tbuckley/cabot-search huggingface dataset:
Next-generation RNA sequencing reveals transcriptomic changes after brief exposure to preoperative nab-paclitaxel, bevacizumab, and trastuzumab.
Authors: Vinay Varadan, Sitharthan Kamalakaran, Angel Janevski, Nila Banerjee, Kimberly Lezon-Geyda, Veerle Bossuyt, Dava Flowers-Poole, Natalie Faye Sinclair, Maysa M. Abu-Khalaf, William M. Sikov, Nevenka Dimitrova, Lyndsay Harris
Journal: Journal of Clinical Oncology (2012)

10508 Background: Identification of differentially expressed transcripts after brief exposure to preoperative therapy can help determine likely response markers. We quantify and compare differential gene and isoform expression using RNA-seq on patient samples with 10 day exposure to one dose of trastuzumab, bevacizumab or nab-paclitaxel. Methods: We sequenced transcriptomes of 23 pairs of core biopsy RNA from breast cancers pre/post 10 day exposure to therapy. Paired-end sequencing was done on the Illumina GAII platform using amplified total RNA with 74bp read length, yielding data on transcript abundance for a total of 22,160 genes and 34,449 transcripts. Differential expression of transcripts between pre/post samples was estimated assuming Poisson-distributed read-counts, followed by multiple testing correction and enrichment analysis of 185 KEGG pathways. Results: PAM50-based clustering showed individual samples cluster together, demonstrating that tumor subtypes do not change over the 10-day treatment (SABCS 2011). We identified genes that were significantly differentially expressed (p&lt;0.05; FDR&lt;0.1) in at least 60% of samples within each therapy arm: 780 genes in trastuzumab, 302 in bevacizumab, and 176 in nab-paclitaxel. Surprisingly, only THAP11 and TINF2 were common amongst them. THAP11 is involved in stem cell maintenance and TINF2 is important for regulation of telomere length. Immune system and metabolism-related pathways were commonly affected (p&lt;0.05) across all arms. The bevacizumab arm showed significant down-regulation of angiogenesis-associated genes: ESM1 and VEGFR2 in &gt; 80% of samples. The nab-paclitaxel arm exhibited changes in TGF-beta signaling, Nod-like receptor and Wnt signaling. The trastuzumab arm exhibited consistent alteration of ErbB2 and mTOR pathways, with SOX11 and TOP2B downregulated in every sample. Conclusions: This is the first study to compare gene expression with brief exposure across therapies using RNA-seq technology. The unique aspects of transcriptional response to each treatment underscore the need for specific markers of therapeutic response to nab-paclitaxel, bevacizumab and trastuzumab.
High- versus low-dose leucovorin in the FOLFOX regimen for metastatic colorectal cancer (mCRC).
Authors: Jana Marie Reynolds, April Chamberland-Tremblay, Juhee Song, Jon D. Herrington, Lucas Wong
Journal: Journal of Clinical Oncology (2014)

e14583 Background: In response to the national leucovorin shortage in 2008, our institution adjusted the FOLFOX6 (5-FU, leucovorin, and oxaliplatin) protocol to utilize a lower-dose of leucovorin (20mg/m2). This decision was based on limited prospective studies suggesting lower doses of leucovorin may be equally effective in 5-FU containing regimens. This retrospective study evaluates outcomes in mCRC patients treated with low (20mg/m2) vs. standard high dose (400mg/m2) leucovorin in the FOLFOX regimen for mCRC. Methods: Consecutive patients from 2004 to 2011 treated at Scott & White for mCRC were included if they received at least one cycle of modified FOLFOX6 with or without bevicizumab as first line therapy. Patients that received a leucovorin dose other than 20mg/m2 or 400mg/m2on their first cycle were excluded. Patient characteristics included demographics, site(s) of metastasis at initial diagnosis, and treatment history including chemotherapy and surgery. Primary outcome was date of death or last contact. Univariate and multivariate Cox proportional hazards regression analyses and Kaplan-Meier survival curves compared the effect of leucovorin dose on overall survival. Results: Of the 129 mCRC patients who received first line modified FOLFOX6, leucovorin 400 mg/m2 was administered to 71 (55%) patients and leucovorin 20mg/m2 to 58 (45%) patients. There were no differences between the groups except age at diagnosis, 61 vs. 66 years for high and low dose, respectively (p=0.02). In both univariate and multivariate Cox proportional hazards regression, lack of metastasis to the omentum at diagnosis (P=0.02) and resection or ablation at site of metastasis (P=0.003) were associated with better overall survival. Median survival time was 23 months for high dose group and 20 months for low dose group. There was no statistically significant difference in overall survival between the two groups (HR 1.020, 95%CI 0.677-1.536). Conclusions: In this single center retrospective study there was no difference in overall survival for mCRC patients treated with low (20mg/m2) vs. standard high dose (400mg/m2) leucovorin in first line FOLFOX. Limitations include the retrospective nature of the study and small sample size.
Estimated long-term outcomes in children newly diagnosed with standard risk acute lymphoblastic leukemia (ALL) based on similarly treated members of the childhood cancer survivor study (CCSS) cohort.
Authors: Stefan Essig, Qiaozhi Li, Yan Chen, Johann Hitzler, Wendy M. Leisenring, Mark L. Greenberg, Charles A. Sklar, Melissa M. Hudson, Gregory T. Armstrong, Kevin R. Krull, Joseph Philip Neglia, Kevin C. Oeffinger, Leslie L. Robison, Yutaka Yasui, Paul C. Nathan
Journal: Journal of Clinical Oncology (2013)

10032 Background: Therapy for ALL has evolved such that the risk for late effects in children treated in early eras is likely different from those that will occur in children treated today. In order to estimate future risks for late effects in newly diagnosed children with standard risk ALL, we examined the long-term outcomes in a cohort of patients enrolled in the CCSS who were treated in a manner analogous to contemporary ALL therapies. Methods: We assessed outcomes that occurred ≥5 years from diagnosis in survivors of ALL enrolled in the CCSS who were aged 1-9.9 years at diagnosis, treated with 0-120 mg/m 2 of anthracyclines and 0-1000 mg/m 2 of alkylating agents, and no radiotherapy. We compared their risks for death, second malignant neoplasms (SMN), chronic physical health conditions and decreased health status with the general population (death and SMN) and the CCSS sibling cohort (remaining outcomes). Results: 556 survivors were eligible. At last assessment, they were a median of 27.8 years old (range 9.1 to 45.7) and 23.4 years (range 5.0-38.0) from diagnosis. 29/556 (5.2%) died (standardized mortality ratio 3.6, 95% CI 2.4-5.2); 12 of these deaths were due to ALL recurrence. Compared to siblings, the rate ratio for ≥1 chronic condition was 1.4 (95% CI 1.3-1.6), and for a severe/life threatening chronic condition was 1.7 (95% CI 1.3-2.3). Four survivors (0.7%) developed a SMN (standardized incidence ratio 1.7, 95% CI 0.5-4.5), 114 were obese (odds ratio (OR) 1.2, 95% CI 1.0-1.5), and 2 (0.4%) reported a stroke. No survivors reported symptomatic congestive heart failure. The OR for reporting adverse general health was 1.2 (95% CI 0.8-1.8), poor mental health 1.3 (95% CI 1.0-1.8), decreased functional status 2.1 (95% CI 1.4-3.0), and activity limitations 1.4 (95% CI 1.1-1.8). Conclusions: Children treated for standard risk ALL on contemporary protocols are at increased risk for future chronic health conditions and decreased health status. Despite excellent survival after leukemia therapy, such survivors will likely benefit from life-long medical care focused on the long-term risks stemming from their therapy.
A method for assessing tumor response to therapy and more precisely guiding treatment decisions so as to improve survival.
Authors: Julia Wilkerson, Laleh Amiri-Kordestani, Ravi A. Madan, Bamidele Adesunloye, Sen Hong Zhuang, Samuel A. Wells, Antonio Tito Fojo, Susan Elaine Bates, Wilfred Donald Stein
Journal: Journal of Clinical Oncology (2012)

e13122 Background: The response of tumors to chemotherapy is monitored using imaging data or tumor markers and this quantitative data provides a rich source for an objective response assessment and treatment decisions. Responses are usually assessed as categorical variables based on percentage increase or decrease in tumor size. Methods: We have developed mathematical equations that describe efficacy as a continuous variable, enabling the extraction of the appropriate rate constants for tumor growth and regression (decay), designated g and d, respectively. Both are used to describe the rates of tumor growth and regression for the fraction of tumor that is growing despite treatment and the fraction dying as a result of therapy, respectively. Results: Using data from randomized phase III trials in kidney and breast cancer, multiple myeloma, and medullary thyroid carcinoma; as well as phase II trials in prostate cancer we have shown that: (1) values of g but not those of d are strongly correlated (negatively) with patient survival; (2) g can be discerned early in treatment, before growth is demonstrated clinically, providing an early efficacy measure; (3) g typically does not change over time, even over years, suggesting resistance is intrinsic and predictable and does not worsen over time; (4) effective therapies both increase d, and reduce g; and (5) in every cancer studied, the evidence suggests tumor growth reverts to its pre-treatment rate when chemotherapy is discontinued. Conclusions: The observation that g remains stable allows one to predict the most likely outcome of continued therapy. The evidence indicates that the increase in g occurring after treatment discontinuation is due to a resumption of a pre-treatment growth rate and not a change in biology. Our hypothesis is that if a favorable growth rate that slows tumor growth can be identified, survival might be improved if therapies that achieve this favorable growth rate are continued despite crossing conventional disease progression boundaries. We plan a prospective test of this model to provide a more informed decision and better survival outcome by maximizing the benefit obtained from approved therapies.
The Definitive Management of Primary Hyperparathyroidism
Authors: Michael J. Campbell
Journal: JAMA (2017)

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Association of genomic alterations with cisplatin resistance (cisR) in advanced germ cell tumors (aGCT).
Authors: Darren Richard Feldman, Aditya Bagrodia, Byron Lee, William Lee, Hikmat Al-Ahmadie, Eugene K. Cha, John Sfakianos, Gopa Iyer, Emily Craig Zabor, Irina Ostrovnaya, Jana Eng, Maria E. Arcila, Raju S.K. Chaganti, Nikolaus Schultz, Victor E. Reuter, Manjit S. Bains, Joel Sheinfeld, Brett Stewart Carver, George J. Bosl, David B. Solit
Journal: Journal of Clinical Oncology (2015)

4510 Background: 20% of patients (pts) with aGCT progress after initial chemotherapy (chemo), displaying at least partial cisR. We sought to characterize the genetic alterations in aGCT and identify markers of cisR. Methods: aGCT pts with available tumor tissue (except pure teratoma or malignant transformation) were eligible. Cisplatin sensitive (cisS) pts had a CR to chemo +/- surgery (if pathology = necrosis or teratoma) or PR + negative tumor markers lasting one year or more. CisR pts had non-teratoma GCT at post-chemo surgery or at relapse. Cis status was inevaluable (IE) if followup (f/u) was too short (without progression) or standard initial chemo was not given. Whole exome sequencing (WES) in 19 pts (10 cisR, 9 cisS) identified several mutations and copy number changes, which we confirmed by targeted exon-capture sequencing of 341 cancer-related genes (MSK-IMPACT). MSK-IMPACT was then preformed for 69 additional pts. Results on all 88 pts were analyzed for associations with clinicopathologic features using Fisher’s exact test and for progression-free survival (PFS) using Cox regression multivariable analysis (MVA). Results: Of 88 pts (65 nonseminoma [NS], 23 seminoma [SEM]), 23 (26%) were cisS, 59 (67%) cisR, and 6 (7%) IE. Primary site was testis in 77, mediastinum in 10, and retroperitoneum (RP) in 1. IGCCCG risk group was good in 39, intermediate in 9, and poor in 36 (4 IE). Forty-two primary and 46 metastatic tumors were sequenced; 47 were obtained pre- and 41 post-chemo. With median follow-up of 25 months, 59 pts progressed, with 10 dying from aGCT. On WES, cisR samples had more nonsynonymous mutations than cisS samples (mean 49 vs 15, p = 0.03). On MSK-IMPACT, TP53 mutations were more common for pts with a mediastinal vs testis/RP primary (60 vs 3%, p < 0.0001) and KRAS mutations more common in SEM vs NS (26 vs 6%, p = 0.018). TP53 mutations and MDM2 amplifications were mutually exclusive and both occurred only in cisR pts (25 vs 0%, p = 0.008). On MVA adjusted for IGCCCG group, TP53/MDM2alteration independently predicted PFS (HR 2.6, 95%CI 1.4-4.8, p = 0.002). Conclusions: Genomic changes in aGCT differ by histology and primary site. As TP53/MDM2 alterations correlate with cisR and predict PFS independent of IGCCCG risk, they may aid prognostic assessment.
Nomogram for predicting the benefit of neoadjuvant chemoradiotherapy for esophageal cancer: A SEER-Medicare analysis.
Authors: Robert Eil, Brian S. Diggs, Samuel J. Wang, James P. Dolan, John G. Hunter, Charles R. Thomas
Journal: Journal of Clinical Oncology (2013)

4073 Background: The impact of neoadjuvant chemoradiotherapy for esophageal cancer remains difficult to establish for specific patient (pt) populations. The primary aim of this study was to create a web-based prediction tool that provides individualized survival projections based on clinically relevant tumor and treatment data. Methods: Pts diagnosed with esophageal cancer between 1997 and 2005 were selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The covariates chosen for retrospective analysis were: sex, T and N stage, histology, total lymph nodes examined, and receipt of neoadjuvant chemotherapy (CT), radiotherapy (RT), or chemoradiotherapy (CRT). After weighting correction by treatment groups, a log logistic regression model for overall survival (OS) was selected based on goodness of fit analysis. Based on bootstrap resampling with 100 repetitions the Concordance Index (CI) was 0.703. Results: 1,128 resected esophageal pts that either did or did not receive neoadjuvant treatment were appropriate for analysis. On log logistic multivariate analysis: age, sex, T stage, N stage, number of lymph nodes harvested, receipt of neoadjuvant CRT, and receipt of chemotherapy were significantly associated with OS. All T stages greater than 1 benefitted from neoadjuvant CRT (p=&lt;0.001). No T stage benefitted from isolated neoadjuvant CT or RT. Patients with nodal metastases benefitted from neoadjuvant CRT (p=&lt;0.001) and CT (p=0.002). Conclusions: SEER-Medicare pts with resected esophageal cancer can be used to produce a survival prediction tool that can: 1) serve as a counseling and decision aid to pts and caregivers regarding their postoperative prognosis and 2) assist in research protocol design. Patients T2 or greater or with lymph node metastases benefitted from neoadjuvant CRT based on our data. This nomogram may underestimate the benefit of neoadjuvant CRT due to its variable downstaging effect on final pathologic stage. This web based tool is available for use at http://skynet.ohsu.edu/nomograms .
Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC).
Authors: Sumanta K. Pal, Guru Sonpavde, Neeraj Agarwal, Nicholas J. Vogelzang, Sandy Srinivas, Naomi B. Haas, Sabina Signoretti, Richard B. Lanman, Kimberly Banks, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

434 Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.
Sixteen years follow-up results of a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Ariel Osvaldo Zwenger, Julieta Leone, Carlos Teodoro Vallejo, Juan Eduardo Perez, Alberto Omar Romero, Mario Raul Machiavelli, Luis Romero Acuna, Maria Ester Dominguez, Mario Langui, Hebe Margot Fasce, Bernardo Amadeo Leone, Eduardo Ortiz, Jose Pablo Leone, Julian Iturbe
Journal: Journal of Clinical Oncology (2013)

1073 Background: Neoadjuvant chemotherapy allows direct evaluation of the tumor’s sensitivity to therapy, eradication of micrometastatic disease and the possibility of performing breast conserving surgery. The aim of this study was to describe long-term results of neoadjuvant chemotherapy in stage III breast cancer patients (pts). Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: Pts characteristics were well balanced in both groups (FAC: 64pts, CMF: 62pts). Median follow-up was 4.5 years (range 0.2-16.4). No significant difference was found regarding acute and long-term toxicity; however, alopecia was more frequent in FAC group. Breast conserving surgery was performed in 13.5% of pts with no difference between groups. Objective response rate (OR) was similar in both groups but pathological complete response was achieved by 4 pts who received FAC. Although both groups had similar locoregional and distant recurrences, contralateral breast cancer was higher in the CMF group (6.5% vs 1.6%, P=NS). Disease free survival (DFS) and overall survival (OS) data are shown in the table. After 16 years of follow-up, 42.1% (n=53) of pts are still alive. Disease progression was the principal cause of death in both groups (78.9% vs 84.2%). Conclusions: To the best of our knowledge, this is the first study to report long-term outcomes of FAC and CMF in the neoadjuvant setting. Within the sensitivity of our study, both regimens showed similar OR, long-term toxicity, DFS and OS rate at 16 years. Around 40% of pts are currently alive. Clinical trial information: NCT00002696. [Table: see text]
Candidates for intensive local treatment in cIIIA-N2 NSCLC: Impact of mediastinal nodal extent and appearance.
Authors: Hidehito Horinouchi, Tomoyasu Mimori, Ayako Tanaka, Hirofumi Utsumi, Kuniko Sunami, Satoru Kitazono, Hidenori Mizugaki, Shintaro Kanda, Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Minako Sumi, Tomohide Tamura
Journal: Journal of Clinical Oncology (2014)

7544 Background: Clinical stage IIIA non-small cell lung cancer (NSCLC) with N2 nodal involvements (cIIIA-N2) includes a broad spectrum of patients. Phase III trials examining higher radiotherapy dose and surgery after neoadjuvant therapy have failed to yield satisfactory results. Methods: Between 1997 and 2010, we analyzed consecutive NSCLC patients diagnosed as having cIIIA-N2 disease and received chemoradiotherapy (CRT). The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete (D) or infiltrative (I) according to the criteria proposed by the ACCP (Silvestri et al., Chest 2013). The extent of MLN involvement (MLNI) was divided into limited (close to the primary tumor) or extended (including upper MLNI in the case of tumors in the lower lobes and vice versa). Results: A total of 148 patients with cIIIA-N2 NSCLC received CRT; male/female, 118/30; median age, 62 years. The disease characteristics were as follows; appearance of the involved MLNs (D/I), 83/63; extent of MLNI (limited [L]/extended [E]), 81/64; histology (squamous [sq] /non-squamous [non-sq]), 36/112. The median progression-free survival (PFS) and median overall survival (OS) (95% confidence interval) in the entire subject population were 9.9 (9.0-12.3) months and 34.7 (28.8-41.1) months, respectively. Discrete appearance, limited extent of MLNI and treatment initiation after 2005 contributed to a significantly better PFS and OS. The percentages of cases with local relapses within the irradiated field according to the disease characteristics were as follows; MLN appearance (D/I), 24.6/18.9%; MLNI (L/E), 25.9/17.9%; histology (sq/non-sq), 52.0/12.6%. Conclusions: Among patients with cIIIA-N2 NSCLC, those with a discrete appearance of the involved MLNs and a limited extent of MLNI could be a favorable subgroup. With regard to local relapses after CRT, development of a better strategy for local treatment in this population (especially patients with a sq histology) is warranted.