bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal stromal tumors (GISTs): Our experience in the management of 26 patients
Authors: Maiello E. , Tozzi L. , Latiano T. P. , De Bonis A. , Bisceglia M. , D’Addetta C. , Di Sebastiano P. , Nanni L. , Valori V. M. , Piano A. 
Published: March 2020

19506 Background: GISTs represents 0.1–3% of gastrointestinal neoplasms; most cases occur in people 40 to 80 years old, and are more common in men than in women. More than half of all GISTs patients present with locally advanced, recurrent, or metastatic disease (mainly to liver or peritoneum). Methods: From January 2001 to December 2005 we observed in our Institution 26 pts with GISTs; all were CD117+.The main characteristics of these pts were as follows: median age: 61 yr; sex (F/M): 14/12; primary tumor site: stomach 13 (50 %), small intestine 7 (27 %), rectum 1 (4 %), retroperitoneum 4 (15 %), liver 1 (4 %); first symptoms: epigastric pain 10 (38 %); abdominal pain 4 (15 %); hematemesis 1 (3 %); anemia 5 (18,5 %), palpable abdominal mass 1 (3 %), defecation disorders 2 (7 %); melena 3 (11 %); rectal bleeding 1 (3 %); ascites 1 (3 %). Results: Radical surgical resection was performed in 21 patients (81 %), 2 patients received a debulking surgery, and no postoperative mortality or major complications were observed; 3 pts showed an advanced disease. Seven pts (33%) developed recurrence, local or at distance, and the median time to relapse was 7,5 months (range 2–11). One pt with advanced disease dead before any treatment and 11 pts received Imatinib (I), at the standard dose (400 mg/d), starting from the date of diagnosis of advanced disease or metastatic relapse and given until development of intolerance or progressive disease. Main toxicities of I included: neutropenia G3 (4%), skin rash (4%), periorbital oedema (4%). We achieved 3 PR (lasting 12+, 21+ and 40 mos), 6 SD and 2 PD. With a median follow-up of 30 months, all but three pts (dead for progressive diseases) are alive. The overall survival rate was 88.5 % and the median overall survival was 16 mos (range 1–49). Conclusions: Surgical resection remains the only effective treatment for GISTs. However, in pts with advanced or relapsed disease treatment with I is effective with an high disease control rate. No significant financial relationships to disclose.
Prediction of response to neoadjuvant chemotherapy in breast cancer
Authors: Hannemann J. , Halfwerk H. , Velds A. , Loo C. , Rutgers E. , Rodenhuis S. , Van de Vijver M. 
Published: March 2020

20005 Background: Neoadjuvant chemotherapy is increasingly employed in operable breast cancer. Our initial studies on a cDNA array platform failed to identify gene expression patterns predicting response to neoadjuvant chemotherapy in breast cancer patients (J Clin Oncol 23:3331, 2005). Now we included more patients and used oligo microarrays. Methods: Patients with operable or locally advanced breast cancer were included in a randomized phase II study or received neoadjuvant chemotherapy off protocol. All except 7 patients began chemotherapy with 3 courses of dose-dense adriamycin and cyclophosphamide (ddAC) and response was evaluated by MRI. Patients with a response and a HER2-positive tumor were then randomized between either 3 additional courses of ddAC or six weekly courses of carboplatin, paclitaxel and trastuzumab (CPT). Patients without response were switched to CPT. Patients with HER2-negative tumors were randomized between 3 courses of either ddAC or capecitabine and docetaxel (CD). After evaluation, patients without response were switched to the alternative treatment arm. From all patients 14G core needle biopsies were taken before treatment and total RNA was isolated. Amplified mRNA was labeled and hybridized to 35k human oligo microarrays from our microarray facility. Results: So far, 77 patients have been included into the study. From 48 of these, good quality RNA from tissue with >50% tumor cells was isolated. 43 patients had received ddAC as initial chemotherapy; 32 of these had not been switched to another regimen. In a training set containing 11 pathological complete remissions (pCR) and 9 non-responders (NR) we could separate these groups by using 20 genes in a supervised classification and a 9-step cross validation. These results could be validated in an independent set of 11 samples (6 pCR, 5 NR). From 10 out of 11 samples, response status could be predicted correctly, independent from the treatment regimen. Although ER-positive tumors have a lower pCR rate than ER-negative ones, the steroid hormone receptors were not present in the classifier. Conclusions: We conclude that it should be possible to identify a reliable gene expression profile associated with response to adriamycin based neoadjuvant chemotherapy in breast cancer. No significant financial relationships to disclose.
HER2 comparison with novel 3-gene marker sets for risk prediction of distant recurrence of breast carcinoma
Authors: Alsobrook J. , Hraber P. , Davis L. , Harris C. , Doherty P. , Hall B. , Williams T. , Hozier J. 
Published: March 2020

20009 Background: The risk of distant recurrence in patients with invasive breast carcinoma (BrCa) is predicted imperfectly by currently used factors (e.g. nuclear grade, hormone receptor status), complicating adjuvant therapy decisions. In an effort to discover biomarkers for recurrence, we retrospectively analyzed BrCa recurrence and tumor gene amplification. Multi-gene marker sets were evaluated for predictive significance and accuracy. Because studies of HER2 as a suitable biomarker report positive and negative results, we compared our marker sets with HER2. Methods: 229 of 723 BrCa patients met inclusion criteria: invasive ductal carcinoma, no isolated local recurrence, minimum 4 years follow-up, and archived specimens adequate for fluorescent in situ hybridization (FISH) assay. Study endpoint was recurrence, or non-recurrence throughout follow-up. FISH was performed on formalin-fixed paraffin sections with probes for previously identified genomic regions. Signals were counted with a Metasystems workstation, and used in a “Prognostic Index” (PI) to categorize recurrence risk. One-sided Fisher’s exact test was used to assess increased incidence of distant recurrence in relation to PI and HER2, and increased incidence of HER2 amplification in relation to PI. Results: Two separate 3-gene marker sets were obtained that predict clinical outcome for hormone receptor + (HR+) and hormone receptor − (HR−) tumors. In HR+ samples a PI based upon regions surrounding CYP24, PDCP6IP, and BIRC5 was the best predictor of recurrence, while for HR- specimens the PI was based on the NR1D1, SMARCE1, and BIRC5 regions. The PIs are significantly associated with recurrence of HR+ and HR− tumors (OR = 9.52, 95% CI > 2.12, p = 0.0024; and OR = 12.3, 95% CI > 1.45, p = 0.0188, respectively). However, tumor HER2 amplification was not prognostic for recurrence (OR = 1.76, 95% CI > 0.77, p = 0.1395). Furthermore, there was no significant association of PI with HER2 status (OR = 1.56, CI > 0.57, p = 0.862). Conclusions: Prognostic Indices based on copy numbers of two 3-gene marker sets significantly predict clinical outcome of stage I-III invasive ductal carcinoma. HER2 amplification, included in our previous whole genome survey but not present in our final marker sets, had no prognostic value. [Table: see text]
Characterization of a subset of CD4+ T cells expressing CD161 in cancer patients and healthy individuals
Authors: Iliopoulou E. G. , Karamouzis M. V. , Perez S. A. , Ardavanis A. , Baxevanis C. N. , Papamichail M. , Rigatos G. 
Published: March 2020

20016 Background: CD161 is a glycoprotein expressed in >90% of NK and 25% of T cells in the peripheral blood of healthy individuals. Several NK receptors on T cells infiltrating tumors have been proven to negatively influence their effector function and therefore play a role in tumor escape. In this study, we investigated T cells expressing CD161 in the peripheral blood mononuclear cells (PBMC), tumor infiltrarting lymphocytes (TIL) or malignant effusions (ME) from patients with several types of cancer. Methods: Expression of CD161 in CD4+ or CD8+ (lacking CD56) T cells, was examined using four-colour flow cytometry. The proliferative capacity and potential cytokine production of purified CD4+CD161+CD56− cells, were studied after weak or strong stimulation, with or without costimulation, in the presence or absence of Interleukin-2 (IL-2). The possible regulatory function of activated CD4+CD161+CD56− cells on T cell allo-responses was also investigated. Results: CD4+CD161+CD56− T cells were significantly increased (P < 0.01) in TIL, either from tumor tissue (n = 8) or metastatic lymph nodes (n = 5), and ME (n = 25), compared to PBMC from both cancer patients (n = 36) and healthy individuals (n = 12). CD4+CD161+CD56− cells from all sources tested, have the same phenotypic characteristics: they comprise a memory T cell population (CD45RO+CD45RA−) expressing high CD28 and CD95 and low CD25, CD38 and HLA-DR. Co-stimulation via CD28 is important for induction of proliferation and production of large amounts of Th1 and Th2 cytokines (IFN-γ, TNF-a, GM-CSF, IL-4 and IL-10). Following co-stimulation, CD4+CD161+CD56− cells also exert a suppressive activity on autologous PBMC allo-responses. The latter effect does not require cell-to-cell contact and is mediated by soluble factors, including IL10, since neutralization of IL10 partially restored the immune response. Conclusions: CD4+CD161+CD56− cells represent a distinct memory T cell population that is significantly increased in TIL and ME in patients with cancer. These cells are capable of secreting large amounts of both Th1 and Th2 cytokines and might play an immunosuppressive role, mainly through IL-10 production, depending on the microenvironment in which they develop. No significant financial relationships to disclose.
Elevated multidrug resistance-associated protein 4 (MRP4) expression in localized prostate cancer—A potential androgen regulated protein
Authors: Horvah L. G. , Ho L. , Kench J. G. , Allen J. A. , Scheffer G. L. , Stricker P. D. , Grygiel J. J. , Sutherland R. L. , Henshall S. M. 
Published: March 2020

20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump which transports prostaglandins, nucleoside analogues, glutamate and phosphate analogues. High MRP4 expression is prognostic of poor outcome in neuroblastoma and also correlates with MYCN amplification, suggesting regulation by this oncogene. Although MRP4 is known to be expressed in normal prostate epithelium, its expression in prostate cancer (PC) is undefined. This study aimed to define the pattern of expression of MRP4 in normal and malignant prostate tissue and assess the association with androgen exposure. Methods: 84 radical prostatectomy specimens from patients with clinically localized PC (22 neoadjuvant androgen ablation therapy, 62 no neoadjuvant treatment), 42 specimens of hyperplasia adjacent to PC and 16 cases of advanced PC were assessed for MRP4 expression using in situ hybridisation and immunohistochemistry. PC cell lines were assessed by immunoblotting. Results: There were significantly higher levels of MRP4 mRNA and protein expression in localized PC compared to hyperplasia (p=0.006). Conversely, MRP4 protein levels were significantly decreased in PCs treated with neoadjuvant androgen ablation therapy compared to cancers exposed to normal testosterone levels (p < 0.0001). There was also a trend towards decreased MRP4 expression in advanced PCs. Furthermore, immunoblotting revealed that MRP4 protein was more highly expressed in androgen-dependent (LNCaP) compared to androgen-independent (PC3/DU145) cell lines. In addition, in a panel of 14 normal human tissues only kidney and prostate tissue expressed MRP4 protein suggesting limited expression of MRP4 in human tissues. Discussion: Elevated MRP4 expression is found in malignant compared to benign prostate tissue while lower MRP4 expression is seen after androgen ablation suggesting that MRP4 may be an androgen-regulated gene. In addition, there is relatively little expression of MRP4 in normal tissues. These data suggest that MRP4 is important in the progression to PC and that it may be a potential therapeutic target. No significant financial relationships to disclose.
Epidermal growth factor receptor expression correlates with histologic grade but not microsatellite instability in primary colon carcinomas
Authors: Rego R. L. , French A. J. , Foster N. R. , Sargent D. J. , Alberts S. R. , Windschitl H. , O’Connell M. J. , Thibodeau S. N. , Sinicrope F. A. 
Published: March 2020

20023 Background: EGFR is a transmembrane receptor tyrosine kinase belonging to the ErbB family of proteins. Anti-EGFR antibodies have shown efficacy as monotherapy and can enhance cytotoxic chemotherapy in patients with advanced colorectal cancers. We studied EGFR expression in primary colon cancers and its association with, microsatellite instability (MSI), clinicopathological variables and patient survival rates. Methods: Archival colon carcinomas were studied from patients with high risk Dukes’ stage B2 (n = 78) and C (n = 230) patients enrolled in a prior adjuvant trial of 5-fluorouracil, leucovorin plus standard dose or high-dose levamisole (NCCTG 91–46–53). EGFR expression (anti-EGFR H11 antibody, DAKO) was analyzed by immunohistochemistry (IHC) and intensity (0–3+), extent and their product (weighted score) were determined. MSI was analyzed using BAT26 and expression of hMLH1, hMSH2 and hMSH6 proteins by IHC. Patients were censored at 5 years after randomization for DFS and censored at 8 years post study randomization for overall survival (OS) data. Results: EGFR protein expression was detected in 216 of 308 (70%) of Dukes’ B2 and C primary colon carcinomas from patients and localized to the plasma membrane. EGFR expression variables (intensity, extent, weighted score) were increased in poor/undifferentiated compared to moderate/well differentiated tumors (p ≤ 0.036). Similar EGFR expression levels were found in MSI-H (n = 27) versus MSS (n = 203) colon cancers and for other clinicopathological variables. EGFR intensity was more likely moderate (2+) or strong (3+) in Dukes’ C versus B2 tumors (p = 0.088). In addition, higher EGFR intensity (2+, 3+) showed a trend toward worse disease-free survival (5 yr DFS %: 62.2 vs. 71.7; p = 0.095), but not overall survival (p = 0.14). Conclusions: EGFR overexpression is associated with increased tumor aggressiveness as indicated by poor tumor cell differentiation and reduced DFS in colon cancer patients receiving adjuvant 5-FU and levamisole. These findings indicate that EGFR may be an important therapeutic target in the adjuvant setting. [Table: see text]
A quantitative reverse transcriptase polymerase chain reaction assay to identify metastatic carcinoma tissue of origin
Authors: Talantov D. , Baden J. , Jatkoe T. , Yu J. , Atkins D. , Mazumder A. , Wang Y. 
Published: March 2020

20024 Background: Carcinoma of unknown primary (CUP) wherein metastatic disease presents without an identifiable primary tumor site represents approximately 3–5% of all cancers. Identifying the origin of the primary tumor in patients with CUP can enable rational choice of therapeutic regimens. We developed an optimized set of ten gene markers for a quantitative reverse transcriptase polymerase chain reaction (qRTPCR) assay, and demonstrated high accuracy in predicting the tissue of origin when used on with formalin-fixed, paraffin-embedded (FFPE) metastatic carcinoma samples. Methods: Twenty-three putative tissue-specific markers for lung, colon, pancreas, breast, prostate and ovarian carcinomas were nominated by querying a gene expression profile database and by performing a literature search. Ten of these marker candidates were then selected based on validation by qRTPCR on 205 FFPE metastatic carcinomas of known tissue origin. Next, we optimized the RNA isolation and qRTPCR methods for these ten markers, and tested the qRTPCR assay on two sets of FFPE metastatic tumors. Results: We applied the 10-gene qRTPCR assay to a set of 260 metastatic tumors of known origin, generating an overall accuracy of 78%. Furthermore we tested an independent set of 48 metastatic samples, including thirty-seven samples where either the tissue of origin was known or which initially presented as CUP but were subsequently resolved. In these 48 samples, our assay demonstrated an accuracy of 76%. Conclusions: Our results suggested that optimized ten-gene markers qRTPCR assay reliably predicts tissue of origin of metastatic carcinomas in FFPE tissues. Such assay can significantly improve the rate of tissue of origin identification for carcinoma of unknown primary. [Table: see text]
Patients with breast and ovarian cancer generate immune responses to the folate receptor alpha
Authors: Knutson K. L. , Kalli K. R. , Krco C. J. , Goodman K. , Kelemen L. E. , Low P. S. , Hartmann L. C. 
Published: March 2020

20043 Background: Studies have demonstrated that the generation of endogenous immunity to specific tumor antigens is associated with improved prognosis for many cancers. Thus, there has been increased efforts to identify tumor-associated antigens to which there is immunity, as these may be tumor rejection antigens. A candidate antigen is the folate receptor alpha (FRα) which is overexpressed in malignancies, especially breast and ovarian cancer. Prior studies involving ovarian and breast cancer patients have demonstrated the presence of FRα-specific cytotoxic T cells in the tumor-associated lymphocyte population. Methods: Using the RANKPEP CD4 T cell epitope prediction algorithm, we predicted promiscuous immunogenic regions of FRα, and tested for immunity in 30 breast or ovarian cancer patients and 18 healthy volunteer donors in order to attain a better understanding of the levels and extent of the endogenous FRα immune response. Immunity was examined using IFN-γ ELIspot analysis and IgG ELISAs. Results: Fourteen peptides were predicted as potential epitopes to which T cells may respond, seven each from the carboxy- and amino-terminus halves of the protein. Greater than 70% of patients demonstrated T cell immunity to at least one of the fourteen peptides. Patients responded to an average of 3 ± 0.7 peptides while healthy donors responded to only 1 ± 0.5 peptides (p = 0.02). Five peptides were recognized by >25% of patients. Responses to three of these peptides were higher (p > 0.05) in the patients than in healthy donors, suggesting that patients generated immunity upon cancer development. Compared to healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor, suggesting natural epitope spreading (p = 0.03). There was no difference between patients and healthy donors in the immune responses to either non-specific stimuli (p = 0.2) or viral peptides (p = 0.5). Patients had detectable FRα-specific IgG antibody consistent with active FRα-specific helper T cell immunity. Conclusions: These findings demonstrate that the FRα is a target of the immune system in patients with breast or ovarian cancer. Understanding the antigens that are naturally targeted by the immune system may be important for diagnosis, prognosis, and immune-based therapies. No significant financial relationships to disclose.
Incidence of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients at primary diagnosis—A potential tool for risk stratification
Authors: Rack B. K. , Schindlbeck C. , Janni W. , Jeschke U. , Hofmann S. , Beckmann M. W. , Pantel K. , Lichtenegger W. , Sommer H. , Friese K. 
Published: March 2020

20053 Background: In metastatic breast cancer, CTCs have been proven an independent predictor for progression-free and overall survival (Cristofanilli, NEJM 2004). Therefore, we evaluated the role of CTCs in peripheral blood of breast cancer patients at primary diagnosis and during adjuvant systemic treatment within the Success-Trial (n = 3,658 pts). First results of the incidence of CTCs prior to chemotherapy will be presented here. Methods: The CellSearchSystem (Veridex) was used for isolation and enumeration of CTCs from 23 ml of peripheral blood. Briefly, after immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish epithelial cells and leukocytes. Patients had been accrued between September and December 2005. Results: We analyzed 124 breast cancer patients at the time of primary diagnosis. The majority of patients presented with small tumors (41% T1, 55% T2, 4% T3), and 32% were node-negative (45% N1, 14% N2, 9% N3). While a positive hormone receptor status was observed in 74% of patients and 31% were her2/neu positive, most tumors showed an intermediate or unfavourable grading (2% G1, 98% G2–3). In this patient group, 32% of patients (n = 40) presented with ≥1CTC in peripheral blood. In patients with the detection of CTCs, the mean number of cells was 5 (range 1–38). In 11 healthy individuals we found 1 CTC in one blood sample. The presence of CTCs did not correlated with tumor size (p = .39), presence of lymph node metastases (p = .25), histopathological grading (p = .33), hormone receptor status (p = .56) or her2/neu status of the primary tumor (p = .14). Conclusions: The isolation of CTCs from peripheral blood of primary breast cancer patients is feasible and might prove as an easy applicable and convenient technique to give further insight into the spread of the disease. The Success-Trial will investigate, whether CTCs can be used for risk stratification to more tailored treatment approaches and for the monitoring of treatment efficacy in individual patients. [Table: see text]
The importance of vascular invasion (vi) in women with breast cancer (bc) and between 1 and 3 positive nodes: Analysis of 272 patients
Authors: Fiorio E. , Auriemma A. , Mandarà M. , Caldara A. , Mercanti A. , Pavarana M. , Micciolo R. , Cetto G. , Molino A. 
Published: March 2020

20062 Background: Node positivity and the number of positive nodes are the most important prognostic factors in BC, and affected patients usually have a worse OS. The presence of VI in primary BC is a prognostic factor correlated with a high risk of metastatic spread whose importance led to it being included in the new classification proposed at the VII St. Gallen Consensus Conference. Methods: We studied VI in 272 pts with invasive BC and 1–3 positive nodes in order to evaluate its importance, and correlate it with the pathological, biological and clinical factors of T (1,2,3,4), diameter (0–10 mm, 11–20 mm, 21–50 mm, ≥50 mm), grading (G1, G2, G3), ER and PgR (positive vs negative), Ki-67 proliferative index (low 0–10%; intermediate 11–25%; high 26–100%), c-erbB2 (positive vs negative), age at diagnosis (≤49, 50–65, ≥65 years), type of diagnosis (asymptomatic vs symptomatic) and type of surgery (conservative vs mastectomy). The data were analysed using the chi-squared test. Results: Unlike those without VI, the tumours with node involvement (N+ 1–3) and VI correlated with poor prognostic factors: they were larger (pT2: 62.5% vs 37.5%; p = 0.001), had higher grades (G2: 50.7% vs 49.3%; G3: 72.2% vs 27.8%; p = 0.0004), and were more likely to be ER- (75.6% vs 24.4%; p = 0.004) and c-erbB2+ (50.6% vs 49.4%; p = 0.06). The patients were younger at diagnosis (63% vs 37% aged ≤49 years; p = 0.01) and more likely to have a symptomatic diagnosis (61% vs 39%; p = 0.001). No association with PgR was found. Conclusion: Our results show that primary BC with N+ 1–3 and VI+ correlates with poorer prognostic factors (diameter >20 mm, G2/G3, ER-, c-erbB2+, younger age and symptomatic diagnosis). These correlations are in accordance with the new classification proposed at the VII St. Gallen Consensus Conference concerning high-risk pts with early BC. As these pts are at high risk of recurrence after good local surgery, it is important to offer them adequate adjuvant therapy as a reasonable treatment opinion on the basis of their endocrinal responsiveness. No significant financial relationships to disclose.