Solid Lung Cancer Research Articles

Abstract 1781: HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors

Abstract Mesothelin (MSLN) is a GPI-linked tumor antigen overexpressed in a variety of solid tumors, including ovarian, pancreatic, lung and triple-negative breast cancer. Normal tissue expression is restricted to single-cell, mesothelial layers lining the pleural, pericardial, and peritoneal cavities. Overexpression of MSLN is associated with poor prognosis in lung adenocarcinoma and triple-negative breast cancer. MSLN has been used as cancer target antigen for numerous modalities, including immunotoxins, vaccines, antibody drug conjugates and CAR-T cells. Early signs of clinical efficacy have validated MSLN as target, but therapies with improved efficacy are still needed to address the significant, unmet medical need posed by MSLN-expressing cancers. HPN536 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) designed to simultaneously bind to MSLN on tumor cells and to CD3ε on T cells with an affinity of 1 nM and 14 nM, respectively. Transient bispecific binding leads to the formation of an immunological cytolytic synapse, T cell activation and redirected tumor cell killing. A third domain of HPN536 binds non-covalently to serum albumin with an affinity of 8 nM to extend serum half-life life. Because TriTACs are built using single domain antibodies, TriTACs are much smaller than full size antibodies and are anticipated to demonstrate improved penetration of human tumors compared to full sized antibodies. HPN536 is produced by eukaryotic cell culture and secreted as a highly stable, single polypeptide. It binds with similar affinity to human and cynomolgus MSLN, albumin and CD3. When incubated in co-cultures with resting, human or cynomolgus T cells and human tumor cells, T cells are induced to release cytokines, to proliferate, and to specifically lyse MSLN-positive target cells with EC50 values at single-digit picomolar concentrations. In an exploratory toxicological study in non-human primates, HPN536 was well tolerated and showed pharmacokinetics in support of weekly dosing in humans. Preclinical characterization suggests that HPN536 is an efficacious and safe novel therapeutic candidate for the convenient treatment of patients with MSLN-expressing malignancies. Citation Format: Richard Austin, Wade Aaron, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Che-Leung Law, Kathryn Kwant, Bryan Lemon, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1781.

Abstract 715: Expression of tumor cell-associated immune checkpoint molecules in multiple human solid tumors

Abstract Cancer immunotherapy using monoclonal antibodies targeting inhibitory immune checkpoint molecules is being established as a new paradigm in cancer treatment. This crucial strategy involves inhibition of the interaction between immune checkpoint receptors, expressed on the immune cells, and their respective ligands, expressed on antigen-presenting cells. While this receptor-ligand concept is well accepted in infection immunology, there have been numerous reports on the expression of immune checkpoint molecules in tumor cells. In addition to well-characterized tumor-intrinsic expression of PD11 and PD-L12, many other checkpoint molecules are associated with tumor cells3, conferring important impact on tumor biology and clinical consequences. In this study, we evaluated in situ single-cell expression profiles of immune checkpoint molecules in the tumor microenvironment (TME) of archived FFPE tissues from multiple solid cancers, including breast, kidney, ovarian, stomach, colorectal, and non-small cell lung cancer. Applying the RNAscope® assay, a highly specific and sensitive in situ hybridization (ISH) technology, tissue microarrays consisting of 20-35 FFPE tumors per each cancer type were stained for key therapeutic targets including PD1, PD-L1, TIM3, and LAG3. We observed that, in addition to PD-L1, all evaluated immune checkpoint molecules were expressed in the tumor cells of multiple tumor types though at a lower level than in immune cells. While there was notable heterogeneity of expression in different tumor regions in some samples, the single-cell expression pattern of each checkpoint molecule across all tumor cells in each region suggested a potential tumor-intrinsic mechanism for the expression of these molecules. In selected lung and ovarian cancers, fluorescence multiplex ISH-IHC staining confirmed that multiple different checkpoint molecules were co-expressed together in individual tumor cells. These findings add to the growing evidence that immune checkpoint genes can be expressed in tumor cells in addition to immune cells, which will be missed by gene expression analysis techniques using bulk tissue. The RNAscope® ISH platform is especially well suited for this type of analysis since it allows for assessing cell type-specific expression of any gene within the native tissue architecture even when it is expressed at very low levels. The approach illustrated in this study may help to better understand the anti-tumor activities of immune checkpoint inhibitors and provide new insights into better predictive biomarkers and therapeutic strategies.

The Ecstacy of Gold: Patent Expirations for Trastuzumab, Bevacizumab, Rituximab, and Cetuximab.

Fully humanized monoclonal antibodies have revolutionized the treatment of many solid tumors, including ovarian, lung, colorectal, and breast cancer. Among the most widely used monoclonal antibodies in clinical oncology are cetuximab, trastuzumab, rituximab, and bevacizumab. This is a review article focusing on the drug patents for cetuximab, trastuzumab, rituximab, and bevacizumab. These four monoclonal antibodies are used in both first and second line treatment regimens for multiple common malignancies. With recent patent expirations, pharmaceutical companies involved in biosimilar manufacture are looking to establish ownership over these financial monopolies. This article will review these four notable monoclonal antibodies, their role in clinical oncology, and the drug patents that are nearing expiration. There are currently only two biosimilars approved in the United States: the trastuzumab biosimilar trastuzumab-dkst (Ogivri) and the bevacizumab biosimilar bevacizumab-awwb (Mvasi). In Europe, SB3, a trastuzumab biosimilar, is approved for use as well as two rituzimab biosimilars, truxima and rixathon.

Histologic subtyping of poorly-differentiated solid lung cancer with molecular testing for epidermal growth factor receptor mutation and ALK gene rearrangement: an analyses of 167 cases

Objective: To study the histological subtyping of poorly differentiated solid lung cancer by using immunohistochemistry and mucin staining along with analysis of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement. Methods: Among 827 cases of non-small cell lung cancer at Beijing Hospital from April 2014 to April 2017, 167 cases of solid poorly differentiated lung cancer were identified and histopathologically subtyped by mucin staining (D-PAS) and immunohistochemistry using 10 antibodies (CK7, vimentin, Ki-67, CK5/6, p40, TTF1, Napsin A, CD56, chromogranin A, and synaptophysin). Paraffin embedded tumor samples were subjected to mutation analysis of exons 18, 19, 20 and 21 of the EGFR gene by amplification refractory mutation system (ARMS) method. Immunohistochemistry (Ventana D5F3) for ALK gene rearrangement was performed followed by ALK fluorescence in situ hybridization (FISH) verification. Results: There were 79 females and 88 males in the study cohort. The patient's age ranged from 35 to 77 years (mean 62 years). Cases with solid growth pattern (at least >10%) and without typical histological features of adenocarcinoma, squamous cell carcinoma or neuroendocrine carcinoma were further divided based on immunohistochemistry and mucin stain into 64 cases(38.32%)of adenocarcinoma, 34 cases(20.35%) squamous cell carcinoma, 21 cases(12.57%)large cell neuroendocrine carcinoma, 5 cases(2.99%)combined large cell neuroendocrine carcinoma, 2 cases(1.20%)adenosquamous carcinoma and 41 cases(24.55%)large cell carcinoma. The Ki-67 positive rate ranged from 5% to 65%. Mutations of EGFR were detected in 5 cases (2.99%, 5/167) of adenocarcinoma(19del in 3 cases and L858R in 2 cases). Two cases(1.20%, 2/167) with ALK-rearranged were identified by immunohistochemistry (Ventana D5F3) and confirmed by ALK FISH. Conclusions: Poorly differentiated solid lung cancer without distinct morphological features can be further histologically subtyped by mucin staining and immunohistochemistry. Molecular testing should be performed for accurate molecular target therapy to improve the prognosis.

Prognostic prediction of clinical stage IA lung cancer presenting as a pure solid nodule.

Clinical stage IA lung cancer presenting as a ground glass opacity (GGO) on imaging is known to be associated with a good prognosis. Conversely, the prognosis of lung cancer presenting as a pure solid nodule is less favorable. The purpose of this study was to identify the predictive factors affecting prognosis in pure solid nodule lung cancer. A total of 328 consecutive patients undergoing curative resection of clinical stage IA pure solid nodule lung cancer were reviewed retrospectively. Recurrence, survival and risk factors for nodal upstaging were analyzed. Of the 328 patients, 277 patients (84.6%) underwent lobectomy (or greater) and 51 patients (15.6%) underwent sublobar resection. Mediastinal lymph node dissection or sampling was performed in 278 patients (84.8%). The 5-year recurrence-free survival rate was 70.0% and the disease-specific survival rate was 86.5%. Intraoperative mediastinal lymph node dissection was the only significant related factor for recurrence and cancer-related death in a multivariate analysis [hazard ratio (HR) =0.485, P=0.020; HR =0.342, P=0.014]. A total of 217 patients underwent lobectomy with mediastinal lymph node dissection and nodal upstaging occurred in 36 patients (16.6%). There were no significant predictive factors for nodal upstaging in a multivariate analysis. Visceral pleural invasion, lymphovascular invasion, and small cell carcinoma histology were the only identified risk factors for nodal upstaging (HR =3.858, P=0.006; HR =8.792, P<0.001; HR =45.908, P=0.017). There were no definite factors predictive of prognosis in clinical stage IA pure solid nodule lung cancer. Only accurate pathologic staging and adequate intraoperative lymph node dissection were shown to be related to prognosis.

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics.

Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Low- and middle-income countries can reduce risks of subsequent neoplasms by referring pediatric craniospinal cases to centralized proton treatment centers

Few children with cancer in low- and middle-income countries (LMICs) have access to proton therapy. Evidence exists to support replacing photon therapy with proton therapy to reduce the incidence of secondary malignant neoplasms (SMNs) in childhood cancer survivors. The purpose of this study was to estimate the potential reduction in SMN incidence and in SMN mortality for pediatric medulloblastoma (MB) patients in LMICs if proton therapy were made available to them. For nine children of ages 2–14 years, we calculated the equivalent dose in organs or tissues at risk for radiogenic SMNs from therapeutic and stray radiation for photon craniospinal irradiation (CSI) in a LMIC and proton CSI in a high-income country. We projected the lifetime risks of SMN incidence and SMN mortality for every SMN site with a widely-used model from the literature. We found that the average total lifetime attributable risks of incidence and mortality were very high for both photon CSI (168% and 41%, respectively) and proton CSI (88% and 26%, respectively). SMNs having the highest risk of mortality were lung cancer (16%), non-site-specific solid tumors (16%), colon cancer (5.9%), leukemia (5.4%), and for girls breast cancer (5.0%) after photon CSI and non-site-specific solid tumors (12%), lung cancer (11%), and leukemia (4.8%) after proton CSI. The risks were higher for younger children than for older children and higher for girls than for boys. The ratios of proton CSI to photon CSI of total risks of SMN incidence and mortality were 0.56 (95% CI, 0.37–0.75) and 0.64 (95% CI, 0.45–0.82), respectively, averaged over this sample group. In conclusion, proton therapy has the potential to lessen markedly subsequent SMNs and SMN fatalities in survivors of childhood MB in LMICs, for example, through regional centralized care. Additional methods should be explored urgently to reduce therapeutic-field doses in organs and tissues at risk for SMN, especially in the lungs, colon, and breast tissues.

Quantitative CT density histogram values and standardized uptake values of FDG-PET/CT with respiratory gating can distinguish solid adenocarcinomas from squamous cell carcinomas of the lung

PurposeTo assess the ability of parameters derived from computed tomography (CT) histograms and the maximum standardized uptake value (SUVmax) of 18F-fludeoxyglucose-positron emission tomography/CT (FDG-PET/CT) images to distinguish solid lung adenocarcinomas from squamous cell carcinomas and to determine if these parameters are correlated. MethodsThis study comprised 43 consecutive patients with solid lung cancer (<3 cm in diameter), who underwent both plain chest CT and FDG-PET/CT (adenocarcinoma, n = 25; squamous cell carcinoma, n = 18). Density histograms of targeted lung cancers were created from chest CT images, and kurtosis and skewness were calculated. On FDG-PET/CT, the SUVmax without/with respiratory gating (RG) were calculated for each lesion. The values for the 4 parameters determined for patients in each diagnostic group were compared by the Mann-Whitney test. The diagnostic characteristics of the parameters were assessed by receiver operating characteristic (ROC) curve analysis. Differences between these parameters were assessed by the chi-square test. SUVmax with RG, kurtosis, and skewness were combined for binary logistic regression analysis, and the differences between the combined parameters and SUVmax with RG were also assessed. Spearman rank correlation analysis was used to determine the correlations for kurtosis or for skewness with SUVmax without/with RG. ResultsThe differences in kurtosis and SUVmax without/with RG between the diagnostic groups were significant (kurtosis, P < 0.004; SUVmax without/with RG both P < 0.0001). ROC curve analysis indicated that each parameter (kurtosis value, skewness value, SUVmax, without/with RG) provided low-high ability to differentiate between 2 groups (area under the curve [AUC]: 0.760, 0.593, 0.900, 0.931, respectively). The ROC of the combined parameters provided the highest ability (AUC: 0.949). Both kurtosis and skewness were significantly correlated with SUVmax without/with RG. Kurtosis and SUVmax with RG were most strongly correlated (ρ = 0.618). ConclusionQuantitative CT histogram values and SUV assessment can differentiate solid lung adenocarcinomas from squamous cell carcinomas. Kurtosis and SUVmax values were strongly correlated. The addition of RG and further combination of the parameters improved the results.

ES 05.05 Lung Cancer Surgery for High Risk Patients

ES 05.05 Lung Cancer Surgery for High Risk Patients

Abstract 38: Target validation, antibody discovery and preclinical data supporting ADAM9 as an antibody-drug conjugate therapeutic target for solid tumors

Abstract Introduction: A target-unbiased approach based on intact cell immunizations with fetal progenitor cells and cancer stem cells, followed by an immunohistochemistry (IHC) screen for cancer-specific candidates, led to the identification of anti-ADAM9 (a disintegrin and metalloproteinase) mAbs with highly differential tumor-versus-normal tissue binding. ADAM9 is a cell surface protein over-expressed in multiple tumors, with a possible role in promotion and progression of cancer through multiple mechanisms, including modulation of adhesion and migration as well as processing of tumorigenic and pro-angiogenic factors. In this preclinical study, we performed target/mAb validation and evaluated the therapeutic potential of anti-ADAM9 antibody-drug conjugates (ADCs) toward ADAM9-expressing solid cancers. Methods: IHC was performed with anti-ADAM9 mAbs to confirm and extend available data of human normal and tumor tissue expression. Epitope mapping studies were conducted to define epitope-specificity. mAbs were also screened to identify those that efficiently internalized into tumor cells. In vitro cellular processing studies were performed to further evaluate the mAbs as ADC candidates. Selected mAbs were converted to ADCs via chemical conjugation to potent anti-microtubule (DM4) or DNA alkylating (DGN549) agents; in vitro cytotoxicity studies were conducted with tumor cell lines representing human cancer types that overexpress ADAM9. A lead mAb was then selected for humanization and affinity maturation to yield a development candidate. Results: Anti-ADAM9 mAbs exhibited strong reactivity toward the tumor epithelium of solid cancers, including pancreatic, kidney, prostate, bladder, breast, colon, lung, and ovarian cancer, but limited reactivity toward normal tissues. Anti-ADAM9 mAbs were efficiently internalized and processed by tumor cell lines, including lines with only modest ADAM9 expression. Anti-ADAM9 ADCs exhibited specific, dose-dependent cytotoxicity toward ADAM9-positive cancer cell lines in vitro, with IC50 values in the sub-nanomolar range. Humanization and affinity maturation of the lead mAb yielded a development candidate that retains potent antitumor activity toward ADAM9-positive tumor cell lines and equivalent, high affinity binding to both human and cynomolgus monkey ADAM9. Conclusion: ADAM9 is a cell surface antigen that is over-expressed on a wide range of solid cancers. Anti-ADAM9 mAbs that were strongly reactive with representative tumors exhibited high affinity for the antigen and were efficiently internalized and processed by ADAM9-bearing tumor cells. Anti-ADAM9 ADCs demonstrated dose-dependent cytotoxicity in vitro toward a panel of ADAM9-positive tumor cell lines. Our findings demonstrate that an ADC targeting ADAM9 may serve as a potential therapeutic for ADAM9-expressing solid tumors. Citation Format: Juniper A. Scribner, Bhaswati Barat, Stuart W. Hicks, Nicholas C. Yoder, Thomas Son, Lusiana Widjaja, Gundo Diedrich, Sergey Gorlatov, Jeff Hooley, Ann Easton, Peter Lung, Anushka De Costa, Francine Chen, Michael Chiechi, Pam Li, Monica Licea, Timothy E. Hotaling, Michael Spliedt, Valentina Ciccarone, Nadia Gantt, James Tamura, Megan E. Fuller, Molly McShea, Scott Koenig, Syd Johnson, Paul A. Moore, Ezio Bonvini, Deryk Loo. Target validation, antibody discovery and preclinical data supporting ADAM9 as an antibody-drug conjugate therapeutic target for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 38. doi:10.1158/1538-7445.AM2017-38

Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition

Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition. NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line. RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.

MA10.05 Proposals for the Novel Clinical T Categories Based on the Presence of Ground Glass Opacity Component in Lung Adenocarcinoma

In lung adenocarcinomas, the histologic lepidic growth pattern tends to correlate with the ground glass opacity (GGO) component, while solid components correspond with invasive adenocarcinoma. The Eighth edition of the TNM staging system suggests that the tumor size be determined according to the invasive size excluding the lepidic component. However, this new concept causes fatal confusion, i.e., tumors are classified into a same T category despite the part-solid or pure-solid appearances provided they showed a same solid component size. Between 2008 and 2012, we retrospectively evaluated 719 surgically resected cN0 lung adenocarcinomas that measures 30mm or less in total dimension to assess the prognostic impact on the presence of GGO among the Eighth TNM classification. According to the new T category, it was defined based on the solid component size as follow: Tis; 0 cm (pure-GGO), T1mi; ≤ 5 mm, T1a; 6-10 mm, T1b; 11-20 mm, T1c; 21-30mm. Furthermore, all tumors were classified into 2 groups, i.e., GGO or Solid arms based on the presence of GGO component. Of the cases, 133 (18%) were categorized in Tis, 88 (12%) in T1mi, 121 (17%) in T1a, 244 (34%) in T1b and 133 (19%) in T1c, respectively. Multivariate analysis revealed that both a presence of GGO and solid component were independently significant prognostic factors (p=0.007, 0.002). The 5y-overall survival (OS) was 99.2% in Tis, 95.8% in T1mi, 96.5% in T1a, 81.8% in T1b and 66.4% in T1c (p=0.038) with a median follow-up period of 56 months. When we evaluated the impact of T category based on GGO presence, the 5y-OS was significantly different between GGO and Solid arm in each T categories (T1a; 99.0% vs. 95.7%, p=0.045, T1b; 89.8% vs. 73.3%, p=0.004, T1c; 90.0% vs. 62.6%, p=0.046). Furthermore, clinical T categories significantly separated the OS in Solid arm (p=0.015) (T1a vs. T1b; p=0.090, T1b vs. T1c; p=0.037). In contrast, the 5y-OS was approximately 90% or more in GGO arm despite their T categories. Moreover, regarding radiological and pathological correlations, the rates of AIS was only 65% in Tis, and 51% showed invasive adenocarcinoma even in T1mi. Clinical T category should be considered based on the presence of GGO on thin-section CT, and tumor size should be applied exclusively to radiological solid lung cancer. In contrast, oncological outcomes of the tumor with GGO component were excellent despite their T categories, which should be described as Tis for pure-GGO, and T1a for part-solid tumor.

SEOM Clinical Guideline for bone metastases from solid tumours (2016)

Bone metastases are common in many advanced solid tumours, being breast, prostate, thyroid, lung, and renal cancer the most prevalent. Bone metastases can produce skeletal-related events (SREs), defined as pathological fracture, spinal cord compression, need of bone irradiation or need of bone surgery, and hypercalcaemia. Patients with bone metastases experience pain, functional impairment and have a negative impact on their quality of life. Several imaging techniques are available for diagnosis of this disease. Bone-targeted therapies include zoledronic acid, a potent biphosfonate, and denosumab, an anti-RANKL monoclonal antibody. Both reduce the risk and/or delay the development of SREs in several types of tumours. Radium 233, an alpha-particle emitter, increases overall survival in patients with bone metastases from resistant castration prostate cancer. Multidisciplinary approach is essential and bone surgery and radiotherapy should be integrated in the treatment of bone metastases when necessary. This SEOM Guideline reviews bone metastases pathogenesis, clinical presentations, lab tests, imaging techniques for diagnosis and response assessment, bone-targeted agents, and local therapies, as radiation and surgery, and establishes recommendations for the management of patients with metastases to bone.

Influence of PEG Molecular Weight on the Drug Release and In vitro Cytotoxicity of Single-Walled Carbon Nanotubes-PEG-Gemcitabine Conjugates.

Gemcitabine (GEM) is a highly hydrophil anticancer drug which extensively used in the clinic for the treatment of a range of solid tumors, including pancreatic and lung cancers. We have designed a drug delivery system based on single-walled carbon nanotubes (SWCNTs) for the anticancer drug GEM, which has limitations under biological conditions, by using polyethylene glycol (PEG) to obtain nanoconjugates with high loading capacity, controlled drug release and effective cytotoxicity. Raw SWCNTs were functionalized through carboxylation, acylation, PEGylation and finally GEM conjugation via a cleavable ester bond. Different characterization techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectrometer (NMR) and differential scanning calorimetry analysis (DSC) were performed to confirm the successful functionalization. Next, the influence of molecular weight (MW) of PEG on the drug loading capacity, drug release and cytotoxicity was studied. Experimental results showed that the drug loading capacity was dependent on the MW of PEG, but the drug release was independent. Also, the results revealed that the nanoconjugates with lower PEG MW caused higher cytotoxicity in A549 and MIA PaCa-2 cancer cells. Our studies indicated which of PEG MWs could be useful for this drug delivery system.

Impact of whole tumor size in part-solid non-small cell lung cancer

In the recent issue of Annals of Thoracic Surgery, Hattori et al . reported the impact of the maximum tumor size and solid component size on the prognosis of patients with non-small cell lung cancer (NSCLC) (1). They evaluated 1,181 surgically resected cases of clinical N0 M0 NSCLC. The patients were divided into three groups according to the radiologically determined consolidation tumor ratio (CTR): the pure ground-glass opacity (GGO) group (CTR =0; n=168), the part-solid (0<CTR<1; n=448) group and the solid (CTR =1; n=565) group. The authors reported that the tumor size had a significantly impact on the 5-year overall survival (OS) of patients with radiologically solid tumors (≤20 mm, 83%; 21–30 mm, 75.4%; 31–50 mm, 56.2%; ≥51 mm, 45.3%; P<0.0001). In contrast, the tumor size did not influence the 5-year OS of patients with radiologically pure GGOs (100%, regardless of the tumor size) or part-solid tumors (≤20 mm, 97.7%; 21–30 mm, 94.6%; 31–50 mm, 93.4%; P=0.1028). In addition, the size of the solid component and CTR were not associated with OS in patients with part-solid tumor. They therefore concluded that the impact of maximum tumor size should only be applied to radiologically solid lung cancer (1).

Clinical and Therapeutic Implications of Follistatin in Solid Tumours.

Follistatin (FST), as a single-chain glycosylated protein, has two major isoforms, FST288 and FST315. The FST315 isoform is the predominant form whilst the FST288 variant accounts for less than 5% of the encoded mRNA. FST is differentially expressed in human tissues and aberrant expression has been observed in a variety of solid tumours, including gonadal, gastric and lung cancer, hepatocellular carcinoma, basal cell carcinoma and melanoma. Based on the current evidence, FST is an antagonist of transforming growth factor beta family members, such as activin and bone morphogenetic proteins (BMPs). FST plays a role in tumourigenesis, metastasis and angiogenesis of solid tumours through its interaction with activin and BMPs, thus resulting in pathophysiological function. In terms of diagnosis, prognosis and therapy, FST has shown strong promise. Through a better understanding of its biological functions, potential clinical applications may yet emerge.

Targeting Stim and Orai Proteins as an Alternative Approach in Anticancer Therapy.

An increase in intracellular Ca2+ concentration plays a key role in the establishment of many cancer hallmarks, including aberrant proliferation, migration, invasion, resistance to apoptosis and angiogenesis. The dysregulation of Ca2+ entry is one of the most subtle mechanisms by which cancer cells overwhelm their normal counterparts and gain the adaptive advantages that result in tumour growth, vascularisation and dissemination throughout the organism. Both constitutive and agonist-induced Ca2+ influx may be mediated by store-dependent as well as store-independent Ca2+ entry routes. A growing body of evidences have shown that different isoforms of Stromal Interaction Molecules (Stim1) and Orai proteins, i.e. Stim1, Stim2, Orai1 and Orai3, underlie both pathways in cancer cells. The alteration in either the expression or the activity of Stim and Orai proteins has been linked to the onset and maintenance of tumour phenotype in many solid malignancies, including prostate, breast, kidney, esophageal, skin, brain, colorectal, lung and liver cancers. Herein, we survey the existing data in support of Stim and Orai involvement in tumourigenesis and provide the rationale to target them in cancer patients. Besides, we summarize the most recent advances in the identification of novel pharmacological tools that could be successfully used in clinical therapy.

Thyroid Function and Cancer Risk: The Rotterdam Study.

In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results. We aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting. The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available. Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically. Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval [CI], 1.12-1.79), lung cancer (HR, 2.33; 95% CI, 1.39-3.92) and breast (HR, 1.77; 95% CI, 1.10-2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk. Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment.

The NF-κB signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-κB can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-κB signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-κB. There is growing interest in identifying novel modulators to inhibit NF-κB activity as impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 4302-8. ©2016 AACR.

A study of CT perfusion imaging before and after radiotherapy for solid lung cancer

Objective To analyze the perfusion status of lung cancer before radiotherapy and the relationship between changes in CT perfusion parameters after radiotherapy and the efficacy of radiotherapy. Methods Twenty-eight patients clinically and pathologically diagnosed with lung cancer were enrolled as subjects. Those patients received CT perfusion imaging scan and perfusion parameters including blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface (PS) were calculated. We use linear correlation analysis for relation between value of CT perfusion imaging and the target volume of lung cancer before radiotherapy, t-test for difference between the remission groups and non-remission groups, compared paired sample t-test for value of CT perfusion imaging before and after radiotherapy. Results According to the efficacy of radiotherapy, 28 patients with lung cancer were divided into response group (n=16) and non-response group (n=12). The response group had significantly smaller tumor sizes before and after radiotherapy than the non-response group (58.72±22.95 cm3vs.24.53±13.79 cm3, P=0.000). However, there was no significant correlation of target volume before radiotherapy with any perfusion parameter (P=0.628). The response group had significantly larger BF and BV than the non-response group before radiotherapy (1.23±1.36 vs.6.42±2.57, P=0.024 and 1.23±0.31 vs.0.59±0.18, =0.041), suggesting a low perfusion state of tumor tissue in the non-response group. However, there were no significant differences in MTT and PS between the two groups (0.93±0.58 vs.0.93±0.66, P=0.851 and 1.46±0.83 vs.1.17±0.56, P=0.141). All the 28 patients had significantly smaller BF, BV, MTT, and PS after radiotherapy (9.81±3.56 vs.7.48±3.31, P=0.006; 0.96±0.41 vs.0.64±0.38, P=0.003; 0.93±0.60 vs.0.53±0.30, P=0.007; 1.34±0.73 vs.0.74±0.44, P=0.001). Conclusions CT perfusion imaging can predict the efficacy of radiotherapy for lung cancer, which may guide the planning and implementation of precise radiotherapy for lung cancer. Key words: Perfusion imaging; Blood flow; Lung neoplasms/radiotherapy