tbuckley/cabot-search huggingface dataset:
Formation of the DNA depurinating N3Ade and N7Gua adducts of 4-hydroxyestradiol by MCF-10F cells cultured with the carcinogenic estrogen metabolite 4-hydroxyestradiol
Authors: Muhammad Saeed, Eleanor Rogan, Ercole Cavalieri, Fathima Sheriff, Sandra Fernandez, Jose Russo
Journal: Cancer Research (2006)

1895  Metabolic conversion of endogenous estrogens, estrone (E1) and estradiol (E2), to the catechol estrogens 4-hydroxyE1/E2 (4-OHE1/E2) has been implicated in the initiation of cancer in rodents and humans. Evidence collected in our laboratories has shown that 4-OHE1/E2 is enzymatically oxidized to E1/E2-3,4-quinone (Q), which has the potential to damage DNA by forming predominantly the depurinating DNA adducts, 4-OHE1/E2-1-N3Ade and 4-OHE1/E2-1-N7Gua. This can lead to the accumulation of mutations and cell transformation. In the present work we are utilizing the human breast epithelial cell line (HBEC) MCF-10F that, when treated with E2 or its metabolite 4-OHE2, is neoplastically transformed. To mimic the intermittent exposure of HBEC to endogenous estrogens, MCF-10F cells were treated with 1 μM 4-OHE2 for 24-hour periods at 72, 120, 192, and 240 hours post-plating. The culture media were collected after each treatment with 4-OHE2. The cell media were extracted by solid-phase extraction and analyzed by HPLC connected with a multichannel electrochemical detector and/or ultra-performance liquid chromatography/tandem mass spectrometry. After the first treatment with 4-OHE2, the media contained 4-OHE1/E2, catechol estrogen conjugates of glutathione and cysteine, and small amounts of the depurinating 4-OHE1/E2-1-N3Ade and 4-OHE1/E2-1-N7Gua adducts. After the second treatment with 4-OHE2, the media contained more depurinating adducts. After the third treatment with 4-OHE2, the depurinating adducts were predominant. The results demonstrate that MCF-10F cells oxidize 4-OHE2 to E1/E2-3,4-Q, which then react with DNA to form the depurinating N3Ade and N7Gua adducts. This DNA damage may play an important role in the 4-OHE2-induced transformation of MCF-10F cells to malignant cells. (Supported by DoD grant DAMD17-03-1-0229)
Characterization of genomic alterations as biomarkers of immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma (mUC).
Authors: Matthew Labriola, Jason Zhu, Rajan Gupta, Shannon McCall, Jennifer Jackson, James R White, Elizabeth Weingartner, Eric Kong, Peter Simone, Eniko Papp, Kelly Gerding, John Simmons, Daniel J. George, Tian Zhang
Journal: Journal of Clinical Oncology (2019)

400 Background: ICIs have expanded therapeutic options for mUC patients (pts); however, biomarkers such as PD-L1 have not served as reliable predictors of treatment efficacy. High tumor mutation burden (TMB) has been previously described as a potential biomarker for predicting ICI response in several indications, but its utility is still being explored in mUC. Here, we compare the genomic landscapes and clinical outcomes of mUC pts following ICI therapy using an investigational solid tissue-based next-generation sequencing assay to assess TMB and identify genetic correlates of ICI response. Methods: 20 pts with mUC treated with ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated with a Personal Genome Diagnostics Assay for somatic variants across &gt; 500 genes, as well as TMB and microsatellite status. Tumor samples were also stained for PD-L1 status using the Dako 22C3 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated using RECIST 1.1 criteria. Results: Pts were grouped by overall response following ICI therapy as either responders (“R”, n = 6) or non-responders (“NR”, n = 13). Pts exhibited a wide range of TMB scores (0.7 to 30.4 mutations/Mb), with a mean TMB score of 9.60 vs. 3.87 mut/Mb in R vs NR groups, respectively; however, this difference was not statistically significant ( p = 0.284). 18 pts were evaluated for PD-L1 status, with only 2 positive samples (one in each group). Rs had significantly more mutations in histone methylation genes (KDM6A, KMT2C, and KMT2D), (67% vs 15% in NRs, p = 0.0039). FGFR3 mutations were also more frequent in R vs NR (67% vs 5%, p = 0.0339). Finally, there was a higher frequency of mutations in TP53 and BRCA1 in the NRs. Conclusions: In this mUC cohort, neither TMB nor PD-L1 correlated with response to ICI therapy. Histone modifying genes and FGFR3 mutations were more frequent in responders, whereas BRCA1 and TP53 mutations were enriched in non-responders, warranting future prospective studies to understand underlying mechanisms of ICI response and resistance in mUC.
Impact of compliance on outcomes for patients on active surveillance for prostate cancer.
Authors: Jay Detsky, Alireza Fotouhi Ghiam, Alexandre Mamedov, Kristina Commisso, Angela Commisso, Laurence Klotz, Stanley K. Liu, Andrew Loblaw, Danny Vesprini
Journal: Journal of Clinical Oncology (2019)

36 Background: Active surveillance (AS) is the standard of care for low-risk prostate cancer to reduce the risk of overtreatment. However, the impact of compliance to AS on outcomes has not been well described. We hypothesized that compliance to an AS protocol and to the recommendation for active treatment would affect subsequent treatment failure. Methods: A prospective, single-arm cohort study was initiated in 1995 to assess an AS program. Triggers for intervention included a PSA doubling time of less than three years and histologic upgrade. The AS protocol was defined as PSA measurements every three months for two years and then twice annually, as well as a confirmatory biopsy within 12 months and then every three years. Compliance to the AS protocol was defined as four PSA tests and a confirmatory biopsy by 1.5 years after enrollment. Compliance to treatment was defined as the initiation of any active therapy within 12 months from the time of any trigger described above. Treatment failure was defined as a PSA &gt; 0.2 after surgery, PSA &gt; nadir + 2 for other treatments, or the development of metastases. Statistics were performed using logistic regression analysis and the Fisher exact test. Results: A total of 1282 patients were included in the final analysis, of which 460 received treatment. Median follow up was 7.1 years. The actuarial rate of biochemical control at five and 10 years amongst treated patients was 78% and 59% respectively. The rates of compliance to biopsy at years one, four and seven were 71%, 36% and 13%. The treatment failure rate was lower for patients compliant to the AS protocol (crude rate 28%) than those non-compliant (crude rate 38%) with an odds ratio of 0.64 (95% CI 0.43-0.94, p = 0.03). Patients compliant to the protocol were also less likely to develop metastases (OR 0.42, 95% CI 0.21-0.88, p = 0.02). There was no impact on treatment failure by adherence to active therapy within 12 months (p = 0.25) after reaching a trigger to come off AS. Conclusions: Non-compliance to an AS protocol leads to a higher risk of subsequent treatment failure and development of metastases. Physicians and patients need to work together diligently to ensure enrollment on an AS program is followed by adherence to regular PSA checks and repeat biopsies.
The antitumor activity of synthetic interferon-alpha in pancreatic cancer cells.
Authors: Naifei Chen, Hongmei Yin, Haofan Jin, Jifan Hu, Jiuwei Cui, Hong Wang
Journal: Journal of Clinical Oncology (2015)

e15272 Background: Interferon alpha (IFNa) has been used to treat a variety of tumors, but its efficacy in the treatment of solid tumors has been significantly hindered by relatively low antitumor efficacy and numerous side effects. In the former work, we found a number of ‘interferon enhancer peptides’ (IEP) and selected a short positive charged peptide derived from the C-terminal of placental growth factor-2 (PLGF-2). In this study we explored whether this novel PLGF-2 IEP was able to potentiate the antitumor activity of IFNa. Methods: We constructed a synthetic Interferon alpha hybrid molecule (SIFa) by fusing the PLGF-2 IEP to the C-terminus of human IFNa. Using the human pancreatic cancer cell lines (ASPC and CFPAC-1) as a model system. After transfection of SIFa via lentivirus vector, ELISA was used to detect the secretion. The effect of SIFa on the proliferation of pancreas cancer cells was examined in vitro by using sulforhodamine B and cell cycle analysis. We also examined the effect of SIFa combining with gemcitabin (GEM) and the impact of SIFa on interferon pathway target genes, RT–PCR was performed. Results: The pancreatic cancer cells with the SIFa stably secreted high level of IFNa (48h: 285±21 pg/ml for ASPC; 48h: 535±13 pg/ml for CFPAC-1). We found that the SIFa exhibited a significantly higher activity than the IFNa in inhibiting cancer cells growth (the inhibition ratio: 44.6% vs 28.0% for ASPC; 53.5% vs 40.7% for CFPAC-1; p < 0.05). The SIFa inhibited cells growth by decreasing the proportion of G0/G1 phase cells compared with the IFNa (the percentage of G0/G1: 49.5%±0.8% vs 53.6%±0.6% for ASPC; 58.9%±0.9% vs 63.4%±0.6% for CFPAC-1; p < 0.05). Meanwhile, we found that the SIFa showed a significantly higher inhibition than IFNa in potentiating the inhibition of cells growth induced by GEM (66.9% vs 38.3% for ASPC; 87.8% vs 66.1% for CFPAC-1; p < 0.05). The enhanced antitumor activity of the synthetic SIFa was correlated with the activation of interferon pathway target genes MX1, IFIT1 and OAS2. Conclusions: The synthetic IFNa/PLGF-2 IEP enhanced antitumor activity in pancreatic cancer cells in vitro through activating of interferon pathway target genes. This study demonstrates the potential of the synthetic SIFa as a novel antitumor agent.
Feasibility and Efficacy of Post-Transplant Consolidation Immunotherapy with Nivolumab Supported By the Reinfusion of Unselected Autologous Lymphocytes in Patients Affected By Relapsed/Refractory Hodgkin Lymphoma
Authors: Fabio Guolo, Paola Minetto, Filippo Ballerini, Filippo Antonio Canale, Michela Frello, Elisa Coviello, Lorenzo Manconi, Annalisa Kunkl, Elisabetta Tedone, Rosa Mangerini, Paola Contini, Daniela Fenoglio, Maurizio Miglino, Alessandra Bo, Maria Carla De Luigi, Maria Rosaria Ruzzenenti, Paolo Carlier, Alberto Serio, Silvia Luchetti, Emanuela Marcenaro, Paolo Strada, Jean Louis Ravetti, Marco Gobbi, Roberto Massimo Lemoli
Journal: Blood (2018)
Performance of a validated urine exosome gene expression test (EPI) in men within the USPSTF suggested age-group of 55 to 69 years at initial biopsy with a PSA 2-10 ng/mL.
Authors: Michael J. Donovan, Mikkel Noerholm, Phillipp Torkler, Johan Skog, Eric Margolis, Gordon Andrew Brown, James M. McKiernan
Journal: Journal of Clinical Oncology (2019)

53 Background: Prostate-specific antigen (PSA) plays a key-role in prostate cancer (PCa) risk stratification but leads to over-diagnosis of low grade PCa. Recently, the USPSTF recommended that the decision to undergo PSA-based screening for men aged 55 to 69 years should be an individual one. We have developed and validated a non-invasive diagnostic test (ExoDx Prostate(IntelliScore), EPI) as a decision aid to guide the initial prostate biopsy decision process for men in the PSA gray zone of 2-10 ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GG 2) from low-grade (GG 1) and benign disease, thereby reducing the number of unnecessary biopsies. Methods: Patient data from two clinical trials were merged and constrained by age (55-69) according to the USPSTF suggested age-group resulting in a cohort of 701 patients with PSA 2-10 ng/mL, scheduled for initial prostate needle biopsy. EPI test results as well as PCPT2.0 risk calculator, ERSPC risk calculator and PSA results are compared with biopsy outcomes. Performances are reported using the area under the receiver operating characteristic curve (AUC), Negative predictive value (NPV), Positive predictive value (PPV), Sensitivity, and Specificity for discriminating ≥GG2 from GG1 and benign disease. Results: EPI showed a superior AUC of 0.70 compared to PSA (AUC: 0.57), PCPT2.0 (AUC: 0.60) and ERSPC (AUC: 0.58) (all p-values &lt; 0.001) for discriminating ≥GG2 PCa from benign and GG1. The previously validated EPI cut-point of 15.6 would avoid 22% of all prostate biopsies and 29% of unnecessary biopsies, with an NPV of 93% and miss only 5.4% of ≥GG2, respectively. Conclusions: EPI is a non-invasive, easy to use urine exosome RNA expression assay to discriminate high-grade (GG2) from low-grade (GG1) PCa and benign disease. EPI significantly outperformed the other standard of care parameters tested and applying the EPI test for risk stratification of patients in the USPSTF suggested age group, should reduce the number of unnecessary biopsies.
Molecular markers in uterine papillary serous carcinoma: Correlation between endometrial biopsy and hysterectomy specimens.
Authors: Elizabeth Lokich, Mohammed Quddus, Christina Raker, Cara Amanda Mathews
Journal: Journal of Clinical Oncology (2015)

e16503 Background: Uterine papillary serous carcinoma (UPSC) has a poor prognosis and a distinct molecular profile characterized by alterations in p53, Her2/neu and PIK3/AKT/mTOR signaling. Neoadjuvant targeted therapy is a potential new treatment paradigm, but it is unclear whether there is a correlation between molecular alterations in the biopsy and final pathology (hysterectomy) specimens; this would determine whether biopsy results could be used to guide neoadjuvant treatment. Our aim was to determine if molecular markers in endometrial biopsy specimens showing histologic diagnosis of UPSC are accurate predictors of molecular markers represented in the final hysterectomy specimens in untreated patients. Methods: Patients with available biopsy and hysterectomy specimens and pathologically proven UPSC were identified. Demographic, surgicopathologic and survival data were obtained. Immunohistochemistry was used to measure the biomarker status of seven markers significant in endometrial cancer: p110, AKT, ER, PR, EGFR, Her2 and PTEN. All laboratory analysis was performed using formalin fixed paraffin embedded (FFPE) tissue and standard, validated laboratory techniques. Staining was then evaluated to calculate the correlation between hysterectomy and biopsy specimens. Results: The most recent 28 patients who met criteria were identified. Average age was 72 and average BMI was 29. 21 patients were fully surgically staged. The distribution of disease was 61% stage I (n = 17), 14% stage II (n = 4), 22% stage III (n = 6) and 4% stage IV (n = 1). Conclusions: The measurement of specific biomarkers correlated well between biopsy and hysterectomy specimens in women with UPSC as measured by pathologist using routine techniques. It appears that endometrial biopsy may be a useful tool for guiding neoadjuvant targeted therapy in UPSC. biopsy +/ hysterectomy+ biopsy -/ hysterectomy- biopsy +/ hysterectomy- biopsy -/ hysterectomy+ Agreement p110 + 15 0 0 0 100% AKT + 9 1 4 1 67% ER + 8 5 3 1 80% PR + 3 8 3 1 73% EGFR + 5 7 3 0 83% Her2 + 17 0 0 0 100% PTEN loss 0 16 0 1 95%
A noninvasive prognostic biomarker for metastatic castration-resistant prostate cancer: Very small nuclear circulating tumor cells.
Authors: Pin-Jung Chen, Yu Jen Jan, Pai-Chi Teng, Jie-Fu Chen, Shirley Cheng, Nu Yao, Mariana Reis-Sobreiro, Amber Lozano, Amy Gomez, Michael Freeman, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2019)

179 Background: Circulating tumor cells (CTCs) have arisen as a contemporary biomarker for prostate cancer (PC). A subgroup of PC CTCs, with particularly small nuclei ( &lt; 8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). The findings led us to explore vsnCTCs as an aggressive biomarker in metastatic castration-resistant PC (mCRPC). We also explored a biological pathway that potentially drives this morphologic phenomenon. Studies showed that the disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, such as emerin, results in nuclear envelope instability and drives cancer cells to an amoeboid phenotype with increasing capacity of migration and invasion. We hypothesized that emerin mislocalization is associated with vsnCTC formation and may be a critical step of metastasis. Methods: Using our NanoVelcro CTC assay, we are able to capture and enumerate CTCs from patients' blood and correlate this data with clinical outcomes. We collected samples from 35 mCRPC patients who failed first-line androgen deprivation therapy and started treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Survival analyses were performed to exam the correlation between vsnCTC counts and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels were analyzed in selected vsnCTC samples. Results: The presence of one or more vsnCTCs correlated with worse overall survival (P = 0.00013), progression free survival (PSA progression: P = 0.012; radiographic progression: P = 0.0015), and faster time to VM (P = 0.024). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei. Conclusions: Our study demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTCs is a putative biomarker for prediction of worse outcome. Additionally, our findings of emerin mislocalization in vsnCTCs suggested a potential biological pathway behind this nuclear morphologic phenomenon.
Plasma-based exploratory biomarker analysis to evaluate GT0918 in a phase I/II study in mCRPC patients.
Authors: Jianjun Yu, Amy Wang, Zhixin Zhao, Shidong Jia, Phoebe Zhang, Karl Zhou
Journal: Journal of Clinical Oncology (2019)

279 Background: GT0918, a novel potent androgen receptor antagonist, has been evaluated in a ph 1/2 study in mCRPC patients for its safety and efficacy. Here using patient plasma samples, we explored cell-free DNA &amp; RNA-based biomarkers to assess their associations with clinical response of GT0918. Methods: Blood samples were prospectively collected from mCRPC patients at baseline, on- and after study during the trial. PredicinePLUS cfDNA+cfRNA assay, a 180-gene targeted NGS Panel, was used to detect genomic alterations in plasma. Statistical analyses were performed in R 3.5.1. Results: Genomic alterations were detected in all 50 blood samples. Top mutated genes are TP53 (52.5%) and AR (32.5%). When combing variants from genes in a signaling pathway, mutation rates in PI3K axis and homologous recombination pathway are 32.0% and 34.0% respectively. Importantly, AR hotspot mutations (W742C, T878A, and S889G) and amplifications are detected in multiple subjects at baseline, suggesting that it may be the driving events for resistance of prior therapies. AR splicing variants (AR-V3, AR-V7) and TMPRSS2-ERG fusion were also detected by cfRNA profiling. Interestingly, patient 001-001 harboring both AR W742C and T878A mutations detected in cfDNA with high mutation frequency didn’t carry corresponding mutations in cfRNA at the baseline but started to accumulate the mutations in C3D1. Patient 004-002 remained in the study with stable disease for 10 treatment cycles while having continuous increase of PSA. cfDNA profiling indicates frequency of prostate-specific SPOP mutation continued to decrease during the treatment. Conclusions: This is a preliminary analysis to explore potential predictive or pharmacodynamic biomarkers in mCRPC in response to GT0918 treatment. As an non-invasive assay, PredicinePLUS assay was able to detect genomic alterations in blood with a high sensitivity and provided useful molecular insights for treatment monitoring and drug sensitivity &amp; resistance mechanisms. Clinical trial information: NCT02826772.
Cost-sharing and financial burden for Medicare patients with newly diagnosed cancer.
Authors: Amol Narang, Lauren Nicholas
Journal: Journal of Clinical Oncology (2015)

6622 Background: Proposals for reducing Medicare spending include measures that increase beneficiary cost-sharing by regulating the extent of supplemental insurance. However, the financial burden on patients of such policies is unclear, particularly for health shocks such as cancer. To address this question, we used the Health and Retirement Study (HRS) to characterize the out-of-pocket (OOP) cost burden of newly diagnosed cancer and its relation with supplemental insurance. Methods: Medicare-eligible, community-dwelling HRS participants who did (N = 1409) or did not (N = 16,757) report a new cancer diagnosis from 2002-2012 were identified. Supplemental insurance was classified in order of increased cost-sharing as public (dual-eligible/VA), private (employer-sponsored/Medigap), or none (Medicare alone). OOP costs included hospital stays, doctor visits, outpatient surgery, prescription drugs, home health, dental, and special facilities. Financial burden was defined as OOP costs over per-capita household income. Multivariable quantile regression was used to assess the median and 90thpercentile (p90) of OOP costs and financial burden. Results: Newly diagnosed cancer patients experienced increased annual OOP costs (median: $2222 vs. $1791, p < 0.001; p90: $10,420 vs. $7807, p < 0.001) and financial burden (median: 9.0% of household income vs. 7.4%, p < 0.001; p90: 51.0% vs. 42.4%, p < 0.001). Supplemental insurance significantly affected cancer patients’ median financial burden (public: 3.3%, private: 9.9%, none: 16.6%, p < 0.001), which was magnified at the 90th percentile (public: 31.8%, private: 48.3%, none: 106.2%, p < 0.001). Importantly, financial burden at the 90thpercentile did not increase following a new cancer diagnosis for patients with public or private supplemental insurance, but significantly increased for patients with Medicare alone (p90: 106.2% vs. 58.1%, p < 0.001). Conclusions: More than 10% of newly diagnosed cancer patients with Medicare alone faced OOP costs greater than their income. Proposals to increase cost-sharing in the Medicare population should include provisions that protect patients from health shocks such as cancer, potentially though OOP cost limits or value-based exceptions.
Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline
Authors: Rachna T. Shroff, Erin B. Kennedy, Melinda Bachini, Tanios Bekaii-Saab, Christopher Crane, Julien Edeline, Anthony El-Khoueiry, Mary Feng, Matthew H.G. Katz, John Primrose, Heloisa P. Soares, Juan Valle, Shishir K. Maithel
Journal: Journal of Clinical Oncology (2019)

To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer.ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population.Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria.Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .