bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective analysis of adjuvant chemotherapy for patients with soft tissue sarcomas at Washington University in St. Louis.
Authors: Schenone Aaron , Luo Jingqin , Montgomery Luke , Ley Jessica C. , Wildes Tanya Marya , Adkins Douglas , Van Tine Brian Andrew
Published: March 2020

e21501

Background: Adjuvant chemotherapy for soft tissue sarcomas (STS) is controversial. We undertook a retrospective analysis to validate the Memorial Sloan Kettering Predictive Nomogram (MSKPN). We then independently analyzed low and high risk patients, as defined by MSKPN 4-year post operative probability of death > 30% for high grade patients to determine if high risk adjuvant chemotherapeutic patients had greater relapse free survival (RFS). Methods: A retrospective review was performed on all STS patients seen between 1/1/2000 and 5/1/10. Data collected included sex, age, race, city, stage, histology, primary lesion site and size, metastatic sites, response to therapy, radiologic response, and cause of death. The wilcoxon rank sum test was used to compare our predicted vs MSKPN predicted probability of death. Results: 170 subjects, 86 dead and 84 alive were assessed. 89 patients were classified as high risk, 17 treated by I/E, 2 by MAID, 3 by T&G and 67 untreated. 35 patients were treated with I/E and 124 received no adjuvant. We validated the MSKPN as predicted by age, histology, site, grade, depth and tumor size with low risk patients having a greater RFS (log rank test p=0.005) vs high risk. High risk patients’ age was significantly lower I/E v. untreated (mean=46 vs. 60.15, p=0.0044). Overall, patients treated with I/E had greater RFS (p=0.01). High risk adjuvant showed greater RFS vs untreated (log rank test p=0.015). Low risk adjuvant treated patients did not show greater RFS (p=0.346). Independent subtype analysis revealed leiomyosarcoma had the greatest RFS vs all other sub-types (p=0.011). High risk patients, with age accounted for, untreated patients have a hazard ratio of 4.67 (95% CI 1.19~18.35, p=0.027) relative to chemotherapy, indicating chemotherapeutic benefit for high risk patients. Conclusions: Presently there is insufficient and conflicting data for adjuvant therapy in the treatment of STS. Our retrospective data, within the limits of a retrospective analysis, demonstrates that our patient population behaves as predicted by the MSKPN. High risk patients given I/E have an overall RFS advantage. We propose a prospective risk stratified adjuvant therapy trial is warranted.
Mimics of gastrointestinal stromal tumors (GISTs): Implications for diagnosis and management—The Cambridge GIST Study Group (CGSG) experience.
Authors: Wong Han Hsi , Chengal Rajani , Hardwick Richard , Horan Gail , Hatcher Helen , Earl Helena Margaret , Pursglove Stephanie , Bulusu Venkata Ramesh
Published: March 2020

e21503

Background: Historically, GISTs were often misdiagnosed as other tumours. However, with the increasing awareness of GISTs, one needs to be careful in confirming the diagnosis since other tumours can simulate GISTs on endoscopy/imaging/histology. We report our 8 year experience of GIST mimics from the CGSG database. Methods: 250 cases discussed in the specialist multidisciplinary meeting from 2004 – 2012 were reviewed. Tumours initially suspected to be GISTs but turned out to be other tumours were included in this analysis. Patient demographics, endoscopic, imaging and histological features were analysed in 41 GIST mimics. Central review by specialist histopathologist was undertaken with immunohistochemical and molecular analysis to differentiate these tumours from GISTs. Results: GIST mimics N= 41. Median age 56 years (range 11 – 82 years), male:female ratio 1:1. Median size 8 cm (range 1.9 – 30 cm). Site of origin of tumours: stomach 34%, oesophagus/junction 15%, mesentery 12%, small bowel 10%, colon 5%, retroperitoneum 5%, pancreas 5%, liver 2% and indeterminate site of origin 12%. Suspicion of GIST was raised from imaging (46%), endoscopy (41%) and histology (39%). The histological subtypes of GIST mimics are summarised in the Table. Conclusions: Many benign and malignant tumours do mimic GISTs on imaging/endoscopy or histology. The diagnosis of GISTs should be made by a specialist multidisciplinary team with experience in imaging and histopathology. Distinguishing GISTs from their mimics is of critical importance both for prognosis and management. [Table: see text]
Generation of a new xenogenic transplantation model for the analysis of undifferentiated pleomorphic sarcoma: NOS in mice.
Authors: Wehler Thomas , Becker Marc , Grebe Nadine , Theobald Matthias , Rommens Pol Maria , Proschek Dirk , Graf Claudine
Published: March 2020

e21505

Background: Undifferentiated pleomorphic sarcoma, NOS (not otherwise specified) formerly known as MFH comprise about 15-20% of all soft tissue sarcomas (STS) in adults. This kind of sarcoma is characterized by low response to radiation or chemotherapy. Thus, surgery with the aim of R0-resection is still the cornerstone for a curative treatment regimen. However, surgery is not always possible. In the recent past, many efforts have been undertaken to refine chemotherapeutic options and to develop new drugs for targeted therapies, such as mTOR-inhibtors or tyrosine kinase inhibitors. Yet, the hoped break through is still lacking. In addition, the further development of entity-based new drugs is difficult due to the low incidence of STS and suitable reproducible animal models. Here, we present a new xenogenic transplantation model of a pleomorphic sarcoma in mice. Methods: After intraoperative resection of the sarcoma, a sarcoma-derived cell line was established. These cultured cells were injected s.c. (1x10E6 cells) in immunocompromised NOD/SCID γc-/- mice and in humanized NOD/SCID γc-/- mice. Results: Tumor growth was reproducibly seen after four to six weeks. When resected after 12 weeks, the xenogenic tumor presented the same histological and morphological characteristics as the original tumor. Tumor infiltrating lymphocytes were detected by immunhistochemical staining. Conclusions: This new xenogenic transplantation model can serve as a basis for the evaluation of manifold questions within the fields of oncology, tumor genetics and tumor immunology.
Multimodality management of synovial sarcoma: Review of single institutional experience.
Authors: Manjunath N.M.L. , Deo S. V. S. , Shukla N. K. , Bakhshi Sameer , Sharma Dayanand
Published: March 2020

e21506

Background: Soft tissue sarcomas (STS) are rare malignancies constituting 1% of all solid tumors. Synovial sarcoma (SS) constitutes 5-10% of all sarcomas. Histopathologically SS is classified as Monophasic, Biphasic and Poorly differentiated varieties and majority are high grade. There is paucity of literature pertaining to SS from developing countries. Methods: Study population was selected from a prospectively maintained STS database at the department of Surgical Oncology, Dr BRAIRCH, AIIMS. All patients with pathological diagnosis of SS were included for the analysis. Results: A total of 446 patients of STS were treated from 1995 to 2009 and 80 cases of pathologically proven SS were selected. Median age at diagnosis was 33 years. There were 53 males (66.3%) and 27 females (33.8%). Most common site was proximal lower limb, majority involving thigh. Sixty one patients presented with prior inadequate interventions including intralesional excision or marginal excision. Sixty seven cases had tumors more than 5 cm in size and 27 more than 10 cm. Lymph nodes were seen in 9 patients (11.3%) but only 4 showed pathological involvement. According to MSKCC staging 83% had stage III disease and stage I and II constituted 10.5%. Ten patients had metastasis at presentation and all of them had lung metastasis. Among the extremity sarcoma, 35 (43.8%) patients had limb salvage surgery and the rest required amputations due to advanced nature of disease. Overall 15% of cases required reconstruction and only 6 had positive margin. Postoperatively 35 patients received radiotherapy and 52 received chemotherapy (Adriamycin Ifosamide based). At a median follow up of 59 months,10 patients had local recurrence and 34 (42.5%) patients had systemic relapse mainly in the lungs (27 patients). At last follow up, 58 patients were alive of which 44 were disease free. The overall 5 year survival was 52%. Conclusions: SS is a rare tumor involving younger age group. Due to lack of awareness among patients and physician, majority present with suboptimal surgical intervention or advanced stage in developing countries resulting in a low limb salvage rate. Most common site of relapse is lung despite multimodality management resulting in a modest 5-year survival of 52%.
Efficacy of trabectedin for advanced soft tissue sarcoma (ASTS): A retrospective single center analysis.
Authors: Martinez-Trufero Javier , Pajares Isabel , Hernandez Garcia Alba , Cebollero Ana , Calera Lourdes , Anton Antonio
Published: March 2020

e21509

Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed patients with ASTS treated with trabectedin from Nov. 2006 to April 2012. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2as a 24-h infusion every 3 weeks. An analysis of response rate, time to progression (TTP) and overall survival (OS) and univariate analyses of prognostic factors were performed. Results: Overall,39 patients (24 men) with mostly high-grade (n=29) ASTS with a median age of 57 years (range 20-81) were analyzed. Most had L-type STS (leiomyosarcoma n=10; liposarcoma n=3), undifferentiated pleomorphic sarcoma (n=11), sarcoma NOS (n=5), or synovial STS (n=2). Eight had one of 6 very rare STS. At baseline patients had metastatic (n=21), bulky (n=4) or metastatic/bulky (n=14) disease and were pretreated with a median of 2 prior chemotherapy lines (range: 0-3; 4 patients received adjuvant chemotherapy only), including anthracycline-based chemotherapy (n=30), gemcitabine plus dacarbazine (GEM-DTIC; n=18), other (n=20). Patients received a median of 4 trabectedin cycles (range 1-34). Among 37 evaluable patients best responses as per RECIST were partial response (PR, n=7), stable disease (SD >3 months, n=9, 5 had SD >6 months) and disease progression (n=19), and 5 patients had a decrease in tumor density. Responses to trabectedin and GEM-DTIC did not exclude responses to the other regimen suggesting the feasibility of sequential treatment. After a median follow-up of 9.37 months, median TTP and OS were 4.4 months (95% CI: 3.5-5.4) and 9.7 months (95% CI: 4.5-14.9), respectively. Univariate analyses identified low/medium-grade STS and growth modulation index >1.13 as favorable prognostic factors for TTP, and retroperitoneal/visceral localization, L-type and rare STS and low/medium-grade STS for OS. Conclusions: The results of this real-life retrospective analysis confirmed the findings of previous trials showing that trabectedin is active drug for ASTS.
Gastrointestinal stromal tumors: Institute of Oncology—Dr. “Luis Razetti” experience, Caracas, Venezuela.
Authors: Chirinos Luis , Fuentes Maria Belen , Perez Maria Angelina , Gotera Gustavo , Parra Jesus Felipe , Garcia Sebastian Cristina
Published: March 2020

e21512

Background: Gastrointestinal Stromal Tumors are a heterogeneous group of tumors with clinical features and specific genetic alterations, which represent 1-3% of all gastrointestinal cancers. Imatinib, is the standard treatment in advanced and localized disease, and has demonstrated benefit in overall survival, progression free survival and disease free survival. Methods: The primary end point was to evaluate overall survival in patients with locally advanced, metastatic and early stage GIST treated with Imatinib; secondary end points were to evaluate disease-free survival and progression free survival. We included 34 patients with GIST treated between January 2005 and December 2011. Results: The most affected gender was male (55.88%), the average age was 51-60 years (26.47%), and most had localized disease at diagnosis (73.52%), mainly in the stomach (52.94%). As for the primary treatment, 25 underwent surgery (73.5%), applying adjuvant Imatinib in 18 patients (75%).The OS and DFS was higher in patients with localized disease compared with age (p = 0.0001 respectively). Regarding the use of adjuvant Imatinib, it produced clinical benefit in DFS and OS of 50 and 60 months respectively, regardless of risk. In patients with advanced or metastatic disease Imatinib was associated with higher PFS (p = 0.055) and OS (p = 0.1120). Relapses occurred in 24% of patients regardless of risk and the use of Imatinib. Conclusions: In our study we concluded that radical surgery and the use of Imatinib in GIST patients produce important clinical benefits which translate into higher survival rates.
Prescribing decision drivers in patients with recurrent gastrointestinal stromal tumor (GIST) previously treated with adjuvant imatinib: A retrospective chart extract-based approach.
Authors: Guérin Annie , Sasane Medha , Gauthier Geneviève , Schwiep Frances Annelies , Keir Christopher Hunt , Magestro Matt , Wu Eric Q. , Conley Anthony Paul
Published: March 2020

e21515

Background: Adjuvant imatinib (IM) is the standard of care for primary resectable GIST. However, little is known about prescribing habits following disease recurrence. This study identifies main prescribing decision drivers in recurrent GIST pts following completion of adjuvant IM treatment. Methods: Using an online data collection system, clinical information was retrieved on 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, who discontinued IM treatment, had a recurrence (while off IM), and subsequently restarted IM or initiated sunitinib. Pt-level data were collected at primary diagnosis and at first recurrence. Prescribing decision drivers were identified using logistic regression models. Physicians were also surveyed to identify factors that influence their prescribing decisions. Results: Following initial disease recurrence, 77% of pts restarted IM and 23% initiated sunitinib. IM duration at primary diagnosis was the main prescribing decision driver; pts treated with IM for a shorter period of time (≤18 months) were 7.0 times more likely to restart IM than pts with longer IM duration (p<.01). Pts who took longer (≥12 months) to develop recurrence after IM discontinuation (Odds ratio [OR]=3.4; p=<.01 ), had a low mitotic rate at recurrence (OR=2.8; p=<.01), or had a recurrence inside the gastrointestinal system (OR=2.7; p=<.01) were also more likely to be prescribed IM following recurrence. These findings were consistent with the top survey responses on factors influential to prescribing decisions after recurrence: time to develop recurrence (55%), pt risk profile (53%), and IM duration prior to recurrence (51%). Conclusions: Based on information of pts who restarted IM or initiated sunitinib, IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location and mitotic rate at recurrence seem to be the main prescribing decision drivers. These findings were consistent with physicians’ main factors reported to influence their prescribing decisions following recurrence.
Practical application of whole genome and transcriptome tumour analysis to guide chemotherapy decision-making for patients with advanced cancers.
Authors: Laskin Janessa J. , Lim Howard John , Gelmon Karen A. , Ho Cheryl , Renouf Daniel John , Yip Stephen , Huntsman David , Tinker Anna , Pleasance Erin , Li Yvonne , Shen Yaoqing , Kasaian Katayoon , Corbett Richard , Mungall Karen , Mungall Andrew , Zhao Yongjun , Schein Jacquie , Roscoe Robyn , Jones Steven , Marra Marco
Published: March 2020

e22020

Background: We propose that applying personal genomic information prospectively, in a clinically realistic timeframe can aid chemotherapy decision-making and result in more effective cancer treatment. We are investigating this approach in a variety of cancers to examine timeliness, deliverability, and rate of actionable targets identified. Methods: Eligible subjects with incurable cancer and limited chemo options have a tumour biopsy and “normal” blood taken for analysis. Archival specimens are concurrently analyzed to look for changes with time and treatment. Samples are subject to both an Ampliseq amplicon panel and in-depth whole genome DNA and RNA sequencing (WGS). Bioinformatics approaches identity genes with somatic and copy number variations, and expression changes. Variants are integrated into a pathway analysis to identify tumour specific processes that may drive the tumour, these are then matched to drug databases, with manual literature reviews, to indentify drugs that may be useful or even contra-indicated. Results: Between July 2012 -Jan 2013, 9 subjects (of 30 planned) are enrolled: 2 cases each of: colorectal and breast and 1 each of: squamous skin, squamous ethmoid sinus, nasopharyngeal, lung, and CLL-peripheral mantle cell cancer. 5 have completed analyses. Cancer panel results correlated well with WGS; although the panel is more rapid, it provides less comprehensive information and has not been as informative for identifying candidate druggable drivers. Extensive pathway mapping uncovered potential drug targets in each case that would not have necessarily been considered without this analyses. To date, 4 subjects have started chemo based on the analyses and 1 patient has had his diagnosis radically changed. There are significant genomic differences between archival and fresh tumour samples. Conclusions: This approach is feasible and yields actionable targets that can inform real-time chemotherapy decision-making. Archival samples do not appear to adequately represent post-treatment cancers. The impact of WGS vs. panel sequencing will require more subjects but it appears a panel may be insufficient for detailed treatment guidance.
Epithelial-mesenchymal transition and metastatic bladder cancer profile under vinflunine treatment.
Authors: Figueroa Angelica , Abella Vanessa , Aparicio Guadalupe , Haz-Conde Mar , Gayo Javier , Antón Aparicio Luis M.
Published: March 2020

e22021

Background: Given the role of vinflunine (VFL) in the microtubule dynamics and the link between microtubules and cell adhesions through cadherins, we have investigated the possible influence of VFL on adherens junctions through its interaction with microtubules. We have studied the implication of VFL on the reversion of epithelial-mesenchymal transition (EMT) in bladder transitional cell carcinoma and explored a possible novel molecular mechanism. Methods: Four human bladder transitional carcinoma cell lines were used to carry out the following experimental procedure: Cytotoxicity assay by using MTT assay, qRTPCR to analyze mRNA markers of the EMT, Western blotting using specific antibodies for EMT markers, and immunofluorescence images, analyzed by epifluorescence microscopy. Results: Cell growth reduction was detected in human bladder carcinoma cells under VFL treatment compared to control. VFL induces mesenchymal to epithelial phenotype and modulates the EMT markers: E-cadherin and Cytokeratin-19 were enhanced under treatment, while significantly reduction of mRNA mesenchymal markers expression (Vimentin, N-cadherin) and EMT-transcriptional factors (Snail and Zeb1) was detected. Strong reduction of Hakai protein was seen under VFL treatment. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin. Epifluorescence images showed that VFL treatment promotes E-cadherin localization specifically at cell-cell contact; while, Hakai expression decreases its expression in the nuclei and cytoplasm. Conclusions: These results suggest that VFL up-regulates E-cadherin contributing to mesenchymal to epithelial transition, and that Hakai modulation might be the molecular mechanism by which the increasing E-cadherin at cell-cell contacts in bladder carcinoma cell lines is detected. Given the relevant in vitro role of VFL on E-cadherin expression and on the reversion of EMT process, we hypothesized that VFL could exert a clinical benefit in delaying the metastasis in urothelial tumors.
Brain microenvironment-induced reduction in microRNAs to promote metastatic tumor growth, drug resistance, and survival.
Authors: Driscoll James , Subramani Arasakumar , Alsidawi Samer , Jagannathan Sajjeev
Published: March 2020

e22030

Background: Brain metastases remain a serious obstacle that negatively impacts cancer patient survival. Most deaths due to cancer result from the progressive growth of metastatic, drug-resistant lesions. Moreover, the incidence of brain metastases is rising as a result of an aging population, superior imaging modalities, earlier cancer detection and more effective treatment of systemic disease. Methods: To investigate the role of the brain microenvironment in metastasis, tumor cells were co-cultured with astrocytes - the most abundant normal cell type in the metastatic brain tumor niche. This led to increased tumor cell viability, proliferation and chemoresistance. Microarray-based profiling was then performed to address the effect of the brain microenvironment on miRNA expression levels in tumor cells. Results: Profiling revealed that astrocyte co-culture reduced miRNAs-768-3p, 886-5p and 200c in tumor cells. Inhibition of miRNA-768-3p increased KRas expression, and a specific binding site was identified in the KRas 3’UTR and validated using a luciferase construct. miRNA-768-3p levels were reduced in patient-derived brain metastases relative to normal adult brain. Additionally, miRNA-768-3p was also lower in brain metastases compared to the primary tumors in matched paired samples. Our data demonstrates that the brain microenvironment modulates miRNA-768-3p in metastatic lesions to enhance KRas-mediated tumor survival and promote metastasis. Conclusions: The brain microenvironment regulates the expression of individual miRNAs in tumor cells to promote growth, survival and drug resistance. The brain microenvironment down-regulates the level of certain miRNAs to promote oncogenic signaling and tumor growth while our studies indicate that chemically-engineered miRNA mimics can restore the loss-of-function to reduce the viability of cancer cells. miRNA replacement therapy is a promising and novel therapeutic concept that could save thousands of patients from ineffective treatment, improve patient quality-of-life, overall survival and reduce the devastating impact of brain metastases on the healthcare system.
Clonal T-cells and monocytosis in cancer patients and relationship to prognosis, and incidence of autoimmunity, fatigue, and second primary malignancies.
Authors: Snyderman Michael , Mikovits Judy
Published: March 2020

e22038

Background: Clonal T-cell expansion and monocytosis could explain inflammation, fatigue and autoimmunity seen with cancer if both cell types release excess amounts of cytokines and disregulate the immune system. Cytokines can also have a paracrine effect and increase malignant cell proliferation. Methods: 48 patients with various neoplasms from an oncology practice were studied. Myeloid dyscrasias were excluded to allow interpretation of monocytosis. Clonal TCR rearrangements were done in a reference lab. Cancer-Related Fatigue (CRF) data as defined by the NCCN was available in 34 patients. The study was done 2010–2013. Results: See Table. Conclusions: Presence of a clonal T-cell expansion was associated with the greatest likelihood of high stage disease, second malignancy, autoimmunity and CRF. Monocytosis had a similar effect but less than clonal T-cell positivity. The patients with the least likelihood of high stage disease and CRF had no detectable clonal T-cell expansion and no monocytosis. Of the 25 originally negative or undetectable clonal T-cell expansions, 4 became positive 1-2 years later. The clonal T-cell and monocyte proliferation are unlikely to be reactive because a true tumor-specific antigen is rare and because there appeared to be a negative rather than a neutral or positive impact on multiple parameters. Further investigation to determine the subsets of T-cells and monocytes that are expanded and their production of proinflammatory cytokines, etiology of their proliferation and their role in the progression of neoplasia could lead to new treatments to improve the course and prognosis of cancer patients. [Table: see text]
Anti-retroviral drugs used to treat a patient with chronic lymphocytic leukemia and cancer-related fatigue.
Authors: Mikovits Judy , Snyderman Michael
Published: March 2020

e22039

Background: The only known human cancer retrovirus, HTLV1 causes adult T-cell leukemia/lymphoma of which some respond to AZT+ alpha interferon. The existence of human retroviruses originating from murine leukemia viruses (MLVs) and their role in human cancer has been debated since the 1970s. A previously untreated 68 y.o. Oncologist with B-cell CLL and Cancer-Related Fatigue (CRF) was studied for retrovirus to determine if he could be treated with anti-retroviral drugs (arvs). His history included autoimmune disorders. Methods: Antibody detection: Alter et al. 2012. Gag detection: Mikovits et al. 2010. Results: Antibody to MLV envelope antigen and Gag RNA was detected. The Gag sequence was similar to MLVs but sufficiently different from the laboratory generated, XMRV which has no natural history in Man to rule it out. Proinflammatory cytokines were elevated. Trisomy 12 was present. By day 571 of his CLL the ALC doubling time decreased to < 1 year and he developed disabling CRF. AZT and raltegravir were started day 899. ALC, cytokine levels and CRF improved. After 9 months CLL parameters relapsed and then responded to adding tenofovir. This response lasted 3 months and then relapsed. Addition of lopinavir induced a response of parameters now ongoing 9 months. Total time on treatment is 29 months without toxicity and with improved CRF. In addition to his CLL there was a measurable T-cell clone and monocytosis both of which rose and fell with relapses and responses of the CLL to arvs but at different rates. Conclusions: A common human neoplasm was successfully treated with arvs. The drugs used were 2 Reverse Transcriptase inhibitors, an Integrase inhibitor and a Protease inhibitor developed for HIV treatment. There is nothing unusual or unique about this patient’s neoplasm and his case should stimulate further research. The role of retrovirus in cancer and CRF and whether arvs could be beneficial to patients identified as having a retroviral associated cancer and CRF should be studied. In addition, the significance of this patient’s clonal T-cell expansion and monocytosis and their production of cytokines should be examined. [Table: see text]
Association of miRNA expression and EGFR mutation status in lung adenocarcinomas.
Authors: Ju Lixia , Zhou Caicun
Published: March 2020

e22044

Background: Epidermal growth factor receptor (EGFR) is frequently found to be activated by mutation or amplification in lung cancer. Though most patients with EGFR activating mutation response to EGFR-TKI, there are still about 30% patients showing no response. miRNA expression is deregulated in lung cancer, and miRNAs can regulate EGFR. So it is important to predict the candidate miRNAs that target EGFR and to investigate the availability of these candidate miRNA regulators in lung cancer. Methods: In this study, we investigated the miRNA expression in lung adenocarcinomas cell lines with mutated EGFR (H1650 and PC-9)and wild-type EGFR (H1299 and A549) using the Phalanx Human Whole Genome Microarray. Results: The expression of 1,732 miRNAs was evaluated and expression of individual miRNAs was validated by individual RT-PCR assays. Overall, miRNAs expression were different between these two groups. Hsa-let-7d-3p, hsa-miR-1307-5p, hsa-miR-141-3p, hsa-miR-200c-3p, hsa-miR-203, hsa-miR-3182, hsa-miR-4510, hsa-miR-934 were upregulated and hsa-miR-3196, hsa-miR-4450, hsa-miR-4649-5p were downregulated in the mutated EGFR group. Conclusions: It is suggested that there are different carcinogenic pathways for EGFR mutation tumors. Those miRNAs that associated EGFR mutation can be further explored for their application in target therapy and prognostics.
Cadherin-11 (Cad11) for detection of epithelial-mesenchymal transition (EMT) in circulating prostate cancer (PCa) cells.
Authors: Zurita Amado J. , Bischoff Farideh Z. , Gorlov Ivan , Mayer Julie Ann , Pircher Tony J. , Mikolajczyk Steve , Logothetis Christopher , Lin Sue-Hwa
Published: March 2020

e22047

Background: CTC are believed to require EMT to metastasize. Cells undergoing EMT may lack or express low levels of epithelial markers such as EpCAM and cytokeratins (CK) and experience a cadherin switch from epithelial to mesenchymal. However, most current detection methods only rely on epithelial markers for enrichment, resulting in failure to recognize other CTC phenotypes. We previously showed that PCa cells expressing the mesenchymal (osteoblast-lineage) marker Cad11 are more likely to home to and colonize bone (Cancer Res 2010). Whether Cad11+ PCa CTC lose CK expression is uncertain. Since Cad11 is an EMT marker relevant to the bone tropism of PCa, we characterized its expression in CTC from patients (pts) with bone metastasis. Methods: Blood from PCa pts (n=86) with different extents of bone involvement was analyzed employing Biocept’s microfluidic CTC technology. For cell capture, we used a PCa CTC-optimized cocktail of antibodies that included epithelial, mesenchymal and putative stem cell markers. Captured cells were scored based on standard stain criteria (CK+/CD45−/DAPI+) and Cad11 expression. To ascertain malignant identity of CK−/CD45−/DAPI+cells, we used FISH to characterize androgen receptor [AR], Myc and PTEN status. Results: Among 69 pts with detectable CK+ CTC, 39% had at least 1 cell co-expressing Cad11. Very rare CK−Cad11− CTC displaying different degrees of aneuploidy were also observed, but only in 4 pts. No single CK−Cad11+ FISH “abnormal” cell was seen. FISH profiling of individual CK+ CTC revealed an association between Myc gain and PTEN loss (P=0.00004). We also found positive correlations between AR and PTEN amplification (r=0.55) as well as AR amplification and Myc loss (r=0.56; both P<10-6). Interestingly, CK−Cad11+cells (range, 1-910) were observed in 45 pts, all with a “normal” pattern of AR, Myc and PTEN expression. Conclusions: Complete loss of epithelial marker expression in CTC (identified by concurrent gene alterations) is a very infrequent event in PCa pts with established bone metastasis. Simultaneous individual CTC profiling of gene gains/losses may provide insights into PCa biology. Evaluation of the identity of CK−Cad11+ cells is ongoing.
Circulating tumor cells (CTC) as a biomarker of response in patients with extensive-stage small cell lung cancer (EX-SCLC).
Authors: Huang Chao H. , Ganti Apar Kishor , Neupane Prakash , Sittampalam G. Sitta , Schmitt Sarah , Nirmalanandhan Sanjit , Williamson Stephen K. , Wick Jo , Smart Janie , Spencer Sarah Ellen , Godwin Andrew K. , Van Veldhuizen Peter J.
Published: March 2020

e22048

Background: SCLC, a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with EX-SCLC. Detection of CTCs is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal and prostate cancer. We initiated a study to study the role of CTC as a biomarker of response and relapse in patients with EX-SCLC. Methods: We collected blood sample from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, following completion of systemic therapy, follow up every 6-8 weeks and at relapse. The CTC was determined using the Cell Search system in a central laboratory. The study was conducted in 4 different sites and it was reviewed and approved by respective Research Review Committee and IRBs. Results: We enrolled 27 patients with EX-SCLC, 1 was excluded due ineligibility, all patients were treated with platinum and etoposide. We observed partial response in 16 patients (61%), stable disease in 3 patients, 1 with progression of disease and not assessed in 7 patients (5 deceased, 2 not available); the baseline CTC of 2 patient were not measured (one due instrument failure and one due insufficient blood). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0 to 3430) and 2 (range 0 to 526), respectively. A significant reduction in CTCs from baseline to post-tx was identified; for the 14 subjects with pre and post treatment CTC, the median reduction was 51.5% (51.5% decrease, range -2904% to +5%, p< 0.001). Conclusions: We were able to demonstrate feasibility of using CTC as a biomarker of response in patients with EX-SCLC in clinical setting. CTC could be a useful biomarker in the management of SCLC to predict response to therapy.
A new tumor biomarker: Serum protein peak at 3144 m/z in patients with node-positive breast cancer.
Authors: Chen zhan-Hong , Xu Shen-Hua , Su Dan , Liu Wei , Yang Hongjian , Xie Shang-Nao , Meng Xuli , Lei Lei , Jia Wang Xiao
Published: March 2020

e22050

Background: To explore the association of the 3144 m/z and the clinicopathological features and its clinical value in the diagnosis and prognosis of breast cancer. Methods: Using SELDI-TOF-MS, we analyzed serum 3144 m/z in 298 patients patients with node-positive breast cancer after mastectomy. The association between 3144 m/z and clinicopathological features was evaluated. We also evaluated their prognosis value in survival using univariable and multivariable statistical analyses. Results: The positive rate was higher in 3144 m/z than CA153 (36.6% versus 11.5%, p <0.001). The 3144 m/z positive rate was no difference in patients with CA153 negative or positive (35.3% versus 29.6%, P =0.563). 3144 m/z was higher elder cases (> 50 years old) than young group( 50-year-old and 31.2% in young,χ2=4.227, P=0.040). The patients with 3144m/z negative (n=189) had higher 3-year OS rate than positive (n=109), 89.5% versus 81.7% (P=0.034). Also in young (P=0.024), postmenopasual (P=0.025), small tumor (P<0.001), node(-) or less (P<0.001), early stage (P<0.001), good molecular type (P=0.019), normal CA153 (P<0.001), neoadjuvant chemotherapy (P=0.001). Using Cox proportional hazards model,analysis showed that basal-like type (worse, P=0.038), CA153 positive (worse, P=0.015), adjuvant chemotherapy (better, P=0.028) and adjuvant radiotherapy (better, P=0.032) were independent prognostic factors in patients with node-positive breast cancer. but the 3144m/z was not. Conclusions: Serum protein peak at 3144 m/z provides a new, practical biomarker for diagnosis and prognosis of breast cancer.
Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil.
Authors: Sasada Shinsuke , Miyata Yoshihiro , Tsutani Yasuhiro , Hihara Jun , Okada Morihito
Published: March 2020

e22053

Background: Metabolomics has developed as an important new tool in cancer research. It is expected to lead to the discovery of biomarker candidates for cancer diagnosis and treatment. The current study aimed to perform a comprehensive metabolomic analysis of the intracellular dynamic responses of human gastric cancer cells to 5-fluorouracil (5-FU), referencing the mechanism of drug action and drug resistance. Methods: Small metabolites in gastric cancer cells and 5-FU–resistant cells were measured by liquid chromatography-mass spectrometry. Candidates for drug targets were selected according to the presence or absence of resistance, before and after 5-FU treatment. In addition, the gene expression of each candidate was assessed by reverse transcription-polymerase chain reaction. Results: The number of metabolites in cancer cells dramatically changed during short-term treatment with 5-FU. Particularly, proline was reduced to one-third of its original level and glutamate was increased by a factor of 3 after 3 h of treatment. The metabolic production of glutamate from proline proceeds by proline dehydrogenase (PRODH), producing superoxide. After 5-FU treatment, PRODH mRNA expression was upregulated 2-fold and production of superoxide was increased by a factor of 3. In 5-FU–resistant cells, proline and glutamate levels were less affected than in non-resistant cells, and PRODH mRNA expression and superoxide generation were not increased following treatment. Conclusions: The authors identified a candidate biomarker, PRODH, for drug effects using the metabolomic approach, a result that was confirmed by conventional methods. In the future, metabolomics will play an important role in the field of cancer research.
FoxM1 as a potential therapeutic target for triple-negative breast cancer.
Authors: Yom Cha Kyong , Lee Kyung-Min , Han Wonshik , Kim Sung-Won , Moon Hyeong-Gon , Noh Dong-Young
Published: March 2020

e22063

Background: Elevated expression or activity of the transcription factor forkhead box M1 (FoxM1) is associated with development and progression of breast cancer. In this study, we show that whether inhibition of FoxM1 in triple negative breast cancer (TNBC) cell lines causes the changes of cancer progress and response to the treatment. Methods: We inhibited FoxM1 using thiostrepton (FoxM1 inhibitor) and identified the activity of VEGF, cyclin B, cyclin D1, p27, CD44 and cleaved capase-3 in MDA-MB-231 cells. Invasion assay was evaluated in BT-20 cells and combination with cisplatin and inhibition of FoxM1 were treated in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, MDA-MB-157, and BT-20. Results: When FoxM1 was inhibited using thiostrepton in MDA-MB-231 cells, expressions of VEFG, cyclin B, cyclin D1, p27, and CD44 were decreased. On the other hand, cleaved caspase-3 expression was increased. Intersetingly, response to inhibition of FoxM1 depended on the expression of p53 in each cell lines. Invasiveness of BT-20 cells is markedly reduced by inhibitioh of FoxM1. Co-treatment with thiotrepton and cisplatin synergistically induced apoptosis of breast cancer cells in MDA-MB-231, MDA-MB-157, and BT-20. Conclusions: Inhibition of FoxM1 increases apoptosis and decreases invasiveness and VEGF exprsssion of TNBC cells. And when inhibition of FoxM1 combines with cisplatin treament, synergistic effect was shown. Therefore, FoxM1 is valuable as a potential target for not only anticancer activity but also overcoming cisplatin resistance in TNBC.
Predicting erlotinib resistance in EGFR wild type NSCLC patients.
Authors: Jensen Peter Buhl , Knudsen Steen , Hansen Anker , Jensen Thomas , Askaa Jon
Published: March 2020

e22065

Background: Cancer patients with wild type EGFR respond to treatment with erlotinib at a lower rate than patients with EGFR mutations. It would be relevant to predict which EGFR wild type patients benefit from erlotinib. We have developed a response predictor based on NCI60 cancer cell lines measurements of erlotinib effect and gene expression measurements. Clinical relevance was improved by filtering the model through expression profiles from more than 3,000 clinical samples.The erlotinib response predictor consists of 94 sensitivity genes and 10 resistance genes and is completely defined before independent validation on patients treated with erlotinib. Methods: Gene expression data from pre-treatment core biopsies from 25 patients with refractory NSCLC (clinicaltrials.gov: NCT00409968) later treated with erlotinib (The BATTLE trial; Kim, ES et al. Cancer Discov. 2011; 1:44-53) were downloaded from Gene Expression Omnibus with accession number GSE33072. PFS after erlotinib treatment was recorded. The erlotinib response predictor was applied retrospectively to the gene expression measurements.Patients with a predicted sensitivity above the 0.15 quantile were categorized as sensitive, patients with a predicted sensitivity below were categorized as resistant.The median was also tested as a cutoff, and correction for multiple testing was taken into consideration. Results: In a Kaplan-Meier analysis of PFS comparing predicted sensitive and predicted resistant patients, the predicted sensitive patients survived longer (PFS 2.3 months (1.9-2.7)) than predicted resistant patients (PFS 1.2 months (0.5-1.8)). A log-rank test for PFS found the difference significant (p=0.005). Hazard ratio 4.6 (1.4-15.2). Conclusions: The small clinical data set validated the cell line derived erlotinib response predictor. It identified a subset of 16% of patients with no apparent benefit from erlotinib. We have performed similar validations for 24 other response predictors in 24 clinical trials. In 20 out of the 24 clinical trials, the agreement between prediction and clinical outcome was statistically significant. Thus, our cell line based method represents a general method for predicting clinical response to cytotoxic or cytostatic agents.
Detection of solid tumors by infrared biochemical analysis of peripheral blood mononuclear cells.
Authors: Kapelushnik Joseph , Zelig A. , Geffen David Barry , Gusakova Irena , Mordichai S.
Published: March 2020

e22069

Background: Detection of malignancies such as breast, colorectal and lung at early stages can improve survival rates from 20% up to 80%. Over the past few years, great efforts have been taken to develop novel, non invasive and effective methods for early diagnosis of cancer; however, a low sensitivity and/or specificity, has prevented their introduction as methods for early detection of cancer in populations at risk Methods: The clinical study was conducted at Todos Medical Ltd., Ben-Gurion University of the Negev and Soroka University Medical Center. 2 ml of peripheral blood was collected from each of 67 cancer patients (breast 26; gastrointestinal 27; lung 13; other 11) and 46 healthy controls. Peripheral blood mononuclear cells (PBMC) were extracted from whole blood and measured under Fourier transformed infrared microscope spectroscopy(FTIR-MSP). The differences between spectra of cancer and controls subjects' PBMCs were analyzed. Results: Significant differences were observed between healthy subjects and cancer patients at multiple bands along the infrared spectra of the PBMCs. Furthermore, we observed a distinct spectral pattern for each type of cancer which may indicate a difference in composition and activity of PBMC population. Several absorption bands may indicate for the stage of the disease.with sensitivity of 84% and specificity 94%. Conclusions: This study suggests the potential of FTIR spectroscopy analysis as a simple, low cost and minimally invasive method for cancer detection. The present research is preliminary and additional clinical trials are required for further validation and verification.
Identification of germ-line 185delAG BRCA1 mutation among breast cancer families in Iran: An experience from northeastern Iran.
Authors: Kooshyar Mohammad Mahdi , Nassiri Mohammad Reza , Mahdavi Morteza , Doosti Mohammad , Parizadeh Amir Reza
Published: March 2020

e22079

Background: The present study evaluated the prevalence of 185DelAG BRCA1 mutation in the group of Iranian women breast cancer patients, or their relative with family history of breast cancer. Breast cancer is the most common malignancy in women and the leading cause of cancer death in females worldwide. BRCA1 is among the best known cancer susceptibility genes with high penetrance and have multiple cellular functions including critical roles in homologous DNA repair. Identifying gremlin BRCA mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. The combination of breast cancer susceptibility alleles together with other risk factors may be important clinically. Methods: Subjects included in this study were thirty nine patients diagnosed with breast cancer and 29 women, from first degree relative of patients. The clinical and demographic details from these individuals were collected from medical records, pathological reports, and when needed and using a detailed questionnaire. Genomic DNA from peripheral blood mononuclear cells was extracted and analyzed by polymerase chain reaction and SSCP methods in order to finding 185DelAG founder mutation. Results: The results indicated that four patients and three healthy relatives had this founder mutation. The identification of these founder mutations facilitates mutation population screening and subsequent management options available to an individual woman including screening or prevention are then dependent on this level of assessed risk. Conclusions: Finally identifying the effective risks regarding breast cancer among Iranian women requires many works. However, a complete BRCA1 gene sequence analysis might be useful, regarding targeted cancer prevention and therapeutics.
Outcomes of patients with advanced cancer and KRAS mutation in phase I clinical trials.
Authors: Tsimberidou Apostolia Maria , Said Rabih , Falchook Gerald Steven , Janku Filip , Naing Aung , Zinner Ralph , Blumenschein George R. , Fu Siqing , Hong David S. , Piha-Paul Sarina Anne , Wheler Jennifer J. , Ye Yang , Hess Kenneth R. , Palmer Gary A. , Wolff Robert A. , Kurzrock Razelle
Published: March 2020

e22086

Background: The prognostic significance of KRAS mutations varies by mutation type. We compared the outcomes of patients with different KRASmutations treated in phase I clinical trials. Methods: Patients with advanced cancer and KRAS mutation who were treated in the phase I program from 9/08 to 12/12 were analyzed. The presence and type of KRAS mutation in the patients’ tumor samples were assessed in a CLIA-certified laboratory using PCR, sequenom analysis or next-generation sequencing. We compared clinical outcomes according to type of mutation, tumor, and therapy. Results: KRAS mutations were identified in 365 patients (codon 12, n=278; codon 13, n = 49; other codon, n = 38). The median age was 59 yrs (range, 18-87); and 46% men. Of 365 patients, 260 had KRAS mutation alone; 105 patients had 130 additional aberrations: PI3KCA, n=45 (39%); p53, n=29 (25.2%); PTEN, n=22 (19%); other, n=34 (29%). Of 260 patients, 159 were treated and evaluable for response. Outcomes in patients with KRAS mutation alone or with KRAS and additional molecular aberrations are shown in the Table. Conclusions: Keeping in mind that the number of patients was small, our results demonstrate heterogeneity in outcomes of patients with KRAS mutations. Combination studies of MEK inhibitors with other drugs may have improved antitumor activity. [Table: see text]