Search

Colorectal cancer typically metastasizes to the peritoneum, liver, and lungs. However, metastases to the fallopian tube and uterus are uncommon. This case report delves into this rare occurrence of metastasis and discusses its characteristics, diagnostic methods, and treatments based on an extensive literature review. We present the case of a 61-year-old female patient who underwent her initial hospitalization for da Vinci robotic surgery to address colorectal cancer, stage pT3N0M0. However, during routine postoperative follow-up 6 months later, a localized rectal recurrence was detected. The patient commenced chemoradiotherapy with full response. Subsequently, the patient was readmitted due to pelvic pain again, and a magnetic resonance imaging scan revealed an abnormal mass in the patient's left fallopian tube and uterine corpus, infiltrating the myometrium. Consequently, total hysterectomy with bilateral adnexectomy was performed, along with omentectomy, which confirmed metastatic involvement from rectal cancer upon postoperative pathological examination. This case may inform further diagnosis and treatment of colorectal cancer metastasis to the fallopian tube. [ABSTRACT FROM AUTHOR]

Copyright of Current Retina Journal / Güncel Retina Dergisi is the property of Anadolu Kitabevi Basim Yayim Medikal Turizm Kirtasiye Tic. Ltd. Sti. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Current Retina Journal / Güncel Retina Dergisi is the property of Anadolu Kitabevi Basim Yayim Medikal Turizm Kirtasiye Tic. Ltd. Sti. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The orofacial region may be the first site for the dissemination of malignancies from the remote regions in the jawbones. The most common location of metastatic lesions in the jawbones is the mandible, with the molar region the most frequently involved site. Radiotherapy, chemotherapy, and surgical resection can be an approach in the treatment protocol depending upon patient age and growth of tumor mass. This case report presents a case of follicular variant thyroid carcinoma, infiltrative type, pT1bN0Mx with mandibular metastasis affecting both hard and soft tissue in a 55-year-old female. [ABSTRACT FROM AUTHOR]

The number of advanced-age patients with spinal metastases is rising. This study was performed to clarify the characteristics and surgical outcomes of spinal metastases in advanced-age patients. We prospectively analyzed 216 patients with spinal metastases from 2015 to 2020 and divided them into three age groups: <70 years (n = 119), 70–79 years (n = 73), and ≥80 years (n = 24). Although there were no significant intergroup differences in preoperative characteristics and surgery-related factors except for age, patients aged ≥80 years tended to have a worse performance status (PS), Barthel index, and EuroQol-5 dimension (EQ-5D) before and after surgery than the other two groups. Although the median PS, mean Barthel index and mean EQ-5D greatly improved postoperatively in each group, the median PS and mean Barthel index at 6 months and the mean EQ-5D at 1 month postoperatively were significantly poorer in the ≥80-year group than the 70–79-year group. The rates of postoperative complications and re-deterioration of the EQ-5D were significantly higher in the oldest group than in the other two groups. Although surgery for spinal metastases improved the PS, Barthel index, and EQ-5D regardless of age, clinicians should be aware of the poorer outcomes and higher complication rates in advanced-age patients. [ABSTRACT FROM AUTHOR]

Introduction: Lungs are one of the most common sites for metastatic tumors in the body. In addition, primary lung tumors are the most common cause of death due to neoplasms in both genders. Treatment strategies are completely different for primary and metastatic lung tumors making accurate diagnosis of lung tumors an effective factor in planning the correct treatment. The development of personalized medicine and targeted therapy, especially in the treatment of primary lung tumors, has highlighted the importance of correct diagnosis of these tumors. Case report: The Pathology Center of Imam Khomeini Hospital Cancer Institute in Tehran, Iran, as a referral center for cancer across the country, is faced with a large number of lung biopsies, and therefore, there will be numerous diagnostic challenges. In this article, we presented two cases of primary female genital tract (cervical) tumors that during follow up lung masses were detected. Diagnosis on lung biopsy assigned as primary lung adenocarcinoma. Both cases referred to our lab for second opinion accompanied with related resected sample and implementation of further supplementary markers documented metastatic origin of tumors. Discussion & conclusion: In both cases, similarity in immunohistochemical characteristics of metastatic tumors with primary lung adenocarcinoma, especially positive nuclear TTF1 staining led to misdiagnosis of lung tumor origin. This finding emphasizes on the use of other specific markers related to primary site of tumor to decrease possibility of incorrect diagnosis of the origin of the tumor in metastatic setting. Due to remarkable influence of primary versus metastatic origin of lung tumor on selection of treatment, pathologists should be considered correct diagnosis and notice to similarity of immunohistochemical markers of primary lung tumors to other organs and implementation of more specific markers are necessary. [ABSTRACT FROM AUTHOR]

Small‐molecule‐based second near‐infrared (NIR‐II) activatable fluorescent probes can potentially provide a high target‐to‐background ratio and deep tissue penetration. However, most of the reported NIR‐II activatable small‐molecule probes exhibit poor versatility owing to the lack of a general and stable optically tunable group. In this study, we designed NIRII‐HDs, a novel dye scaffold optimized for NIR‐II probe development. In particular, dye NIRII‐HD5 showed the best optical properties such as proper pKa value, excellent stability, and high NIR‐II brightness, which can be beneficial for in vivo imaging with high contrast. To demonstrate the applicability of the NIRII‐HD5 dye, we designed three target‐activatable NIR‐II probes for ROS, thiols, and enzymes. Using these novel probes, we not only realized reliable NIR‐II imaging of different diseases in mouse models but also evaluated the redox potential of liver tissue during a liver injury in vivo with high fidelity. [ABSTRACT FROM AUTHOR]

Small‐molecule‐based second near‐infrared (NIR‐II) activatable fluorescent probes can potentially provide a high target‐to‐background ratio and deep tissue penetration. However, most of the reported NIR‐II activatable small‐molecule probes exhibit poor versatility owing to the lack of a general and stable optically tunable group. In this study, we designed NIRII‐HDs, a novel dye scaffold optimized for NIR‐II probe development. In particular, dye NIRII‐HD5 showed the best optical properties such as proper pKa value, excellent stability, and high NIR‐II brightness, which can be beneficial for in vivo imaging with high contrast. To demonstrate the applicability of the NIRII‐HD5 dye, we designed three target‐activatable NIR‐II probes for ROS, thiols, and enzymes. Using these novel probes, we not only realized reliable NIR‐II imaging of different diseases in mouse models but also evaluated the redox potential of liver tissue during a liver injury in vivo with high fidelity. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of 2 techniques of semi-hepatic alternating radiotherapy on diffuse hepatic metastasis in patients with breast cancer. Methodology: A total of 68 breast cancer patients with diffuse liver metastasis were randomly divided into Group A (semi-hepatic alternating radiotherapy) and Group B (semi-hepatic sequential radiotherapy). In Group A (semi-hepatic sequential radiotherapy), the liver was divided into the first semi-liver and second semi-liver and alternatively treated with semi-hepatic intensity-modulated radiation therapy (IMRT). The interval between the 2 instances of semi-hepatic radiotherapy was 6 h. The average radiotherapy dose to the semi-livers was both 2 Gy/fraction, once a day, 5 times per week, with a total dose of 30 Gy for 15 days. The total radiation therapy time in Group A was 15 days in Group B (semi-hepatic sequential radiotherapy), the livers were divided into the first semi-liver and second semi-liver and treated with semi-hepatic sequential IMRT, The first semi-liver was first treated in the initial stage of radiation therapy, the average radiotherapy dose to the semi-liver was 2 Gy/fraction, once a day, 5 times per week, with a total dose of 30 Gy for 15 days. The second semi-liver was treated next in the second stage of radiation therapy, the average radiotherapy dose to the semi-liver was 2 Gy/fraction, once a day, 5 times per week, with a total dose of 30 Gy for 15 days. The total radiation therapy time in group B was 30 days. Results: The objective response rate (complete response + partial response) of Group A and Group B were 50.0% and 48.5%, respectively (p =.903). The median survival time after metastasis (median survival of recurrence) of Group A and Group B was 16.7 months and 16.2 months, respectively (p =.411). The cumulative survival rates of 6 months, 1 year, 2 years, and 3 years of Group A and Group B were 90.6% (29 of 32) and 84.8% (28 of 33) (p =.478), 65.6% (21 of 32) and 60.6% (20 of 33) (p =.675), 31.2% (10 of 32) and 27.3% (9 of 33) (p =.725), and 15.6% (5 of 32) and 0 (0 of 33) (p =.018), respectively. The differences between the 2 groups showed no statistical significance in terms of cumulative survival rates in 1 year, 2 years, however, the 3-year survival rate was significantly different. The main toxic reactions were digestive tract reactions, abnormal liver functions, and myelosuppression. The incidence of I to II degree gastrointestinal reactions was 78.13% (25 of 32) in Group A and 72.73% (24 of 33) in Group B (p =.614). The incidence of I to II abnormal liver function was 53.13% (17 of 32) in Group A and 48.48% (16 of 33) in Group B (p =.708). The differences between the 2 groups showed no statistical significance. The incidence of I to II myelosuppression was 59.38% (19 of 32) in Group A and 51.52% (17 of 33) in Group B (p =.524), respectively. The differences between the 2 groups showed no statistical significance in terms of adverse effects. Conclusion: Semi-hepatic alternating IMRT was an effective palliative treatment for diffuse liver metastasis in patients with breast cancer. Semi-hepatic alternating radiotherapy showed a trend of prolonged survival time when compared with semi-hepatic sequential radiotherapy. Compared with the former, the latter showed a trend of lower incidences of side effects without any statistical differences. Moreover, the side effects from the 2 radiotherapy techniques can be controlled through appropriate management, which is worthy of further exploration and applications. [ABSTRACT FROM AUTHOR]

Aim: This retrospective study investigated bevacizumab in treating refractory brain edema in patients with brain-metastatic tumors from different sources. Methods: From January 2013 to December 2019, 83 patients with brain metastases and refractory brain edema were treated with bevacizumab. They were divided into lung cancer group and breast cancer group. The clinical data, the efficacy, and the side effects of bevacizumab were recorded. Magnetic resonance imaging was performed before and after bevacizumab treatment. The volume of tumor and brain edema were measured respectively. Results: After treatment with bevacizumab, 72 cases of refractory brain edema were significantly relieved. The edema control rate was 93.75% in the lung cancer group and 77.14% in the breast cancer group (P <.05). The brain edema volume was significantly reduced after bevacizumab treatment from 198,286.84 ± 60,564.40 to 114,677.71 ± 42,337.38mm3 (P <.01), and the edema index was reduced from 26.14 ± 7.24 to 17.18 ± 5.14 (P <.01). Hypertension was observed in 14 cases. Conclusion: Bevacizumab could significantly reduce refractory brain edema with a control rate of 86.75%. The efficacy of bevacizumab in the treatment of refractory brain edema caused by lung cancer is better than that of breast cancer. [ABSTRACT FROM AUTHOR]

Objective. To determine the incidence and identify the clinical-morphological risk factors for the development of epileptic seizures in patients with glial and metastatic brain tumors. Materials and methods. The study included 225 patients (88.6%) with glial and 29 (11.4%) with metastatic brain tumors. Results. Statistically significant differences in the incidence of epileptic seizures depending on age and histological characteristics of tumors, level of malignancy, location, involvement of the cerebral cortex, and displacement of midline structures were found. Conclusions. Epilepsy and epileptic seizures developed in 51.11% and 24.14% cases of glial and metastatic brain tumors, respectively. Risk factors for epileptic seizures were younger age (up to 57 years), histological characteristics corresponding to diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, and oligoastrocytoma, malignancy grades I–III, lesions to the temporal lobe, and involvement of the cerebral cortex. Factors decreasing the risk of seizures were age over 57 years, histological characteristics corresponding to glioblastoma, metastatic tumors, malignancy grade IV, subcortical location of neoplasm, lesions to the occipital cortex, involvement of the conducting tracts (commissures) in the pathological process, subtentorial tumor location, absence of lesion in the temporal and frontal lobes of the brain, involvement of both hemispheres of the brain in the pathological process, lesions of two or more lobes of the brain, and displacement of midline structures. [ABSTRACT FROM AUTHOR]

Background: Cancer is one of the leading death causes globally with about 8.2 million deaths per year and an increase in numbers in recent years. About 90% of cancer deaths do not occur due to primary tumors but due to metastases, of which most are not clinically identifiable because of their relatively small size at primary diagnosis and limited technical possibilities. However, therapeutic decisions are formed depending on the existence of metastases and their properties. Therefore non-identified metastases might have huge influence in the treatment outcome. The quantification of clinically visible and invisible metastases is important for the choice of an optimal treatment of the individual patient as it could clarify the burden of non-identifiable tumors as well as the future behavior of the cancerous disease. Results: The mathematical model presented in this study gives insights in how this could be achieved, taking into account different treatment possibilities and therefore being able to compare therapy schedules for individual patients with different clinical parameters. The framework was tested on three patients with non-small cell lung cancer, one of the deadliest types of cancer worldwide, and clinical history including platinum-based chemotherapy and PD-L1-targeted immunotherapy. Results yield promising insights into the framework to establish methods to quantify effects of different therapy methods and prognostic features for individual patients already at stage of primary diagnosis. [ABSTRACT FROM AUTHOR]

Background: The combination of radiotherapy and immunotherapy can bring benefits to patients, especially advanced patients. However, conventional radiotherapy brings about great adverse reactions. How about the hypofractionated low-dose radiotherapy? Materials and Methods: In this retrospective cohort study, we included 32 patients with metastatic solid tumors treated with hypofractionated radiotherapy combined with an immune checkpoint inhibitor. Patients underwent radiotherapy of 4Gy/Fx on day 1, 3, and 5, and received single-drug immunotherapy of PD-1 inhibitor on day 2. We evaluated the following outcomes: objective response rate (ORR), disease control rate (DCR), change of nonirradiated and irradiated lesions, quality of life, and symptom improvement. Results: Among the 32 patients, the ORR was 9.4% (3/32) and the DCR was 56.25% (18/32). Hypofractionated radiotherapy combined with immunotherapy showed a remarkable efficacy of local control on metastatic tumor patients. Local masses irradiated in two patients (6.25%) were complete remission, partial response rate was 37.5% (12 patients), and 56.25% was stability (18 patients). Out of those 18 patients, 15 patients had the local masses shrank more or less. The ORR of local control reached 43.75%, and its DCR was 100%. In addition, the intratumor necrosis rate was 44.4% in the SD patients. Median progression-free survival was 3.8 months (95%Cl: 2.2– 5.4). By treating the local mass, the symptoms of most patients were alleviated, and the quality of life was improved. Conclusion: Our retrospective analysis revealed that hypofractionated radiotherapy combined with immunotherapy was effective in local control, it also relieved clinical symptoms and improved quality of life. The adverse effect rate was low. However, the incidence of abscopal effects was low either. This mode was suitable for the palliative treatment and expected to improve survival for patients with metastatic tumors. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the role of diffusion-weighted magnetic resonance imaging (DW-MRI) in differentiating enlarged cervical lymph nodes due to tularemia and metastatic tumors. Methods: We evaluated 59 patients with cervical lymphadenopathy (LAP) (32 patients with tularemia, 27 patients with metastatic tumors), retrospectively. We analyzed contrast enhancement patterns of LAP in postcontrast fat sat T1WI. We evaluated T2, DWI, and ADC signals of LAP in a 5-point scale system. Moreover, the mean ADC values of solid and necrotic LAP in both groups were quantitatively measured and compared statistically. Receiver operating characteristic curves of quantitative ADC values were obtained to determine the diagnostic performance. Results: There was no difference between solid and necrotic LAP enhancement patterns in two groups. Solid LAP and peripheral parts of necrotic LAP showed diffusion restriction, whereas central parts necrotic LAP had high ADC and low DWI signal in both tularemia and metastatic groups. Signal characteristics were similar in two groups. In solid LAP, there was no significant difference between ADC values in two groups. In necrotic LAP, total, central, and peripheral quantitative ADC measurements were higher in the metastatic group than in the tularemia group. Conclusions: Conventional MRI findings were not sufficient to differentiate metastatic LAP from tularemia. DW-MRI was not helpful in solid LAP; however, ADC values of metastatic necrotic LAP were significantly higher than tularemia. Microagglutination tests would be useful for differentiation; however, DW-MRI might also be useful for differentiation and may expedite the diagnosis. [ABSTRACT FROM AUTHOR]

The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia. [ABSTRACT FROM AUTHOR]

Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy. [ABSTRACT FROM AUTHOR]

The progression of cancer through local expansion and metastasis is well recognized, but preventing these characteristic cancer processes is challenging. To this end, a new strategy is required. In this study, we presented a novel dual functional podophyllotoxin derivative, 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxPdp), which inhibited both matrix metalloproteinases and Topoisomerase II. This new podophyllotoxin derivative exhibited significant anti-proliferative, anti-metastatic that correlated with the downregulation of matrix metalloproteinase. In a xenograft animal local expansion model, PtoxPdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that PtoxPdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp could also inhibit epithelial–mesenchymal transition, which was achieved by downregulating both PI3K/AKT/mTOR and NF-κB/Snail pathways. Taken together, our results reveal that PtoxPdp is a promising antitumor drug candidate. [ABSTRACT FROM AUTHOR]

Background: Pleural fluid homocysteine (HCY) can be useful for diagnosis of malignant pleural effusion (MPE). There are no published studies comparing the diagnostic accuracy of HCY with other tumour markers in pleural fluid for diagnosis of MPE. The aim was to compare the accuracy of HCY with that of carcinoembryonic antigen (CEA), cancer antigen (CA) 15.3, CA19.9 and CA125 in pleural fluid and to develop a probabilistic model using these biomarkers to differentiate benign (BPE) from MPE. Methods: Patients with pleural effusion were randomly included. HCY, CEA, CA15.3, CEA19.9 and CA125 were quantified in pleural fluid. Patients were classified into two groups: MPE or BPE. By applying logistic regression analysis, a multivariate probabilistic model was developed using pleural fluid biomarkers. The diagnostic accuracy was determined by receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC). Results: Population of study comprised 133 patients (72 males and 61 females) aged between 1 and 96 years (median = 70 years), 81 BPE and 52 MPE. The logistic regression analysis included HCY (p<0.0001) and CEA (p = 0.0022) in the probabilistic model and excluded the other tumour markers. The probabilistic model was: HCY+CEA = Probability(%) = 100×(1+e-z)-1, where Z = 0.5471×[HCY]+0.3846×[CEA]–8.2671. The AUCs were 0.606, 0.703, 0.778, 0.800, 0.846 and 0.948 for CA125, CA19.9, CEA, CA15.3, HCY and HCY+CEA, respectively. Conclusions: Pleural fluid HCY has higher accuracy for diagnosis of MPE than CEA, CA15.3, CA19.9 and CA125. The combination of HCY and CEA concentrations in pleural fluid significantly improves the diagnostic accuracy of the test. [ABSTRACT FROM AUTHOR]

Background: Personalized targeted treatment in metastatic breast cancer relies on accurate assessment of molecular aberrations, e.g. overexpression of Human Epidermal growth factor Receptor 2 (HER-2). Molecular interrogation of circulating tumor cells (CTCs) can provide an attractive alternative for real-time biomarker assessment. However, implementation of CellSearch-based HER-2 analysis has been limited. Immunofluorescent (IF) image interpretation is crucial, as different HER-2 categories have been described. Major questions in CTC research are how these IF categories reflect gene expression and amplification, and if we should consider ‘medium’ HER-2 expressing CTCs for patient selection. Methods: Tumor cells from spiked cell lines (n = 8) and CTCs (n = 116 samples) of 85 metastatic breast cancer patients were enriched using CellSearch. Comparative analysis of HER-2 expression by IF imaging (ACCEPT, DEPArray, and visual scoring) with qRT-PCR and HER-2/neu FISH was performed. Results: Automated IF HER-2-profiling by DEPArray and ACCEPT delivered comparable results. There was a 98% agreement between 17 trained observers (visual scoring) and ACCEPT considering HER-2neg and HER-2high expressing CTCs. However, 89% of HER-2med expressing CTCs by ACCEPT were scored negative by observers. HER-2high expressing tumor cells demonstrated HER-2/neu gene amplification, whereas HER-2neg and HER-2med expressing tumor cells and CTCs by ACCEPT were copy-number neutral. All patients with HER-2-positive archival tumors had ≥1 HER-2high expressing CTCs, while 80% of HER-2-negative patients did not. High relative gene expression of HER-2 measured on enriched CTC lysates correlated with having ≥1 HER-2high expressing CTCs. Conclusion: Automated images analysis has enormous potential for clinical implementation. HER-2 characterization and clinical trial design should be focused on HER-2high expressing CTCs. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) that primarily target angiogenesis are approved to treat several cancers in the metastatic setting; however, resistance is common. Sequential treatment or ‘switching’ from one TKI to another following failure can be effective, but predicting which drugs will have cross-over sensitivity remains a challenge. Here we examined sitravatinib (MGCD516), a spectrum-selective TKI able to block MET, TAM (TYRO3, AXL, MerTK) and multiple receptor families (including PDGFRs, VEGFRs, and Ephs). Transcriptomic analysis of several mouse and human cell lines revealed diverse molecular changes after resistance to two TKIs (sunitinib and axitinib) with multiple sitravatinib targets found to be upregulated. Sitravatinib treatment in vitro resulted in enhanced anti-proliferative effects in resistant cells and was improved compared to TKIs with similar target profiles. In vivo, primary tumor growth inhibition after sitravatinib treatment in mice was enhanced in resistant tumors and metastasis suppression improved when tumors were surgically removed. Together, these results suggest that the diverse and often inconsistent compensatory signaling mechanisms found to contribute to TKI resistance may paradoxically improve the tumor-inhibiting effects of broad-spectrum TKIs such as sitravatinib that are able to block multiple signaling pathways. Sitravatinib in the second-line setting following antiangiogenic TKI treatment may have enhanced inhibitory effects in local and disseminated disease, and improve outcomes in patients with refractory disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the rate of discordance of epidermal growth factor receptor (EGFR) mutation between primary lung tumor and paired distant metastases in non-small-cell lung cancer (NSCLC). Methods: We performed a meta-analysis of 17 studies (518 cases) assessing discordance rates of EGFR mutation in primary tumors and paired distant metastases. We performed subgroup analyses based on EGFR mutation status in primary tumor (mutant or wildtype), site of distant metastasis (bone, central nervous system (CNS) or lung/ pleural), methods of testing (direct sequencing or allele-specific testing) and timing of metastasis (synchronous or metachronous). Results: The overall discordance rate in EGFR mutation was low at 10.36% (95% CI = 4.23% to 18.79%) and varied widely between studies (I2 = 83.18%). The EGFR discordance rate was statistically significantly higher in bone metastases (45.49%, 95% CI = 14.13 to 79.02) than CNS (17.26%, 95% CI = 7.64 to 29.74; P = 0.002) and lung/ pleural metastases (8.17%, 95% CI = 3.35 to 14.85; P < 0.001). Subgroup analyses did not demonstrate any significant effect modification on the discordance rates by the EGFR mutation status in primary lung tumor, methods of testing and timing of metastasis. Conclusion: The overall discordance rate in EGFR mutation between primary lung tumor and paired distant metastases in NSCLC is low, although higher discordance rates were observed in bone metastases compared with CNS and lung/pleural metastases. Future studies assessing the impact of EGFR mutation discordance on treatment outcomes are required. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) exhibits a variety of phenotypes with regard to disease progression and treatment response. This variability complicates clinical decision-making despite the improvement of survival due to the recent introduction of FOLFIRINOX (FFX) and nab-paclitaxel. Questions remain as to the timing and sequence of therapies and the role of radiotherapy for unresectable PDAC. Here we developed a computational analysis platform to investigate the dynamics of growth, metastasis and treatment response to FFX, gemcitabine (GEM), and GEM+nab-paclitaxel. Our approach was informed using data of 1,089 patients treated at the Massachusetts General Hospital and validated using an independent cohort from Osaka Medical College. Our framework establishes a logistic growth pattern of PDAC and defines the Local Advancement Index (LAI), which determines the eventual primary tumor size and predicts the number of metastases. We found that a smaller LAI leads to a larger metastatic burden. Furthermore, our analyses ascertain that i) radiotherapy after induction chemotherapy improves survival in cases receiving induction FFX or with larger LAI, ii) neoadjuvant chemotherapy improves survival in cases with resectable PDAC, and iii) temporary cessations of chemotherapies do not impact overall survival, which supports the feasibility of treatment holidays for patients with FFX-associated adverse effects. Our findings inform clinical decision-making for PDAC patients and allow for the rational design of clinical strategies using FFX, GEM, GEM+nab-paclitaxel, neoadjuvant chemotherapy, and radiation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the value of CXC subfamily ligands in stage I-III patients with colorectal cancer, in order to find a new predictor for CRC patients. Methods: We used Gene Expression Omnibus (GEO) database to collect the gene expression of CXC subfamily ligands and corresponding clinical data. The survival analysis was performed by "survival" package of Rsoftware. The CRC patients’ DFS and the relationship between the expression levels of CXC subfamily ligands were evaluated by the univariate Cox regression analysis. Results: By using microarray data, there were 14 CXC subfamily ligands identified from dataset GSE39582. Seven CXC subfamily ligands were significantly correlated with DFS in CRC patients. (p<0.05),including CXCL1, CXCL3, CXCL9, CXCL10, CXCL11, CXCL13, and CXCL14. From multivariate Cox regression analyze, four CXC subfamily ligands (CXCL9, CXCL10, CXCL11, and CXCL13) were significantly associated with CRC patients’ DFS (all p<0.05). Three CXC subfamily ligands (CXCL10, CXCL11, and CXCL13) were significantly associated with CRC patients’ Overall survival (OS) (all p<0.05). Both CXCL11 and CXCL13 had the similar prediction values for DFS and OS. Conclusion: There were seven CXC subfamily ligands were significantly correlated with DFS in CRC patients. Different expression level of four CXC subfamily ligands (CXCL9, CXCL10, CXCL11, and CXCL13) and Three CXC subfamily ligands (CXCL10, CXCL11, and CXCL13) were related to CRC patients’ DFS and OS. There are still needs more experiments to confirm our conclusions. Next step we will make animal experiment about the genes in order to verified the predictive value of the CXC subfamily ligands. [ABSTRACT FROM AUTHOR]

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel “sibling” 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancers (CRCs) deficient in the DNA mismatch repair protein MutL homolog 1 (MLH1) display distinct clinicopathological features and require a different therapeutic approach compared to CRCs with MLH1 proficiency. However, the molecular basis of this fundamental difference remains elusive. Here, we report that MLH1-deficient CRCs exhibit reduced levels of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1), and that tumor progression and metastasis of CRCs correlate with SPTAN1 levels. Methods and results: To investigate the link between MLH1 and SPTAN1 in cancer progression, a cohort of 189 patients with CRC was analyzed by immunohistochemistry. Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient CRCs, whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. Overall, we identified a strong correlation between MLH1 status and SPTAN1 expression. When comparing TNM classification and SPTAN1 levels, we found higher SPTAN1 levels in stage I CRCs, while stages II to IV showed a gradual reduction of SPTAN1 expression. In addition, SPTAN1 expression was lower in metastatic compared with non-metastatic CRCs. Knockdown of SPTAN1 in CRC cell lines demonstrated decreased cell viability, impaired cellular mobility and reduced cell-cell contact formation, indicating that SPTAN1 plays an important role in cell growth and cell attachment. The observed weakened cell-cell contact of SPTAN1 knockdown cells might indicate that tumor cells expressing low levels of SPTAN1 detach from their primary tumor and metastasize more easily. Conclusion: Taken together, we demonstrate that MLH1 deficiency, low SPTAN1 expression, and tumor progression and metastasis are in close relation. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. The detailed analysis of SPTAN1 is now mandatory to substantiate its relevance and its potential value as a candidate protein for targeted therapy, and as a predictive marker of cancer aggressiveness. [ABSTRACT FROM AUTHOR]

The article offers information on the analysis of prostate cancer in terms of mutated genes. It mentions result of analysis that found mutated genes follows a long tail, with genes containing a substitution in comparatively many tumors, and many genes containing a substitution in few tumors. It also mentions ranking genes discovered by the prevalence of the mutations that are observed at high frequencies.

Angiogenesis is important for the progression of cutaneous melanoma. Here, we analyzed the prognostic impact of the angiogenic factor urokinase plasminogen activator resecptor (uPAR), vascular proliferation index (VPI) and tumor necrosis as a measure of hypoxia in a patient series of nodular melanomas (n = 255) and matched loco-regional metastases (n = 78). Expression of uPAR was determined by immunohistochemistry and VPI was assessed by dual immunohistochemistry using Factor-VIII/Ki67 staining. Necrosis was recorded based on HE-slides. As novel findings, high uPAR expression and high VPI were associated with each other, and with increased tumor thickness, presence of tumor necrosis, tumor ulceration, increased mitotic count and reduced cancer specific survival in primary melanoma. In matched cases, VPI was decreased in metastases, whereas the frequency of necrosis was increased. Our findings demonstrate for the first time the impact on melanoma specific survival of uPAR expression and VPI in primary tumors, and of increased necrosis as an indicator of tumor hypoxia in loco-regional metastases. These findings support the importance of tumor angiogenesis in melanoma aggressiveness, and suggest uPAR as an indicator of vascular proliferation and a potential biomarker in melanoma. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 ‘trios’ of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity. [ABSTRACT FROM AUTHOR]

Purpose: Many surgeons participate in the management of superficial soft tissue masses, and a preoperative incorrect diagnosis frequently results in dismal oncological outcomes. The aim of this study was to identify distinguishing magnetic resonance imaging features between malignant and non-malignant lesions. Methods: The clinicopathological data for 219 patients (men 114; women 105) with superficial soft tissue masses treated from January 2007 to December 2016 in our institution were retrospectively analyzed. The median age at the first visit was 55.6 years (range 1–90 years). MRI findings of tumor size, margin, lobulation, intratumoral hemorrhage, peritumoral edema, and tumor-fascia relationship were compared with the final histological diagnosis and tumor grade. Results: Univariate analysis revealed significant relationships between histologically malignant lesions and tumor size ≥5 cm (p = 0.035), positive peritumoral edema (p = 0.031), and tumor-fascia relationship (p<0.001), but not margin (p = 0.107), lobulation (p = 0.071), and intratumoral hemorrhage (p = 0.17). In addition, using multivariate analysis, the tumor-fascia relationship (p<0.001) and tumor size were significant factors. A significant correlation between tumor-fascia relationship and malignancy (p<0.001) was observed; such a relationship was, however, not observed for tumor grade (p = 0.43). Conclusions: Tumors measuring ≥5 cm and the tumor-fascia relationship on magnetic resonance imaging are highly indicative of malignancy. When superficial soft tissue masses cross the superficial fascia and form obtuse angles with the fascia, sarcoma should be considered. The tumor-fascia relationship can offer surgeons useful information regarding the status of superficial soft tissue masses. [ABSTRACT FROM AUTHOR]

Cutaneous mast cell tumours are one of the most common canine cancers. Approximately 25% of the tumours metastasise. Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations. Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy. Available prognostic tests do not reliably predict whether a tumour will metastasise. In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise. The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis. Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery. Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility. Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis. Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing. Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90–100% and 70–100%, respectively. The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR. [ABSTRACT FROM AUTHOR]

Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs. [ABSTRACT FROM AUTHOR]

Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to-tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction. [ABSTRACT FROM AUTHOR]

We have identified nine highly connected and differentially expressed gene subnetworks between aggressive primary tumors and metastatic lesions in endometrial carcinomas. We implemented a novel pipeline combining gene set and network approaches, which here allows integration of protein-protein interactions and gene expression data. The resulting subnetworks are significantly associated with disease progression across tumor stages from complex atypical hyperplasia, primary tumors to metastatic lesions. The nine subnetworks include genes related to metastasizing features such as epithelial-mesenchymal transition (EMT), hypoxia and cell proliferation. TCF4 and TWIST2 were found as central genes in the subnetwork related to EMT. Two of the identified subnetworks display statistically significant association to patient survival, which were further supported by an independent validation in the data from The Cancer Genome Atlas data collection. The first subnetwork contains genes related to cell proliferation and cell cycle, while the second contains genes involved in hypoxia such as HIF1A and EGLN3. Our findings provide a promising context to elucidate the biological mechanisms of metastasis, suggest potential prognostic markers and further identify therapeutic targets. The pipeline R source code is freely available, including permutation tests to assess statistical significance of the identified subnetworks. [ABSTRACT FROM AUTHOR]

Background & aim: Liver metastasis has been found to affect outcome in prostate, pancreatic and colorectal cancers, but its role in lung cancer is unclear. The 5 year survival rate remains extensively low owing to intrinsic resistance to conventional therapy which can be attributed to the genetic modulators involved in the pathogenesis of the disease. Thus, this study aims to generate a model for early diagnosis and timely treatment of liver metastasis in lung cancer patients. Methods: mRNA expression of 15 genes was quantified by real time PCR on lung cancer specimens with (n = 32) and without (n = 30) liver metastasis and their normal counterparts. Principal Component analysis, linear discriminant analysis and hierarchical clustering were conducted to obtain a predictive model. The accuracy of the models was tested by performing Receiver Operating Curve analysis. Results: The expression profile of all the 15 genes were subjected to PCA and LDA analysis and 5 models were generated. ROC curve analysis was performed for all the models and the individual genes. It was observed that out of the 15 genes only 8 genes showed significant sensitivity and specificity. Another model consisting of the selected eight genes was generated showing a specificity and sensitivity of 90.0 and 96.87 respectively (p <0.0001). Moreover, hierarchical clustering showed that tumors with a greater fold change lead to poor prognosis. Conclusion: Our study led to the generation of a concise, biologically relevant multi-gene panel that significantly and non-invasively predicts liver metastasis in lung cancer patients. [ABSTRACT FROM AUTHOR]

Here we investigated different cell populations within ovarian cancer using single-cell RNA seq: fourteen samples from nine patients with differing grades (high grade, low grade and benign) as well as different origin sites (primary and metastatic tumor site, ovarian in origin and fallopian in origin). We were able to identify sixteen distinct cell populations with specific cells correlated to high grade tumors, low grade tumors, benign and one population unique to a patient with a breast cancer relapse. Furthermore the proportion of these populations changes from primary to metastatic in a shift from mainly epithelial cells to leukocytes with few cancer epithelial cells in the metastases. Differential gene expression shows myeloid lineage cells are the primary cell group expressing soluble factors in primary samples while fibroblasts do so in metastatic samples. The leukocytes that were captured did not seem to be suppressed through known pro-tumor cytokines from any of the cell populations. Single cell RNA-seq is necessary to de-tangle cellular heterogeneity for better understanding of ovarian cancer progression. [ABSTRACT FROM AUTHOR]

Background: Aldehyde dehydrogenase 1A1 (ALDH1A1) encodes an enzyme that oxidizes aldehydes to their corresponding carboxylic acids. In colorectal cancer ALDH1A1 marks cancer stem cells and plays putative roles in tumor progression and drug resistance. However, the potential value of ALDH1A1 as a diagnostic marker or target for therapy remains unclear. Here, we have analyzed ALDH1A1 mRNA and protein levels in relation to clinical, histopathological and molecular tumor features in large series of human colorectal cancer. Methods: ALDH1A1 protein levels were determined by immunohistochemistry in a series of primary colorectal tumors and their corresponding liver metastases (n = 158). ALDH1A1 mRNA levels were analyzed in several large patient cohorts of colorectal cancer. ALDH1A1 mRNA and protein levels were then related to overall survival and to clinical, histopathological and molecular tumor features. Results: High levels of ALDH1A1 were associated with a poorly differentiated histology and a right-sided tumor location, but not to a mesenchymal-like molecular subtype. Liver metastases contained significantly higher levels of ALDH1A1 compared to the corresponding primary tumors. Radio- and/or chemotherapy prior to tumor resection was associated with increased ALDH1A1 levels regardless of the molecular subtype. Finally, ALDH1A1 protein expression in primary tumors and metastases correlated with shorter overall survival. Conclusions: ALDH1A1 expression is associated with features of poor prognosis, including a poorly differentiated histology and ‘right-sidedness’ of the primary tumor, and with shorter overall survival. ALDH1A1 is also highly expressed in therapy-surviving tumors and in liver metastases. These results warrant further research into the potential value of targeting ALDH1A1 in order to improve the efficacy of standard treatment and thereby preventing tumor recurrence. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic impact of circulating tumor cells (CTC) on disease recurrence, progression and survivals in patients with head and neck squamous cell carcinoma (HNSCC) has not been adequately described. The objective of this study was to determine the impacts of the presence of CTC on loco-regional recurrence and survival of HNSCC patients by conducting a systematic review and meta-analysis. Methods: A comprehensive search for articles published between 1990 and 2016 was conducted and data from these studies were extracted, using the MEDLINE, Cochrane Library, and EMBASE databases. The main outcomes were overall survival (OS) and recurrence-free survival (RFS) of HNSCC patients. Pooled hazard ratio (HR) and 95% confidence intervals (95%CI) were calculated using the random effect model for outcomes. The quality of the studies, heterogeneity and publication bias were assessed with the appropriate statistical methods. Results: Six eligible studies with 429 patients were identified. The presence of CTC was significantly associated shorter RFS (HR = 4.88 [95%CI: 1.93–12.35], P < 0.001). However, it could not predict patients’ OS (HR = 1.92 [95%CI: 0.93–3.96], P = 0.078). The following analyses using univariable values of each study also made the similar results (HR = 1.70 [95%CI: 0.83–3.45] for OS, HR = 3.79 [95%CI: 2.02–7.13] for RFS). Heterogeneity and publication bias were not significant, except one enrolled study. Conclusions: The presence of CTC is not a significant prognostic indicator for OS of patients with HNSCC, although it could reflect the outcomes of loco-regional disease. [ABSTRACT FROM AUTHOR]

Background: First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first line fluoropyrimidine containing systemic therapy in patients with mCRC. Methods: MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC. Results: Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts. Conclusion: A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored. [ABSTRACT FROM AUTHOR]

Since microRNAs (miRNAs, miRs) have been implicated in oncogenesis, many of them have been identified as therapeutic targets. Previously we have demonstrated that miRNA-10b acts as a master regulator of the viability of metastatic tumor cells and represents a target for therapeutic intervention. We designed and synthesized an inhibitor of miR-10b, termed MN-anti-miR10b. We showed that treatment with MN-anti-miR10b led to durable regression/elimination of established metastases in murine models of metastatic breast cancer. Since miRNA-10b has been associated with various metastatic and non-metastatic cancers, in the present study, we investigated the effect of MN-anti-miR10b in a panel of over 600 cell lines derived from a variety of human malignancies. We observed an effect on the viability of multiple cell lines within each cancer type and a mostly dichotomous response with cell lines either strongly responsive to MN-anti-miR10b or not at all even at maximum dose tested, suggesting a very high specificity of the effect. Genomic modeling of the drug response showed enrichment of genes associated with the proto-oncogene, c-Jun. [ABSTRACT FROM AUTHOR]

In the tumor progression, transforming growth factor β1 (TGFβ1) plays a critical role in tumorigenesis as well as metastasis. It is known that high plasma level of TGFβ1 in patients with advanced non-small cell lung cancer (NSCLC) is correlated with poor prognostics. In addition, the generation of cancer stem-like cells is associated with metastasis, drug resistance, and tumor recurrence, which also lead to poor outcomes in NSCLC patients. However, it remains unclear how TGFβ1 promotes NSCLC cells to acquire stem-like properties and accelerate tumor metastasis. In our study, we found that short term TGFβ1 treatment resulted in a significant epithelial-mesenchymal transition (EMT) morphological change in TGFβ1–sensitive NSCLC cells but not in insensitive cells. Western blotting confirmed increased Vimentin and reduced E-Cadherin protein expression after TGFβ1 treatment in A549, NCI-H1993, and NCI-H358 cells. TGFβ1 incubation dramatically decreased in vitro cell proliferation and increased cell invasion in TGFβ1–sensitive NSCLC cells but not in NCI-H1975, NCI-H1650, and HCC827 cells. Moreover, TGFβ1 was able to enhance the mRNA expression of Oct4, Nanog and Sox2 and drastically increased anchorage-independent colony formation in TGFβ1–sensitive NSCLC cells, suggesting the acquisition of cancer stem-like properties. Interestingly, we found that vascular endothelial growth factor receptor 3 (VEGFR3) mRNA expression was significantly elevated in TGFβ1–sensitive NSCLC cells compared to insensitive cells. And TGFβ1 was capable of inducing VEGF-C gene expression. Pharmacological blocking TGFβ type I receptor kinase (ALK5) significantly inhibited TGFβ1-induced VEGF-C expression. Silencing of ALK5 by siRNA also dramatically reduced TGFβ1-induced VEGF-C expression in TGFβ1–sensitive NSCLC cells. Therefore, TGFβ1 contributes for NSCLC metastasis through promoting EMT, generation of high invasive cancer cells with stem-like properties, and increasing VEGF-C expression. Blocking TGFβ pathway is a potential therapeutic target in human non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS. [ABSTRACT FROM AUTHOR]

Niche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors. [ABSTRACT FROM AUTHOR]

Mouse models of breast cancer with specific molecular subtypes (e.g., ER or HER2 positive) in an immunocompetent or an immunocompromised environment significantly contribute to our understanding of cancer biology, despite some limitations, and they give insight into targeted therapies. However, an ideal triple-negative breast cancer (TNBC) mouse model is lacking. What has been missing in the TNBC mouse model is a sequential progression of the disease in an essential native microenvironment. This notion inspired us to develop a TNBC-model in syngeneic mice using a mammary intraductal (MIND) method. To achieve this goal, Mvt-1and 4T1 TNBC mouse cell lines were injected into the mammary ducts via nipples of FVB/N mice and BALB/c wild-type immunocompetent mice, respectively. We established that the TNBC-MIND model in syngeneic mice could epitomize all breast cancer progression stages and metastasis into the lungs via lymphatic or hematogenous dissemination within four weeks. Collectively, the syngeneic mouse-TNBC-MIND model may serve as a unique platform for further investigation of the underlying mechanisms of TNBC growth and therapies. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid progenitor cells that are expanded in cancer and act as potent suppressors of the anti-tumor immune response. MDSCs consist of two major subsets, namely monocytic (M-) MDSCs and granulocytic (G-) MDSCs that differ with respect to their phenotype, morphology and mechanisms of suppression. Here, we cultured bone marrow cells with IL-6 and GM-CSF in vitro to generate a population of bone marrow MDSCs (BM-MDSCs) similar to G-MDSCs from tumor-bearing mice in regards to phenotype, morphology and suppressive-function. Through fluorescent labeling of these BM-MDSCs and optical imaging, we could visualize the recruitment and localization of BM-MDSCs in breast tumor-bearing mice in vivo. Furthermore, we were able to demonstrate that BM-MDSCs home to primary and metastatic breast tumors, but have no significant effect on tumor growth or progression. Ex vivo flow cytometry characterization of BM-MDSCs after adoptive transfer demonstrated both organ-and tumor-specific effects on their phenotype and differentiation, demonstrating the importance of the local microenvironment on MDSC fate and function. In this study, we have developed a method to generate, visualize and detect BM-MDSCs in vivo and ex vivo through optical imaging and flow cytometry, in order to understand the organ-specific changes rendered to MDSCs in breast cancer. [ABSTRACT FROM AUTHOR]

Angiogenesis plays an essential role in tumors development. In case of central nervous system tumors, the most important role in this process plays VEGF-A. The purpose of this study was to determine the plasma concentration of this agent in patients treated surgically because of intracranial tumors. The study involved 48 adult patients, both sexes, treated surgically because of a brain tumor. The control group consisted of 50 adult volunteers of both sexes, without cancer diagnosis. Based on the studies, it was found that serum VEGF-A levels before surgery are higher in patients with central nervous system tumors (10.39–150.57 pg/ml, median 41.70 pg/ml) than in non-cancer patients (0.00–130.77 pg/ml, median 22.56 pg/ml). The association between serum VEGF-A level and malignancy and histological type of intracranial tumor has not beed confirmed. The highest average preoperative serum VEGF-A level was found in patients with low grade gliomas, slightly lower (close to each other) in those with high grade gliomas and meningiomas, while the lowest level was characteristic for metastatic tumors. High variation in results was observed in patients with low grade gliomas (52.56 pg/ml)—higher than those reported in patients with high grade gliomas (32.38 pg/ml). In the rest types of tumors the differentiation was similar and oscillated within 23.08–27.50 pg/ml. [ABSTRACT FROM AUTHOR]

Background: Lymph node stage prior to treatment is strongly related to disease progression and poor prognosis in non-small cell lung cancer (NSCLC). However, few studies have investigated metabolic imaging features derived from pre-radiotherapy 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) of metastatic hilar/mediastinal lymph nodes (LNs). We hypothesized that these would provide complementary prognostic information to FDG-PET descriptors to only the primary tumor (tumor). Methods: Two independent cohorts of 262 and 50 node-positive NSCLC patients were used for model development and validation. Image features (i.e. Radiomics) including shape and size, first order statistics, texture, and intensity-volume histograms (IVH) () were evaluated by univariable Cox regression on the development cohort. Prognostic modeling was conducted with a 10-fold cross-validated least absolute shrinkage and selection operator (LASSO), automatically selecting amongst FDG-PET-Radiomics descriptors from (1) tumor, (2) LNs or (3) both structures. Performance was assessed with the concordance-index. Development data are publicly available at and Dryad (doi:). Results: Common SUV descriptors (maximum, peak, and mean) were significantly related to overall survival when extracted from LNs, as were LN volume and tumor load (summed tumor and LNs’ volumes), though this was not true for either SUV metrics or tumor’s volume. Feature selection exclusively from imaging information based on FDG-PET-Radiomics, exhibited performances of (1) 0.53 –external 0.54, when derived from the tumor, (2) 0.62 –external 0.56 from LNs, and (3) 0.62 –external 0.59 from both structures, including at least one feature from each sub-category, except IVH. Conclusion: Combining imaging information based on FDG-PET-Radiomics features from tumors and LNs is desirable to achieve a higher prognostic discriminative power for NSCLC. [ABSTRACT FROM AUTHOR]

Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors. [ABSTRACT FROM AUTHOR]

Cancer results from alterations at essential genomic sites and is characterized by uncontrolled cell proliferation, invasion and metastasis. Identification of driver genes of metastatic progression is essential, as metastases, not primary tumors, are fatal. To gain insight into the mutational concordance between different steps of malignant progression we performed exome sequencing and validation with targeted deep sequencing of successive steps of malignant progression from pre-invasive stages to asynchronous distant metastases in six breast cancer patients. Using the ratio of non-synonymous to synonymous mutations, a surprisingly large number of cancer driver genes, ranging between 3 and 145, were estimated to confer a selective advantage in the studied primary tumors. We report a substantial amount of metastasis specific mutations and a number of novel putative metastasis driver genes. Most notable are the DCC, ABCA13, TIAM2, CREBBP, BCL6B and ZNF185 genes, mainly mutated exclusively in metastases and highly likely driver genes of metastatic progression. We find different genes and pathways to be affected at different steps of malignant progression. The Adherens junction pathway is affected in four of the six studied patients and this pathway most likely plays a vital role in the metastatic process. [ABSTRACT FROM AUTHOR]

Background: Metastatic spinal cord compression (MSCC) treatment depends on life expectancies. Data regarding palliative decompression outcomes is scarce. We demonstrate that surgical timing has a significant impact on survival in MSCC patients treated with palliative decompression. Methods: Eighty-nine consecutive MSCC patients at a tertiary referral medical center were enrolled between January 2012 and February 2016. Wide laminectomy was performed for tumors invading the vertebral body. Debulking surgery was done for tumors damaging the posterior column of the spine. Patient records were retrospectively analyzed. Results: Better survival was observed in patients with preoperative intact motor function (Group A, n = 37) than in those with motor deficit (Group B, n = 52, p = 0.0031). In Group B, survival was better in those who underwent surgery within 7 days of motor deficit onset than in those who underwent surgery 7 days after onset (p = 0.0444) and in postoperative ambulant patients than in nonambulant patients (p = 0.0120). In Group B, Frankel grade improved in patients who underwent surgery within 48 h than in those who underwent surgery after 48 h (p = 0.0992). Group A patients had a shorter hospital stay and higher revised Tokuhashi score than Group B patients. Overall survival was better in patients with a lower Tomita score (≤5, p = 0.0012), higher revised Tokuhashi score (≥9, p = 0.0009), better preoperative Frankel grade (p < 0.0001), and younger age (≤55 years, p = 0.0179). There were no significant differences in age, sex, tumor type, involved vertebrae level, Tomita score, intraoperative blood loss, operation time, incidence of infection, and postoperative complications between groups. Conclusion: We can improve the survival of MSCC patients with palliative decompression before motor deficits occur. After motor deficit onset, survival can still be improved with surgery within 7 days. Overall survival was better in patients aged ≤55 years. [ABSTRACT FROM AUTHOR]

Background: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues. Methods: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors Result: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients. Conclusion: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease. [ABSTRACT FROM AUTHOR]