % of all pancreatic neoplasms. Here we reported the extremely rare case of ASC derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas with intensive pathological and molecular analysis. Methods: A 72-year-old diabetic male with five-year history of non-alcoholic chronic pancreatitis was admitted to our hospital with complaint of epigastric pain. The patient was diagnosed as pancreatic cancer associated with IPMN and pylorus preserving pancreaticoduodenectomy was performed in April 2012. The resected pancreas was fixed in 10% formaldehyde, and the whole specimen was sliced at a thickness of 5-mm for i) pathological analyses using hematoxylin-eosin (H-E) staining and immunostaining with specific antibodies against MUC-1, -2, -5AC, -6, p63 and CD5/6, and ii) deep sequencing of multiplex PCR amplicons of 50 cancer-associated genes utilizing Ion Torrent PGM platform. DNA was obtained from intraepithelial lesions of IPMN, invasive squamous cell carcinoma (SCC) and adenocarcinoma (AC) after enrichment for neoplastic cellularity, using manual microdissection. Results: Pathological findings showed IPMN extended from main pancreatic duct to branch ducts. The invasive tumor was predominantly consisted of poorly-differentiated SCC and small poorly-differentiated AC was also found in the edge of the SCC. All IPMN area analyzed shared combination of the mutations, KRASG12D and GNASR201C. The identical mutations in KRAS and GNAS as IPMNs were also found in SCC and AC. Conclusions: It generally difficult to fully discriminate IPMN-derived cancer (invasive IPMN) from concomitantly and independently developed de novo pancreatic ductal adenocarcinoma (PDA) originating from the “field defect”. In the current case, although SCC is a rare histotype of IPMNs, we considered that the invasive carcinoma was derived from IPMN based on their mutational profile.

RARβ Promoter Methylation as an Epigenetic Mechanism of Gene Silencing in Non-small Cell Lung Cancer.

The retinoid acid receptor-p (RARβ) gene is one of the tumor suppressor genes (TSGs), which is frequently deleted or epigenetically silenced at an early stage of tumor progression. In this study we investigated the promoter methylation and expression status of the RARβ gene in 60 surgically resected non-small cell lung cancer (NSCLC) tissue samples and 60 corresponding unchanged lung tissue samples, using methylation-specific PCR and real-time-polymerase chain reaction (qPCR) techniques. We correlated the results with the pathological features of tumors and clinical characteristics of patients. qPCR analysis detected a significantly lower RARβ expression in the patients with adenocarcinoma (AC) and large cell carcinoma (LCC) than in those with squamous cell carcinoma (SCC) (AC vs. SCC, p = 0.032; AC and LCC vs. SCC, p = 0.0 13). Additionally, significantly lower expression of the RARβ gene was revealed in the patients with non-squamous cell cancer with a history of smoking assessed as pack-years (PY < 40 vs. PY ≥ 40, p = 0.045). Regarding RARβ promoter methylation, we found significant differences in the methylation index in the SCC group when considering pTNM staging; with higher index values in T1a + T1b compared with T2a + T2b and T3 + T4 groups (p = 0.024). There was no correlation between the methylation status and expression level of the RARβ gene, which suggests that other molecular mechanisms influence the RARβ expression in NSCLC patients. In conclusion, different expression of the RARβ gene in SCC and NSCC makes the RARβ gene a valuable diagnostic marker for differentiating the NSCLC subtypes.

Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma

Recent advances in the treatment of non-small cell lung cancer (NSCLC) with new agents require accurate histological subtyping at diagnosis to avoid the higher risk of an adverse response and to obtain the maximum therapeutic response. However, interobserver variability, tumor heterogeneity and the degree of differentiation may affect the decision concerning a pathological diagnosis of NSCLC. Therefore, the aim of this study was to identify specific microRNAs (miRNAs) as standardized biomarkers with high sensitivity and specificity in order to distinguish between squamous cell carcinoma (SCC) and adenocarcinoma (AC). Quantitative polymerase chain reaction (qPCR)‑based miRNA array analysis was performed to identify microRNAs differentially expressed between SCC and AC using 86 resected NSCLC samples in addition to adjacent normal tissues. The results were confirmed by independent qRT-PCR assays with the same test samples and 88 additional validation samples, and from this we evaluated the usefulness of the identified miRNAs as biomarkers to distinguish between SCC and AC. Three miRNAs (hsa-miR-196b, hsa-miR-205 and hsa-miR-375) were identified. Discriminant analysis combining the three miRNAs appeared to distinguish SCC from AC accurately in the test and validation samples, demonstrating a sensitivity and specificity of 76 and 80%, and 85 and 83%, respectively. hsa-miR-196b, hsa-miR-205 and hsa-miR-375 were identified as biomarkers capable of distinguishing between lung SCC and lung AC. These newly identified miRNAs may prove to be highly valuable molecular markers for the classification of NSCLC histological subtypes and may contribute to the pathogenesis of each subtype of NSCLC.

Development and clinical validation of an adeno/squamous multiplexed diagnostic assay for NSCLC.

e19057 Background: The diagnosis of adenocarcinoma (ADC) vs. squamous cell carcinoma (SCC) in NSCLC is critical since new therapies (e.g. pemetrexed) are restricted to non-squamous NSCLC. Most diagnoses are made based on histopathology, though IHC is often performed as well. Since IHC is not quantitative, interpretation of intensity is subjective, and reproducibility can be problematic. Using the Liquid Tissue-SRM mass spectrometry (MS) platform, we have developed a quantitative, multiplexed clinical diagnostic assay to measure the adeno/squamous markers TTF-1/CK7 (ADC) and K5 and p63/40 (SCC) in FFPE tissue. This proteomic assay is epitope independent, and highly reproducible. Methods: Recombinant K5, K7, TTF-1 and p63/p40, were subjected to trypsin digestion mapping to identify peptides for MS analysis. Heavy isotope labeled peptides were synthesized as positive control peptides for quantitation. The multiplexed assay was technically validated on cell lines, and human tumor tissues. Results: ADC/SCC proteomic analysis was performed on a training set of 39 NSCLC tissues from U. of Chicago (20 ADC and 19 SCC). Principal Component Analysis was used to define optimal quantitative cutoffs for each of the four markers for the two tumor subtypes. The ADC diagnosis was unequivocal for all 20 ADC samples, however within the 19 SCC’s, one sample appeared to be ADC and two samples had markers for both ADC and SCC. Proteomic analysis of a test set of 194 NSCLC tumors (98 ADC and 98 SCC based on pathology reports) from MD Anderson Cancer Center was consistent with the observations in the training set. 93/98 ADC cases were confirmed by proteomic analysis, four ADC cases showed mixed or SCC phenotypes. Proteomic analysis confirmed 58/98 SCC cases but identified 27 cases as mixed ADC SCC or ADC based on TTF1/K5 expression. Further studies are ongoing to determine the clinical utility of these findings. Conclusions: These data demonstrate that quantitative proteomic analysis can define cut offs for ADC and SCC Biomarkers profiles in NSCLC tumors. These profiles can determine ADC, SCC and mixed phenotypes and provide physicians with accurate information to help them stratify their patients to the right evidence based treatment therapy.

ROS1 Rearrangements in Lung Cancer: A New Genomic Subset of Lung Adenocarcinoma

During the last decade, the treatment of advanced non–small-cell lung cancer (NSCLC) has rapidly evolved from a one-size-fits-all approach to one of personalized medicine. Lung adenocarcinoma, the most common form of NSCLC, is composed of several different genomic subsets defined by unique oncogenic alterations (Fig 1). In most cases, these oncogenic alterations are mutually exclusive with one another. A major therapeutic goal has been to develop specific therapies for each genomic subset of patients with lung cancer. To date, clinically effective targeted therapies exist for patients with NSCLC whose tumors harbor epidermal growth factor receptor (EGFR) mutations (eg, EGFR kinase inhibitors gefitinib and erlotinib) and for those with anaplastic lymphoma kinase (ALK) rearrangements (eg, ALK kinase inhibitor crizotinib). Randomized clinical trials have demonstrated improved response rate and progression-free survival with gefitinib and erlotinib when administered as first-line systemic therapy for advanced EGFR-mutant NSCLC compared with systemic chemotherapy. These agents have become the preferred initial therapy for advanced disease in patients with NSCLC whose tumors harbor EGFR mutations. Clinical trials comparing crizotinib with combination chemotherapy are currently under way for advanced ALK-rearranged NSCLC. Although many of the genomic subsets of lung adenocarcinoma comprise only a small percentage of all adenocarcinomas, each subset translates into a significant number of patients, because lung cancer is such a common disease. For example, in the United States, there will be approximately 6,000 new patients diagnosed annually with ALKrearranged NSCLC (incidence of approximately 3%), which is greater than the number of new patients diagnosed with chronic myeloid leukemia. Thus it will be critical to develop systematic screening strategies to identify genomic subsets of patients with NSCLC, because effective clinical therapies are available. In Journal of Clinical Oncology, Bergethon et al examine ROS1 translocations in patients with NSCLC. Genomic alterations in ROS1 have been described in a subset of gliomas and identified a few years ago to also occur in NSCLC. An original report identified a ROS1 translocation in an Asian patient with NSCLC, but additional studies on the prevalence of this genetic alteration in Asian and white patients have been lacking. In the current study, Bergethon et al identify ROS1 rearrangements in 1.7% (18 of 1,073) of patients with NSCLC using fluorescence in situ hybridization. Patients with lung cancer whose tumors harbored ROS1 rearrangements were more likely to have adenocarcinoma and to be Asian, younger (median age of approximately 50 years), and never smokers, clinical features that are also associated with both EGFR mutations and ALK rearrangements. Preclinical studies have also identified a kinase inhibitor, TAE684, that effectively inhibited the growth of the HCC78 lung cancer cell line harboring a ROS1 translocation. In the current study, the authors show that crizotinib inhibits growth of the HCC78 cell line. On the basis of this result, Bergethon et al used crizotinib to treat a patient with NSCLC whose tumor had a ROS1 rearrangement; the patient had a remarkable clinical response and near-complete radiographic response to crizotinib, clinically confirming the concept of oncogene addiction in ROS1-rearranged cancers. The findings from the current study suggest that patients with lung cancer with ROS1 rearrangements represent another unique population for whom there may be an effective targeted therapy. Given the prevalence of 1.7%, this will translate to 3,000 to 4,000 new patients diagnosed annually with ROS1-rearranged NSCLC in the United States alone. This is a significant number of new patients for whom crizotinib may be an effective systemic therapy. Adenocarcinoma Squamous cell carcinoma

Abstract 4956: Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma

Abstract Introduction: Recent advances in the treatment of non-small-cell lung cancer (NSCLC) with new agents require accurate histological subtyping at diagnosis in order to avoid the higher risk of an adverse response and obtain a maximum therapeutic response. However, interobserver variability, tumor heterogeneity and the degree of differentiation may influence the decision concerning a pathological diagnosis of NSCLC. We therefore in this study attempted to identify specific microRNAs as standardized biomarkers with high sensitivity and specificity for distinguishing between squamous cell carcinoma (SCC) and adenocarcinoma (AC). Methods: Quantitative real time polymerase chain reaction (qRT-PCR) based microRNA array was performed to identify microRNAs differentially expressed between SCC and AC using 86 resected NSCLC samples as well as adjacent normal tissues. The results were confirmed by independent qRT-PCR assays with the same test samples and an additional 88 validation samples and the usefulness of the identified microRNAs as biomarkers to distinguish between SCC and AC was evaluated. Results: Three microRNAs (hsa-miR-196b, hsa-miR-205 and hsa-miR-375) were identified. Discriminant analysis combining all 3 microRNAs appeared to distinguish SCC from AC accurately in the test samples and the validation samples, showing sensitivity and specificity of 76% and 80%, and 85% and 83%, respectively. Conclusions: Hsa-miR-196b, hsa-miR-205 and hsa-miR-375 were identified as biomarkers capable of distinguishing between lung SCC and lung AC. These newly identified microRNAs may prove to be highly valuable molecular markers for the classification of NSCLC histologic subtypes, and could potentially contribute to the pathogenesis of each subtype of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4956. doi:10.1158/1538-7445.AM2011-4956

Second Cancers After Squamous Cell Carcinoma and Adenocarcinoma of the Cervix

Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk. We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR). Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors. The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors.

MO-D-I-609-03: Fast Dynamic MR Imaging for Tracking Lung Tumor Motion During the Respiratory Cycle

Purpose: To compare two MR sequences, HASTE and trueFISP, to track lung tumor motion and to assess tumor conspicuity and image artifacts. Method and Materials: A lung tumor motion phantom, three healthy volunteers and two lung tumor patients were examined using a clinical 1.5-T scanner (Sonata, Siemens, Germany) with the following parameters: trueFISP (TE/TR 1.5/204.2ms; FA/55o; FOV/300×300; matrix/128×128; slice-thickness/5mm), and HASTE (TE/TR 25/800ms; FA/160o; FOV/325×400; matrix/123×256; slice-thickness/5mm). No contrast agent or gating was used. Parenchyma signal intensity, lung regions and diaphragm displacement were measured in three healthy subjects. Tumor displacement, tumor SNR and tumor-to-parenchyma CNR were calculated in the two lung tumor patients. Tumor conspicuity and imaging artifacts were evaluated in all subjects by two radiation oncologists. Results: HASTE visualized better in peripheral vessels, but blurred tumor and central vessels. TrueFISP visualized better in non-peripheral vessels, but demonstrated ghost artifacts in the phase-encoding direction. Relative to CT, both sequences showed high SNR and CNR in patient ♯1 with the metastatic adenocarcinoma (HASTE 42.26/24.48; trueFISP 37.72/17.41; CT 42.04/29.98), but reduced SNR and CNR in patient ♯2 with the primary squamous cell carcinoma adenocarcinoma (HASTE 24.51/4.81; trueFISP 8.54/1.73; CT 36.67/26.84). Conclusion: HASTE and trueFISP can both monitor lung tumor motion during free breathing. Tumor conspicuity and imaging artifacts depend upon the tumor type, size and location.

Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling

Thymidine kinase 1 (TK1) is a key enzyme involved in the synthesis of DNA precursors and thus, cell proliferation-dependent. Antibodies against TK1 have provided attractive tools for cancer diagnosis. Expression of TK1 in 158 non-small cell lung cancer (NSCLC) patients with 59 adenocarcinoma (AC) and 99 squamous cell carcinoma (SCC) was determined by anti-TK1 monoclonal antibody (mAb) 1E3 (AC, n=50; SCC, n=70). Parallel tumor sections were stained for Ki-67 (MIB-1), and TK1 expression was also investigated with anti-TK1 chicken IgY Ab (AC, n=9; SCC, n=29; normal lung tissues, n=10). In one AC and one SCC patient, gene profiling was done by cDNA array. Using the mAb 1E3, a significantly higher TK1 labeling index (LI) of AC patients was found (68%) compared to the LI of Ki-67 (36%). This difference was due to a significantly higher TK1 LI of tumor stage II and grade 2. Although no difference in the LI of TK1 and Ki-67 of SCC patients was found (54 vs. 53%), significantly higher TK1 LI of SCC patients of tumor grade 1 was found. Using the anti-TK1 IgY Ab, a higher TK1 LI of AC patients (78%) and SCC patients (66%) was found compared to staining with mAb 1E3 (68 vs. 54%), but it was not significantly different. Samples stained only for TK1 represented mostly tumor stages I and II and grades 1 and 2 of both AC and SCC. AC patients whose samples stained only for Ki-67 were found to be in stage I and grade 1. cDNA profiling showed that the expression of BRCA1, cyclin B1 and cdc2p34 was higher in AC compared to SCC, while the expression of IGFBP-3 and EGFR was higher in SCC. TK1 is apparently a more reliable marker in AC patients than Ki-67. However, a combination of the two markers may help identify patients of different stages and grades more efficiently, and cyclin/kinase complexes and growth factors/receptors may be useful markers in distinguishing AC from SCC.

Biopsy Pathology and Cytology of the Cervix

Cytological methods defining the lesion for biopsy histological methods and types of biopsy the normal cervix cervical cytology - the normal smear infection, inflammation and repair polyps, cysts and other benign lesions metaplastic, hyperplastic and reactive changes in the cervical epithelium cervical intraepithelial neoplasia (CIN) microinvasive and occult invasive squamous carcinoma primary malignant epithelial tumours - classification and squamous cell carcinoma adenocarcinoma in situ and glandular atypia of the cervix malignant epithelial tumours - glandular, adenosquamous and undifferentiated myoid, miscellaneous and metastatic tumours.