tbuckley/cabot-search huggingface dataset:
Integrated analysis identifies microRNA-195 as a suppressor of Hippo-YAP pathway in colorectal cancer
Authors: Min Sun, Haibin Song, Shuyi Wang, Chunxiao Zhang, Liang Zheng, Fangfang Chen, Dongdong Shi, Yuanyuan Chen, Chaogang Yang, Zhenxian Xiang, Qing Liu, Chen Wei, Bin Xiong
Journal: Journal of Hematology & Oncology (2017)

With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a "pre-laboratory" integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear. In this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo. Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3'-untranslated region (3′-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot. Four downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR-195-5p independently associated with prognosis in CRC. Our results demonstrated that miR-195-5p was a potent suppressor of YAP1, and miR-195-5p-mediated downregulation of YAP1 significantly reduced tumor development in a mouse CRC xenograft model. In the clinic, miR-195-5p can serve as a prognostic marker to predict the outcome of the CRC patients.
ESR1 gene amplification and protein expression in 946 patients with resected breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) translational research study.
Authors: George E. Pentheroudakis, Anna Batistatou, Urania Dafni, Mattheos Bobos, Eleftheria Tsolaki, Vassiliki Kotoula, Eleftherios Kampletsas, George Lazaridis, Christos A. Papadimitriou, Helen Gogas, Konstantine T. Kalogeras, Nicholas Pavlidis, George Fountzilas
Journal: Journal of Clinical Oncology (2012)

592 Background: Discrepant data have been reported on the incidence of ESR1 gene amplification in breast cancer, its correlation to clinicopathologic characteristics and its impact on prognosis. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 946 patients participating in two adjuvant chemotherapy phase III trials (HE10/97 and HE10/00) were centrally assessed in tissue microarrays by immunohistochemistry (IHC) for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). FISH was also performed for HER2, TOP2A and ESR1 using commercially available dual (for ESR1) and triple (for HER2 and TOP2A) hybridization probes. Results: The majority of patients had &gt;T2 (69%), node-positive, ER-positive (&gt;1% stained cells, 73%) tumors managed with resection, chemotherapy and hormonotherapy (76%). Only 38 tumors (4.0%) had ESR1 gene amplification (ESR1/CEN6 ratio &gt;2) and 514 (54.3%) ESR1 gene gain (1&lt;ratio&lt;2). The number of ESR1 gene copies was 3-4 in 251 (26.5%) and 5-10 in 42 (4.4%) of cases. HER2 and TOP2A gene amplification was seen in 234 (25.3%) and 101 (10.9%) of tumors, respectively. We studied the immunohistochemical expression of ER protein by evaluating the percentage of stained cells, the Allred score (0-2, 26.8%; 3-6, 62.5%; 7-8, 10.7% of tumors) and the semiquantitative H-Score (50-100, 13.8%; 101-200, 36.8%; 201-300, 15% of tumors). ESR1 gene amplification was significantly associated with taxane therapy, age &gt;50, postmenopausal status, grade III-IV, absence of HER2 amplification and ER protein expression (p&lt;0.05). At a median follow-up of 92 months, univariate Cox regression analysis showed that ER protein expression, but not ESR1 gene status, was a predictor of favorable outcome. In multivariate analysis, tumor size &gt;5 cm, &gt;4 involved nodes and negative/low ER protein expression by Allred score were independent adverse prognostic factors. Conclusions: Our data showed a rather low incidence of ESR1 gene amplification and failed to confirm its prognostic/predictive utility. ESR1 mRNA expression data will be presented at the meeting.
Prostate-specific membrane antigen (PSMA) PET-CT guided radiotherapy in oligometastatic prostate cancer.
Authors: Benedikt Engels, Ozan Cem Guler, Cem Onal, Mark De Ridder
Journal: Journal of Clinical Oncology (2017)

213 Background: Metastases-directed therapy by metastasectomy or radiotherapy (RT) might delay disease progression and postpone systemic treatment in patients with oligometastatic prostate cancer. Here, we evaluated retrospectively the efficacy and toxicity of 68 Ga prostate-specific membrane antigen (PSMA) PET-CT guided radiotherapy (RT) in the treatment of oligometastatic prostate cancer. Methods: A total of 23 prostate cancer patients with biochemical relapse, of which 13 castration-sensitive and 10 castration-resistant, were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤ 3 metastases detected by 68 Ga PSMA PET-CT. Androgen deprivation therapy was continued in castration-resistant patients. Local control (LC), progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Results: A total of 38 metastases were treated. Involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), para-aortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.06 ng/ml (range 0.10 – 29.0 ng/ml). A median dose of 43.5 Gy (range, 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range, 2-17 months), 19 patients (83%) are in remission. Four patients (17%) developed distant recurrence. The actuarial 1-year LC, PFS and OS rates were 100%, 51% (95% CI 8-83%) and 100%. Castration-sensitive patients displayed a statistically significantly superior PFS on univariate analysis as compared to castration-resistant patients (1-year PFS 67% vs 0%, p &lt; 0.01). One patient experienced grade 2 acute gastro-intestinal toxicity. No grade 3 or more toxic events were observed. Conclusions: By providing optimal LC, low toxicity and a promising PFS in castration-sensitive patients, the current retrospective study illustrated that 68 Ga PSMA PET-CT guided RT may be an attractive treatment option in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.
A randomized phase II study (B2151005) of the intravenous phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor PF-05212384 plus irinotecan versus cetuximab plus irinotecan in patients with wild-type <i>KRAS</i> metastatic colorectal cancer (mCRC).
Authors: Josep Tabernero, Nicoletta Brega, Craig Davis, Ashwin Gollerkeri, Kristen Pierce, Mie Suzuki, Jennifer Vermette
Journal: Journal of Clinical Oncology (2014)

TPS3649 Background: The combination of cetuximab plus irinotecan is considered a standard of care regimen for third-line treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC). However, the combination of cetuximab plus irinotecan provides limited tumor control and is associated with skin rash, diarrhea, and neutropenia. Thus, the need for more efficacious and better tolerated regimens remains high. Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway is associated with resistance to a variety of antitumor agents. This association has been described in pre-clinical studies for cytotoxic chemotherapeutic agents with different mechanisms of action, including taxanes and DNA-damaging agents. In the clinic, activation of the PI3K pathway in tumors has been correlated with decreased response to therapy and worse clinical outcomes. Preliminary data from the phase I study B1271002 indicate that the combination of the intravenous PI3K/mammalian target of rapamycin (mTOR) inhibitor PF-05212384 and irinotecan is well tolerated and shows promising antitumor activity in patients with mCRC, suggesting the need to further explore this regimen. Methods: This trial was designed to investigate whether the combination of PF-05212384 plus irinotecan is superior to the combination of cetuximab plus irinotecan in prolonging progression-free survival in patients with wild-type KRAS mCRC. Additionally, the study includes a lead-in cohort to determine the safety of this combination in Japanese patients. The study is being conducted in men and women with wild-type KRAS mCRC whose disease has progressed following treatment with irinotecan, oxaliplatin and fluoropyrimidine therapy in the metastatic setting. Eligible patients will be randomly assigned to either treatment arm. This global trial is open to enrollment and has recruited its first patients. Clinical trial information: NCT01925274.
Low objective response and high toxicity to single-agent mitotane in patients with metastatic adrenocortical carcinoma (ACC): A 25 year experience at MSKCC.
Authors: Betty Y Lung, Emily Valentino, Scott R. Gerst, Brian R. Untch, Seth Katz, Vivian E. Strong, Nitya Prabhakar Raj, Kelly Olino, Leonard Saltz, Diane Lauren Reidy
Journal: Journal of Clinical Oncology (2015)

4105 Background: ACC is a rare but devastating disease, with short life expectancy in the setting of metastatic, unresectable disease. Mitotane, an oral adrenocorticolytic agent, is often used as a systemic treatment though its therapeutic window is narrow. We retrospectively assessed outcomes of patients (pts) with metastatic ACC who received single-agent mitotane therapy to determine treatment toxicities and effectiveness. Methods: In this retrospective IRB-approved study, we identified 35 pts with metastatic ACC treated with single-agent mitotane at MSKCC from 3/15/1989-9/18/2014. All pts had follow-up at MSKCC and all imaging was reviewed according to RECIST 1.1 by reference radiologists. We reviewed pt demographics, clinical symptoms, toxicity (based on CTCAE Version 4), and treatment outcomes. Results: 35 pts were identified with mean age of 53 years (range, 23-87), 60% female. 18/35 tumors (51%) were functional: estradiol (n = 1), cortisol (n = 12), testosterone (n = 3), or both testosterone and cortisol (n = 2). Grade 3 toxicities were observed in 15 of the 35 pts (43%). Severe toxicities included anorexia (9%), depression (6%), fatigue (20%), rash (6%), nausea (11%), vomiting (11%), and abdominal pain (6%). Radiographic progression of disease occurred in 30 of 35 pts (86%) and 1 pt (3%) experienced clinical progression. 2 pts (6%) had a complete response, 1 pt (3%) had partial response, and 1 pt (3%) had stable disease. The 3 pts (9%) with response (CR+PR) were asymptomatic prior to initiating mitotane; all had low volume indolent disease limited to one site (1 pt lung only; 1 pt retroperitoneal LN; 1 pt liver). All 3 pts experienced grade 3 toxicities on mitotane requiring treatment interruption and/or discontinuation. Conclusions: Among pts with ACC treated with mitotane-based therapy, 43% experienced grade 3 toxicities and 89% experienced POD. Response was noted in only 9% of pts and came with significant toxicity. The tumors in these responders are currently undergoing next generation sequencing analysis and results will be reported at the annual meeting. More effective and less toxic therapies are desperately needed in this rare disease.
Octreotide LAR (OCT-L) among elderly patients with stage IV neuroendocrine tumors (NETs): A survival analysis of SEER-Medicare data.
Authors: Chan Shen, Ya-Chen T. Shih, Ying Xu, James C. Yao
Journal: Journal of Clinical Oncology (2014)

4112 Background: OCT-L is approved in the US for the management of secretory syndromes among patients with NETs. Two placebo-controlled studies have recently demonstrated that somatostatin analogues delay time to progression. The effect of OCT-L on overall survival (OS) has not been evaluated. Methods: Stage IV NET patients diagnosed between 1/1999 and 12/2009 were identified from the SEER-Medicare database. Those under age 65, with poorly differentiated histology, enrolled in HMOs, or without continuous enrollment were excluded. HCPCS codes, J2352 and J2353, were used to identify OCT-L use. Current analysis compares the OS of those who started OCT-L within 12 months of diagnosis to those who did not receive OCT-L during the observation period. Presence of secretory syndrome was defined as having ≥ 2 claims for carcinoid syndrome, flushing, diarrhea, or malignant islet cell neoplasm either before the start of OCT-L for those who received it; or within 12 months of diagnosis for those who did not receive OCT-L. Analyses included Kaplan-Meier estimation and Cox proportional hazard modeling with covariates including age, gender, race, region, comorbidity score, urban/rural status, tumor characteristics, other treatments received, neighborhood socioeconomic status and year of diagnosis. Results: Among 1,149 patients, 231 (20%) received OCT-L within 12 months of diagnosis, 394 (34%) had secretory syndrome. Median OS from diagnosis among patients who started OCT-L within 12 months (35.4 [95%CI, 28.3 – 49.3] months) was longer than those who did not receive OCT-L during the observational period (20.3 [95%CI, 17.3 – 24.2] months; P<0.001). Multivariate Cox proportional hazard regression showed that OCT-L was associated with significant improvement in survival both for the whole study group (HR=0.69, P<0.001) and in the subgroups with (HR=0.64, P=0.003) and without (HR=0.56, P=0.002) secretory syndrome. Other significant predictors were age, gender, race, comorbidity score, primary tumor site, and surgery. Conclusions: This population-based study suggests potential survival benefits for use of OCT-L among elderly stage IV NET patients with or without secretory syndrome.
Dose-dense R-CHOP (administered every 2 weeks) with sargramostim in patients with newly diagnosed diffuse large B-cell lymphoma.
Authors: Preeti Chaudhary, Susan G. Groshen, Denice D Tsao-Wei, Imran Siddiqi, Vinay Duddalwar, Nancy Berman, Christine Duran, Teh-Chun Wang, Anil Tulpule
Journal: Journal of Clinical Oncology (2013)

8554 Background: R-CHOP administered every 3 weeks is standard of care for the treatment of diffuse large B-cell lymphoma (DLBCL). There are conflicting reports regarding the superiority of dose dense (DD) regimen (R-CHOP administered every 2 weeks), compared to the standard R-CHOP regimen. In a Phase II study, the tolerability and efficacy of DD-RCHOP+Sargramostim was evaluated. Methods: All patients received intravenous rituximab, 375 mg/m 2 ; cyclophosphamide, 750 mg/m 2 ; doxorubicin, 50 mg/m 2 and vincristine, 1.4 mg/m 2 on day 1; prednisone 100 mg orally on days 1-5 and sargramostim 250 mg/m 2 subcutaneously on days 3-13. Chemotherapy cycles were repeated every 2 weeks. Results: We studied50 newly diagnosed, previously untreated DLBCL patients (median age 54.1 years, range 21.4-80.3 years). Stage III and IV disease was noted in 12 (24%) and 29 (58%) patients, respectively. Baseline characteristics included the following: high-intermediate or high-risk IPI score (n=38, 76%), extranodal involvement (n=32, 64%), bone marrow infiltration (n=5, 10%), B-symptoms (n=23, 46%), median LDH level (272, range 118-3797) and good baseline performance status (n=45, 90%). The median follow up from the start of treatment was 12.7 months (range 0.1-41.4 months). Among the 46 patients evaluated for response, complete response (CR) or unconfirmed CR (CRu) was observed in 36 (78%) patients, partial response (PR) or an unconfirmed PR in 9(20%) patients and 1 patient had stable disease. The probability of overall survival (OS) at 18 months was 0.84. The probability of disease free survival in complete responders at 9 months was 0.89. Neutropenia was the most common hematological toxicity and accounted for delays in 40 (20%) treatment cycles. There were no episodes of fever/sepsis in the 33 patients (66%) with grade 3 or 4 neutropenia. IgG, IgA and IgM levels decreased during therapy and returned to normal in 2-4 months post therapy. No opportunistic infections were reported. Conclusions: The administrationof DD-RCHOP+Sargramostim regimen is safe, tolerable and effective in patients with newly diagnosed DLBCL. However, neutropenic episodes were significant, accounting in many cases for treatment delays.
<i>Period</i> 2 (PER-2) biologic profile in advanced colorectal cancer (ACC) patients (pts).
Authors: Elisa Melucci, Angela Torsello, Annamaria Ruzzo, Isabella Sperduti, Elisa Giacomini, Massimo Zeuli, Alain Gelibter, Virginia Ferraresi, Maria G. Diodoro, Mauro Magnani, Marcella Mottolese, Francesco Cognetti, Carlo Garufi
Journal: Journal of Clinical Oncology (2013)

e22206 Background: Circadian rhythms modulated by clock genes expression as the Period genes (PER-1, PER-2, PER-3) are involved in cancer growth. PER-2 loss in colorectal cancer cell lines and in animal models increases tumorigenesis by β-catenin and cyclin D activation (Wood P, Cancer Res 2008). PER-2 loss in ACC pts was linked to a worse prognosis (Iacobelli S, ASCO 2008). The aim of our study was to identify a PER-2 biological profile related to proliferative indexes and treatment activity. Moreover miRNA related to clock genes were studied as miR-219, target of CLOCK and B-MAL1, miR-206 which affect mammalian circadian clock, miR-132 acting at the SCN level. Methods: We retrospectively evaluated 59 ACC pts, treated with first line chronomodulated triplet combination (Irinotecan+Oxaliplatin+Folinic Acid+5-Fluorouracil) ± Cetuximab. Immunostaining for PER-2, EGFR, ERβ1, ERβ2, Cyclin D1, β-catenin, K-RAS and B-RAF mutations, miRNAs -206, -132, -192, -194, and -219 evaluated on FFPE tumor tissues and their expression levels by quantitative PCR were examined. Results: Clinical data: M/F 32/27; median age 57 y; liver involvment 53%; Cetuximab use: 38%; liver resection: 42%; response to first line chemotherapy: PR 61%, SD 25.4%, PD 10.2%; pts 2.4% not evaluable. Biological data: PER-2 negative (-) /positive (+) 44/56%; EGFR (+)/(-) 54/46%; KRAS wt/mut 75/25%; ERβ1 (-)/(+) 36/65%; ERβ2 (-)/(+) 39/61%; Cyclin D1 (-)/(+) 51/49%; β-catenin(-)/(+) 31/69%. PER-2(-) patients expressed more frequently EGFR (73%) (p&gt;0.0001), ERβ1 (77%) (p=0.07), ERβ2 (88.5%) (p&gt;0.0001), Cyclin D1 (69.2%) (p=0.06) and β-catenin (84.6%) (p=0.02). PER-2(-) was also associated to high miR-206, miR-192 and miR-219 expression. Explorative multiple correspondence analysis showed response to chemotherapy related to a profile including PER-2 (+), EGFR (-), ERβ1 (-), ERβ2 (-), β-catenin (-) and low expression of miR-206. Conclusions: Our data confirmed that: 1) PER-2 loss was associated to activation of cell proliferation confirming in vitro data; 2) PER-2 expression was linked to negative activation of cell proliferation, low miR-206 expression and response to chemotherapy.
Identifying genetic factors in Parkinson disease [6] (multiple letters)
Authors: Matt Farrer, John Hardy, Mike Hutton, Demetrius Maraganore, Yoshio Tsuboi, Zbigniew K. Wszolek, Margaret A. Pericak-Vance, William K. Scott, Eden R. Martin, Jeffery M. Vance, Jonathan L. Haines
Journal: JAMA (2002)
Correlation of hand-foot skin reaction (HFS) with treatment efficacy in pancreatic cancer (PC) patients (pts) treated with gemcitabine/capecitabine plus erlotinib: A subgroup analysis from the AIO-PK0104 randomized, cross-over phase III trial in advanced PC.
Authors: Michael Haas, Stefan Hubert Boeck, Ruediger Paul Laubender, Dominik Paul Modest, Ursula Vehling-Kaiser, Dirk Waldschmidt, Erika Kettner, Angela Maerten, Cornelia Winkelmann, Stefan Klein, Georgi Kojouharoff, Thomas C. Gauler, Ludwig Fischer Von Weikersthal, Michael Clemens, Michael Geissler, Tim F Greten, Susanna Hegewisch-Becker, Oleg Rubanov, Ulrich Robert Mansmann, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

4023 Background: AIO-PK 0104 investigated the efficacy and safety of gemcitabine/erlotinib (G/E) followed by capecitabine (C) vs. C/E followed by G. The present subgroup analysis evaluated the correlation between C-associated skin toxicity and outcome parameters in PC. Methods: Within this multicenter phase III trial, pts with confirmed advanced PC were randomly assigned to 1 st -line treatment with either C (2,000 mg/m 2 /d, d1-14 q d21) plus E (150 mg/d, arm A) or G (1,000 mg/m 2 over 30 min weekly x 7, then d1, 8, 15 q d28) plus E (150 mg/d, arm B). A cross-over to either G (arm A) or C (arm B) was performed after treatment failure (e. g. disease progression or unacceptable toxicity). Time to treatment failure after 1 st - and 2 nd -line therapy (TTF2) was the primary study endpoint. Treatment-related skin toxicity was evaluated separately for each treatment arm/each regimen based on NCI-CTCv2. Results: Of 279 eligible pts, 47 had locally advanced, 232 had metastatic disease and 141 pts received second-line chemotherapy. For the present subgroup analysis data on skin toxicity were available from 255 pts. For the 73 pts (29%) with a HFS (any grade documented at any time during the treatment strategy), TTF2 and OS both were significantly prolonged compared to pts without HFS (7.4 vs 4.0 months, p&lt;0.001 and 9.7 vs 5.5 months, p=0.002, respectively). Considering HFS during 1 st -line treatment in 123 pts within the CE arm, these results could be confirmed for the 47 pts (38%) with a documented HFS of any grade (TTF2: 7.6 vs. 3.2 months, p&lt;0.001; OS: 10.2 vs. 4.4 months, p=0.001). In pts receiving 1 st -line treatment with G/E (n=132) no difference in outcome was observed for pts with (n=13) or without (n=119) HFS of any grade (TTF2: 5.7 vs. 4.2 months, p=0.375; OS: 8.4 vs. 6.6 months, p=0.505). Conclusions: The current subgroup analysis of AIO-PK0104 supports the assumption of a correlation between HFS in PC pts treated with capecitabine or capecitabine/erlotinib and efficacy endpoints like TTF2 and OS. A capecitabin-associated HFS thus might be predictive for efficacy in patients with advanced PC.