tbuckley/cabot-search huggingface dataset:
Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.
Authors: Xiao Bi, Siming Zhao, Adebowale Adeniran, Harriet M. Kluger, Zuoquan Xie, Cayce Nawaf, Maria J Merino, Vladimir Valera, Allan J. Pantuck, Jonathan W. Said, Arie S. Belldegrun, Richard P Lifton, Brian M. Shuch
Journal: Journal of Clinical Oncology (2016)

509 Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10 -4 ). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
Authors: Seng-Ryong Woo, Mercedes B. Fuertes, Leticia Corrales, Stefani Spranger, Michael J. Furdyna, Michael Y.K. Leung, Ryan Duggan, Ying Wang, Glen N. Barber, Katherine A. Fitzgerald, Maria-Luisa Alegre, Thomas F. Gajewski
Journal: Immunity (2015)
Somatic gene mutations predict outcome of patients receiving adjuvant active specific immunotherapy after resection of stage IV melanoma
Authors: R. Essner, J. H. Lee, H. T. Itakura, Y. Huynh, T. Zogakis, D. L. Morton
Journal: Journal of Clinical Oncology (2005)

7522 Background: Cyoreductive surgery plus adjuvant active specific immunotherapy can improve prognosis in stage IV melanoma, if patients are carefully selected. Chemokine receptor 5 (CCR5) is involved in T-cell immunity and dendritic cell activation. Interleukin-10 (IL-10) is immunosuppressive in melanoma. We hypothesized that a somatic CCR5 gene mutation (delta) 32 bp deletion, in conjunction with increasing CD14-derived IL-10 might reflect an unfavorable immune response and ultimately a poorer survival after complete resection and postoperative immunotherapy for stage IV melanoma. Methods: Stage IV melanoma patients enrolled for at least 6 months in phase II trials of Canvaxin specific active immunotherapy (CancerVax Corp, Carlsbad, CA) after complete resection were randomly identified. Genomic DNA extracted from peripheral blood monocytes (PBM) was screened for CCR5 mutation; PCR product size and sequencing verified mutations. Double-staining flow cytometry of serial PBM specimens determined IL-10 levels from CD14+ monocytes. Statistical tests were log-rank, chi-square and student’s T-test. Results: Of the 91 patients, 53 (58%) were men. Median age was 47 years (range, 19–82). Twenty-eight (31%) patients had M1a, 22 (24%) M1b, and 41 (45%) had M1c metastases. Seventy-four (81%) patients had wild-type (Wt) CCR5 gene, 13 (14%) had heterozygous (HtM) CCR5 mutation, and 4(5%) had homozygous (HoM) mutation. At a median follow-up of 38 months, 5-year survival was significantly (p=0.031) higher with Wt CCR5 than HtM/HoM CCR5 (55.6±6.1% vs. 21.4±10.8%). Increasing IL-10 levels (n=10) combined with CCR5 mutation decreased median survival to 9 months and eliminated 5-year survival; by contrast, Wt CCR5 plus decreasing IL-10 was associated with 5-year survival of 76±5% (p<0.0001). Multivariate analyses confirmed the prognostic superiority of CCR5 mutation and IL-10 level vs. age, gender or M stage. Conclusions: Somatic mutations of CCR5 and increasing expression of CD14-derived IL-10 were correlated with poor outcome in stage IV melanoma. These somatic-derived gene products might be used to identify patients for active specific immunotherapy or other treatments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerVax CancerVax
KLF4 and ER as biomarkers for prognosis of breast cancer patients.
Authors: Takuya Nagata, Kousi Matsui, Yutaka Shimada, Kazuhiro Tsukada
Journal: Journal of Clinical Oncology (2012)

174 Background: Some of the induced pluripotent stem cell (iPS cell)-inducing factors have been reported to be expressed in breast cancer. The aim of the present study was to examine the relationship between the expression of KLF4 that was one of iPS cell-inducing factors and the prognosis of breast cancer patients. Methods: In 162 breast cancer patients, the expression of KLF4 was determined by immunohistochemistry using a tissue microarray analysis. The relationship with the expression of the estrogen receptor (ER) was also examined. Results: Patients with strong expression of KLF4 (KLF4 high: n=76, 46.9%) had significantly better disease-free survival (DFS; p=0.002) and overall survival (OS; P=0.0006) rates than those with weak expression of KLF4 (KLF4 low: n=86, 53.1%). And also, patients with expression of ER (ER+; n=135, 83.3%) had better DFS (p=0.018) and OS (p=0.0018). About the relationship of KLF4 and ER, KLF4low, ER+ group were better DFS (p=0.0024) and OS (p&lt;0.0001) than KLF4low, ER- group. Conclusions: It was suggested that expressions of KLF4 and ER were useful as biomarkers of prognosis for breast cancer patients respectively. It was also suggested that KLF4 was not cooperative with ER to control the metastasis or progression of breast cancer cells.
Biological impact of skip metastasis in patients with gastrointestinal cancers undergoing sentinel lymph node mapping.
Authors: S. Saha, M. Mozayen, S. Sirop, A. Korant, S. Nalluri, O. L. Machek, M. Manyam, P. L. Ng, S. Nagpal, D. Wiese
Journal: Journal of Clinical Oncology (2011)

499 Background: As in melanoma and breast cancers, sentinel lymph node (SLN) mapping has been successfully used in gastrointestinal (GI) cancers (Ca) for accurate nodal staging. However, due to variable incidence of skip metastasis between different parts of the GI tract, its usefulness has been questioned for the proper staging. Hence, we aimed to evaluate the rates of skip mets, its mechanism and its biological impact in GICa. Methods: A search of English literature was performed incorporating MEDLINE and Cochrane library database using the following terms: skip metastasis, sentinel node, colorectal, gastric, and esophageal cancer. The following were excluded: comments, case reports, reviews, fewer than 40 patients in the study. The remaining were used for data extraction. Results: Between 2000-2009, 27 studies including 3,589 patients (122 esophageal, 1,185 gastric, 2,113 colon, and 169 rectal cancers) were reviewed. The overall success rate of SLNM was 95% (96.6% in esophageal, 94% in gastric, 94.3% in colon, and 95.6% in rectal cancer). Nodal positivity (positive SLN and/or non-SLN) was 34% in esophageal, 36.6% in gastric, 48.1% in colon, and 41% in rectal cancers. Rates of skip mets were 18%, 14%, 20%, and 15% in esophageal, gastric, colon, and rectal cancers respectively. In patients with skip mets, T3/T4 disease was found in 65%, 44%, and 82.5% of patients with esophageal, gastric and colon cancers respectively. The average tumor size ranged between 3 cm in gastric to 4.4 cm in colon cancer. The most common primary site for skip mets in colon cancer was the right side (50%), and in LN basin 7, 8, 9 in gastric cancer. All node positive (true and false negative) patients were staged as stage III and were treated with adjuvant chemotherapy. Conclusions: Skip mets are common in T3/T4 disease, and in larger tumors suggesting difficulty injecting the dye circumferentially. All node positive patients (true positive and skip mets) are treated with chemotherapy. Hence, skip mets has no real clinical impact on either the staging, treatment, or the outcome of the disease. No significant financial relationships to disclose.
Evaluation of usefulness of Royal Marsden Hospital prognostic index in second-line chemotherapy of advanced gastric cancer.
Authors: Takahide Sasaki, Yoshito Komatsu, Satoshi Yuki, Kazuaki Harada, Yoshimitsu Kobayashi, Hiraku Fukushima, Naoya Sakamoto
Journal: Journal of Clinical Oncology (2014)

163 Background: Royal Marsden Hospital prognostic Index (RMH-I), which was based on performance status, ALP, liver metastasis and peritoneal metastasis, was reported as prognostic factor of advanced esophago-gastric cancer before first line chemotherapy (Chau I, et al. J Clin Oncol 22:2395-2403, 2004). Usefulness of RMH-I in second line chemotherapy is not elucidated. Methods: Advanced gastric cancer patients who started second line chemotherapy in Hokkaido University Hospital from July 2001 to May 2013 with prior fluoropyrimidine plus platinum administration were retrospectively analyzed. Univariate and multivariate analysis for overall survival were performed using patient characteristics (RMH-I, hemoglobin, CRP, CEA, Alb, TTP in first line, primary lesion resection, and bone metastasis). Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. Results: There were 77 eligible patients. Male/Female were 52/25, median age was 60 years (range 31-80) and unresectable/recurrent were 70/7. Median survival was 7.1 months. The distribution and median survival for RMH-I groups were as follows: good risk (n = 8), 8.2 months; moderate risk (n = 57), 9.6 months; and poor risk (n = 12), 4.4 months. Although poor risk group showed shorter survival time, there were not significant difference regardless of RMH-I in Cox multivariate analysis (HR 1.12, 95%CI 0.61-2.09, P=0.72). Conclusions: In this retrospective analysis, RMH-I was not independent prognostic factor in second line chemotherapy of advanced gastric cancer. Prognostic factors in this population need to be investigated further.
Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma.
Authors: W. H. Sharfman, F. S. Hodi, D. P. Lawrence, K. T. Flaherty, R. K. Amaravadi, K. B. Kim, R. Dummer, S. Gobbi, I. Puzanov, J. A. Sosman, K. Dohoney, L. P. Lam, S. Kakar, Z. Tang, O. Krieter, M. B. Atkins
Journal: Journal of Clinical Oncology (2011)

8508 Background: RAF265 is an oral small molecule inhibitor of mutant (mut) BRAFV600E(EC50= 0.14µM) and VEGFR2 (EC50 = 0.19µM). It displays dose dependent inhibition of tumor growth and regression in mut BRAFV600Etumor xenografts, including primary human melanoma models. Methods: This is a FIH, dose escalation study to identify the maximum tolerated dose (MTD), safety, PK, PD and anti-tumor activity of RAF265 using different schedules for its administration: Daily (QD), weekly and intermittent. Results for QD dosing are presented here, where patients (pts) were treated by a loading dose (LD) followed by continuous QD RAF265 oral solution at escalated dose levels (DLs). A Bayesian logistic regression model with overdose control guided the dose escalation. Results: 76 pts (43m/33f) were treated on 8 DLs (LD/QD): 8mg/2mg (3pts), 16/3 (3), 29/6 (4), 58/12 (10), 115/24 (15), 230/48 (22), 322/67 (9) and 288/67 (10). Median age: 60 years (range 26-81). RAF265 was rapidly absorbed, with Cmax at ~3hrs post dose (1-8 hrs). Plasma concentrations (Cmax and AUC0-last) increased proportionally. The mean t1/2 of RAF265 was 11 days. Mutations in BRAF and NRAS were detected 59% and 16% of evaluated tumor samples (n=70), respectively. 18F-FDG uptake decrease from baseline (-2.6 to -57.2%) was noted in 16/31 (52%) mut BRAF pts, with partial tumor metabolic response (SUVmax ≥ -25%) in 8/31 (26%). Plasma angiogenesis markers showed decreases of sVEGFR2 and increases in PlGF across DLs. Of 71 evaluable pts, six experienced dose limiting toxicities within 1st cycle (28 days): Pulmonary embolism (2), visual disturbances (2), hyperlipasemia (1), diarrhea (1) and ataxia (1). Thrombocytopenia Grade 3 (6) and 4 (2) occurred at 67mg QD in 2nd cycle and was also considered dose limiting. The overall response rate by RECIST 1.0 was 6/37 (16%) for mut BRAF pts and 4/30 (13%) for wt (3)/unknown (1) BRAF pts. Conclusions: The MTD of oral RAF265 on a continuous daily schedule was defined at 48mg. Clinical activity was observed at multiple dose cohorts in pts with BRAF mut and wt melanoma. Since RAF265 QD at 67mg consistently caused delayed dose limiting hematologic toxicity, an intermittent schedule is being explored.
Prostate-specific antigen testing among primary care physicians and urologists: Patterns of care and impact of professional society guidelines.
Authors: Sandip M. Prasad, G. Caleb Alexander, Scott E. Eggener
Journal: Journal of Clinical Oncology (2012)

40 Background: During the past decade, the incidence of prostate cancer in the United States has declined. We hypothesized this was related to lower rates of prostate-specific antigen (PSA) testing and sought to evaluate PSA testing rates nationally. Methods: Using the National Ambulatory Medical Care Survey, a nationally representative sample of outpatient visits in the United States, we analyzed rates of PSA testing in men age 40 years or older who visited PCPs or urologists from 1997 to 2008. Results: An estimated 26.6 million (95% CI: 24.8-28.4 million) PSA tests were ordered during 94.5 million (95% CI: 90.9-98.1 million) office visits to urologists and 95 million (95% CI: 87.5-102.8 million) tests were ordered during 1.17 billion (95% CI: 1.15-1.18 billion) visits to PCPs, with an annual increase of 3.4% and 6.0%, respectively (P=0.055 and P&lt;0.001 for trend). After adjusting for year, race, ethnicity, region, insurance and provider type, testing by PCPs was more likely among older men and highest among men aged 60 to 69 years (reference: 40-49 years; OR 2.32, 95% CI: 1.88-2.85). Compared to men without a chronic medical condition, those with one chronic condition had greater odds of receiving a PSA test (OR 1.28, 95% CI: 1.08-1.52). Conclusions: Prostate cancer incidence has declined over the past decade despite increasing rates of office-based PSA testing by PCPs and urologists during the period. Increasing rates of PSA testing merit scrutiny, especially in men with limited life expectancies who are unlikely to benefit from screening.
Comparative effectiveness of intensity-modulated radiation therapy versus three-dimensional conformal radiation for localized prostate cancer.
Authors: Talha Shaikh, Karen Ruth, Nicholas George Zaorsky, Mark Hallman, Daniel M. Geynisman, Alexander Kutikov, Marc C. Smaldone, David Y. T. Chen, Mark L. Sobczak, Eric M. Horwitz
Journal: Journal of Clinical Oncology (2016)

89 Background: Intensity-modulated radiation therapy (IMRT) has become the standard radiation delivery option for patients (pts) with localized (PCa) prostate cancer despite limited prospective data and increased cost relative to three-dimensional conformal radiation therapy (3D-CRT). The purpose of this study was to compare the treatment outcomes and toxicities of pts undergoing definitive dose-escalated radiation therapy using either 3D-CRT or IMRT for localized PCa. Methods: We identified men with clinically localized PCa treated with definitive external beam radiation at a single institution using &gt;74 Gy between 1997-2013. Within each NCCN risk group, propensity score matching of 3D-CRT pts with one or two IMRT pts was performed accounting for age, race, diabetes, hypertension, Gleason score, T-stage, PSA, and hormone use. Conditional logistic and conditional Cox proportional hazards models were used to adjust for matched groups, with dose included as a separate covariate. Results: After matching,1,253 men (474 3D-CRT, 779 IMRT) were included. There were no significant differences between the IMRT and 3D-CRT pts according to clinical or treatment factors. There was no difference in biochemical failure (BCF), distant metastasis (DM), cancer specific survival (CSS), or overall survival (OS) amongst the low or intermediate risk subgroups. When examining the high-risk subgroup, pts receiving IMRT had higher rates of DM (HR 2.21 95% CI 1.04-4.74 p=0.040). There was a trend towards increased rates of BCF in pts receiving IMRT for high-risk disease (HR 1.60 95% CI 0.96-2.66 p=0.072). There was no difference in CSS or OS in the high-risk subset. In the intermediate risk group, patients receiving IMRT had increased rates of acute grade 3+ genitourinary toxicity versus 3D-CRT patients (OR 8.30 95% CI 2.13-2.15 p=0.002). There were otherwise no differences in acute or late grade 3+ genitourinary or gastrointestinal toxicity amongst IMRT versus 3D-CRT pts. Conclusions: Despite the widespread adoption of IMRT for localized PCa, our results do not demonstrate an improvement in outcomes or toxicity versus 3D-CRT. Further research is warranted to explain these findings.
N0338 phase II trial of docetaxel and carboplatin administered every two weeks as induction therapy for stage II or III breast cancer
Authors: V. Roy, B. A. Pockaj, D. W. Northfelt, J. B. Allred, H. Liu, D. A. Nikcevich, B. I. Mattar, E. A. Perez
Journal: Journal of Clinical Oncology (2008)

563 Background: Neoadjuvant chemotherapy is increasingly used in the treatment of stage II/III breast cancer (BC). Pathologic complete response (pCR) after neoadjuvant therapy is associated with improved clinical outcome. Based on activity of docetaxel (D) and carboplatin (C) in metastatic BC, we investigated a dose-dense schedule of D and C combination for neoadjuvant therapy of patients with stage II/III BC. Methods: A two-stage phase II study was conducted with pCR (disappearance of all invasive tumor from breast and axilla) rate as the primary endpoint. Rate of breast-conserving surgery, clinical response rate, and toxicity were secondary endpoints. Pts with stage II/III BC, > 18 y, ECOG PS 0–1, and adequate organ function were eligible. Treatment consisted of 4 cycles of D 75 mg/m2 and C AUC=6 on day 1 and pegfilgrastim 6mg SQ on day 2 of a 14 day cycle. The study required 55 evaluable patients to test the null hypothesis that pCR rate was at most 15% against the alternative of at least 30%. Results: Fifty-seven women were enrolled between Sept, 05 and June, 07. All patients were evaluable. Median age 53 y (27–79y). 38 (67%) had ER+, 31 (54%) PR+,6 (11%) HER2+; 9 had ER/PR and HER2 neg BC A median of 4 (1–4) cycles were administered. 3 (6%) pts progressed during treatment, 3 (6%) discontinued treatment because of toxicity, and 3 (6%) for other reasons. Nine (16%, 90% CI :10%-28%) patients had pCR; 2 pts had only DCIS and 1 had nodal disease only at surgery. 4 of 9 (44%) pts with ER/PR and HER2 neg BC had pCR 43 (75%, 95%CI: 62%-86%) out of 57 eligible patients had clinical response (15 cCR, 28cPR). 48 (87%, 95% CI:72%-93%) patients had breast-conserving surgery. The median dose administered was 75 mg/m2 for D and AUC=6 for C for cycles 1–4. The most common gr 3/4 adverse events (AE) were thrombocytopenia 11 (19%), fatigue 7 (12%) and anemia 5 (9%). 54% (31/57) and 9% of patients had gr 3 and 4 AE. Conclusions: 4 cycles of bi-weekly D and C are feasible and tolerable and result in pCR rate of 16%. This regimen can be considered for neoadjuvant treatment of BC, especially in patients not suitable for anthracycline therapy. Immune and molecular predictors of efficacy are being evaluated. Partially supported by NIH CA25224 No significant financial relationships to disclose.
Conformal therapy improves the therapeutic index in patients treated with radiation therapy and concurrent chemotherapy
Authors: T. Vuong, N. Kopek, L. Portelance, B. Bahoric, K. Sultanem, S. Devic
Journal: Journal of Clinical Oncology (2005)

3588 Background:At McGill University, conformal therapy has been introduced in the treatment of patients with anal cancer to alleviate treatment related acute toxicities in one of the two radiation oncology departments (Institution A). In institution B, conventional radiation technique was maintained. This study is reporting the long-term outcomes of the patients from the two institutions. Material and Methods: From 1997–2003, 54 consecutive patients from institution A were treated with conformal therapy (6-fields arrangement) to deliver 54 Gy in 30 fractions without interruption and concurrently 2 cycles of chemotherapy during weeks 1 and 6 of radiation using 5-Fluorouracil (5-Fu, 1000 mg/m2/day, 96 hours continuous infusion) and Mitomycin C (MMC, 10 mg/m2, bolus on day 1) In institution B, 59 patients received conventional radiation techniques with an antero-posterior field followed by a 3 fields arrangement, to deliver 52–59.4 Gy in 25–33 fractions in split course therapy with 2 cycles of concurrent 5-Fu chemotherapy and either MMC or cisplatinum (75 mg/m2) in bolus on day 1. Results: Patients treated with conformal therapy and conventional therapy had respectively an actual 5-year local free recurrence rates of 90.7% and 66.1% (p< 0.02), a 5-year disease free survival rates of 74% and 48%(p=0.0095) and an overall survival rate of 74% and 55% (p=0.01) In the multivariate analysis, the nodal status is the most significant factor for local control (p<0.0003) followed by radiation technique (conformal > conventional) (p<0.02). Tumor and acute toxicity data from the two institutions are showed in Table 1. Conclusion: Conformal therapy contributes significantly in the local control, disease free and overall survival and improves the therapeutic index of patients with anal canal cancer. It is integrated presently as standard treatment regimen in both institutions. No significant financial relationships to disclose.