tbuckley/cabot-search huggingface dataset:
Final overall survival from a phase 3 trial of <i>nab</i>-paclitaxel versus dacarbazine (DTIC) in chemotherapy-naive patients with metastatic melanoma.
Authors: Evan Hersh, Michele Del Vecchio, Michael Paul Brown, Richard Kefford, Carmen Loquai, Alessandro Testori, Shailender Bhatia, Ralf Gutzmer, Andrew Mark Haydon, Caroline Robert, Mingyu Li, Ileana Elias, Markus Frederic Renschler, Axel Hauschild
Journal: Journal of Clinical Oncology (2014)

9045 Background: In a phase 3 trial, nab-paclitaxel significantly improved progression-free survival (PFS) compared with DTIC (4.8 vs 2.5 months; hazard ratio [HR] 0.792; P = 0.044) in chemotherapy-naive patients with metastatic melanoma thereby meeting the primary study endpoint. A trend toward improved overall survival (OS; HR 0.831; P= 0.094) at the interim analysis (64% of patients with an event) was also shown. Here we report the final OS analysis. Methods: 529 patients with chemotherapy-naive, stage IV melanoma (M1c, 65%; elevated lactate dehydrogenase [LDH], 28%) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomized to receive nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265). The randomization was stratified by metastatic stage, region, and baseline LDH. BRAF status was known in 67% of patients; of these, 37% had mutant and 63% had wild-type BRAF melanoma. September 20, 2013, was the clinical cutoff date for the final OS analysis. Results: At the final OS analysis (median follow-up, ≈ 30 months for censored patients), 427 patient deaths occurred: 215 (81%) in the nab-paclitaxel vs 212 (80%) in the DTIC arm. Median OS trended in favor of nab-paclitaxel, but did not reach statistical significance vs DTIC (12.6 vs 10.5 months; HR 0.897;95% CI 0.738 - 1.089; P = 0.271. OS favored nab-paclitaxel vs DTIC across most patient subgroups, including patients aged ≥ 65 years and those with M1c stage disease, elevated LDH, and any BRAF status melanoma. The use of poststudy anticancer therapy did not differ by treatment arm, with 77% vs 73% of patients in the nab-paclitaxel arm vs DTIC arm receiving poststudy therapy. The use of a BRAF inhibitor (13% vs 10%) or ipilimumab (31% vs 32%) was also similar between treatment arms. As previously reported, the most common grade ≥ 3 adverse events with nab-paclitaxel were peripheral neuropathy (25% vs 0% with DTIC) and neutropenia (20% vs 10% with DTIC). Conclusions: The study met the primary endpoint with a significant improvement in PFS. At final analysis, nab-paclitaxel continued to demonstrate a trend toward improved OS vs DTIC. Clinical trial information: NCT00864253.
A proposal for standardized grading of chronic changes in native kidney biopsy specimens
Authors: Sanjeev Sethi, Vivette D. D’Agati, Cynthia C. Nast, Agnes B. Fogo, An S. De Vriese, Glen S. Markowitz, Richard J. Glassock, Fernando C. Fervenza, Surya V. Seshan, Andrew Rule, Lorraine C. Racusen, Jai Radhakrishnan, Christopher G. Winearls, Gerald B. Appel, Ingeborg M. Bajema, Anthony Chang, Robert B. Colvin, H. Terence Cook, Sundaram Hariharan, Loren P. Herrera Hernandez, Neeraja Kambham, Michael Mengel, Karl A. Nath, Helmut G. Rennke, Pierre Ronco, Brad H. Rovin, Mark Haas
Journal: Kidney International (2017)
The impact of diabetes mellitus and metformin on survival of patients with advanced pancreatic cancer receiving chemotherapy.
Authors: Do-Youn Oh, Younak Choi, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

4044 Background: A causal relationship between diabetes mellitus (DM) and pancreatic cancer (PC) is well established. However, in patients with advanced PC (APC) who receive palliative chemotherapy, the impact of DM on prognosis is unclear. Methods: Between 2003 and 2010, we enrolled consecutive patients with APC, all recipients of palliative chemotherapy, with the provision that DM disease status could be properly defined. Enrollees were stratified by diagnosis, in accordance with 2010 DM criteria (AHA/ADA). DM at least 2 years' duration prior to diagnosis of APC qualified as remote-onset DM (vs recent-onset). Clinical characteristics and outcomes were then analyzed. Results: Of the 349 enrollees with APC, 183 (52.4%) had DM. In patients with DM, 160 had DM at the time APC was diagnosed (remote onset, 87; recent onset, 73); and the remaining 23 developed DM during the course of APC treatment. Ultimately, 73.2% (134/183) of DM patients received antidiabetic medication (metformin (56), sulfonylurea (62), insulin (43)). By multivariate analysis, cancer extent (HR, 1.792; p &lt; 0.001) and weight loss during chemotherapy (HR, 1.270; p = 0.08) were associated with diminished overall survival (OS), whereas a diagnosis of DM (HR, 0.788; p = 0.05) conferred a positive effect on OS ( OS 8.4 months in DM patients vs 7.5 months in non-DM patients, p = 0.04). Among DM patients, recent-onset DM trended toward prolonged OS, compared with remote-onset/subsequent DM (9.8 months vs. 7.9 months, respectively; HR, 0.789; p = 0.142). Neither antidiabetic medication in general nor sulfonylurea or insulin specifically affected OS. However, recipients of metformin survived longer than non-recipients (HR, 0.693; 95% CI, 0.492-0.977; p = 0.036). Relative to the APC cohort overall including non-DM patients, metformin conferred better survival as well (11.0 months vs. 7.8 months, HR 0.712, p = 0.067), given similar baseline clinical characteristics. Conclusions: In patients with APC receiving palliative chemotherapy, recent-onset DM (within 2 years of APC diagnosis) and metformin treatment are positive prognosticators, associated with prolonged OS.
Preoperative chemoradiotherapy for advanced lower rectal cancer using SOX+Bev regimen.
Authors: Jun Higashijima, Mitsuo Shimada, Kozo Yoshikawa, Masaaki Nishi, Hideya Kashihara, Chie Takasu
Journal: Journal of Clinical Oncology (2017)

708 Background: We have performed preoperative CRT for advanced lower rectal cancer patients using S-1 or UFT. To improve response rate, we are performing phase 2 trial of preoperative CRT using S-1/ Oxaliplatin /Bevacizumab (SOX+Bev) regimen. In this study, we show the results of the trial and the promising predictive factor. Methods: Twenty-five patients (SOX+Bev) and 59 patients (S-1 or UFT) were included in this study. S-1(80mg/m2), UFT(300mg/m2) were administered orally every day on radiation therapy, and S-1(80mg/m2,Oxaliplatin(40-60mg/m2),Bevacizumab(5mg/kg) were administered in SOX+Bev group. Total dose of radiation was 40Gy with four field technique. As a predictive factor, we measured miR-223 with real-time PCR using pre CRT biopsy specimens. Results: Clinical response by RECIST were as follows: SOX+Bev group: CR/PR/SD/PD = 1/21/3/0, S-1/UFT group: CR/PR/SD/PD = 1/32/26/0. Clinical response rate were 88% in SOX+Bev group, higher than 56.0% in S-1/UFT group. Pathological response grade were as follows: SOX+Bev group: 1a/1b/2/3 = 5/4/10/6,S-1/UFT group :1a/1b/2/3 = 13/16/27/3. Pathological response rate was 64% in SOX+Bev group, 51% in S-1/UFT group and there was no significant difference. The pCR rate was 24% in SOX+Bev group, significantly higher than 5% in S-1/UFT group (p &lt; 0.05)B In S-1 group, miR-223 in responder group tended to be higher than non-responder group (p = 0.06). And in SOX+Bev group, miR-223 in Grade 3 group(8.89±9.41) was significantly higher than other group (3.19±4.64) (p = 0.05). Conclusions: Preoperative CRT with SOX+Bev regimen can improve response rate and bring high pCR rate. miR-223 may be promising predictive factor and useful to perform order made therapy. Clinical trial information: 13267.
Clinical next generation sequencing (NGS) to reveal high frequency of alterations to guide targeted therapy in lung cancer patients.
Authors: Siraj M. Ali, Norma Alonzo Palma, Kai Wang, Jeffrey S. Ross, Philip J. Stephens, Roman Yelensky, Gary A. Palmer, Doron Lipson, Vincent A. Miller
Journal: Journal of Clinical Oncology (2013)

8020 Background: Cancer genomic profiling via NGS in a clinical setting can reveal additional actionable genomic alterations (GA) in patients with lung cancer (LC) previously tested only by hotspot analysis and leading to unanticipated avenues of targeted treatment. Methods: We performed an NGS-based diagnostic test (FoundationOne) to characterize all classes of GA across 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on 386 LC FFPE specimens in a CLIA-certified lab (Foundation Medicine). Specimens included fine needle aspirates, core needle biopsies, and malignant effusions. 95% of cases were NSCLC (367/386). Actionable GAs are defined as those linked to targeted anti-cancer therapies approved or being evaluated in clinical trials. NGS confirmed known hotspot results for EGFR, KRAS and EML4:ALK in 100% of cases. Results: Genomic profiles were generated from 364/386 (94%) of lung cancer cases, identifying 1205 GA, averaging 3.31 alterations per tumor (range 0 to 10). 85% of tumors (310) harbored at least one actionable GA, with a mean of 1.79 GA per tumor (range 0 to 6). In 68% of tumors (248), at least one GA was detected that would be missed by current ‘hotspot assays’. ERBB2 harbored base substitutions or indels in 1.3% of cases. BRAF and C-Kit were altered at frequencies of 2% and 1% respectively. The mTOR/PI3K pathway is likely to be activated via alterations in tumor suppressors STK11 (11%), NF1 (6%) and PTEN (4%), as well as by alterations of PIK3CA (10%) and in AKT1/2/3 (4%), suggesting possible benefit from mTOR/PI3K inhibitors. The Hedgehog pathway (PTCH1/SMO/SUFU) was altered in 2% of cases. ALK and RET were rearranged in 4% and 2% of cases, respectively, with several cases initially diagnosed negative by FISH testing. Conclusions: Profiling the tumor genomes of 364 LC patients led to the identification of a series of GA not detectable by hotspot testing that could significantly inform targeted treatment decisions. Moreover, actionable GA appeared in unexpected tumor type, i.e. an EGFR mutation in a SCLC, reinforcing the likely utility of clinical cancer genomic profiling for the personalized treatment of LC patients.
Effect of extended postoperative recovery on long-term oncological outcomes.
Authors: Elizabeth Poli, Yurie Sekigami, Rahul Rajeev, T. Clark Gamblin, Kiran Turaga
Journal: Journal of Clinical Oncology (2017)

765 Background: Curative cancer surgery remains the cornerstone of treatment of localized malignancies. Extended post operative recovery (eLOS) is associated with debility and immunosuppression. We hypothesized that eLOS is associated with worse long term oncological outcome. Methods: The NCDB participant user file from 2004-13 was utilized to identify patients with localized gastrointestinal malignancies undergoing curative cancer resections. Quartiles (Qx) of length of stay (LOS) were calculated based on histology and site specific indicators. Survival modeling was performed using cox-proportional hazards and conditional models were created. Alpha of 0.05 was set for statistical significance. Results: Of 1,616,215 patients in the cohort, 577,860 patients were included who met inclusion criteria. Majority of patients were ≥65 years (56%) with a predominance of colon cancer (70%). The median length of stay (LOS) varied from 5 days (partial hepatectomy) to 10 days (esophagectomy). After adjusting for age, gender, stage, and site of disease, increasing length of stay was significantly associated with worse oncological survival with a dose response effect (Q1 HR 1.0, Q2 1.12 (1.10-1.14) p&lt;0.001, Q3 1.42 (1.41-1.44) p&lt;0.001 and Q4 1.82(1.80-1.85), p&lt;0.001). Conditional overall survival for patients who survived 3, 6 and 12 months after surgery, was worse with eLOS (p&lt;0.001). Conclusions: Longer than expected length of stay after an index curative cancer operation leads to worse overall oncological outcomes. This effect persists even after excluding patients who suffer delayed post-operative mortality within 12 months after the operation. More research needs to be done to determine if this outcome is related to perioperative immunosuppression.
<i>BRAF</i> and <i>KRAS</i> mutation testing in plasma cell-free DNA with ICE COLD-PCR in patients with advanced cancers.
Authors: Benjamin L. Legendre, Katherine Richardson, Gerald Steven Falchook, Aung Naing, Veronica R. Holley, Siqing Fu, David S. Hong, Sarina Anne Piha-Paul, Jennifer J. Wheler, Ralph Zinner, Vivek Subbiah, Apostolia Maria Tsimberidou, Rajyalakshmi Luthra, Funda Meric-Bernstam, Agop Y. Bedikian, Cathy Eng, Vlada Melnikova, Marcia Lewis, Razelle Kurzrock, Filip Janku
Journal: Journal of Clinical Oncology (2014)

e22147 Background: Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable and repeatedly available source of biologic material for mutation analysis and monitoring of molecular changes throughout cancer therapy. Methods: DNA in plasma from patients with advanced cancers who progressed on systemic therapy was tested for BRAF V600 and KRAS G12 and G13 mutations using the ICE COLD-PCR platform, which selectively amplifies mutant DNA by exploiting differences in denaturation temperatures between mutant DNA duplexes and normal “wild-type” DNA duplexes. Amplicons were analyzed using Sanger sequencing and results were compared to the mutation status of archival primary or metastatic tumor tissue as determined in a CLIA-certified laboratory during routine clinical care. Results: Plasma samples from 83 patients with advanced cancers and known tumor tissue BRAF and/or KRAS mutation status (colorectal cancer, n=43; melanoma, n=17; non-small cell lung cancer, n=7; other cancers, n=16) were obtained before treatment and, if possible, sequentially during therapy and tested for BRAF (44), KRAS (38) or BRAF and KRAS (1) mutations in cfDNA. BRAF mutations were detected in 93% (42/45) of archival tumor samples compared to 69% (31/45) of plasma cfDNA samples (agreement 76%). In addition, 20 patients treated with systemic therapy had serial plasma samples collected and the change in relative abundance of BRAF-mutant compared to wild-type cfDNA corresponded with the clinical course of 14 patients and was discrepant for 1 patient; in 5 patients no BRAF mutated cfDNA was detected at any time point. KRAS mutations were detected in 82% (32/39) of archival tumor samples compared to 74% (29/39) of plasma cfDNA samples (agreement 82%). In addition, 12 patients treated with systemic therapy had serial plasma collected and the change in relative abundance of KRAS-mutant compared to wild-type cfDNA corresponded with clinical course in 10 patients; in 2 patients no KRAS mutated cfDNA was detected at any time point. Conclusions: Detection ofBRAF and KRAS mutations in cfDNA can provide a fast and noninvasive alternative to mutation testing in tumor tissue with a potential to be used for monitoring response to cancer therapy.
Cardiac safety and efficacy of concomitant liposomal doxorubicin, docetaxel, and trastuzumab as neoadjuvant therapy in HER2-overexpressing breast cancer: A retrospective analysis.
Authors: Christine Brunner, Thomas Jaeger, Christoph Suppan, Elisabeth Mueller-Holzner, Zerina Jasarevic, Marija Balic, Georg Goebel, Christian Marth, Herbert Stoeger, Hellmut Samonigg, Michael Hubalek, Alois Lang
Journal: Journal of Clinical Oncology (2013)

583 Background: Concurrent therapy of trastuzumab, anthracycline and taxane for the neoadjuvant treatment of breast cancer (BC) results in an improved rate of pathological complete response (pCR). However, there is considerable concern about the cardiac safety of this combination. The use of liposomal doxorubicin might be a valuable alternative with lower cardiotoxicity. We report cardiac safety and pCR-rate of a single arm, retrospective, multicenter analysis of neoadjuvant treatment for BC with liposomal doxorubicin, trastuzumab, and docetaxel. Methods: In this study 84 women with BC and HER2 overexpression were investigated in 3 oncological departments in Austria. All patients were treated with liposomal doxorubicin (50 - 60 mg/m²), docetaxel (75 mg/m²) and concurrent with trastuzumab for 6 cycles as neoadjuvant therapy. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥ 55%. Cardiac function was by LVEF and was examined at regular intervals(cycles 0-3, cycle 6, FU). Clinical response was evaluated by diagnostic breast imaging after cycles 3 and 6. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 2.4 years. Results: Median age of the patients was 50 years. After 6 cycles of treatment the pCR rate was 46%. In this cohort a negative estrogen-and/or progesteron receptor was predictive for pCR (p&lt;0.001). No patient progressed during treatment. None of the patients suffered symptomatic heart failure. Only one patient (1.6%) with asymptomatic LVEF of 45% was observed during follow-up. Conclusions: In this multicenter analysis we observed a considerably high rate of pCR in HER2-positive BC treated with liposomal doxorubicin, docetaxel and trastuzumab. The addition of liposomal doxorubicin instead of conventional doxorubicin or epirubicin entails a very favorable cardiotoxicity profile. This regimen is a safe treatment option in patients with HER-2 positive breast cancer.
Gene expression profile test (GEP) prediction of metastasis-free (MFS) and overall survival (OS) in a cohort of cutaneous melanoma (CM) patients undergoing sentinel lymph node biopsy (SLNB).
Authors: David H. Lawson, Maria C. Russell, Jeff Wilkinson, Gilchrist L. Jackson, Anthony Greisinger, Rodale N Amaria, Rene Gonzalez, Stephen Lyle, Clare Johnson, Kristen M. Oelschlager, John F Stone, Derek Maetzold, Robert W. Cook, Laura Ferris, Keith A. Delman, Pedram Gerami
Journal: Journal of Clinical Oncology (2014)

9022 Background: We recently validated a GEP test that provides accurate prediction of metastatic risk for CM cases. The GEP of 31 genes provides a binary outcome of Class 1 (low risk of metastasis) or Class 2 (high risk). This study evaluated the prognostic. Methods: Of 406 patients with successful GEP results and clinical data, 217 had a documented SLNB. All samples and clinical data were collected under an IRB approved, multicenter protocol. Quantitative PCR analysis was performed to assess expression of the gene signature, and Radial Basis Machine predictive modeling was used to determine risk prediction (Class 1 vs. Class 2). Results: SLNB+ status (n=58) was associated with greater median Breslow thickness, increased mitotic rate, and ulceration. Metastasis was reported for 37 of 58 (64%) SLN+ cases and 70 of 159 (44%) SLN- cases. While positive predictive values for Class 2 and SLN+ status were comparable (69% vs. 64%, resp.), negative predictive values of 75% and 49% were observed for low risk Class 1 and SLN- cases, respectively. Kaplan-Meier (K-M) analysis revealed 5-year MFS of 34% and 37%, respectively, for GEP Class 2 and SLN+ cases, and OS of 54% and 62% for the two groups, respectively. K-M analysis of MFS and OS for GEP and SLN in combination resulted in outcomes shown in Table 1. Cox multivariate analysis showed that GEP Class 2 and positive SLN status were significant predictors of MFS (HR=4.9 and 1.7, resp., p<0.01), but that GEP, in this group of patients, was the only significant predictor of OS (HR=5.1, p<0.0001). Conclusions: In this study cohort, GEP provided an objective, non-invasive tool that accurately predicted MFS and OS in SLN eligible patients. Importantly, in the discordant Class 2/SLN- group, predicted outcomes more closely reflected Class 2 status. Incorporation of GEP class in treatment planning may enable improved patient management. MFS and OS association with class and SLN status. N 5-yr MFS 5-yr OS Class1/SLNB- 67 83% 91% Class1/SLNB+ 9 53% 78% Class2/SLNB- 92 35% 54% Class2/SLNB+ 49 33% 57%
Exposure and clearance of bevacizumab in patients with first-line advanced gastric cancer.
Authors: Martina A. Sersch, Kelong Han, Mauricio Maia, Jin Jin, David Allison
Journal: Journal of Clinical Oncology (2013)

2603 Background: Bevacizumab (BEV), rhuMAB VEGF, in combination with chemotherapy (CT) is currently approved in various types of cancer. Recently, BEV+CT was evaluated in 1st line advanced gastric cancer (AGC) in a double-blind randomized phase 3 trial (AVAGAST), but failed to meet the primary OS endpoint (HR=0.87; p=0.1002). BEV pharmacokinetics (PK) is well established by a reference population PK (PPK) model, and BEV PK is consistent across multiple cancer indications. However, BEV PK in AGC was never evaluated. We aimed to assess BEV exposure (EXP) and PK in AGC and to explore the influence of demographic, prognostic and biochemical (DPB) factors. Methods: BEV concentrations (Cp) were measured from plasma samples collected following disease progression from 182 patients (7.5mg/kg Q2W) in AVAGAST. Expected BEV Cp [median and 90% prediction interval (PI)] were simulated using the PPK model and compared to the observed BEV EXP. BEV clearance (CL) in AGC was estimated using NONMEM and compared between subgroups stratified by DPB factors. Results: All DPB factors of AGC are similar to those in other cancers except for lower body weight. No cachexia was observed. BEV Cp was detectable in 162 patients. 85% of observed BEV Cp was below the median BEV Cp simulated using PPK model and 38% below the lower limit of the 90% PI. Median BEV CL in AGC was 4.5 L/day/kg vs. 3 L/day/kg in other cancers. BEV CL was significantly higher (p=0.0012) in patients without prior gastrectomy (4.9 L/day/kg, n=120) than those with gastrectomy (4.1 L/day/kg, n=42). CL appeared to be higher in AGC patients with higher ECOG scores, lower albumin, more metastatic sites, poorer response and later stage AGC. Tumor location (GE Jct vs. Stomach), VEGF-A and ethnicity (Asian vs. Non-Asian) did not correlate with BEV CL. Conclusions: Overall, AGC patients exhibited significantly lower BEV EXP due to a 50% increase in BEV CL vs. other cancers. In addition, BEV is cleared significantly faster in patients without prior gastrectomy. The low BEV EXP in AGC could potentially reduce the effect of BEV in AGC. The underlying mechanism for faster BEV CL in AGC is unknown and warrants further research and potential BEV dose modifications.