Primary Tumor Invasion Research Articles

Skull base aneurysms: a retrospective review of fifteen cases focusing on the involvement of internal carotid artery

Objective: To explore the diagnosis and clinical features of internal carotid artery aneurysm in the skull base. Methods: The data of 15 patients with internal carotid aneurysms in the skull base diagnosed and treated by digital subtraction angiography (DSA) or CT angiography (CTA) in the Provincial Hospital Affiliated to Shandong First Medical University from 1995 to 2017 were collected and analyzed. Among the 15 patients, 12 were males, and 3 were females, aging from 17 to 67 years old, with a median age of 44 years. Thirteen patients were diagnosed by DSA; the other two patients were diagnosed by CTA. Thirteen patients were diagnosed with pseudoaneurysm with the first symptom of epistaxis, in which eight patients underwent head trauma and 5 underwent radiotherapy of skull base tumor. The other two patients were diagnosed with true aneurysm presented headache and cranial nerve disorder. All patients were followed up for 2 to 12 years after treatment to see whether they were cured and survived. Results: Among the eight patients with a history of trauma, five patients were cured by embolization, two patients without embolization died of massive epistaxis, one patient died of progressive cerebral infarction after embolization. Among the five patients with radiotherapy of skull base tumor, one patient died of cerebral infarction after embolization, two patients died out of the hospital due to the recurrence of the primary tumor and intracranial invasion, one patient recovered well after embolization and surgical operation, one patient gave up treatment and died of massive hemorrhage out of hospital. In the other two patients with symptom of headache, one received embolization treatment outside the hospital after receiving mistake operation, and another one gave up treatment and died due to personal reasons. In total, four patients died in hospital, four died out of the hospital, and seven patients survived. Conclusions: Internal carotid artery aneurysm is a high-risk disease of anterior and middle skull base. For patients with epistaxis with a history of trauma and radiotherapy or patients with headaches and cranial nerve disorders, the possibility of the internal carotid artery aneurysm should be considered, in which DSA or CTA examination is essentially required for ensured diagnosis and disease evaluation.. The correct diagnosis and treatment by the otolaryngologist are crucial to the prognosis of the patient.

Identification of differentially expressed proteins and clinicopathological significance of HMGB2 in cervical cancer

To investigate the complexity of proteomics in cervical cancer tissues, we used isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry analysis on a panel of normal cervical tissues (N), high-grade squamous intraepithelial lesion tissues (HSIL) and cervical cancer tissues (CC). Total 72 differentially expressed proteins were identified both in CC vs N and CC vs HSIL. The expression of HMGB2 was markedly higher in CC than that in HSIL and N. High HMGB2 expression was significantly correlated with primary tumor size, invasion and tumor stage. The up-regulated HMGB2 was discovered to be associated with human cervical cancer. These findings suggest that HMGB2 may be a potentially prognostic biomarker and a target for the therapy of cervical cancer.

Acetylcholinesterase and human cancers.

The enzyme acetylcholinesterase (AChE) is a serine hydrolase whose primary function is to degrade acetylcholine (ACh) and terminate neurotransmission. Apart from its role in synaptic transmission, AChE has several "non-classical" functions in non-neuronal cells. AChE is involved in cellular growth, apoptosis, drug resistance pathways, response to stress signals and inflammation. The observation that the functional activity of AChE is altered in human tumors (relative to adjacent matched normal tissue) has raised several intriguing questions about its role in the pathophysiology of human cancers. Published reports show that AChE is a vital regulator of oncogenic signaling pathways involving proliferation, differentiation, cell-cell adhesion, migration, invasion and metastasis of primary tumors. The objective of this book chapter is to provide a comprehensive overview of the contributions of the AChE-signaling pathway in the growth of progression of human cancers. The AChE isoforms, AChE-T, AChE-R and AChE-S are robustly expressed in human cancer cell lines as well in human tumors (isolated from patients). Traditionally, AChE-modulators have been used in the clinic for treatment of neurodegenerative disorders. Emerging studies reveal that these drugs could be repurposed for the treatment of human cancers. The discovery of potent, selective AChE ligands will provide new knowledge about AChE-regulatory pathways in human cancers and foster the hope of novel therapies for this disease.

Overexpression of a Long Non-Coding RNA BC037916 is Associated with Pancreatic Tumorigenesis and Poor Prognosis.

BackgroundPancreatic cancer is one of the most lethal malignancies. Accumulating evidence supports for the critical contribution of long noncoding RNAs (lncRNAs) to the cancer development and progression. We tried to identify novel lncRNAs involved in the pancreatic carcinogenesis.Materials and MethodsTwo independent datasets (Gene Expression Omnibus datasets: GSE16515 and GSE32688) were obtained from the Gene Expression Omnibus (GEO). The level of BC037916 was detected in pancreatic cancer tissues and adjacent no-tumorous tissues (n=86) by qRT-PCR. Effects of BC037916 on proliferation, apoptosis, and invasion of pancreatic cancer cells were examined.ResultsWe identified a novel lncRNA BC037916 involved in the pancreatic carcinogenesis by analyzing GEO datasets. Quantitative RT-PCR analysis showed that 86.0% (74/86) pancreatic cancer tissues had increased BC037916 expression as compared with normal counterparts. Further, positive correlation was observed between BC037916 expression and clinical stage, primary tumor, and regional lymph node invasion. Importantly, BC037916 was an independent prognostic factor of pancreatic cancer. Functionally, knockdown of BC037916 repressed cell proliferation, inhibited cell invasion, halted cell cycle progression, and promoted apoptosis in both PANC-1 and SW1990 cells. In contrast, overexpression of BC037916 in CAPAN-1 had opposite effects. Moreover, silencing of BC037916 significantly inhibited the tumor growth of xenografted SW1990 cells in vivo. Results of Western blot assays suggested that BC037916 knockdown also suppressed the activation of JAK2/STAT3 and TGF-β signaling. Further experiments suggested that BC037916 positively regulated the expression of Twist through miR-3145-3p.ConclusionBC037916 exhibited oncogenic potential in pancreatic cancer development.

Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.

Tumor cell MT1-MMP is dispensable for osteosarcoma tumor growth, bone degradation and lung metastasis

The membrane-anchored matrix metalloprotease MT1-MMP is a potent collagenolytic enzyme with a well-established role in extracellular matrix turnover and cellular invasion into collagen-rich tissues. MT1-MMP is highly expressed in various types of cancer and has been demonstrated to be directly involved in several stages of tumor progression, including primary tumor growth, angiogenesis, invasion and metastasis. Osteosarcoma is the most common type of primary bone cancer. This disease is characterized by invasive tumor growth, leading to extensive bone destruction, and metastasis to the lungs. The tumor cells in human osteosarcoma display a strong expression of MT1-MMP, but the role of MT1-MMP in osteosarcoma progression is currently unknown. In this study, we investigated the role of MT1-MMP during various stages of osteosarcoma development. We utilized an optimized orthotopic murine osteosarcoma model and human osteosarcoma cells in which the MT1-MMP gene was knocked out using CRISPR/Cas9. We observed a strong expression of MT1-MMP in wildtype cells of both primary tumors and lung metastases, but, surprisingly, MT1-MMP deficiency did not affect primary tumor growth, bone degradation or the formation and growth of lung metastases. We therefore propose that, unlike findings reported in other cancers, tumor-expressed MT1-MMP is dispensable for all stages of osteosarcoma progression.

Smoking cessation and survival among people diagnosed with non-metastatic cancer

BackgroundWe aimed to estimate the effects of smoking cessation on survival among people diagnosed with cancer.MethodsWe used data from a Comprehensive Community Cancer Program that is part of a large urban safety-net hospital system. Eligible patients were diagnosed with primary invasive solid tumors between 2013 and 2015, and were current smokers at time of diagnosis. Our exposure of interest was initiation of smoking cessation within 6 months of cancer diagnosis. We estimated inverse probability weighted restricted mean survival time (RMST) differences and risk ratio (RR) for all cause 3-year mortality.ResultsOur study population comprised 369 patients, of whom 42% were aged < 55 years, 59% were male, 44% were racial/ethnic minorities, and 59% were uninsured. The 3-year RMST was 1.8 (95% CL: − 1.5, 5.1) months longer for individuals who initiated smoking cessation within 6 months of cancer diagnosis. The point estimate for risk of 3-year mortality was lower for initiation of smoking cessation within 6 months of diagnosis compared with no initiation within 6 months (RR = 0.72, 95% CL: 0.37, 1.4).ConclusionsOur point estimates suggest longer 3-year survival, but the results are compatible with 1.5 month shorter or 5.1 longer 3-year overall survival after smoking cessation within 6 months of cancer diagnosis. Future studies with larger sample sizes that test the comparative effectiveness of different smoking cessation strategies are needed for more detailed evidence to inform decision-making about the effect of smoking cessation on survival among cancer patients.Implications for Cancer survivorsThe benefits of smoking cessation after cancer diagnosis may include longer survival, but the magnitude of benefit is unclear.

CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways.

Increased Stiffness Inhibits Invadopodia Formation and Cell Migration in 3D

Cancer cells typically invade through basement membranes (BMs) at key points during metastasis, including primary tumor invasion, intravasation, and extravasation. Cells extend invadopodia protrusions to create channels in the nanoporous BM through which they can invade, either via proteolytic degradation or mechanical force. Increased matrix stiffness can promote cancer progression, and two-dimensional (2D) culture studies indicate that increased stiffness promotes invadopodia degradation activity. However, invadopodia can function mechanically, independent of their degradative activity, and cells do not form fully matured invadopodia or migrate in the direction of the invadopodia in 2D environments. Here, we elucidated the impact of matrix stiffness on the mechanical mode of invadopodia activity of cancer cells cultured in three-dimensional BM-like matrices. Invadopodia formation and cell migration assays were performed for invasive breast cancer cells cultured in mechanically plastic, nanoporous, and minimally degradable interpenetrating networks of reconstituted BM matrix and alginate, which presented a range of elastic moduli from 0.4 to 9.3 kPa. Across this entire range of stiffness, we find that cells form mature invadopodia that often precede migration in the direction of the protrusion. However, at higher stiffness, cells form shorter and more transient invadopodia and are less likely to extend invadopodia overall, contrasting with results from 2D studies. Subsequently, cell migration is diminished in stiff environments. Thus, although previous studies indicate that increased stiffness may promote malignant phenotypes and the degradative activity of invadopodia, our findings show that increased stiffness physically restricts invadopodia extension and cell migration in three-dimensional, BM-like environments.

Characteristics and prognosis of primary malignant melanoma of the esophagus.

Primary malignant melanoma of esophagus (PMME) is a rare malignant tumor of esophagus. This study aimed to investigate the clinic pathologic characteristics and analyze the factors that might affect the prognosis of PMME patients.A total of 20 PMME patients who underwent surgical treatment in our hospital from 1975 to 2017 were analyzed. The clinical data, surgical and pathologic features of all patients were collected.For 20 PMME patients, the average age was 57.3 ± 10.7 years, and the male patients account for 75%. Most of the tumors (95%) were located in the middle and lower of the esophagus. There were 7 patients with primary tumor invasion beyond the muscular layer (T3 + T4) and 10 patients with lymph node metastasis (LNM). The median survival time of 20 patients was 12 months, and the 1-year and 5-year survival rates were 50% and 16.9%, respectively. The probability of LNM in tumors confined to submucosa (T1) and myometrium (T2) was lower than that in tumors with deeper invasion (T3, T4) (P = .035). Multivariate analysis showed that tumor node metastasis (TNM) staging was the independent prognostic factor for survival of PMME patients (hazard ratio [95% confidence interval], 4.15 [1.36–12.67]; P = .012).For PMME patients, tumors with deeper invasion were more likely to have LNM, and TNM staging was an independent predictor of prognosis for survival. Early detection of the disease and radical resection of the tumor are critical for better survival of the PMME patients.

Association of Single-Nucleotide Polymorphism (rs833061) of Vascular Endothelial Growth Factor with Breast Cancer Risk

Background: Breast cancer is the most common cancer among women and one of the most important causes of death among them. Angiogenesis is an important step for primary tumor growth, invasiveness, and metastases. Vascular endothelial growth factor (VEGF) is involved in angiogenesis associated with tumors. Objective: To investigate the association of single nucleotide polymorphisms (SNPs) of VEGF gene located in the promoter region at position 460T/C (rs833061) with the risk of breast cancer. Patients and Methods: This study was conducted on (40) Egyptian female patients who were diagnosed as breast cancer according to histopathological examination of breast biopsy (Group 1, Patients), in addition to (40) age-matched apparently healthy females serving as controls (Group II, Controls). Detection of SNP of VEGF gene located in the promoter region 460T/C (rs833061) was done by real-time polymerase chain reaction technique. Results: There was no significant difference in frequency of the (C/C, T/C and T/T) genotypes of VEGF 460T/C (rs833061) in group I compared with group II (p>0.05). None of the studied VEGF genotypes had shown significant difference in distribution related to clinico-pathological parameters as tumor size, histological grade, hormone receptors, HER2/new status, regional lymph node and distant metastasis (p>0.05). Conclusion: This study revealed that there was no significant association of the (C/C, T/C and T/T) genotypes of VEGF 460T/C (rs833061) and breast cancer risk. Moreover, VEGF polymorphism 460T/C (rs833061) was not associated with breast cancer patients’ clinico-pathological characteristics and tumor markers levels.

Serum proteome profiling reveals SOX3 as a candidate prognostic marker for gastric cancer.

Searching for the novel tumour biomarkers is pressing for gastric cancer diagnostication and prognostication. The serum specimens from patients diagnosed with locally advanced gastric carcinoma before operation and 4 week after surgery were collected, respectively, and serum proteome profiling was conducted by liquid chromatography–mass spectrometry (MS)/MS. Fifty‐five proteins were identified to be up‐regulated and 16 proteins were down‐regulated, and these differentially expressed proteins participated in various biological processes. Serum levels of SOX3, one of down‐regulated proteins, in stomach cancer patients were higher than in healthy controls. SOX3 levels in cancer tissues were remarkably related to tumour differentiation, lymph node metastasis, primary tumour invasion and pTNM (pathological TNM) stage. Analysis with The Cancer Genome Atlas database indicated that SOX3 level and pTNM stage were the independent risk factors for the patient survival and that the overall survival was negatively associated with the SOX3 levels. Loss‐of‐function showed that SOX3 promoted gastric cancer cell invasion and migration in vitro and in vivo. SOX3 silence inhibits the expression of MMP9, and SOX3 is responsible for MMP9 expression transcriptionally. Our study highlights the potentiality of the paired pre‐ and post‐operation serum proteome signatures for the detection of biomarkers and reveals that SOX3 may serve as a candidate prognosis marker for gastric cancer.

Video-assisted thoracoscopic surgery is safe and reliable for large and invasive primary mediastinal tumors.

IntroductionVideo-assisted thoracoscopic surgery (VATS) was not considered for the treatment of primary mediastinal tumors of large sizes or with local invasion.AimTo investigate the clinical outcomes of VATS for large and invasive mediastinal tumors.Material and methodsOne hundred and thirteen patients with primary mediastinal tumors were treated by VATS. Twenty-nine patients had bulky tumors (diameter > 6 cm) and 5 patients had invasive tumors. Clinical data were documented and compared.ResultsNo patients suffered from any complications after VATS. No relapse or metastasis occurred in the patients with bulky tumors, while 1 patient with invasive thymoma suffered a relapse after VATS. The 2-year disease-free survival and overall survival in patients with bulky tumors were 100% and 100%, while those in patients with invasive tumors were 75% and 100%. There were no differences in hospital stay after VATS between the patients with bulky tumors and smaller tumors, nor between the patients with invasive tumors and non-invasive tumors. Patients with bulky tumors lost more blood than those with smaller tumors, while more blood loss occurred in patients with invasive tumors than non-invasive tumors. Longer operative time was needed for patients with bulky tumors and invasive tumors. Mediastinal tumors with large size or invasion should not be contraindicated for VATS. The prognosis of such patients treated with VATS was comparable to that of traditional open surgery.ConclusionsVATS is a safe and effective procedure for large and invasive mediastinal tumors.

Correlation of CXCR4 expression with clinicopathological characteristics and prognosis of patients with non-small cell lung cancer: a Meta-analysis

Objective To systematically evaluate the relationship between CXCR4 and the clinicopathological characteristics and prognosis of patients with non-small cell lung cancer (NSCLC). Methods The PubMed, EMbase, Cochrane Library, CNKI, Wanfang and China Biology Medicine databases were searched by the computer to collect the publicly published cohort studies on the correlation between CXCR4 expression and prognosis of NSCLC. The retrieval time was from the establishment of the database to May 31, 2018. Literature screening, data extraction and risk of bias were performed independently by two reviewers, and Meta-analysis was performed by using Stata 12.0 software. Results Finally, 20 studies were included, with a total of 2 124 NSCLC patients. The positive expression rate of CXCR4 in patients with adenocarcinoma was 51.8% (337/650) and it was 50.3% (224/445) in patients with squamous cell carcinoma, the difference was statistically significant (RR=1.22, 95% CI 1.09-1.38, P=0.001). The positive expression rate of CXCR4 in patients with stageⅠ-Ⅱ was 41.1% (317/772), and the rate was 57.0% (348/610) in patients with stage Ⅲ-Ⅳ, the difference was statistically significant (RR=0.62, 95% CI 0.55-0.69, P < 0.01). The positive expression rate of CXCR4 in patients with distant metastasis was 55.3% (268/485), and the positive rate of CXCR4 in those without distant metastasis was 39.2% (256/653), the difference was statistically significant (RR=1.78, 95% CI 1.54-2.06, P < 0.01). The expression of CXCR4 was not related to the size and invasion of the primary tumor, the positive expression rates of CXCR4 in T1-T2 and T3-T4 patients were 41.0%(215/524) and 53.8%(84/156) (RR=0.71, 95% CI 0.60-0.84, P=0.053). The overall survival rate of patients with CXCR4-positive was lower than that of patients with CXCR4-negative, and the difference was statistically significant (30.1% vs. 66.9%, RR=0.45, 95% CI 0.30-0.61, P < 0.01). The disease-free survival rate of patients with CXCR4-positive was lower than that of patients with CXCR4-negative (38.0% vs. 20.1%, RR=1.89, 95% CI 1.45-2.47, P=0.002). Conclusions The pathological type, tumor staging and distant metastasis of NSCLC patients are correlated with CXCR4 expression level. The expression level of CXCR4 in tumor tissues has a predictive value for the prognosis of NSCLC patients; and the higher the expression level of CXCR4 is, the lower the overall survival and disease-free survival rates are. Key words: Carcinoma, non-small-cell lung; CXCR4; Prognosis; Meta-analysis

Abstract OT3-01-02: Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes: A multicenter randomized clinical trial. Sinodar One Study

Abstract Introduction Sentinel lymph node (SLN) staging is currently used to avoid complete axillary lymph node dissection (ALND) in breast cancer (BC) patients with negative SLNs without jeopardizing survival or regional control. International guidelines keep recommending ALND in the presence of positive (+) SLNs. However SLN is the only site of axillary metastasis (MTS) in many cases (60%). Retrospective studies have also shown a low risk of locoregional relapse in patients with SLNs+ not receiving ALND.This latter finding was recently confirmed in a randomized trial comparing SLN biopsy (SLNB) alone with SLNB followed by ALND in patients with 1-2 SLNs+. However the observation of both similar relapse rate and survival in the 2 arms and the conclusion of a non-inferiority of SLNB compared to ALND require cautiousness because of some study limitations: premature enrollment cessation due to death rate lower than expected, short follow-up (6 years), small tumor size (≤2cm in 70% of cases), frequent presence of only microMTS in SLN (40%), prevalent use of “whole breast” adjuvant radiotherapy (&amp;gt;90%) which irradiates the breast but also the I° axillary level, thereby contributing to the low rate of regional relapse in the SLNB arm due to lymph node sterilization. Consequently further randomized trials with more precise selection criteria based on homogeneous clinico-pathological features and with longer follow-up are needed to confirm that performing only SLNB does not affect survival or relapse risk in patients with 1-2 SLNs+. Materials and Methods Primary and secondary aims of the present 2-arm randomized trial are to assess whether ALND omission in BC patients with 1-2 SLNs+ is associated with worse survival and/or increased rate of regional/distant relapse, respectively, thus evaluating whether SLNB is or is not inferior to ALND. Patients receive either conservative surgery or mastectomy and radiotherapy. They all undergo intraoperative SLNB and SLN evaluation, and are randomly assigned to either further dissection of level I-II axillary lymph nodes (standard ALND arm) or absence of any axillary surgery (experimental SLNB arm). According to International Guidelines post-surgery treatments. Eligibility criteria are: age 40-75 years; primary invasive T1-T2 tumor; axillary nodes clinically N0; no more than 2 SLNs presenting macroMTS at intraoperative or definitive histological evaluation; no distant MTS; no neoadjuvant therapy; no previous invasive BC, signed informed consent. Exclusion criteria are: in situ, inflammatory, contralateral BC; presence of only microMTS in the SLN+; pregnancy or breast feeding; comorbidity impeding adjuvant therapy. Follow-up controls foresee: clinical examination every 6 months for 5 years and yearly thereafter; annual mammography and breast echography; annual axillary echography for patients in the SLNB arm; additional laboratory and instrumental surveys in case of suspected onset of distant MTS. The primary endpoint is overall survival (OS). Secondary endpoints are disease-free survival (DFS) referring to distant MTS and to locoregional (ipsilateral breast or axillary, internal mammary or sopraclaveolar lymph nodes) disease recurrence. All analyses are performed both on all patients according to the Intention-To-Treat principle and excluding those patients who did not receive the axillary treatment randomly assigned. Citation Format: Corrado Tinterri, Emilia Marrazzo, Federico Frusone, Wolfgang Gatzemeier, Erika Barbieri, Andrea Sagona, Alberto Bottini, Valentina Errico, Alberto Testori, Giuseppe Canavese. Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes: A multicenter randomized clinical trial. Sinodar One Study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-01-02.

Abstract OT2-02-02: MONARCH E: A phase 3 study of standard adjuvant endocrine therapy with or without abemaciclib in patients with high risk, node positive, hormone-receptor positive, human epidermal growth factor receptor 2-negative early-stage breast cancer

Abstract Background: Abemaciclib is an oral selective inhibitor of CDK 4 &amp; 6 administered on a continuous schedule and demonstrated clinically meaningful efficacy in patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET) in MONARCH 2 and MONARCH 3. Neoadjuvant abemaciclib + anastrozole (ANZ) (neoMONARCH) given for 2 weeks significantly reduced expression of Ki67 relative to ANZ alone. Endocrine monotherapy is the current endocrine standard of care (SOC) in the adjuvant setting, although risk of relapse remains a problem for patients with high-risk disease, identified by clinical and pathological characteristics of disease. Improving adjuvant therapy for patients with high-risk disease is an important need. Trial design: monarchE (NCT03155997) is a multicenter, randomized, open-label phase 3 trial evaluating adjuvant abemaciclib in patients with node-positive, high-risk, HR+, HER2- early advanced breast cancer. Patients are randomized 1:1 to abemaciclib 150 mg twice daily + SOC adjuvant ET vs SOC adjuvant ET alone and stratified by prior chemotherapy (neoadjuvant, adjuvant, or none), menopausal status (premenopausal or postmenopausal), and region (North America/Europe, Asia or Other). Patients in the investigation arm receive abemaciclib for up to 2 years or until discontinuation criteria are met. All patients receive ET for 5 years or as clinically indicated. Patients are followed for 10 years or until study completion, whichever comes first. The final evaluation for overall survival will mark study completion. Eligibility criteria: Patients must have early stage resected HR+, HER2- invasive advanced breast cancer with either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1 to 3 pathological pALNs with at least one of the following high-risk factors: primary invasive tumor size ≥5 cm, histological grade 3 tumor, or central Ki67 index ≥20%. Patients must have completed definitive locoregional therapy (+/- [neo]adjuvant chemotherapy). Before randomization, patients may receive up to 12 weeks of ET after completing their last non-ET and must be randomized within 16 months of the definitive surgery. Specific aims: The primary objective is to evaluate invasive disease-free survival (IDFS) per the STEEP System.1 Secondary objectives include IDFS in patients with central Ki67 index ≥20%, distant relapse-free survival, overall survival, safety, pharmacokinetics, and health outcomes. Statistical methods: Assuming an IDFS hazard ratio of 0.73, the study is powered to ~85% to test the superiority of abemaciclib + standard ET at a 1-sided α=.025 using a stratified log-rank test. Target accrual: This study will be conducted in ~600 centers in 38 countries to enroll ~4580 patients. Accrual began in July 2017. Recruitment is complete. Contact information: 1-877-285-4559 Reference: 1. Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25(15):2127-32. Citation Format: Priya Rastogi, Masakazu Toi, Miguel Martin, Joyce O'Shaughnessy, Desiree Headley, Jennifer Wei, Joanne Cox, Nadia Harbeck, Stephen Johnston. MONARCH E: A phase 3 study of standard adjuvant endocrine therapy with or without abemaciclib in patients with high risk, node positive, hormone-receptor positive, human epidermal growth factor receptor 2-negative early-stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-02.

The scaffold protein IQGAP1 is crucial for extravasation and metastasis

IQGAP1 is a scaffold protein involved in a range of cellular activities, including migration, invasion, adhesion and proliferation. It is also oncogenic in a variety of cancers, promoting primary tumor growth and invasiveness. However, the role of IQGAP1 in tumor progression and metastasis remains unclear. In this study, we use both knockdown and knockout of IQGAP1 to investigate its role in the metastatic cascade of both melanoma and breast cancer cells in vivo. We find that reduction of IQGAP1 expression decreases the formation of both spontaneous and experimental metastases, without limiting primary or metastatic tumor growth. Furthermore, IQGAP1 knockout significantly inhibits extravasation of tumor cells from circulation, possibly involving invadopodial function. By expressing mutant forms of IQGAP1 in a knockout context, we also determine that IQGAP1’s pro-metastatic functions are dependent on multiple domains and functions. These data demonstrate that IQGAP1 is crucial for metastasis in vivo through regulation of extravasation and suggest that it may represent a valid therapeutic target for inhibiting metastasis.

Twist1-Induced Epithelial Dissemination Requires Prkd1 Signaling.

Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)-directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell-cell contacts and persistent activation of Prkd1. In patients with breast cancer, TWIST1 and PRKD1 expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, Prkd1 knockdown in vivo blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination. SIGNIFICANCE: Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/2/204/F1.large.jpg.

Immediate breast reconstruction with latissimus dorsi flap for patients with local recurrence of breast cancer

BackgroundIpsilateral breast cancer recurrence (IBTR) occurs in about 7% of patients with primary invasive breast tumor. Salvage mastectomy and breast reconstruction are often discussed and latissimus dorsi (LD) flap is frequently proposed. MethodsWe retrospectively investigated 111 consecutive locally relapsing patients who underwent salvage mastectomy and immediate LD reconstruction. All included patients with IBTR previously underwent conserving surgery for BC, and received a postoperative irradiation. Primary endpoints were disease free survival and overall survival. Secondary endpoints were surgical complications and re-interventions. ResultsInvasive ductal cancer was the most frequent histotype (60.4%) of breast cancer reappearance. rpT1, rpT2 and rpT3 were observed respectively in 50.5%, 20,7% and 3,6% of the patients. rpTis occurred in 11,7% of cases. Positive axillary nodes were observed in 9,9% of patients at reappearance. Post-operative complication other than seroma occurred in 17,1% of patients, while seroma at the donor site was observed in 61.3% of cases. At 5-year after surgery overall survival was 92% (95% CI: 85%–96%) and disease free survival was 78% (95% CI: 69%–85%). ConclusionsImmediate latissimus dorsi flap reconstruction in selected patients with isolated breast tumor recurrence, which occurred after breast irradiation, provides an effective treatment with a satisfactory outcome.

Фактор роста эндотелия сосудов и растворимые формы его рецепторов 1-го и 2-го типов при раке желудка

Comparative evaluation of blood content of VEGF, sVEGFR1, and sVEGFR2 in 104 primary gastric cancer patients and 65 healthy persons was performed and associations of these markers with the principal clinical and morphological characteristics of gastric cancer were analyzed. The median levels of VEGF and sVEGFR1 in gastric cancer patients significantly surpassed the control: by 1.5 (p<0.001) and 1.2 times (p<0.01), respectively. On the contrary, sVEGFR2 level in patients was below the control (p<0.001). The best sensitivity-specificity ratio (64 and 65%, respectively) was observed for VEGF at 347 pg/ml cut-off value, which is insufficient for the use of this parameter as a clinically valuable serological marker for gastric cancer. No significant associations of these markers with the disease stage, depth of primary tumor invasion, its histological type, grade, or localization were found. The serum level of VEGF in patients with metastases to more than 7 regional lymph nodes (N3) was significantly higher than in patients without lymph node metastases (N0). Blood content of sVEGFR1 in patients with distant metastases (М+) was lower than in patients without distant metastases (М0). Thus, VEGF and its receptors circulating in the peripheral blood do not play significant diagnostic role in gastric cancer, but could be useful in monitoring and prognosis of the efficiency of antiangiogenic therapy.