bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ewing tumors of the chest wall: Local control and long-term outcomes
Authors: Indelicato D. J. , Keole S. R. , Shahlaee A. H. , Morris C. G. , Gibbs C. P. , Scarborough M. T. , Islam S. , Marcus R. B. 
Published: August 2020

e21501 Background: Primary sarcomas of the lungs and mediastinum are rare and few data are reported on treatment and results of therapy. Methods: We reviewed our experience from 1980 and 2008 including 31 patients (pts). Pts characteristics: median age 41 (19–80 y), male/female 19/12; symptoms at diagnosis: dyspnoea (42%), chest and shoulder pain (39%), cough (35%), hemophtoae (13%), discomfort (10%). 4 pts had a previous history of mediastinal radiation for Hodgkin's and non-Hodgkin's linfomas. 5 mediastinal tumours were located as follows: 2 in anterior part, 1 in posterior and 2 in the middle (sarcomas of the heart). 26 lung sarcomas presented as a singular mass in 23 cases and as a metastatic disease in 3. Results: In 20/31 cases the tumour was immediately resected (3 mediastinal masses and 17 lung sarcomas). In 8/31 cases only biopsy was possible. FNA was done in 25 pts. Neoadjuvant chemotherapy was performed in 4 cases (3 resected). Resection was complete in 11/23 cases and in 12/23 incomplete. The histology were: peripheral nerve tumour 7, leiomyosarcoma 4, MFH 2, fibrosarcoma 2, liposarcoma 1, angiosarcoma 2, undifferentiated sarcoma 1, solitary fibrous tumour 2, rhabdomyosarcoma 2, synovialsarcoma 2, pulmonary artery sarcoma 1, pleuropolmonary blastoma 1, malignant hemangiopericytoma 1, mixoid chondrosarcoma 1, ectopic osteosarcoma 1, aggressive fibromatosis 1. Only 4 pts received neoadjuvant chemotherapy, 11 adjuvant CT, 5 exclusive CT + RT for inoperable disease. Radiotherapy was completed in 26 pts (21 adjuvant). Local relapse or metastatic progression were recorded in 16/23 pts and 12 received one or more lines of palliative CT. Data about survival are disposable only for the more recently recorded pts (1998–2008: 17 pts). Of these only 8 are alive (2 with disease). Volume of disease, complete resection and grading are the dominant prognostic factors. Conclusions: Primary sarcomas of the lungs and mediastinum have a very severe prognosis. Surgical resection is the fundamental therapy, but in the future the role of neoadjuvant CT will increase. No significant financial relationships to disclose.
Ezrin immunohistochemical expression in advanced soft tissue sarcoma biopsy specimens from patients treated in a phase II trial of dose-dense doxorubicin- and ifosfamide-based chemotherapy
Authors: Almeida G. F. , Siqueira S. A. , Castro G. , Snitcovsky I. L. , Akaishi E. H. , Camargo O. P. , Oliveira C. R. , Filippi R. Z. , Federico M. H. 
Published: August 2020

e21508 Background: Ezrin is a member of the ERM (ezrin, radixin, moesin) protein family and links F-actin to the cell membrane, and it is involved in regulating growth and metastatic behaviour of cancer cells. Ezrin expression is associated with tumor progression and metastasis in several cancers, including sarcomas. This study evaluated ezrin expression as a predictor of response to chemotherapy and as a prognostic factor in soft tissue sarcoma (STS) patients (pts) treated in a dose-dense schedule protocol. Methods: 21 chemotherapy-naïve pts diagnosed with high-grade STS, not candidates for a limb-sparing surgery, were enrolled in a prospective phase II study of a sequential and dose-dense regimen consisting of doxorubicin 30 mg/m2 d1–3 q2w and ifosfamide 2.5 g/m2 d1–5 q3w, 3 cycles each, with G-CSF support. Ezrin expression was analyzed by immunohistochemistry on slides from formalin-fixed, paraffin-embedded, primary tumor biopsy blocks, with the anti-ezrin antibody clone AB-1(3C12) (NeoMarkers). Cytoplasmic immunostaining in more than 10% of tumor cells was considered as positive. Ezrin expression was correlated with response rate, progression-free (PFS) and overall survival (OS). Results: Leiomyo-, synovial and sarcoma NOS were the most frequent subtypes (5 pts each). 13 out of 21 pts (62%) presented distant metastasis. Protocol was halted after 3 toxic deaths. Three pts achieved partial response (RR 14%). With a median follow-up of 11.7 mo, median PFS and OS were 8.9 and 20.1 mo, respectively. In univariate analysis, OS was higher for synovial sarcoma pts (not reached vs. 14.2 mo, HR 0.0, 95%CI 0.06–0.82, p=0.02), and for those aged 45 y or less (20.1 vs. 4.2 mo, HR 0.30, 95%CI 0.03–0.88, p=0.04). Ezrin expression was available for 20 pts: it was positive in 9 pts (45%) and negative in 11 pts (55%). Ezrin expression was not related to tumor response (p = 0.40), and no significant association was detected between ezrin expression and median PFS or OS. Conclusions: Expression of ezrin was not a useful marker to predict outcomes in STS pts treated with dose-dense doxorubicin- and ifosfamide-based chemotherapy. No significant financial relationships to disclose.
Primary sarcomas of the lungs and mediastinum: Clinicopathological study and therapy results of Piedmontese Group for Sarcomas
Authors: Comandone A. , Boglione A. , Pochettino P. , Berno E. , Inguì M. , Papotti M. , Borasio P. , Maggi G. , Brach del Prever E. , Gino G. 
Published: August 2020

e21509 Background: Primary sarcomas of the lungs and mediastinum are rare and few data are reported on treatment and results of therapy. Methods: We reviewed our experience from 1980 and 2008 including 31 patients (pts). Pts characteristics: median age 41 (19–80 y), male/female 19/12; symptoms at diagnosis: dyspnoea (42%), chest and shoulder pain (39%), cough (35%), hemophtoae (13%), discomfort (10%). 4 pts had a previous history of mediastinal radiation for Hodgkin's and non-Hodgkin's linfomas. 5 mediastinal tumours were located as follows: 2 in anterior part, 1 in posterior and 2 in the middle (sarcomas of the heart). 26 lung sarcomas presented as a singular mass in 23 cases and as a metastatic disease in 3. Results: In 20/31 cases the tumour was immediately resected (3 mediastinal masses and 17 lung sarcomas). In 8/31 cases only biopsy was possible. FNA was done in 25 pts. Neoadjuvant chemotherapy was performed in 4 cases (3 resected). Resection was complete in 11/23 cases and in 12/23 incomplete. The histology were: peripheral nerve tumour 7, leiomyosarcoma 4, MFH 2, fibrosarcoma 2, liposarcoma 1, angiosarcoma 2, undifferentiated sarcoma 1, solitary fibrous tumour 2, rhabdomyosarcoma 2, synovialsarcoma 2, pulmonary artery sarcoma 1, pleuropolmonary blastoma 1, malignant hemangiopericytoma 1, mixoid chondrosarcoma 1, ectopic osteosarcoma 1, aggressive fibromatosis 1. Only 4 pts received neoadjuvant chemotherapy, 11 adjuvant CT, 5 exclusive CT + RT for inoperable disease. Radiotherapy was completed in 26 pts (21 adjuvant). Local relapse or metastatic progression were recorded in 16/23 pts and 12 received one or more lines of palliative CT. Data about survival are disposable only for the more recently recorded pts (1998–2008: 17 pts). Of these only 8 are alive (2 with disease). Volume of disease, complete resection and grading are the dominant prognostic factors. Conclusions: Primary sarcomas of the lungs and mediastinum have a very severe prognosis. Surgical resection is the fundamental therapy, but in the future the role of neoadjuvant CT will increase. No significant financial relationships to disclose.
Mechanisms of nicotine-induced resistance to treatment with chemotherapy and radiotherapy
Authors: Warren G. W. , Kudrimoti M. , McGarry R. , Arnold S. , Rangnekar V. 
Published: August 2020

e22008 Background: Nicotine (NIC), used for smoking cessation in cancer patients, is associated with increased tumor growth, angiogenesis, migration, invasion, growth factor production, and inhibition of apoptosis. The effects of NIC on the efficacy of radiotherapy (XRT) and/or chemotherapy (CT) have not been well characterized. Methods: A review of the literature produced a construct demonstrating that NIC generates more than 100 interactions with 40 proteins involved in tumor promotion and progression. From this construct, nicotinic acetylcholine receptors (nAChR), PI3K/Akt, and MAPK were identified as potential critical upstream targets modulating the effects of NIC. The effect of NIC on cell proliferation, cell survival, and protein activation was analyzed following CT, XRT, or chemoradiotherapy (CRT) in FaDu, A549, and H460 human cancer cell lines. Results: Proliferation measured with the WST-1 (tetrazolium) assay demonstrated that NIC increased proliferation following cisplatin, XRT, and cisplatin with XRT. NIC administration increased cell survival (colony survival) following XRT and following CT (cisplatin, doxorubicin, or etoposide) regimens in all cell lines. nAChR expression was verified in each cell line using Western blot. Non-specific inhibition of nAChR demonstrated no consistent effect on preventing NIC induced resistance to CT, XRT, or CRT; however, specific inhibition of the alpha-3- or alpha-7-nAChR had variable cell specific ability to prevent NIC induced resistance. Inhibition of MAPK activity (using PD98059) produced marked reduction in proliferation of all cell lines, but generally had no effect on NIC induced resistance. PI3K inhibition (using LY294002) generally increased sensitivity to cisplatin and XRT; however, some PI3K activity was required to achieve the full effect of cisplatin. NIC prevented LY294002 induced sensitization to chemotherapy with no effect on sensitization to XRT. Conclusions: Nicotine induces a broad spectrum of resistance to CT, XRT, and CRT and serves as an excellent model of treatment resistance. Mechanisms of NIC induced resistance to CT and XRT appear to diverge. These findings have significant clinical implications including smoking cessation, treatment efficacy, and outcomes research in cancer patients. No significant financial relationships to disclose.
Validation of a microarray-based gene expression test for tumors with uncertain origins using formalin-fixed paraffin-embedded (FFPE) specimens
Authors: Pillai R. , Deeter R. , Rigl C. T. , Halks-Miller M. , Henner W. D. , Buturovic L. 
Published: August 2020

e22015 Background: Microarray-based gene expression has been validated as an aid in the diagnosis of tumors with uncertain origins when the specimen is frozen tissue. Microarray use has been largely limited to RNA derived from frozen specimens. This study evaluated performance of a microarray-based test in identifying the tumor type in FFPE specimens. Methods: ZFFPE human tumor specimens (n=405) representing the 15 tissue of origin sites on the Pathwork® Tissue of Origin Test panel were blinded and evenly distributed between two independent processing labs. All specimens consisted of a 10-μm-paraffin curl containing at least 60% viable tumor and were either metastatic or poorly differentiated primaries. Each specimen was processed through RNA extraction, amplification, labeling, hybridization to a Pathchip® microarray, and was scanned to generate a qualified data file. A pre-specified classification algorithm utilizing more than 1500 genes was applied to each data file to yield Similarity Scores corresponding to the 15 tissues on the test panel. Results were then unblinded and compared to the available diagnoses. Results: Of the 405 specimens, 352 yielded qualified data files (87%). Based on the top Similarity Score, the overall agreement with available diagnoses was 89% (95% CI, 85%-92%) and for each specimen an average of 12 out of 15 tissues could be ruled out with > 99% probability. Results for all tissue types were highly informative with diagnostic odds ratios ranging from 178 to 28509. Performance was similar for metastatic (n=150; 91% agreement) and poorly differentiated primary specimens (n=202; 87% agreement). Conclusions: The large size of this study allows an accurate estimate of the confidence of test predictions for both ruling in and ruling out tissues as likely sites of primary origin. The Pathwork Tissue of Origin Test makes the potential benefits of microarray-based gene expression tests for tumors with uncertain origins available for use with the most common type of histology specimen, FFPE. [Table: see text]
Correlation of CXCR4 expression in resected pancreatic adenocarcinoma (PA) with relapse and survival after adjuvant radiochemotherapy (RCT)
Authors: Maréchal R. , Demetter P. , Berton A. , Salmon I. , Van Laethem J. 
Published: August 2020

e22022 Background: The chemoreceptors CXCR4, CXCR7 and the hypoxia inductible factor-1 alpha (HIF-1α) are implicated in PA growth, dissemination and angiogenesis. These protagonists are expected to play a key role in radiotherapy and chemotherapy resistance in PA. Methods: We conducted a retrospective study of patients undergoing curative surgery (R0 resection) for PA between 2001 and 2006 in our institution. All were treated with adjuvant RCT (treatment group). The treatment group was case-matched with resected PA patients who did not receive any adjuvant therapy (control group). FFPE specimens were subjected to immunohistochemical analysis using tissue microarray and monoclonal antibodies against human CXCR4, CXCR7, and HIF-1α. Based on the intensity (I) and the extend (E) of staining, cases were stratified into those with high (E x I>3) or low (E x I ≤ 3) expression of CXCR4, CXCR7 and HIF-1α and results were correlated with disease-free survival (DFS) and overall survival (OS). Results: 31 PA patients (median age: 57years, range: 39–76) were analysed in the treatment group and 30 (median age: 59 years, range: 38–81) in the control group. The two groups were well-matched in terms of age, sex, tumor stage (T1-T2 vs T3-T4), tumor differentiation (poor vs well-moderate), lymph node (LN) status (N0 vs N+), lymphatic and vascular embols. In univariate analysis, CXCR4 expression and LN status were associated with DFS and OS (OS, CXCR4low/high: HR, 5.43, 95%CI: 2.03–14.49, p=0.001; N0/N+: HR: 4.62, 95% CI, 1.33–13.12, p=0.016; DFS: CXCR4low/ CXCR4high : HR, 3.01, 95%CI: 1.21–7.46, p=0.018; N0/N+: HR: 3.30, 95% CI, 1.09–9.90, p=0.034) in the treatment group while in the control group LN status was the only variable significantly correlated with DFS and OS. CXCR4 appeared to be the only independant predictor for DFS (CXCR4low/high: HR, 4.95, 95%CI: 1.68–14.71, p=0.007) and OS (CXCR4low/high: HR, 4.76, 95%CI: 2.03–14.49, p=0.004) in the treatment group but not in the control group. Conclusions: CXCR4 was an independant predictor for DFS and OS after adjuvant RCT in resected PA patients. This chemoreceptor could be implicated in the resistance of pancreatic cancer cells to RCT and its targeted inhibition deserves clinical evaluation. No significant financial relationships to disclose.
Correlation of hENT1 expression with response and survival in non-small cell lung cancer patients treated with gemcitabine-containing chemotherapy
Authors: Oguri T. , Achiwa H. , Ozasa H. , Nakao M. , Uemura T. , Ohta C. , Takakuwa O. , Miyazaki M. , Maeno K. , Sato S. , Ueda R. 
Published: August 2020

e22032 Background: The most active gemcitabine uptake has been found via the human equilibrative nucleoside transporter 1 (hENT1). This study was to explore the prognostic impact of the hENT1 on response and survival in Non-small lung cancer (NSCLC) patients treated with gemcitabine-containing chemotherapy. Methods: We developed polyclonal antibody for hENT1. Then we stained hENT1 expression by immunohistochemical analysis in 24 biopsy samples of NSCLC which was formaline-fixed, paraffin- embedded tissues. We were treated with gemcitabine alone or gemcitabine-containing chemotherapy until third-line regimen. Results: They comprised 16 males and 8 females with a median age of 63 years (range 45–82 years). Seventeen patients had adenocarcinomas, six had squamous-cell carcinomas, and one had a large-cell carcinoma. All patients were treated with gemcitabine- containing chemotherapy, with 9, 12, and 3 patients receiving this as a first-, second-, and third-line therapy, respectively. The hENT1-positive staining in NSCLC samples was significantly associated with response to gemcitabine-containing chemotherapy (Fisher's exact test, P<0.05). Responses to gemcitabine-containing chemotherapy were evident in none of the seven patients with no hENT1 expression. Further 3 years survival differed by hENT1 staining: 714 days for hENT1-positive, 316 days for hENT1-negative (HR 2.86; 95%CI 1.13–15.16, P<0.05). Conclusions: While there are some determinants for gemcitabine sensitivity, hENT1 expression may be a predictive maker for the response and survival to gemcitabine-containing chemotherapy in NSCLC. No significant financial relationships to disclose.
HER2 FISH ratio cut-points and pathologic complete response (pCR), residual tumor (RT), HER2 status, and survival prediction in HER2-positive breast cancer (BC)
Authors: Mehta R. S. , Jackson D. , Schubbert T. , Hsiang D. 
Published: August 2020

e22033 Background: We demonstrated that pCR is correlated with increasing HER2-FISH ratio, while disease-free survival (DFS) with pCR and ER-positivity in HER2-positive breast cancer treated with trastuzumab (SABCS 2008). It is known that quantitative HER2-FISH ratio correlates with ER levels and HER2-positivity imparts a higher grade in ER-positive BC. Collectively, we hypothesized that combined ER (≥10) and a HER2 ratio cut-point may subdivide HER2-positive BC into pCR predictive subtypes.Methods: Of the 80 HER2-positive (IHC3+/FISH+) BC, quantitative HER2 FISH ratio (widely spread over 1–18.3) and ER correlation was noted (r=0.34, p=0.002). Moreover, HER2 ratio (>4) correlated with higher Ki-67 (r= 0.5, p=0.01) and grade (p trend=0.05) in ER-positive subtype, inferring a biologic cut-point. Results: Of patients with stage I-IV BC treated neoadjuvantly (92% trastuzumab-based), pCR was 0% (0/13) in ER-positive-low-HER2 compared to 77% (10/13, p=0.0001), 75% (24/32, p<0.0001) and 37.5% (3/8, p=0.043) in ER-positive-high-HER2, ER-negative-high-HER2 and ER-negative-low-HER2, respectively. DFS was 100, 90, 80% and 60% (logrank-trend p<0.05) in these 4 subtypes (excluding stage IV), respectively, at a median follow-up of 38 months (range 6–72). In ER-negative subtypes, DFS was 97% and 29% (logrank p=0.0001) in patients with or without pCR; of the six with RT, 0% DFS was noted in four with HER2-negative/HER2-reduced (HER2-R) RT, compared to 100% in the two with unchanged HER2 (p=<0.05, logrank test). In ER-positive subtypes, DFS is 95% overall, and 100% in patients with RT; 7 of 10 tested RT were HER2- R. Conclusions: pCR is crucial and high in ER-negative-high-HER2 and is crucial (but low) in ER-negative-low-HER2-positive BC for improved outcome. Improved DFS is associated with high pCR in ER-positive-high-HER2 BC, but is independent of the low pCR in ER-positive-low-HER2-subtype. Thus, combined HER2 and ER offer improved prediction. In hypothesis generating analysis, HER2-R may underlie relapse in ER-negative subtypes (HER2-basal-transitional-residual), while it may be beneficial in ER-positive subtypes (luminal-B- A-transitional) by reducing HER2-pathway mediated endocrine resistance. [Table: see text]
Informative rate and reproducibility of the investigational GeneSearch ProCaM assay in a multicenter laboratory setting
Authors: Baden J. , Markiewicz J. , Painter J. , Jones J. , Curtin K. , Canning S. , Quijano J. , Guinto W. , Wang Y. , Green G. 
Published: August 2020

e22038 Background: PSA tests have low specificity, which frequently results in unnecessary biopsy and typically limits screening to patients with PSA values >4.0 ng/mL. The investigational ProCaM assay detects CpG island methylation within the promoter regions of three markers (GSTP1, RARß2, and APC) that are indicative of the presence of prostate cancer. The objective of this research study was to assess assay testing reproducibility and lot-to-lot variability. Methods: Assay reproducibility: 8 operators from 4 external clinical laboratories tested a panel comprised of a negative panel member (NM2C5 cells) for the internal control (ß-Actin), a high positive and low positive panel members (LNCaP cells) for all 3 markers and ß-Actin. Variability of assay results based on marker cycle threshold (Ct) values was determined. Lot variability: 3 unique lots of the ProCaM Test Kit were evaluated on DNA extracted from 169 post-DRE urine samples to show reproducibility across kit lots. Urine samples were collected from consenting subjects that were scheduled for prostate biopsy and tested by 3 operators at the same facility. Results: Assay reproducibility: The informative rate was 98% (766 valid results of 782 total tests). The overall intersite %CV and SD values for Cts were = 9.2% and 1.49%, respectively. The percent agreement with qualitative (positive/negative) outcome for High, Low, and Negative panel members was = 98% for GSTP1, RARß2, APC, and ß-Actin. Lot variability: Of the 169 biopsy results a histology positivity rate of 39% (66/169) was shown. Urine sample results for these samples showed that the areas under the curve for the 3 unique ProCaM Test Kit lots were equivalent (0.72, 0.74, 0.75, p > 0.263). Using the result categories of negative and positive with identical cutoffs for GSTP1, RARß2, APC for samples with >5 ssDNA copies 98% concordance was observed for all 3 lots evaluated. Conclusions: The investigational assay produces a qualitative result without the requirement for normalization or sample dilution and requires only one reaction per patient sample. Current results demonstrate that the assay has a high informative test rate and that results are reproducible across sites, operators runs, and kit lots. [Table: see text]
Association of expression of bcl-2 with outcome in non-small cell lung cancer
Authors: Anagnostou V. , Lowery F. , Syrigos K. , Frangia K. , Zolota V. , Panagopoulos N. , Dougenis D. , Tanoue L. , Detterbeck F. , Homer R. , Rimm D. 
Published: August 2020

e22039 Background: BCL-2 promotes cell survival by inhibiting adapters needed for the activation and cleavage of caspases thus blocking the proteolytic cascade that ultimately dismantles the cell. It is preferentially expressed in squamous cell carcinomas of the lung and has been investigated as a potential prognostic parameter in lung cancer patients with conflicting results. Here, we quantitatively assessed BCL-2 protein expression in two large and independent data sets to investigate the impact of BCL-2 on patient survival. Methods: AQUA, a fluorescent-based method for analysis of in situ protein expression, was used to measure BCL-2 protein levels and classify tumor by BCL-2 expression in a cohort of 180 lung cancer patients from Yale New Haven Hospital (training set). An independent cohort of 360 lung cancer patients from Sotiria General Hospital and Patras University Hospital in Greece was used to validate BCL-2 classification and evaluate outcome (validation set). Results: Tumors expressed BCL-2 in 57% and 53% of the cases in training and validation cohorts respectively and squamous cell carcinomas expressed higher levels of BCL-2 expression compared to adenocarcinomas (mean AQUA score 42 and 26 respectively, p=0.007); BCL-2 was not associated with other standard clinical or pathological characteristics. Survival analysis showed that patients with high BCL-2 expression had a longer median overall survival compared to the low expressers (20 vs 15 months, log rank p=0.016). Multivariate analysis revealed an independent lower risk of death for lung cancer patients with BCL-2 expressing tumors (HR=0.58, 95% CI 0.39–0.86, p=0.006). Conclusions: BCL-2 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of lung cancer patients as well as incorporation of BCL-2 into clinical decisions. [Table: see text]