tbuckley/cabot-search huggingface dataset:
Changes in adjuvant breast cancer chemotherapy regimen selection over time in the community.
Authors: Debra A. Patt, Janet L. Espirito, Brian Turnwald, J. Russell Hoverman, Marcus A. Neubauer, Thomas H. Cartwright, Leslie T. Busby, Barry Don Brooks, Mark A. Sitarik, Michael A. Kolodziej, Roy A. Beveridge
Journal: Journal of Clinical Oncology (2012)

6109 Background: Adjuvant breast cancer (BC) chemotherapy (CT) treatment has evolved over time due to improved understanding of risk conveyed by pathology and patient (pt) characteristics, as well as emergence of new and mature data for survival and toxicity. We aimed to evaluate how CT regimen selection has changed in recent years in various subgroups. Methods: Using iKnowMed EHR data from The US Oncology Network, we retrospectively identified female pts diagnosed with stage I-III BC between 1/2007 and 12/2010 at practices with EHR data available at time of diagnosis. Pts with &lt;5 office visits, those with a second primary or previous cancer diagnoses were excluded. Age, ER, HER2, nodal status, stage and year of diagnosis were captured. CT utilization was determined by the number of pts who received CT within 6 months of their diagnosis. Clinical trial pts were included. Regimens were categorized by the initial CT title and drugs assigned. Pts with metastatic regimens were excluded. CT regimens were analyzed by subgroups and trended over time. Results: During the time period, 26,095 stage I-III BC pts were identified. A CT regimen within 6 months of diagnosis was documented in 56% of pts. CT utilization was 83% in HER2+ pts, 85% in ER-/HER2- pts, and 45% in ER+/HER2- pts. CT utilization decreased overall with increasing pt age (71%, 64%, 51%, 33%, and 13% for pts in their 4 th , 5 th , 6 th , 7 th and ≥8 th decade of life). In HER2+ pts, use of non-anthracycline containing regimens increased from 26 to 62%, and anthracyline-taxane combination regimens decreased from 33 to 15%. In HER2-/ER+ pts, the most used non-anthracycline regimen was docetaxel + cyclophosphamide (TC) at 41%. Anthracycline-taxane combinations were used more often in the HER2-/ER- group (32%). Conclusions: In the 4 year study period, this data suggests that ER and HER2 status may drive chemotherapy choice more than nodal status. Anthracycline containing regimens are being used less often possibly due to similar efficacy but less cardiac toxicity, particularly when combined with trastuzumab. These results suggest a change away from anthracyclines in specific subgroups with the controversy over the benefits of that change unsettled, and cost implications yet unquantitated.
Time-dependent estimates of recurrence and survival in colon cancer: clinical decision support system tool development for adjuvant therapy and oncological outcome assessment.
Authors: Scott Steele, Anton Bilchik, Eric Johnson, Aviram Nissan, George Earl Peoples, John Eberhardt, Philip Kalina, Benjamin Petersen, Bjoern L. D. M. Bruecher, Mladjan Protic, Itzhak Avital, Alexander Stojadinovic
Journal: Journal of Clinical Oncology (2013)

e14500 Background: Unanswered questions remain regarding treatment efficacy in colon cancer (CC), especially those determining high-risk node-negative cohorts that may benefit from adjuvant therapy. We sought to evaluate the use of machine learning and classification modeling to estimate survival and recurrence in CC. Methods: We used the Department of Defense Automated Central Tumor Registry (ACTUR) to identify primary CC patients treated between January 1993 and December 2004. Cases with events or follow-up that passed quality control were stratified into one-, two-, three-, and five-year survival cohorts. ml-BBNs were trained using machine-learning algorithms and k-fold cross-validation, and receiver operating characteristic (ROC) curve analysis used for validation. Results: There were 5,301 cases stratified into cohorts. Survival cohort Areas-Under-the-Curve (AUCs) ranged from 0.85–0.90, positive-predictive-values (PPVs) for recurrence and mortality ranged from 78-84% and negative-predictive-values (NPVs) from 74-90%. Cross-validation showed that the ml-BBNs produce robust individual estimates of recurrence (p&lt;0.001) and mortality (p&lt;0.001) based on readily available clinical-pathological information in the context of adjuvant chemotherapy. Conclusions: Tumor registry data and machine-learned Bayesian Belief Networks produce robust classifiers. These Clinical Decision Support System tools yield clinically relevant estimates of outcomes that may assist clinicians in treatment planning.
Let-7 and MicroRNA-148 Regulate Parathyroid Hormone Levels in Secondary Hyperparathyroidism
Authors: Vitali Shilo, Irit Mor-Yosef Levi, Roy Abel, Aleksandra Mihailović, Gilad Wasserman, Tally Naveh-Many, Iddo Z. Ben-Dov
Journal: Journal of the American Society of Nephrology (2017)

Secondary hyperparathyroidism commonly complicates CKD and associates with morbidity and mortality. We profiled microRNA (miRNA) in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis and studied the function of specific miRNAs. miRNA deep-sequencing showed that human and rodent parathyroids share similar profiles. Parathyroids from uremic and normal rats segregated on the basis of their miRNA expression profiles, and a similar finding was observed in humans. We identified parathyroid miRNAs that were dysregulated in experimental hyperparathyroidism, including miR-29, miR-21, miR-148, miR-30, and miR-141 (upregulated); and miR-10, miR-125, and miR-25 (downregulated). Inhibition of the abundant let-7 family increased parathyroid hormone (PTH) secretion in normal and uremic rats, as well as in mouse parathyroid organ cultures. Conversely, inhibition of the upregulated miR-148 family prevented the increase in serum PTH level in uremic rats and decreased levels of secreted PTH in parathyroid cultures. The evolutionary conservation of abundant miRNAs in normal parathyroid glands and the regulation of these miRNAs in secondary hyperparathyroidism indicates their importance for parathyroid function and the development of hyperparathyroidism. Specifically, let-7 and miR-148 antagonism modified PTH secretion in vivo and in vitro , implying roles for these specific miRNAs. These findings may be utilized for therapeutic interventions aimed at altering PTH expression in diseases such as osteoporosis and secondary hyperparathyroidism.
Distinctive lipid profiles of human breast cancer and adjacent normal tissues by desorption electrospray ionization mass spectrometry imaging.
Authors: Diana L. Caragacianu, Xiaohui Liu, Isaiah Norton, Jennifer Ide, Andrea Richardson, Deborah Dillon, Ferenc A. Jolesz, Mehra Golshan, Nathalie Y.R. Agar
Journal: Journal of Clinical Oncology (2013)

1132 Background: Routine intra-operative distinction between normal breast tissue and tumor is currently not possible in breast conserving surgery (BCS). This limitation affects the success of surgery, resulting in up to 40% requiring more than one operative procedure. Desorption electrospray ionization mass spectrometry (DESI MS) has been successfully used to discriminate between normal and cancerous human tissues from anatomical sites such as the liver and brain. The aim of this proof of concept study was to determine the feasibility of using DESI MS imaging for tissue identification and differentiation of breast cancer versus normal tissue. Methods: DESI MS imaging was carried out on 14 human invasive breast cancer samples. Breast cancer and adjacent normal paired human tissue sections (margin of tumor, 2cm and 5 cm from tumor) from 14 patients undergoing mastectomy were flash frozen in liquid nitrogen, sectioned, and thaw mounted to glass slides. All samples were imaged using DESI MS at 200 μm imaging resolution. DESI MS images were overlaid and compared with hematoxylin and eosin (H&amp;E) images of the same sections. Results: Discrimination between cancer and adjacent normal tissue was achieved on the basis of the spatial distribution and varying intensities of particular fatty acids and lipid species. Several fatty acids such as oleic acid (m/z 281) and arachidonic acid (m/z 303) displayed much greater signal intensities in the cancer specimen compared to low or undetectable intensities in normal tissue. The cancer margins delineated by the DESI MS images of these molecules were consistent with H and E images of the tumor edge. Cancerous tissue was distinguished from normal tissue based on the qualitative assessment of molecular signatures and the distinction was in agreement with expert histopathology evaluation in 85% of samples. Conclusions: Our findings offer proof of concept that examination and classification of breast normal and cancer tissue by mass spectrometry imaging is highly accurate. The results are encouraging for development of a MS-based method that could be utilized intra-operatively for rapid detection of residual cancer tissue in the lumpectomy bed in BCS.
Aldehyde dehydrogenase activity in serous ovarian carcinoma.
Authors: Petra M. Bareiss, Tanja N. Fehm, Anna Fischer, Matthias Grauer, Philipp Kokorsch, Hans-Joerg Buehring, Deborah Pham, Annette Staebler, Diethelm Wallwiener, Falko Fend, Lothar Kanz, Claudia Lengerke
Journal: Journal of Clinical Oncology (2012)

e15577 Background: Only specific subpopulations of tumor cells, so called cancer stem cells (CSC) may initiate and maintain tumors. The phenotype and molecular properties of ovarian CSC remain elusive. Aldehyde dehydrogenase (ALDH) activity characterizes (cancer) stem cells in different tissues and has been associated with ovarian CSC (Silva et al, 2011; Kryczek et al, 2012). Contradictory results have been reported on ALDH1 expression and prognosis in ovarian carcinoma. In this study, we explore the role of ALDH in serous ovarian carcinoma (SOC). Methods: Aldefluor-staining was used to assess ALDH activity in different ovarian carcinoma cell-lines and patient samples. ALDH+ and ALDH- cells isolated by FACS and ALDH1 versus control siRNA treated cells were analyzed in sphere forming, proliferation, BrdU and cell cycle assays. In vivo tumorigenicity assays including serial re-transplantations were performed in NOD/SCID/IL2Rγ null mice. ALDH1 and Ki67 expression were assessed immunohistochemically on a tissue microarray of 152 SOC samples. Results: ALDH+ cells formed more tumor spheres than ALDH- cells from the OVCAR-3 cell line and primary SOC and larger spheres (&gt; 5.000 µm²) developed solely from ALDH+ cells. However, in vivo both cell fractions gave rise to tumors. Tumors contained both ALDH+ and ALDH- cells irrespective of the starting population. Notably, ALDH+ cells generated tumors more rapidly and induced larger tumors, suggesting a higher proliferative capacity. Immunohistochemical analysis of a larger cohort of SOC patients confirmed association of ALDH1 expression with the proliferation marker Ki67 (p=0.007). Surprisingly, co-stainings revealed that ALDH1 positive cells were mostly Ki67 negative and cell cycle synchronisation experiments using different agents showed ALDH induction in G0-enriched OVCAR-3 cells. However, inhibition of ALDH by treatment with three distinct siRNAs against ALDH1 did not alter cell cycle distribution. Conclusions: Our data suggest that ALDH is a correlative marker indicating, but not actively sustaining a quiescent stem-cell like state in SOC. Upon exit from G0, ALDH+ cells lose ALDH expression and induce a proliferative response.
Phase I study of neoadjuvant 5-fluorouracil (5FU) chemoradiation (CRT) and trametinib in patients with locally advanced rectal cancers (LARC).
Authors: Christina Sing-Ying Wu, Terence M Williams, Lai Wei, Hamida Umar, Sameh Mikhail, Kristen Keon Ciombor, Anne M. Noonan, Sameek Roychowdhury, Samer S El-Dika, Somashekar Krishna, Bennie Upchurch, Sean T McCarthy, Mark Arnold, Alan Harzman, Sherif Abdel-Misih, William Cirocco, Amber Traugott, Tanios S. Bekaii-Saab, Evan John Wuthrick
Journal: Journal of Clinical Oncology (2017)

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m 2 /day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]
Correlation of in vitro chemotherapy drug resistance assay to clinical response to carboplatin and paclitaxel combination chemotherapy in ovarian carcinoma.
Authors: Kit Cheng, Iuliana Shapira, Lisa M Rosen, Veena S. John, John L. Lovecchio, Andrew Menzin, Jill Suzanne Whyte, Lisa A. Dos Santos, Diana Contreras, Karin Shih, Rajasree Roy, Annette Lee, Christi Hayes, Nazish Ahmad, Pragati Tandon, Mark Allan Hoffman
Journal: Journal of Clinical Oncology (2013)

e16546 Background: Carboplatin sensitivity in drug resistance assays has been shown to be an independent predictor of longer progression free interval with conflicting results in overall survival. We evaluated in vitro drug resistance for carboplatin and paclitaxel combination and its correlation with progression free survival (PFS) and overall survival (OS). Methods: From April 1, 2006 to December 12, 2011, in vitro drug resistance assays were sent after cytoreductive surgery for primary epithelial ovarian cancer. Patients were analyzed according to drug resistance scoring system of low drug resistance (S), intermediate drug resistance (I), and extreme drug resistance (R). Retrospective chart review was performed to evaluate PFS and OS. The Kaplan Meier product limit method was used to estimate OS and PFS. Survival curves were compared between groups using the log rank test. Results: From a total of 142 patients: 57 were S, 52 I, and 33 R; 77% were responsive (S+I) to carboplatin and paclitaxel combination. At median follow-up of 18 months, PFS and OS rates were 58.1 and 91.3% respectively for S, 66.1 and 78.7% for I, and 43.2% and 84.3% for R. At 36 months, the PFS and OS rates were 52.3 and 61.1% for S, 51.3 and 55.3% for I and 39.3% and 48.7% for R. There was OS advantage between the S and I compared to R. There were no significant differences in PFS curves (p&lt;0.281) or OS curves (p&lt;0.46). Conclusions: Although sensitivity to carboplatin/ paclitaxel resulted in longer OS, the results were not statistically significant. Our cohorts were small and we may not have had the power to capture statistical significance. A larger multicenter analysis would be needed to further evaluate this finding. In addition, one of the regimens our patients received on relapse was bevacizumab which was not evaluated in the in vitro assay sensitivity assay. Bevacizumab has also been included in first line treatment in combination with platinum/ taxane regimen. Future analysis of in vitro assays may need to include biologics.
A randomized open-label study of bortezomib, melphalan, and prednisone (VMP) versus daratumumab (DARA) plus VMP in patients with previously untreated multiple myeloma (MM) who are ineligible for high-dose therapy: 54767414MMY3007 (Alcyone).
Authors: María-Victoria Mateos, Michele Cavo, Andrzej J. Jakubowiak, Robin L. Carson, Ming Qi, Rajesh Bandekar, Wendy Crist, Tahamtan Ahmadi, Jesus F. San Miguel
Journal: Journal of Clinical Oncology (2015)

TPS8608 Background: Based on the results of the VISTA study (San Miguel JF et al. NEJM 2008), VMP is considered a standard of care for newly diagnosed patients with MM not considered suitable for high-dose chemotherapy and stem cell transplantation (SCT). DARA is a human anti-CD38 IgG1κ monoclonal antibody in clinical development for MM. DARA has shown promising efficacy and a favorable safety profile in ongoing phase I/II studies as monotherapy and in combination with chemotherapy (lenalidomide/dexamethasone) in patients with relapsed or relapsed, refractory MM (Lokhorst HM et al. ASCO 2014; Plesner T et al. ASH 2014) as well as in combination with VMP in newly diagnosed MM (Moreau P et al. ASH 2014). Methods: This is a phase III randomized, open-label, multicenter study of VMP versus DARA + VMP in patients aged ≥ 18 y with previously untreated MM who are ineligible for high-dose therapy. Main inclusion criteria are documented MM satisfying the CRAB criteria, measurable disease, and newly diagnosed and not considered a candidate for high-dose chemotherapy with SCT. Approximately 700 eligible patients will be stratified by International Scoring System, region (Europe vs others), and age ( < 75 vs ≥ 75 y) and randomized in a 1:1 ratio to VMP or DARA + VMP. All patients will receive up to 9 cycles (1 cycle = 6 wk) of VMP (bortezomib 1.3 mg/m2 SC twice weekly [Weeks 1, 2, 4, and 5] in Cycle 1, then once weekly [Weeks 1, 2, 4, and 5] in Cycles 2-9; melphalan 9 mg/m2 and prednisone 60 mg/m2 PO Day 1-4 of each cycle). Patients in the DARA + VMP arm will receive DARA 16 mg/kg IV weekly x 6 wk (Cycle 1), then every 3 wk for Cycles 2-9; patients will then continue to receive DARA every 4 wk until progression. The primary endpoint is progression-free survival (PFS). An Independent Data Monitoring Committee will conduct reviews of the efficacy and safety data. The primary analysis will occur when approximately 360 PFS events have been observed. Approximately 200 sites in 24 countries will participate. The first patient was enrolled in January 2015. Clinical trial information: NCT02195479.
Outcomes of North American, Japanese, and European extensive-disease small cell lung cancer (ED-SCLC) patients under irinotecan-platinum or etoposide-platinum therapy: Systematic review and meta-analysis.
Authors: Joao Paulo Da S.N. Lima, Andre Deeke Sasse, Emma C. Sasse, Lucas Vieira dos Santos
Journal: Journal of Clinical Oncology (2013)

e18534 Background: Superiority of irinotecan-platinum (IP) regimens over etoposide-platinum (EP) in ED-SCLC has been extensively debated, with ethnic and pharmacogenomics issues hypothesized as causes of the divergent findings. We undertook a systematic review to scrutinize the data according to geographic origin. Methods: Randomized controlled trials comparing first-line EP doublets versus IP in ED-SCLC patients were searched in major meeting proceedings and databases. The outcomes were overall survival (OS), one-year survival, two-year survival, and safety. Meta-analyses were performed using random-effects model. Subgroup analyses and meta-regression were undertaken to compare and measure the impact of geographical origin of study over the estimated effect size. Results: Seven studies (2,029 patients) were included. IP improved OS worldwide (HR = 0.83; 95% CI 0.76-0.92; P&gt;0.001; I²=0%). However, the impact of IP on OS was different according to geographic origin, with relevant benefit for Japanese, little benefit for North American/Australian and intermediate for European patients (P for interaction = 0.029, table 1). One year survival was homogenously improved from 34% with EP to 40% with IP (P=0.006). IP improved two year survival just for Japanese and European patients but not to North American ones (Table). Toxicity was not impacted by trial origin. Conclusions: IP improved survival for both Western and Eastern patients, but seems to exist a gradient of benefit according to geographic origins, with maximal benefit for Japanese, some relevant for European ones and little, if any, for North American/Australian patients. These findings should be taken in account when considering IP or EP as first-line therapy for ED-SCLC patients worldwide. [Table: see text]
Phase I/II study of a combination of capecitabine, cisplatin, and intraperitonealdocetaxel (XP ID) in patients with advanced gastric cancer with peritoneal metastasis.
Authors: Hyungwoo Cho, Min-Hee Ryu, Changhoon Yoo, Baek-Yeol Ryoo, Sook Ryun Park, Kyu-Pyo Kim, Beom Su Kim, Moon-Won Yoo, Jeong Hwan Yook, Byung Sik Kim, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2015)

4026 Background: More than one third of patients with advanced gastric cancer (AGC) have peritoneal metastasis, and their prognosis is poor. This study was conducted to determine the recommended dose (RD) of intraperitoneal docetaxel (ID) in combination with systemic capecitabine and cisplatin (XP), and to evaluate its efficacy and safety at the RD in AGC patients with peritoneal metastasis. Methods: AGC patients with peritoneal metastasis received XP ID, which consists of 937.5 mg/m2 of capecitabine twice daily on days 1-14, 60 mg/m2 of intravenous cisplatin on day 1, and ID at 3 different dose levels (60, 80, or 100 mg/m2) on day 1, every 3 weeks. In the phase I study, the standard 3+3 method was used to determine the RD of XP ID. For the phase II study, patients received RD of XP ID until disease progression, unacceptable toxicity, or consent withdrawal. A maximum of 8 cycles of ID was provided. Results: In the phase I study, 3 patients experienced no dose limiting toxicity (DLT) at each of 60 or 80 mg/m2 of ID. ID 100 mg/m2was determined as the RD with 1 DLT (ileus) out of 6 patients. Between June 2011 and December 2013, 39 AGC patients with definite peritoneal metastasis were enrolled in the phase II study and received RD of XP ID. With a median follow-up duration of 20.8 months (range, 13.1-40.3) in surviving patients, median progression-free survival was 11.0 months (95% CI, 6.9-15.1), and median overall survival was 15.1 months (95% CI, 9.1-21.1). Among 30 patients with ascites, complete resolution of ascites was observed in 12 patients (40.0%), and more than 10% reduction in amount of ascites was observed in 8 patients (26.7%). The most frequent grade 3 or 4 adverse events were neutropenia (38.6%), abdominal pain (30.8%), and anemia (25.6%). Of these adverse events, the incidence of abdominal pain cumulatively increased in the later treatment cycles. There was no treatment-related mortality. Conclusions: Our study indicated that XP ID was effective with manageable toxicities in AGC patients with peritoneal metastasis. Considering cumulative incidence of abdominal pain probably related to bowel irritation by ID, it may be necessary to modify the dose of ID. Clinical trial information: NCT01525771.