tbuckley/cabot-search huggingface dataset:
Analysis of the p38MAPK pathway in the prognosis of patients with surgically resected stage I-II NSCLC.
Authors: Pablo Pardo-Coto, Emilio Esteban, Aurora Astudillo, Jose Manuel Gracia, Norberto Corral, Marta Izquierdo Manuel, Carolina Muriel Lopez, Miguel F. Sanmamed, Eduardo Gutierrez Restrepo, Miguel Valle Pereda, Carlos Alvarez Fernandez, Quionia Pérez Arnillas, Jose Pablo Berros Fombella, Paula Jiménez, Jose Maria Vieitez de Prado, Joaquin Fra
Journal: Journal of Clinical Oncology (2013)

e18513 Background: TNM staging is the most important prognostic factor in Non-Small Cell Lung Cancer (NSCLC). The MAPK pathway, including p38, JNK and ERK, has been slightly studied in NSCLC, with controversial prognostic significance. Methods: The records of 211 patients with stage I-II NSCLC, surgically resected at Asturias University Hospital between 2000 and 2004 were retrospectively reviewed. Formalin-fixed, paraffin-embedded histological tumour specimens were used to construct tissue microarrays. The nuclear level of phosphorilated p38alpha (nP-p38), JNK (nP-JNK) and ERK (nP-ERK) was assessed using inmunohistochemistry (IHC). Phosphorilated protein expression was considered positive if the staining was present in at least 100% of the nucleus studied. EGFR was also analyzed with IHC following previous studies and was considered positive (EGFR+) if staining was observed in &gt;10% of the cells. Clinicopahological data and outcome differences in terms of overall survival (OS) were compared between positive and negative patients. Results: Patients with nP+ for p38, JNK or ERK had a trend to better OS than those respectively negative for each protein (HR=0.68, p=0.14; HR= 0.75, p=0.16; HR=0.64, p=0.14), and the difference was significative for nP-p38+ in adenocarcinoma histology (p=0.012). EGFR+ patients had worse OS than EGFR- (HR=1.59, p=0.02), but in nP-p38+ patients, those with EGFR+ tumors had similar survival than EGFR- (p=0.9). Fifteen patients were positive for the three MAPK (MAPK “Triple Positive”, MTP), and had better OS than the rest not MTP (HR=0.20, p=0.01). In the univariant analysis, stage, histologic grade, surgery (pneumonectomy vs lobectomy), EGFR status and MTP had significant influence on OS. Multivariant analysis only confirmed the stage as an independent factor (p=0.01). Conclusions: TNM staging remains the most important factor in the prognosis of NSCLC. The activation of the MAPK pathway, its interaction with EGFR, and the MTP feature might have prognostic influence in this tumor and warrant confirmation in a large prospective trial. The potential therapeutic implications of pharmacological manipulation of the MAPK pathway highlight the importance of this study.
Prospective surveillance using l-dex monitoring results in significant reductions in the chronic rate of breast cancer related-lymphedema (BCRL) in high-risk breast cancer patients.
Authors: Alison L. Laidley, Beth V. Anglin
Journal: Journal of Clinical Oncology (2017)

118 Background: Survivorship represents an increasing focus in the management of breast cancer with chronic toxicities including breast cancer-related lymphedema (BCRL). This study looked at prospective surveillance using bioimpedance spectroscopy (BIS) to reduce risks of chronic BCRL requiring referral for complete decongestive therapy (CDT). Methods: 132 patients at high-risk for the development of BCRL were prospectively followed using BIS with serial monitoring. This included a pre-operative baseline assessment and a minimum of two post-operative follow up assessments. Interventions were initiated when the L-Dex score increased by greater than 10 units from baseline and consisted of conservative treatment with a compression sleeve for four weeks. Patients were also clinically monitored for the development of BCRL. Results: Median follow-up was 19.3 months (range 4-54 mos). Of the 132 patients evaluated, 24 (18.1%) were subsequently diagnosed with elevated L-Dex scores and underwent intervention. Of the 24 that underwent treatment, 14 (58%) had resolution of their elevated L-Dex scores following four weeks of therapy with 10 having persistent elevations and clinical BCRL which necessitated referral to physical therapy for CDT. A further 7 subjects were diagnosed and not treated for elevated L-Dex scores, but had complete resolution (return to baseline) at last visit. At last follow-up, only 10 patients (7.6 %) had unresolved, clinical stage 1, BCRL. Conclusions: The use of L-Dex to prospectively follow our high-risk patients and prescribe intervention with a compression sleeve for 4 weeks when scores are elevated resulted in only a 7.6 % rate of stage 1, chronic BCRL. This rate of BCRL has been reported as 15-20%, suggesting that a prospective program of screening and intervention using L-Dex does result in clinically meaningful reductions in this long-term sequelae of treatment.
Scavenger receptor class B member 1 ( SCARB1 ) variants modulate hepatitis C virus replication cycle and viral load
Authors: Sandra Westhaus, Maximilian Deest, Anna T.X. Nguyen, Frauke Stanke, Dirk Heckl, Rui Costa, Axel Schambach, Michael P. Manns, Thomas Berg, Florian W.R. Vondran, Christoph Sarrazin, Sandra Ciesek, Thomas von Hahn
Journal: Journal of Hepatology (2017)
Il-23r is a major determinant of ankylosing spondylitis risk - The tasc study
Authors: J D Reveille, X Zhou, L A Bradbury, L R Cardon, J C Davis, P Deloukas, D M Evans, A Keniry, R McGinnis, J Pointon, M M Ward, M H Weisman, P Wordsworth, M A Brown
Journal: Annals of the Rheumatic Diseases (2007)
Clinical Characteristics and Treatment Outcomes of Clear Cell Chondrosarcomas: MD Anderson Cancer Center Series.
Authors: Anthony Paul Conley, Robert L Satcher, Wei-Lien Wang, Alexander J. F. Lazar, Patricia S Fox, Patrick P. Lin, Bryan Moon, Justin E Bird, Dejka M. Araujo, Vinod Ravi, Neeta Somaiah, Shreyaskumar Patel, Robert S. Benjamin, Valerae O. Lewis
Journal: Journal of Clinical Oncology (2015)

10531 Background: Clear cell chondrosarcomas (CChs) represent 2% of all chondrosarcomas and are defined by cells with abundant clear vacuolated cytoplasm surrounded by a cartilaginous matrix. Understanding clinical characteristics and treatment patterns may improve outcomes. We reviewed our institutional experience with this rare disease. Methods: With IRB-approval, CChs patients (pts) treated at MD Anderson Cancer Center from 1994 to 2013 were identified through Tumor Registry and Sarcoma Pathology Database. Descriptive statistics, survival analysis (RFS, OS), and Cox proportional hazards regression models were performed including Kaplan-Meier plots were provided for OS and RFS. All statistical analyses were performed using SAS 9.3 for Windows. Results: 15 pts were identified. Median age at diagnosis was 42 years (range 25 to 74 years). 80% were male. Ethnicity included Caucasians (12 pts; 80%), Asians (2 pts; 13%), and Hispanics (1 pt, 7%). The most common presenting symptom/sign was pain (10 pts; 67%) followed by fracture (3 pts; 20%). The most common site of disease was proximal humerus (7 pts; 47%). All pts had MSTS stage I disease. Primary therapy included radical resection in 12 (80%), curettage/resection in 1 (7%), and curettage in 2 (13%) pts. Of 12 pts, 11 had R0 resection. Median tumor size was 5 cm (range, 2.5 cm to 9.6 cm). Local relapse (LR) occurred in 4 (27%) pts; 1 also had distant relapse (DR). 2 pts had DR alone. DR sites included lungs, liver, and bone. 2 LR were associated with intra-lesional procedures, 1 LR with decompressive laminectomy, the LR+DR had fracture at diagnosis while 2 pts with DR occurred despite radical resection with R0 margins. 1 of 3 DR pts received systemic therapy. Median follow-up time from treatment was 55.1 months (range, 10.4 months to 202.1 months). Median RFS was 102.2 months with 95%CI (33.2 months to 200.2 months). Median OS was 185.8 months. Of 3 deaths only 1 was disease-specific. No significant predictors of RFS or OS were identified. Conclusions: CChs is a rare tumor for which complete surgical resection can be curative. Relapse may occur years later so long-term follow up is advised. Understanding predictors of metastasis may require a collaborative effort.
Outcomes based on age in the phase 3 METEOR trial of cabozantinib (cabo) versus everolimus (eve) in patients with advanced renal cell carcinoma (RCC).
Authors: Frede Donskov, Robert J. Motzer, Eric Voog, Elizabeth J. Hovey, Carsten Grüllich, Louise M. Nott, Katharine Cuff, Thierry Gil, Niels Viggo Jensen, Christine Chevreau, Sylvie Negrier, Reinhard Depenbusch, Lothar Bergmann, Izzy Cornelio, Anne Champsaur, Bernard Escudier, Sumanta K. Pal, Thomas Powles, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

517 Background: In the METEOR study (NCT01865747), cabo demonstrated improved progression-free survival (median 7.4 vs. 3.8 mo; HR 0.58, 95% CI 0.45–0.74; p&lt;0.0001), OS (median 21.4 vs. 16.5 mo; HR 0.66, 95% CI 0.53-0.83, p=0.0003), and objective response rate (17% vs. 3%; p&lt;0.0001) compared with eve in patients (pts) with advanced RCC who had received prior VEGFR TKI therapy (Choueiri NEJM 2015, Lancet Oncol 2016). Here we evaluate the impact of changes in target lesion size from baseline on OS. Methods: 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed per independent radiology review by CT/MRI scans at baseline, every 8 weeks for the first 12 months, and every 12 weeks thereafter. Three subgroups were defined by best change in target lesion size from baseline: decrease ≥30%, decrease &lt;30%, and any increase. Results: The rate of target lesion regression was higher in the cabo arm (75%) compared with the eve arm (48%). A higher fraction of pts had a decrease ≥30% in target lesion size in the cabo arm, while a higher fraction of pts had an increase in target lesion size in the eve arm (Table). Medians for OS with cabo were not estimable (NE) (95% CI, NE‒NE), 20.8 mo (95% CI, 18.1‒NE), and 11.1 mo (95% CI, 7.6‒15.2) for the ≥30% decrease, &lt;30% decrease, and any increase subgroups, respectively. Medians for OS with eve were NE (95% CI, 19.3‒NE), 18.0 mo (95% CI, 15.9‒20.4), and 14.0 mo (95% CI, 10.5‒16.3) for the ≥30% decrease, &lt;30% decrease, and any increase subgroups, respectively. Median duration of follow-up for OS was 18.7 mo (IQR 16.1–21.1) for cabo and 18.8 mo (16.0–21.2) for eve. A higher proportion of pts received subsequent anticancer therapy in the any increase subgroup compared with the other subgroups. Conclusions: Cabo demonstrated a higher rate of tumor target lesion regression than eve, and greater target lesion regression was associated with improved OS in pts with advanced RCC. Clinical trial information: NCT01865747.
Long-term outcome after R1 resection for colorectal liver metastases: Is a cure possible?
Authors: Isamu Hosokawa, Oriana Ciacio, Gabriella Pittau, Maximiliano Gelli, Marc Antoine Allard, Mylene Sebagh, Pasquale F Innominato, Daniel Cherqui, Antonio Sa Cunha, Eric Vibert, Francis Levi, Jean F. Morere, Denis Castaing, Rene Adam
Journal: Journal of Clinical Oncology (2015)

3579 Background: Increasingly efficient chemotherapy regimens have improved the outcomes after R1 resection (tumor-free margin < 1 mm) for colorectal liver metastases (CLM). However the long-term survival benefit and the potential of cure after R1 resection are not clearly demonstrated. The aim of this study was to evaluate long-term outcomes after R1 resection using an aggressive strategy consisting of modern perioperative chemotherapy and repeated surgeries, and to define factors predictive of cure after R1 resection. Methods: All resected CLM patients at our institution from 2000 to 2009 were prospectively evaluated. Exclusion criteria were: presence of extrahepatic disease, use of ablative treatment modalities, and incomplete macroscopic (R2) resection. Cure was defined as a disease-free interval ≥ 5 years from last hepatic or extrahepatic resection to last follow-up. Results: Of 639 patients consecutively resected for CLM, 384 (60%) were eligible for the study, 193 (30%) of whom underwent R0 resection (tumor-free margin ≥ 1 mm), and 191 (30%) underwent R1 resection. The 5-year overall survival rates (OS) for patients with R0 resection and R1 resection were 65% and 56%, respectively (P = 0.15). Of the 191 patients who underwent R1 resection, 121 patients had a more than 5 years follow-up. Of these, 23 patients (19%) were considered “cured” and 88 patients (73%) were considered “non-cured”. For the included 111 patients, after a mean follow-up of 57 months, 5- and 10-year OS were 47% and 32%, respectively, and disease-free survival rates were 15% and 14% at 5 and 10 years, respectively. Although there were no significant differences in the number or maximum size of metastases at diagnosis between the two groups, cured patients more often responded to first-line chemotherapy (P = 0.02) with fewer cycles (P = 0.002). Independent predictive factors of cure included: ≤ 10 total cycles of preoperative chemotherapy and objective response following preoperative chemotherapy. Conclusions: In the era of modern chemotherapy, cure can be achieved overall in 19% of patients after R1 resection for CLM. The best conditions to achieve cure after R1 resection rely on a good response to an efficient and relatively short first-line chemotherapy.
International Observational Study On Bortezomib (VELCADE) in Relapsed Multiple Myeloma: Preliminary Efficacy and Quality of Life (QoL) Results From the Belgian Population.
Authors: Michel Delforge, Hadewijch De Samblanx, Hilde Demuynck, Greet Bries, Philippe Mineur, Nathalie Meuleman, Fritz Offner, Chantal Doyen, Walter Feremans, Ann Van de Velde, Christophe Ravoet, Isabelle Vande Broek, Jan Van Droogenbroeck, Gabry Kuijten-Celzo, Joris Diels, Rita Ganguly, Ravinder Dhawan
Journal: Blood (2009)
Aurora-A mitotic kinase and induction of endocrine resistance through downregulation of erα expression in initially erα+ breast cancer cells.
Authors: Mateusz Opyrchal, Jeffrey L. Salisbury, Shuya Zhang, James McCubrey, John Hawse, Matthew P. Goetz, Tufia C. Haddad, Amy C. Degnim, Carol A. Lange, James N. Ingle, Evanthia Galanis, Antonino D'Assoro
Journal: Journal of Clinical Oncology (2014)

2568 Background: Development of endocrine resistance during tumor progression represents a major clinical challenge in the management of ERα+ breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point toward the ‘cross-talk' between ERα and MAPK signaling pathways as the key in the development of estrogen-independent growth of initially ERα+ and hormone sensitive breast cancer cells. Methods: In this study we employed a metastatic, Mcf-7, ERα+, breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance. Patient samples were tested for expression of Aurora-A. Results: In vitro cells showed resistance to endocrine therapies. Development of endocrine resistance was functionally linked to ERα down-regulation both in vitro and in vivo. Because resistant cells also overexpressed Aurora-A kinase, we investigated the causal role of Aurora-A kinase in regulating ERα expression. Inhibition of Aurora-A kinase activity employing a specific inhibitor, Alisertib, resulted in re-expression of ERα and increased sensitivity to endocrine therapies as well as decreased p~SMAD5. The role of SMAD5 was also tested by overexpressing SMAD5 in MCF-7 cells, which led to loss of ERα expression. Aurora-A over-expression in ERα+ patient breast tumor tissues was associated with increased risk of recurrence. Conclusions: We demonstrate for the first time the causal role of Aurora-A kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas. Our findings may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 axis to eradicate endocrine resistant cancer cells and suppress tumor progression and the onset of distant metastases with consequent clinical benefit to breast cancer patients.
Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant FOLFOX IV.
Authors: Anna Maria Frezza, Gaia Schiavon, Bruno Vincenzi, Raffaele Addeo, Vincenzo Catalano, Francesco Graziano, Daniele Santini, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2012)

e14135 Background: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40% of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. Methods: 169 completely resected CRC patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcemia, hypomagnesaemia, hypoalbuminemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, B12 deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Results: Incidence of neuropathy was found to be higher in patients with pretreatment anaemia (p=0.001), hypoalbuminemia (p=0.01) and hypomagnesemia (p=0.001) as well in those with habit to alcohol consumption (p=0.003). Neuropathy durations was conversely associated with age, being longer in younger patients (p=0.03), and again with hypoalbuminemia (p=0.04) and hypomagnesemia (p=0.002). No correlation was found with gender, hypocalcemia, diabetes and CRF. The correlation between vitamin B12 and folate levels and the development of neurotoxicity was not analysed because of the high number of missing data in the population. Conclusions: Age, anaemia, hypoalbuminemia, hypomagnesemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin induced neuropathy.
ODM-204 a novel dual inhibitor of CYP17A1 and androgen receptor: Early results from phase I dose escalation in men with castration-resistant prostate cancer.
Authors: Karim Fizazi, Robert Hugh Jones, Christophe Massard, Egils Vjaters, Katriina Johanna Peltola, Pirjo Nykänen, Annamari Vuorela, Riikka Oksala, Pasi Pohjanjousi, Mika VJ Mustonen, Petri Bono
Journal: Journal of Clinical Oncology (2017)

246 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression, various AR mutations and persistent activation of AR signaling axis by residual tissue androgens and other steroids. Inhibiting both the AR and androgen biosynthesis may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and the AR that has shown activity in nonclinical tumor models. Methods: We report early data of the DUALIDES phase I dose escalation part (NCT02344017), in which patients with metastatic CRPC (mCRPC) were enrolled into ODM-204 dose levels of 50, 100, 200, 300, 500 mg twice daily. Data cut-off was Oct 14 th 2016. Results: In the trial 23 patients with progressive mCRPC received increasing doses of ODM-204. At baseline, the median age of patients was 70 yrs (57-84 yrs), and median PSA was 46.5 ng/mL (0.7-249.6 ng/mL). Median time on treatment was 11.6 weeks (0.3-60.4 wks). Nine (39%) patients continued treatment for more than 12 weeks, and 4 (17.4%) patients were still receiving treatment at the time of data cutoff. ODM-204 was generally well tolerated, and the most commonly reported adverse events (AEs) were fatigue (n = 6, 26%), nausea (n = 6, 26%), decreased appetite (n = 5, 22%,) diarrhea (n = 5, 22%), and vomiting (n = 5, 22%). Two patients discontinued treatment due to an AE. The AUC t and C max values of ODM-204 in plasma increased with dose up to 300 mg after a single dose. Steady state values on day 8 were unexpectedly decreased in most patients, especially at higher doses, contrary to what was observed in the nonclinical monkey studies. Further, decreased predose concentrations were observed on day 29. PSA decreases were seen in 7 (30%) patients, and the median decrease was 47% (2-99%). At 12 weeks, 3 (13%) patients had a PSA response ( ≥ 50% reduction from baseline). Conclusions: Although evidence of anticancer activity was provided with ODM-204 in mCRPC, decreasing steady state concentration was observed. Clinical trial information: NCT02344017.
Accuracy of Wif1 methylated gene test and microbial changes identifying colorectal cancer.
Authors: Iradj Sobhani, Hicham Mansour, Jean Pierre Furet, Yazid Belkacemi, Philippe Langella, Thomas Aparicio, Christophe Tournigand, Florence Canoui-Poitrine
Journal: Journal of Clinical Oncology (2013)

e14525 Background: Faecal blood test (FOBT) is recommended for CRC screening. However, it had fair sensitivity and specificity (both around 50%). CRC results from genetic and epigenetic alterations involving Wnt pathway. Environmental factors can methylate Wnt inhibitory factor1 (Wif1). Colon microbiota dysbiosis, consequence of environment, is also associated with CRC. The aim was to assess the diagnosis accuracies of dysbiosis, methylated genes and FOBT for identifying CRC versus colonoscopy. Methods: A cross-sectional study included subjects referred (2003 up to 2007) for colonoscopy. Clinical factors (age, gender, personal/familial history of cancer, BMI, diabetes, and treatments) were recorded. Effluents (fresh stools, sera-S and urines-U) were harvested prior to colonoscopy and FOBT was performed. Seven dominant and subdominant bacterial populations in stools and methylation genes’ (Wif1, ALX4, and vimentin) levels in stools, S and U were quantified using qPCR. Gene markers (Kras mutations, Bat25, Bat 26) have been detected in tissues and stools. Calibration was assessed by Hosmer-Lemeshow chisquare and discrimination by Area Under ROC curve (AUC). Results: 247 patients were included (mean age 60.8, 52% men). Colonoscopy and pathology identified 90 pts with CRC (n=66) or large adenomas (&gt;10 cm). Wif1 was the more sensitive gene marker. A multivariate model adjusted for age, gender, previous personal/familial history of polyps/cancer leaded to AUC of 81.5% (95%CI: 75.7-87.4). After supplementary adjustment in different models, for dysbiosis, AUC increased to 83.4% (77.9-88.9) (bacteroides and leptum levels) (p= 0.08), to 84.9% (79.6-90.3) (p=0.02) after adjustment for FOBT, to 90.1% (85.8-94.4) (p&lt;0.001) after adjustment for Wif1 (S or U). When adjusted jointly for clinical parameters, FOBT, dysbiosis and Wif1, FOBT and wif1 remained independently associated with CRC whereas dysbiosis were not. However, the AUC of the full-adjusted multivariate model did not increase significantly (91.7; 87.8-95.6; p=0.075). Conclusions: Wif1 methylated marker in S or U improved diagnosis accuracy for identifying CRC compared to FOBT while microbial changes in dominant or subdominant bacteria populations did not.