tbuckley/cabot-search huggingface dataset:
Association of gene expression module biomarkers with clinical and therapeutic endpoints and their use with a universal companion diagnostic assay.
Authors: S. A. Tomlins, P. Williams, S. Sadis, P. Wyngaard, K. Oades, B. Lee, S. Chattopadhyay, Y. Wang, J. Monforte, D. Rhodes
Journal: Journal of Clinical Oncology (2011)

228 Background: Gene expression patterns are increasingly capable of stratifying patients based on prognosis and response to therapy. Given the limited availability of sample tissue, however, it is not feasible to utilize every test for every patient, suggesting the need for a universal companion diagnostic assay that is informative with respect to multiple clinical and therapeutic endpoints. Key challenges are identification of appropriate gene expression biomarkers, translation of biomarkers to clinical assays, and development of reliable gene expression profiling of formalin-fixed clinical specimens. Here we describe a novel RT-PCR biomarker assay optimized for FFPE clinical samples that has broad prognostic and predictive potential. Methods: A co-expression meta-analysis of 5,339 breast tumors from 56 microarray datasets identified highly co-expressed sets of genes (modules) across multiple datasets. Module biomarkers were tested for their ability to associate with prognostic and predictive targets in published datasets. In addition, each module was reduced from 10–1000 genes to 2-3 genes for use in companion diagnostic assays based on degree of co-expression across the meta-analysis, and validated against an independent panel of tumor samples. Results: This study demonstrates that a single test utilizing multiple module biomarkers is informative with respect to standard parameters such as ER, PR and Her2, and in addition reproduces existing prognostic and predictive genomic signatures. Furthermore, we show that modules of 10-1000 genes can be represented by 2-3 genes for direct use in companion diagnostics development. Conclusions: The molecular heterogeneity of breast cancer can be summarized by discrete gene expression modules that individually represent distinct biological programs, and that collectively can be represented by as few as 96 genes. Modules, together with outlier genes, allow for summation of the entire transcriptional program and provide a universal assay with broad application to companion diagnostics development.
Time for guidelines on safety netting?
Authors: Peter J Edwards, James O Seddon, Rebecca K Barnes
Journal: BMJ (2016)

Nicholson and colleagues say that safety netting “has come to be regarded as ‘best practice’ in relation to cancer diagnosis in non-specialist settings.”1 Safety netting is widely endorsed across a range of conditions by multiple professional institutes, but there is limited research evidence to guide clinicians and no widely accepted definition. NICE provides two different definitions in separate guidelines,2 3 which both differ from that of the RCGP curriculum.4

One possible …
Metabolomics and histology on exactly the same ex vivo prostate biopsy.
Authors: Dean A Troyer, Jeffrey R Shuster, Raymond S. Lance
Journal: Journal of Clinical Oncology (2012)

166 Background: Histopathology is the standard method for diagnosis and histological grading and staging of cancer. Molecular biomarkers are associated with cancer aggressiveness. One drawback to some molecular studies is that the portion of the tissue to be analyzed is processed in a manner that is destructive to the tissue. We present here a new method for performing analysis of small molecule biomarkers and histology in exactly the same biopsy tissue. The process, molecular Preservation by Extraction and Fixation (mPREF), allows traditional histological examination to be combined with qualitative and quantitative analysis of small molecule biomarkers. Methods: 18 gauge core biopsies were obtained ex vivo from prostatectomy specimens. One core biopsy/specimen container was immersed in aqueous alcohol. After 12-24 hrs, biopsies were transferred to UMFIX, and the original alcohol retained. Histologic sections of biopsies were stained by routine methods and the immunohistochemical (IHC) stain, PIN4. Small molecular weight molecules in the retained alcohol were examined by a mass spectrometry-based method. Results: Light Microscopy: Tumor and grade were evaluable and IHC for PIN4 performed well. Metabolomics of Retained Alcohol: From a single core biopsy, 260 named biochemical compounds and their relative concentrations WERE detected. 83 were different between the cancer and non-cancer biopsy extracts (p&lt; .05). 18 of the 20 common amino acids, and a number of long chain fatty acids and phospholipids were increased. Highest fold changes, 4- to 6-fold, were observed in cysteine, dihomo-linoleate, docosapentaenoate, N-acetylaspartate, N-acetylglucosamine, uracil, xanthine, and 1-stearoylglycerophosphoinositol. A sub-set of candidate biomarkers were differentially expressed in pT3 vs pT2 disease. Conclusions: MPREF allows for both histology and detection of small molecules in exactly the same tissue. The results suggest a higher metabolic state in cancer as compared with non-cancer containing biopsy tissues. Differential expression of small molecules from pT2 vs pT3 disease suggests that quantitative prognostic molecular and histologic data can be obtained from a single core biopsy.
Phase II study of AT-101 to abrogate Bcl-2-mediated resistance to androgen-deprivation therapy (ADT) in patients (pts) with newly diagnosed androgen-dependent metastatic prostate cancer (ADMPC).
Authors: M. N. Stein, I. Khan, M. Hussain, G. Liu, G. Wilding, E. M. Posadas, W. M. Stadler, C. Jeyamohan, S. Eddy, R. S. DiPaola
Journal: Journal of Clinical Oncology (2011)

137 Background: Preclinical studies demonstrate that Bcl-2 is over-expressed in most pts with prostate cancer, causes drug resistance to ADT, and that modulation of Bcl-2 improves sensitivity of tumor cells. We are conducting a phase II study for men with ADMPC to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, improves clinical results of pts initiating ADT for metastatic prostate cancer. Building on results from SWOG 9346 (Hussain JCO 2006) demonstrating that PSA nadir after 7 mo of ADT predicts survival, we are using a novel phase II trial design, in which the primary endpoint is the percentage of patients with PSA ≤ 0.2 ng/ml at 7 mo of ADT plus AT-101. Methods: Pts had ADMPC, PSA &gt; 5.0 ng/ml within 12 wks prior to registration and no prior ADT for metastatic disease. ADT with LHRH agonist and bicalutamide started 6 wks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28 day cycle. Pts received up to 8 cycles of ADT and AT-101. A total of 55 pts were enrolled (to obtain 48 evaluable pts) to in a two stage design with null hypothesis 48% versus alternative 68% with PSA ≤ 0.2 at 7 mo. With α = 0.1 and β = 0.9, &gt; 27 pts meeting this endpoint are required to recommend further study. Results: 55 pts were enrolled, median age 61.5 y; Gleason score (GS) 6 (5%),GS 7 (30%), GS 8 (24%), and GS 9 (41%). 3 pts had visceral mets and the remaining pts had bone or nodal metastasis. 42 pts have discontinued (9 toxicity, 9 progression, 1 withdrew) or completed (n = 23) 7 mo of treatment. In intention to treat analysis, 11 of 42 pts (26%) met the primary endpoint 10, of 42 (23%) pts had PSA &gt; 0.2 and &lt; 4.0 ng/ml after 7 mo. Grade 1/2 toxicities (%) included fatigue (36/9), nausea (20/9), vomiting (13/7), anorexia (15/2), AST/ALT (25/5), hypercalcemia (9/0), constipation (13/3), dry skin (9/0), anemia (18/0), sensory neuropathy (7/7), vomiting (12/7), hyperglycemia (7/4). Grade 3 toxicities were sensory neuropathy 2 pts, GI obstruction 1 pt, syncope 1 pt. Conclusions: Although final study results are pending the analysis of pts currently on therapy, 26% of pts achieved an undetectable PSA at 7 mo in a population with aggressive disease (66% GS ≥ 8). No significant financial relationships to disclose.
A Prospective Comparision of Intranasal (I.N.) and Subcutaneous (S.C.) Desmopressin (DDAVP) Therapy in Type 2M Von Willebrand Disease (VWD).
Authors: Scott Herbert, Rekha Parameswaran, Amy D. Shapiro, Jorge Di Paola, Jon Winay, Chris Roberson, Anne Greist
Journal: Blood (2006)
Induction of Antigen-Specific T-Cell Responses through Dendritic Cell Vaccination in AML: Results of a Phase I/II Trial and Ex Vivo Enhancement By Checkpoint Blockade
Authors: Felix S. Lichtenegger, Katrin Deiser, Maurine Rothe, Frauke M. Schnorfeil, Christina Krupka, Christian Augsberger, Thomas Köhnke, Veit L. Bücklein, Torben Altmann, Andreas Moosmann, Monika Brüggemann, Mirjam H.M. Heemskerk, Georg Wittmann, Beate Wagner, Wolfgang Hiddemann, Iris Bigalke, Gunnar Kvalheim, Marion Subklewe
Journal: Blood (2016)
The effects of acellular dermal matrix in expander-implant breast reconstruction after total skin-sparing mastectomy: Results of a prospective practice improvement study.
Authors: A. W. Peled, R. D. Foster, E. Garwood, C. A. Ewing, M. Alvarado, E. S. Hwang, L. Esserman
Journal: Journal of Clinical Oncology (2011)

1068 Background: Outcomes after total skin-sparing mastectomy and expander-implant breast reconstruction using acellular dermal matrix (Alloderm) have not been well-documented, nor has a strategy for optimal case selection for Alloderm use been described. Methods: Single-institution review of three patient cohorts from 2006-2010 undergoing total skin-sparing mastectomy and immediate expander-implant breast reconstruction was performed. Cohort 1 (“No Alloderm”) was composed of 59 consecutive patients who did not have Alloderm placed. Cohort 2 (“Consecutive Alloderm”) consisted of the next 65 consecutive patients, who all received Alloderm. Cohort 3 (“Selective Alloderm”) consisted of the next 159 patients, who had selective use of Alloderm based on intra-operative assessment of mastectomy skin flap thickness. Cohorts were compared by chi-square analysis using STATA 10. Results: A total of 283 patients (444 breasts) underwent expander-implant reconstruction. Mean follow-up was 23.7 months. Patient and treatment characteristics including age, BMI, co-morbidities, post-mastectomy radiation therapy, and systemic therapy were not significantly different between cohorts. Overall, 23% of patients had post-mastectomy radiation therapy, 34% had neoadjuvant chemotherapy, and 20% had adjuvant chemotherapy. The incidence of post-operative infection requiring intravenous antibiotics was 15.3% for the No Alloderm cohort, 9.9% for the Consecutive Alloderm cohort, and 11.2% for the Selective Alloderm cohort (p = 0.048). Unplanned return to the operating room was required in 22.3%, 11.9%, and 9.7% of patients, respectively (p = 0.009). Expander/implant loss occurred in 8.2%, 4%, and 5.8% of patients, respectively (p = 0.007). Conclusions: The use of Alloderm in expander-implant reconstruction after total skin-sparing mastectomy reduced major post-operative complications in this study. Selective use of Alloderm conferred the same benefit as use in all patients with resultant optimization of patient outcomes and cost-effective care.
A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU).
Authors: S. George, M. von Mehren, M. C. Heinrich, Q. Wang, C. L. Corless, J. E. Butrynski, J. A. Morgan, A. J. Wagner, E. Choy, W. D. Tap, J. Manola, J. T. Yap, A. D. Van Den Abbeele, S. Solomon, J. A. Fletcher, G. D. Demetri
Journal: Journal of Clinical Oncology (2011)

10007 Background: Resistance remains a challenge in GIST after the failure of IM and SU. Regorafenib, a novel oral kinase inhibitor, blocks VEGFR2-3, c-KIT, TIE2, PDGFR beta, FGFR1, RET, RAF and p38 MAPK and has a broad spectrum of antitumor activity in preclinical and early phase trials. We conducted an investigator initiated, multi-center phase II trial of regorafenib in patients with advanced GIST after prior therapy with at least IM and SU. Methods: Eligible pts received regorafenib 160mg/day orally d1-21 of each 28d cycle. Pts were assessed for response by RECIST 1.1 every 2 cycles. Primary endpoint was clinical benefit rate (CBR) defined as CR, PR, and SD > 16 weeks. Tumor genotyping and optional pre and d15 tumor biopsies were performed. Results: 34 pts were enrolled from Feb 2010 – Dec 2010. 33 pts received at least one dose of study drug. Median age was 54 yrs, median number of prior therapies = 3. As of Dec 1, 2010, 121 cycles of regorafenib have been administered (range 1 – 11). 19 pts required at least one dose reduction due to toxicity. Most common grade 3 treatment emergent toxicities were hypertension, hand-foot skin reaction, and hypophosphatemia, (29%, 25% and 14% of pts respectively). There were two grade 4 events, one hyperuricemia and one thrombosis. As of Dec 30, 2010, 22 eligible pts had been on protocol for at least 16 wks. 12 had restaging scans after 16 wks showing sustained clinical benefit (2 PR, 10 SD) CBR 54.5% (90% CI, 35.3% - 72.9%). 1 pt progressed at 7 wks. 2 pts withdrew prior to 16 wks. The remaining 7 pts demonstrated stable disease at a range of 14.9 - 15.6 wks. Therefore, 19 of 22 pts were without disease progression after 4 cycles of study drug dosing. Benefit was seen in pts whose tumors had primary KIT exon 11 mutations, KIT exon 9 mutations or wildtype kinase genotype. Immunoblotting of pre-study and day15 matched biopsies demonstrated ~50% inhibition of KIT and AKT phosphorylation, in 3 of 4 patients, all with SD for at least 4 cycles. Conclusions: Regorafenib has significant activity in pts with advanced GIST previously treated with IM and SU. An international phase III trial is currently underway in pts with advanced GIST following treatment with IM and SU.
Reply: Promise and Limitations of Relaxin-based Therapies in Chronic Fibrotic Lung Diseases
Authors: Jiangning Tan, Daniel J. Kass
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

blots or included any controls to allow the reader to assess the validity of the findings shown.Furthermore, the histopathology and the ensuing dramatic change in cellular composition in IPF-derived samples compared with the normal controls may alter the amount of RXFP1 mRNA expression in the whole-tissue samples.As experiments were done using fibroblasts, it is also important to recognize that one of the main sites of expression of RXFP1 is the bronchial epithelium (6) and that epithelial cells are highly secretory and may be highly influential on the underlying mesenchymal cells, including fibroblasts and myofibroblasts via cytokines and growth factors.Therefore, it would also be interesting to examine the expression of RXFP1 in these cells under similar conditions.Interestingly, when systemically administered to a mouse model of chronic allergic airways disease (in which RXFP1 expression was decreased compared with that in saline-treated controls), human relaxin increased RXFP1 expression in the airway epithelium (6).In summary, the findings of Tan and colleagues provide further impetus for research into the potential clinical utility of relaxinbased therapies in IPF and in less fulminant, fibrotic diseases of the lung.They also draw attention to how little is known about the regulation of RXFP1 expression and the need for reliable serum and local assays to measure the relaxin-RXFP1 system.
Abstract 19878: Burden of Systolic and Diastolic Left Ventricular Dysfunction Among Hispanics in the United States - Insights From the Echocardiographic Study of Latinos (ECHO-SOL)
Authors: Hardik Mehta, Anderson Armstrong, Katrina Swett, Sanjiv Shah, Matthew A Allison, Barry Hurwitz, Shrikant Bangdiwala, Rupal Dadhania, Dalane Kitzman, William Arguelles, Joao Lima, Marston Youngblood, Neil Schneiderman, Martha L Daviglus, Daniel Spevack, Gregory Talavera, Ajit Raisinghani, Robert C Kaplan, Carlos J Rodriguez
Journal: Circulation (2015)

Introduction: Population-based estimates of cardiac dysfunction and clinical heart failure (HF) remain undefined among Hispanic/Latino adults. Hypothesis: Among Hispanic/Latino adults, prevalence of clinical HF and subclinical cardiac dysfunction is high. Methods: Adult participants of Hispanic/Latino origin were enrolled into the Echocardiographic Study of Latinos (ECHO-SOL). Left ventricular systolic dysfunction (LVSD) was defined as an ejection fraction (EF) less than 50%; left ventricular diastolic dysfunction (LVDD) was defined using the Redfield and American Society of Echocardiography criteria. Baseline diagnosis of clinical HF was defined according to self-report; and those with cardiac dysfunction without clinical HF were characterized as having subclinical or unrecognized cardiac dysfunction. Results: Of the 1818 participants (mean age 56.4 years; 42.6% male) enrolled in ECHO-SOL, 52.7% had some form of cardiac dysfunction. The prevalence of LVSD was 3.6%, while LVDD was detected in 53.5%. Participants with LVSD were more likely to be males and current smokers and have lower socioeconomic status (all p&lt;0.05). Female sex, hypertension, diabetes, higher body-mass index and renal dysfunction were more common among those with LVDD (all p&lt;0.05). LVSD prevalence did not vary by Hispanic/Latino background group; however, in age-sex adjusted models, individuals of Central American and Cuban backgrounds were almost two-fold more likely to have LVDD compared to those of Mexican backgrounds. Prevalence of clinical HF with LVSD was 7.3%; prevalence of clinical HF with LVDD was 3.6%. Among those with cardiac dysfunction, 96.2% of the cardiac dysfunction was subclinical or unrecognized. Among those with cardiac dysfunction, prevalent coronary heart disease was the only factor independently inversely associated with subclinical or unrecognized cardiac dysfunction (odds ratio: 0.14; 95% confidence interval: 0.05-0.38).Conclusion: Among Hispanics/Latinos, most cardiac dysfunction is subclinical or unrecognized, and there is a high prevalence of diastolic dysfunction. This suggests that Hispanics/Latinos are a high-risk population for the development of clinical HF.
Effects of chemotherapy for superficial meso and hypopharyngeal cancers with concomitant esophageal cancer.
Authors: Toshiro Iizuka, Daisuke Kikuchi, Shu Hoteya, Mitsuru Kaise, Harushi Udagawa
Journal: Journal of Clinical Oncology (2012)

134 Background: Recently, the frequency of superficial meso and hypopharyngeal cancer (Ph ca) has increased and elucidation of its biological behaviors is needed. There are no reports to analyze if superficial Ph ca responds to chemotherapy. Therefore, the aim of this study was to clarify the effects of chemotherapy for esophageal cancer on superficial Ph ca. Methods: A total of 48 patients and 57 lesions with superficial Ph ca with concurrent esophageal cancer were enrolled from November 2007 to December 2010. Among these, 29 patients and 31 lesions for which no chemotherapy had been administered for the esophageal cancer, and two patients for whom details of the treatment regimen or evaluation after chemotherapy were not available were excluded. So 17 patients with 24 lesions were included. The maximum diameter of the Ph ca was measured before and after the treatment by endoscopy, the lesion was graded as CR, PR, NC and PD, and the response rate (CR + PR) was analyzed retrospectively. Results: All patients were male with a mean age of 61.1 years. The Ph ca was located in the left piriform sinus in 9 lesions, right piriform sinus in 10 lesions, posterior wall of the hypopharynx in one lesion, and mesopharynx in 4 lesions. The mean diameter of the tumor was 16.3 mm. Among the concurrent esophageal cancers, 6 were classified into the superficial type and 11 into the advanced type. For treatment, DCF was administered for 4 patients and 5 lesions, FP for 8 patients and 11 lesions, FAN (doxorubicin + 5FU + nedaplatin) for one patient and two lesions, CPT11 + CDDP for one patient and one lesion, VP-16 + CDDP for one patient and two lesions, and weekly docetaxel for one patient and one lesion. Radiation therapy for concurrent esophageal cancer was administered in 8 cases. As a treatment response, 7 lesions showed CR, 7 showed PR, 9 showed SD, and one showed PD, so a total response rate was 58.3%. Especially for the 15 lesions whose tumor diameter was less than 20 mm, the response rate was 67%. Conclusions: The response rate was 58.3%, which is relatively good. We believe that the results of this study would serve as important indicators for determining the treatment strategy for superficial Ph ca with concurrent esophageal cancer.
Surgical resection of the primary tumor in patients with distant metastatic breast cancer at diagnosis: Results of a retrospective series.
Authors: S. Arifi, f. Z. Hijri, Z. Benbrahim, K. Bendahou, Y. Akasbi, C. Nejjari, O. El Mesbahi
Journal: Journal of Clinical Oncology (2011)

145 Background: Among women with de novo stage IV breast cancer, the primary tumor is treated only when it causes symptoms. Recent data suggest that resection of in-breast tumors may avoid uncontrolled chest wall disease and may improve long-term survival. The authors evaluated the effect of surgery on chest wall status, and time to first progression (TTP) in such patients. Methods: We reviewed the records of all stage IV breast cancer patients, treated at our institution between 2007 and 2010, who underwent a surgery for their primary tumor. Information collected included demographics, tumor characteristics, treatments, disease progression. Prognostic factors affecting loco regional relapse and TTP were assessed. Results: Of 36 patients identified, 14 (38.9%) had postoperative diagnosis of distant metastases, and 22 (68.75%) were presented with intact primary tumor. The mean patient age was 50.22 (range 22–75) years. 52.8 were pre-menopausal women. 88.9% of tumors were hormone receptors (HR) positive while 11.1% were HR negative. HER2 was assessed in 18 cases and was positive in 16.7%. 77.7% women presented with locally advanced breast cancer, 61% were T4 with 25% T4d, and 16.7% were T3. Node status was N0 (16.6%), N1 (38.8%), N2 (16.6%), and N3 (13.8%). 86.1% patients had bone metastasis, 39% liver, 25.1% lung metastasis and 2.8% brain metastasis. All patients underwent mastectomy. Excision margins were positive in 2 cases. 55.6% had axillary lymph node dissection. All women received systemic therapy. Preoperative systemic therapy was given in 68.75%. First-line therapy consisted of anthracycline-based regimen (n=36) and/or taxane (n=9) and/or endocrine therapy (n= 30). None of the HER2-positive patients received trastuzumab. pCR occurred in 5 patients. Loco regional radiotherapy (RT) was given to 4 women (11.1%). Local recurrence (LR) occurred in 6 patients (16.7%). Median time to first progression was 17 months. LR was related to axillary lymph node dissection (p=0.027). Conclusions: Most of our patients had locally advanced breast cancer and the mastectomy improved local symptoms in this group of patients, with acceptable rate of LR and TTP.