Solid Adenocarcinoma Research Articles

歯肉転移で発見された粘液産生充実型肺腺癌の1剖検例

歯肉転移で発見された粘液産生充実型肺腺癌の1剖検例

Reply to Baisi et al.

We thank Baisi et al. [1] for their interest in, and comments on, our article [2]. First, all of the patients in this retrospective study underwent brain computed tomography (CT) or brain magnetic resonance imaging (MRI) to evaluate brain metastasis, and most underwent F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for systemic screening to evaluate the N and the M parameters. For the small-sized pure ground glass opacities without solid component, PET scans were sometimes skipped. To our understanding, the current clinical TNM staging system, assessing tumour extent, is essentially based on morphological evaluation by means of chest X-ray, CT or MRI [3]. To date, the role of PET scan in TNM staging is supplemental. In this study, we tried a morphological approach to adenocarcinoma, and it may work well at least in the area of adenocarcinoma. We totally agree that the current TNM staging system is not totally affordable and, therefore, a more precise evaluation is required to predict survival. We know that adenocarcinoma includes a wide spectrum, and the biological behaviour of each subclass varies very much (i.e. adenocarcinoma in situ vs solid predominant invasive adenocarcinoma). By FDG-PET, tumour extent can be assessed precisely [4]. Moreover, previous studies clearly show that grading the FDG uptake may distinguish the intrinsic biological behaviour of the tumours, probably reflecting tumour pathology [5]. The application of FDG-PET for the evaluation of tumour aggressiveness seems to be a promising approach, however, the heterogeneity of PET techniques and performance and the difficulty of interinstitutional standardization are challenges in need of solutions [2, 5] before incorporating PET findings into TNM staging, particularly into the T-factor. The current TNM staging system involves of three-dimensional assessment. Adding new vectors reflecting biological factors (‘B-factor’: CEA level, FDG uptake, pathological grading, etc.) might be necessary for a new-generation system.

Response to Erlotinib in Patients with EGFR Mutant Advanced Non–Small Cell Lung Cancers with a Squamous or Squamous-like Component

We previously reported that although EGFR mutations are not a feature of pure squamous cell carcinomas (SCC) of the lung, these mutations do occur in adenosquamous carcinomas (AD-SCC) and in rare solid adenocarcinomas, both of which can mimic SCC in small samples. Here we present an expanded series of these cases with a focus on sensitivity to erlotinib. The study included 13 patients with EGFR mutant lung carcinomas, which after detailed pathologic review were classified as AD-SCC (n = 11) or solid adenocarcinoma (n = 2). The majority received a diagnosis of SCC in at least 1 sample. All patients were treated with erlotinib. Eight of 11 patients with AD-SCC were evaluable for response. Their overall response rate was 88% (7/8; 95% CI, 47% to 99%). One of 2 solid adenocarcinoma patients responded to erlotinib. As a group, median progression-free survival was 12 months (95% CI, 8 to not reached); median overall survival was 29 months (95% CI, 27 to not reached). In conclusion, EGFR mutant AD-SCC and solid adenocarcinoma show a response to erlotinib that is comparable to that seen in patients with conventional adenocarcinoma. These tumors can mimic SCC in small samples. We propose an approach to increase the capture of these rare histology patients for EGFR mutation testing.

Radiologic Implications of the 2011 Classification of Adenocarcinoma of the Lung

Now the leading subtype of lung cancer, adenocarcinoma received a new classification in 2011. For tumors categorized previously as bronchioloalveolar carcinoma (BAC), criteria and terminology had not been uniform, so the 2011 classification provided four new terms: (a) adenocarcinoma in situ (AIS), representing histopathologically a small (≤3-cm), noninvasive lepidic growth, which at computed tomography (CT) is usually nonsolid; (b) minimally invasive adenocarcinoma, representing histopathologically a small (≤3-cm) and predominantly lepidic growth that has 5-mm or smaller invasion, which at CT is mainly nonsolid but may have a central solid component of up to approximately 5 mm; (c) lepidic predominant nonmucinous adenocarcinoma, representing histopathologically invasive adenocarcinoma that shows predominantly lepidic nonmucinous growth, which at CT is usually part solid but may be nonsolid or occasionally have cystic components; and (d) invasive mucinous adenocarcinoma, histopathologically showing lepidic growth as its predominant component, which at CT varies widely from solid to mostly solid to part solid to nonsolid and may be single or multiple (when multifocal, it was formerly called multicentric BAC). In addition, new histopathologic subcategories of acinar, papillary, micropapillary, and solid predominant adenocarcinoma are now described, all as nonmucinous, predominantly invasive, may include a small lepidic component, and at CT are usually solid but may include a small nonsolid component. The micropapillary subtype has a poorer prognosis than the other subtypes. In addition, molecular genetic correlations for the subcategories of adenocarcinoma of the lung are now a topic of increasing interest. As the new classification enters common use, further descriptions of related correlations can be anticipated.

KIF5B/RET fusion gene in surgically-treated adenocarcinoma of the lung

Recently, a novel fusion gene resulting from a linkage between the kinesin family member 5B gene (KIF5B; 10p11.22) and the rearranged during transfection gene (RET; 10q11.21) was identified in non-small cell lung cancer (NSCLC). However, the correlation between the KIF5B/RET fusion gene status and the clinicopathological features of surgically-treated lung cancer has not been well characterized. In this study, we have independently investigated the KIF5B/RET fusion gene status in 371surgically-treated NSCLCs (270 were adenocarcinomas and 101 were squamous cell carcinomas), 60 breast cancers, 11metastatic lung cancers from colon cancers and thyroid papillary adenocarcinoma cases at the Nagoya City University Hospital. The fusion gene status was analyzed by an RT-PCR-based assay and by using direct sequencing. We detected 3 of 270 cases of KIF5B/RET fusion genes in adenocarcinomas (1.1%) consisting of female and never smokers with mixed subtype adenocarcinomas. The fusion genes were detected exclusively with other mutations, such as EGFR, Kras, Braf, erbB2 mutations, and EML4/ALK fusion. KIF5B/RET fusion was not detected in the cases with squamous cell carcinoma or other types of cancers. From the 3cases, 2were KIF5B (exon 15); RET (exon 12) fusions with papillary dominant and 1case was KIF5B (exon 22); RET (exon12) fusion with solid dominant adenocarcinoma. The matched normal lung tissues did not display translocation. We reported KIF5B/RET fusion genes as a driver somatic mutation of lung adenocarcinomas. The cinicopathological backgrounds of the KIF5B/RET fusion-positive patients were similar with those of the EML4/ALK fusion-positive patients. The chimeric oncogene may be a promising molecular target for the personalized diagnosis and treatment of NSCLC.

A Novel EML4-ALK Variant: Exon 6 of EML4 Fused to Exon 19 of ALK

Cytotoxic chemotherapy remains the mainstay of treatment for most patients with advanced disease. Recently, anaplastic lymphoma kinase (ALK) expression as a major target for successful treatment with ALK inhibitors was detected in a subset of non-small-cell lung carcinomas, usually as a result of echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangements. Although the chromosomal breakpoint within the EML4 gene varied, the breakpoint within ALK was most frequently reported within intron 19 or rarely in exon 20. Therefore, the different EML4-ALK variants so far contain the same 3' portion of ALK starting with exon 20. Here, we report a novel EML4-ALK variant detected by reverse transcription polymerase chain reaction analysis. Subsequent sequencing revealed an EML4-ALK fusion variant in which exon 6 of EML4 was fused to exon 19 of ALK. It occurred in a predominant solid pulmonary adenocarcinoma of a 65-year-old woman with a clear split signal of ALK in fluorescence in situ hybridization analysis and a weakly homogeneous ALK expression in immunohistochemical staining. Because of the growing number of fusion variants a primary reverse transcription polymerase chain reaction-based screening for ALK-positive non-small-cell lung carcinoma patients may not be sufficient for predictive diagnostics but transcript-based approaches and sequencing of ALK fusion variants might finally contribute to an optimized selection of patients.

Characteristic Immunophenotype of Solid Subtype Component in Lung Adenocarcinoma

Lung adenocarcinomas represent a morphologically heterogeneous tumor composed of an admixture of different histologic subtypes (lepidic, papillary, acinar, and solid subtype). The presence of a solid subtype component is reported to be associated with a poorer prognosis. The aim of this study was to evaluate the characteristic immunophenotype of the solid subtype component compared with the immunophenotypes of other components. We analyzed the clinicopathological characteristics of stage I adenocarcinoma patients with predominant solid subtype disease. Furthermore, we immunostained adenocarcinomas with predominant lepidic, papillary, acinar, and solid subtype components (n=23 each) for 10 molecular markers of tumor invasiveness and scored the results. Patients showing predominance of the solid subtype component (solid subtype adenocarcinoma) had a poorer prognosis than those showing predominance of the lepidic, papillary, or acinar component. Lymphovascular invasion was more often detected in solid subtype tumors than in others. The solid subtype component showed a significantly stronger staining intensity of laminin-5 expression than the lepidic, papillary, and acinar components (P<0.001, P<0.001, and P=0.016, respectively). The fibronectin and vimentin expression levels were also significantly higher in the solid subtype component than in other components. This immunostaining character was validated by using mixed-subtype adenocarcinomas containing all four components in the same tumor. This study concluded that the solid subtype component in lung adenocarcinomas exhibit the invasive immunophenotype, including increased laminin-5 expression, compared with the other components, which may be associated with a poorer prognosis.

Abstract 2179: Histopathologic and genetic features of lung adenocarcinomas with loss of chromatin remodeling factors, BRG-1 and BRM

Abstract We have recently demonstrated that lung adenocarcinoma could be classified into two groups; Group1 is characterized by (1) high expressions of bronchial epithelial markers (TTF-1, MUC1, CK7, and E-cadherin), (2) high phosphorylation of EGFR and MET, (3) frequent mutation or amplification of EGFR, MET and HER2, (4) high expressions of the genes associated with invasion (HER3, MET, Cox-2, laminin β2), and (5) sensitivity to gefitinib and resistance to cisplatin; Group2 is characterized by negative expression of bronchial epithelial markers, no or a little phosphorylation of EGFR and MET, no mutation or amplification of EGFR, MET and HER2, low expressions of many of the genes associated with cancer invasion, and resistance to gefitinib and sensitivity to cisplatin (Matsubara et al, AJP 2010). The activations of receptor tyrosine kinase EGFR and MET would participate in the regulatory network of cancer-associated genes in Group 1. In contrast, rare genetic alterations of EGFR and MET in Group 2 suggest that this group of tumors might have different processes of carcinogenesis. BRG-1 and BRM are two core catalytic ATPase subunits in human SWI/SNF chromatin remodeling complexes, and they have been suggested as tumor suppressors. Now we aimed to reveal the histopathologic/genetic features of lung adenocarcinomas with loss of BRG1 and BRM. METHODS: We analyzed (1) the publicly available data set of 442 lung adenocarcinomas (Shedden et al, Nat Med 2008), and (2) 93 primary lung adenocarcinomas resected in our institution. For the latter set, we analzed the expression of BRG-1 and BRM by immunohistochemistry. RESULTS: Our analysis of the Shedden et al. data revealed that high expressions of BRG1 and BRM were frequently seen in cases with high expressions of bronchial epithelial markers, and that cases with loss of BRG1 or BRM showed significantly poorer prognosis. Among the 93 cases of lung adenocarcinoma in our institution, 11 showed BRG1 loss, and 13 showed BRM loss. BRG1 loss was significantly more frequent in the Group2 (70%) than the Group1 (7%) (p&amp;lt;0.0001), but no significant difference was seen in the frequency of BRM loss between the two groups; 13% in the Group1and 28% in the Group2. Most cases with BRG1 loss were heavy smokers and showed components of solid adenocarcinoma, but lacked lepidic growth pattern. In contrast, cases with BRM loss frequently showed both components of solid adenocarcinoma and adenocarcinoma with lepidic growth pattern. BRG1 loss and EGFR mutations were mutually exclusive, but EGFR mutations were found in about half of the cases with BRM loss. Conclusions: BRG1 loss occurs exclusively in EGFR wild-type tumors and tumors without lepidic growth pattern. BRG1 loss might be associated with carcinogenesis of the Group 2 tumors. In contrast, BRM loss might be involved in the progression of Group1 tumors from adenocarcinoma with lepidic growth into solid adenocarcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2179. doi:1538-7445.AM2012-2179

Abstract LB-103: Conditional loss of ErbB3 delays mammary gland hyperplasias induced by mutant PIK3CA in transgenic mice, but does not affect mammary tumor latency, gene expression or signaling

Abstract The phosphatidylinositol-3-kinase (PI3K) pathway is the most frequently mutated pathway in breast cancer. Signaling through the ErbB family of receptor tyrosine kinases (RTKs) strongly activates PI3K. Six YXXM PI3K binding motifs in ErbB3 make this RTK a strong upstream activator of PI3K. Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are associated with increased PI3K activity, enhanced transformation, and drug resistance. We hypothesized that upstream receptors, such as ErbB3, are still required to localize PI3K to the plasma membrane and maximally drive tumor formation induced by mutant PI3K. To test this hypothesis, we generated a doxycycline (Dox)-inducible system in triple transgenic mice (MMTV-rtTA, Tet-Op-HA-PIK3CAH1047R-IRES-Luc and Tet-Op-Cre) which are homozygous or heterozygous for floxed ErbB3 alleles. In this model, referred to as iPI3K.iCre.ErbB3FL/FL, Dox induces the expression of PIK3CAH1047R and Cre recombinase. This results in Cre-mediated deletion of floxed ErbB3 alleles in mammary cells expressing PIK3CAH1047R. Loss of ErbB3 delayed mammary hyperplasias induced by PIK3CAH1047R in 12-week old animals. The mean mammary tumor latency of iPI3K.iCre.ErbB3FL/+ animals was 398 days compared to 419 days in iPI3K.iCre.ErbB3FL/FL animals (p=0.93). Both ErbB3FL/Fl and ErbB3+ tumors showed mixed pathologies of solid, papillary or cribiform adenocarcinomas (with and without squamous metaplasia). The heterogeneity of PI3K mutant tumors was also shown by the mixed expression of cytokeratin 8-positive (luminal-like) and cytokeratin 5-positive (basal-like) epithelial cells, which was not altered by loss of ErbB3. Microarray analysis of tumors revealed similar gene expression patterns in tumors with or without ErbB3. Immunoblot analysis of tumor lysates confirmed the absence of ErbB3 protein in iPI3K.iCre.ErbB3FL/FL tumors. However, downstream effectors of PI3K such as Akt, PDK1, SGK1, GSK3, 4EBP1 and S6 were similarly phosphorylated in tumors with and without ErbB3 expression. RTKs other than ErbB3, such as ErbB2, PDGFR, EGFR and MSPR, were phosphorylated in both tumor types. In ErbB3+ tumors, P-ErbB3 associated with p85, the regulatory subunit of PI3K, and coprecipitated with p85 antibodies. In ErbB3-deficient tumors and in breast cancer cell lines where ErbB3 was knocked down with RNAi, several P-Tyr proteins remained bound to p85, including the adaptor molecules IRS-1 and Gab2. We speculate these molecules circumvent a potential requirement for ErbB3 in cancers induced and driven by mutant PIK3CA. However, ErbB3 is required for the early mouse mammary hyperplasias induced by mutant PI3K. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-103. doi:1538-7445.AM2012-LB-103

Imaging features of small (≤3 cm) pancreatic solid tumors on gadoxetic-acid-enhanced MR imaging and diffusion-weighted imaging: an initial experience

ObjectiveThe objective was to determine imaging features that distinguish small (≤3cm) solid pancreatic adenocarcinoma, neuroendocrine tumor (NET) and solid pseudopapillary tumor (SPT) on gadoxetic-acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighed imaging (DWI). Materials and methodsTwenty-four adenocarcinomas, 10 NETs and 8 SPTs were retrospectively included. Two radiologists analyzed morphologic features, signal intensity of the tumors on MR images including DWI (b=800) and dynamic enhancement pattern with consensus. Tumor-to-parenchyma ratio and tumor apparent diffusion coefficients (ADCs) were quantitatively assessed. ResultsAll adenocarcinomas had an ill-defined margin and irregular shape, and more frequently had pancreatic duct dilatation compared with other tumors (P<.05). All SPTs and all but one of the adenocarcinomas (95.8%) had no arterial enhancement with progressively increased enhancement, whereas seven NETs (70%) had arterial enhancement with progressively decreased enhancement (P<.01). The mean value of tumor-to-parenchyma ratio on arterial and portal phases was significantly higher for NETs, and the mean value of tumor ADCs was significantly lower for SPTs than for other tumors (P<.05). ConclusionsGadoxetic-acid-enhanced MRI may aid in differentiation between small adenocarcinomas, NETs and SPTs based on morphologic features with dynamic enhancement pattern in adenocarcinomas, dynamic enhancement pattern with tumor-to-parenchyma ration on arterial and portal phases in NETs, and dynamic enhancement pattern with lower ADC value in SPTs.

Number of Circulating Endothelial Progenitor Cells and Intratumoral Microvessel Density in Non-small Cell Lung Cancer Patients: Differences in Angiogenic Status between Adenocarcinoma Histologic Subtypes

Angiogenesis plays a significant role in tumor progression. This study examined the association between the number of circulating endothelial progenitor cells (EPCs), intratumoral microvessel density (MVD) (both of which may be markers for neovascularization), and lung cancer histological types, particularly adenocarcinoma histological subtypes. A total of 83 stage I non-small cell lung cancer (NSCLC) patients underwent complete tumor resection between November 2009 and July 2010. The number of EPCs from the pulmonary artery of the resected lungs was measured by assaying CD34/vascular endothelial growth factor receptor 2 positive cells, and the MVD was assessed immunohistochemically in tumor specimens by staining for CD34. A statistically significant correlation between the number of EPCs from pulmonary artery and intratumoral MVD was found (p < 0.001). No statistically significant differences in the number of EPCs and the MVD were observed between the adenocarcinomas and the squamous cell carcinomas. Among the adenocarcinoma histological subtypes, a higher number of EPCs and MVD were found significantly more frequently in solid adenocarcinomas than in nonsolid adenocarcinomas (p < 0.001 and p = 0.011, respectively). In addition, solid adenocarcinomas showed higher levels of vascular endothelial growth factor using quantitative real-time polymerase chain reaction in the tumor tissue samples than in the nonsolid adenocarcinomas (p = 0.005). The higher number of circulating EPCs and the MVD of solid adenocarcinoma may indicate the presence of differences in the tumor angiogenic status between early-stage adenocarcinoma histological subtypes. Among adenocarcinoma patients, patients with solid adenocarcinoma may be the best candidates for antiangiogenic therapies.

A Case of Adenocarcinoma Arising within Intra-Abdominal Bronchogenic Cyst

Gastric foregut duplication cyst is a rare congenital anomaly. There have been very few reports of bronchogenic cysts in the abdominal cavity attached to the stomach. We report a case of a 57-year-old Korean man with an adenocarcinoma arising within a bronchogenic cyst of the stomach. Pathologic findings revealed ciliated columnar epithelium lining the cyst and a solid papillary adenocarcinoma involving the subserosa of the stomach and the skeletal part of the diaphragm. Surgical resection is the treatment of choice for foregut cysts of the stomach, and the possibility of malignancy should be considered in patients with gastric duplication cysts. (Korean J Med 2012;82:374-377)

Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers

EML4-ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFRwt/wt lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK-rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK-rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK-rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80–100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non-EML4-ALK ALK-rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step.

The Pim Kinases: New Targets for Drug Development

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

Abstract A94: Dose determination of LY2603618, a Chk1 inhibitor, administered in combination with gemcitabine in patients with advanced cancer.

Abstract Background: LY2603618 is a selective inhibitor of Chk1, a protein kinase that plays a key role in the DNA damage checkpoint. Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine. Methods: This study is a Phase 1–2 study in patients with solid tumors (Phase 1) and advanced pancreatic adenocarcinoma (Phase 2). In Phase 1, gemcitabine (1000 mg/m2) was administered on Days 1, 8, and 15 of a 28-day cycle. LY2603618 was administered on Days 2, 9, and 16. Patients were assessed for safety, tolerability, and dose-limiting toxicity (DLT). A recommended Phase 2 dose (RP2D) was determined based on safety, dose intensity, and pharmacokinetics (PK). Results: A total of 50 patients were enrolled. Patients were treated at 70 (n =3), 105 (n=3), 150 (n=7), 200 (n=11), 250 (n=6) mg/m2and at 2 additional flat-fixed dose cohorts of 200 (n=10) and 230 (n=10) mg. The most frequent AEs reported included fatigue, thrombocytopenia, anemia, nausea, neutropenia, and constipation, which are consistent with those reported with gemcitabine monotherapy. During escalation, DLTs included neutropenia, infusion-related reaction and thrombocytopenia, with thrombocytopenia being dose limiting. The maximum tolerated dose (MTD) was determined to be 200 mg/m2. The systemic exposure of LY2603618 increased in a dose-dependent manner and the LY2603618 systemic clearance was dose-independent across all doses on average. The mean LY2603618 half-life varied across doses but was consistent with a half-life (i.e., &amp;gt;10 hr and &amp;lt;24 hr) suitable for maintaining required human exposures while minimizing intra and intercycle accumulation. The administration of gemcitabine approximately 24 hours before LY2603618 administration did not alter LY2603618 PK. Following dose escalation, identification of the MTD and results from a population PK analysis, 2 additional flat-fixed dose cohorts of 200 and 230 mg (n=10 in each cohort) were added in an effort to minimize dose reduction/omissions of gemcitabine and reduce PK variability. At a dose of 230 mg, the plasma exposures that correlate with the maximal pharmacodynamic (PD) effect in nonclinical models (i.e., AUC(0−∞) &amp;gt;21,000 ng hr/mL and Cmax &amp;gt; 2000 ng/mL) were achieved by all but one patient. Based on safety/tolerability, the ability to maintain dose intensity, and PK, a RP2D of 230 mg was selected. A total of 17 of 30 patients received more than 2 cycles of therapy. Conclusions: LY2603618 administered in combination with gemcitabine demonstrated an acceptable safety profile; the MTD for this regimen was defined at 200 mg/m2 in the originally designed study. However at a fixed dose of 230 mg, LY2603618 in combination with gemcitabine had an acceptable safety profile and the observed exposures exceed those required for biological effect in nonclinical models. This dose is being evaluated in the Phase 2 component of the study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A94.

Histological Subtypes of Lung Adenocarcinoma Have Differential 18F-Fluorodeoxyglucose Uptakes on the Positron Emission Tomography/Computed Tomography Scan

Previous studies have shown that lung squamous cell carcinoma has higher ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) than adenocarcinoma. We hypothesized that histological subtypes of lung adenocarcinoma were also different in ¹⁸F-FDG uptake. Patients who had preoperative PET/computed tomography (CT) scan and had undergone complete resection for lung adenocarcinoma between April 2007 and December 2009 were enrolled in this study. Because of the limitation of spatial resolution on PET/CT, tumors less than 1 cm were excluded for analysis. Two independent classification systems were used to categorize histological subtypes of adenocarcinoma; one was modified from the current World Health Organization classification and the other used the morphological features of the terminal respiratory unit (TRU). The maximal standardized uptake value (SUVmax) on PET/CT and the glucose transporter type 1 (GLUT-1) expression of the tumors were measured and correlated to the histology of lung adenocarcinoma. One hundred fifty-two patients with 153 primary lung adenocarcinomas were included. There was a significant difference in SUVmax among different histological subtypes. Namely, solid predominant adenocarcinomas had significantly higher SUVmax than those with other predominant histology (p < 0.001), and TRU-type adenocarcinomas had significantly lower SUVmax than non-TRU-type adenocarcinomas (p < 0.001). Consistently, GLUT-1 expression was higher in tumors with a solid growth pattern than those without (p < 0.001) and in tumors with non-TRU type than TRU type (p < 0.001). The histological subtypes of lung adenocarcinomas differ in GLUT-1 expression and ¹⁸F-FDG uptake on the PET/CT scan, suggesting that histological subtyping not only has morphological but also biological implications.

A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

BackgroundEpidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth.MethodsWe crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice.ResultsTTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands.ConclusionUsing the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.

Response to EGFR TKIs in never smokers with stage IV EGFR mutant squamous cell carcinoma of the lung (SQCC).

e18020 Background: The NCCN guidelines for NSCLC do not support EGFR mutation testing in SQCC. This is based on the paucity of EGFR mutations (~3%) (Forbes, Nuc Acids Res, 2010) and poorly characterized predictive value of EGFR mutations in SQCC. Because lung cancers can exhibit intratumoral histologic heterogeneity in the form of adenosquamous carcinoma (AD-SQC), histology determined from small specimens (biopsy/cytology) may misdiagnose AD-SQC as pure SQCC, adding uncertainty as to the actual rate of mutations in SQCC. Evidence for this comes from detailed morphologic and IHC reassessment of EGFR mutant SQCC in small specimens which found under-sampled AD-SQC or solid adenocarcinoma (ADC) in nearly all cases (most never-smokers), whereas no mutations were identified in 50 surgically resected SQCC (Rekhtman, abstract submitted, ASCO 2011). To address management, we sought to determine the response to EGFR TKIs in the never-smokers from this series. Methods: We reviewed the patient characteristics and clinical outcomes of 7 never-smokers with stage IV EGFR mutant lung carcinoma reported as “SQCC” that on histologic and IHC reassessment were determined to represent under-sampled AD-SQC (N=6) or solid ADC (N=1). Testing for the EGFR exon 19 deletion and L858R mutation was performed as previously described. Results: See table. All patients received an EGFR TKI (erlotinib=7, afatinib+cetuximab=1). 6/7 patients were evaluable for response. ORR=50% (CR=0; PR=3; SD=3; PD=0). Median TTP=15 mo. Conclusions: We identified a series of patients initially diagnosed with EGFR mutant SQCC through small specimens in whom clinicopathologic review in all evaluable cases revealed a component of AD-SQC and in whom the benefit from an EGFR TKI approached that of EGFR mutant ADC. Never-smokers in whom diagnosis of SQCC was obtained through a small specimen should be tested for EGFR mutations and treated with an EGFR TKI accordingly. Patient Age Gender Race EGFR mutation Best response* OS (months) TTP (months) 1 61 M White Exon 19 del PR 28 12 2 76 M White Exon19 del PR 5+ N/A 3 58 M Asian L858R PR 3+ N/A 4 58 F White Exon 19 del SD 28+ N/A 5 88 F Asian L858R SD 17 8 6 71 F White Exon 19 del SD 25+ 20 7 44 F White Exon 19 del N/A 15 15 * RECIST v1.1

Antitumor and anticoagulant activities of collagen protein from the holothurian Apostichopus japonicas modified by proteolytic enzymes

A collagen preparation with antitumor and anticoagulant activity was obtained from the body of the holothurian (sea cucumber) Apostichopus japonicus treated with a complex of proteolytic enzymes. Administration of the collagen preparation inhibited in vivo growth of Ehrlich solid adenocarcinoma 2-fold (P < 0.05) and contributed to the survival of ascitic tumor-bearing mice, increasing their life span by 29.4 ± 3.2% (P < 0.05). With its moderate anticoagulant activity, this preparation is a preferential inhibitor of the initial link of the blood coagulation system. The biomedical properties and the character of the chemical structure of the collagen protein obtained from A. japonicus suggest that the mechanism of its action is similar to that of the collagen-like protein endostatin and sulfated polysaccharides. The obtained protein may be applied as a nontoxic agent of supplementary therapy for oncological and cardiovascular diseases.

Mo1424 Prospective Randomized Evaluation of Multiple Versus Single Needle Use in Endoscopic Ultrasound Guided Fine Needle Aspiration for Establishing Diagnosis of Solid Pancreatic Adenocarcinoma

Mo1424 Prospective Randomized Evaluation of Multiple Versus Single Needle Use in Endoscopic Ultrasound Guided Fine Needle Aspiration for Establishing Diagnosis of Solid Pancreatic Adenocarcinoma