tbuckley/cabot-search huggingface dataset:
Transcriptome-wide analysis of matched biopsy and prostatectomy to measure genomic classifiers of prostate cancer progression and field effect.
Authors: Beatrice Knudsen, Jeffry P. Simko, Lucia L.C. Lam, Nicholas Erho, Thomas Sierocinski, Imelda Tenggara-Hunter, Hugh Wellman, Elai Davicioni, June M. Chan, Peter Carroll, Hyung Lae Kim, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2014)

85 Background: Active surveillance (AS) allows patients with localized prostate cancer to delay and even avoid treatments that carry risk of significant side-effects. However, biomarkers are needed to more accurately risk-stratify patients and enhance acceptance of AS. Challenges with biomarkers measured from needle biopsy specimen that need to be address include limited material, tumor and specimen heterogeneity and fragmentation of RNA. Methods: A total of 23 patients with matched formalin-fixed paraffin-embedded (FFPE) biopsy and radical prostatectomy (RP) specimens were identified at University of California, San Francisco and Cedar Sinai. For each patient, samples were taken from tumor, non-neoplastic tissue adjacent to tumor (NAT) and non-neoplastic tissue contralateral to tumor (NCT) from both biopsy and RP specimens. RNA expression was measured in 130 samples using the 1.4 million feature Affymetrix Human Exon 1.0 ST arrays. Results: From 1 mm cylindrical cores punched from FFPE blocks, sufficient RNA was extracted for the assay from 63 out of 69 (91%) biopsy specimens and 69 out of 69 (100%) RP specimens. Median RNA yield from biopsies was lower than RP specimens but a similar quantity and quality of cDNA was amplified from the 100 ng RNA required for the assay. RNA from 62/63 (98%) of the biopsy specimens and 68/69 (99%) of the RP specimens generated expression data that passed quality control. Genomic classifiers (GC) predicting metastasis (GC1) and presence of high Gleason grade tumor (GC2) were highly correlated between matched biopsy and RP specimens with R=0.74 (p=0.0003) and R=0.63 (p=0.004), respectively. For GC2, matched tumor and NAT from RP had a higher correlation (R=0.57, p=0.0045) than matched tumor and NCT (R=0.10, p=0.67). There was no relationship between percentage of stromal contamination in the biopsy and the GC scores for either classifier, R=0.02 (p=0.91) and R=-0.16 (p=0.28) respectively. Conclusions: RNA expression levels can be measured in FFPE needle biopsy on a genome-wide scale with similar data quality compared to RP specimens. GC scores from biopsies and RP samples correlate well, are robust to stromal contamination, and are present in adjacent non-neoplastic tissue.
Induction chemotherapy followed by chemoradiotherapy and total mesenteric excision for locally advanced rectal cancer with resectable metastases.
Authors: Carla Hajj, Andrea Cercek, Leonard Saltz, Neil Howard Segal, Diane Lauren Reidy, Zsofia Kinga Stadler, Nancy E. Kemeny, Abraham Jing-Ching Wu, Martin R. Weiser, Philip Paty, Jose G. Guillem, Garrett Michael Nash, Larissa K. F. Temple, Julio Garcia-Aguilar, Karyn A. Goodman
Journal: Journal of Clinical Oncology (2013)

526 Background: Optimal management of patients with locally advanced rectal cancer (LARC) and synchronous, resectable metastases remains controversial and treatment decisions benefit from a multidisciplinary approach. To better characterize the role of induction chemotherapy followed by chemoradiation and surgery, we evaluated patterns of distal progression and overall survival in this subset of patients. Methods: We reviewed records of 25 LARC patients with synchronous resectable metastases treated with induction chemotherapy (ICT) followed by 5-fluorouracil-based concurrent chemoradiation (CRT) at our institution between December 2006 and December 2010. Radiation was delivered using a standardized three-field technique or IMRT. The incidence and sites of failure were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated from the completion of CRT using the Kaplan-Meier method. Results: Of the 25 patients who received ICT followed by CRT, 21 (84%) underwent total mesorectal excision and metastectomy. Eleven patients (44%) had liver metastases. The median ICT duration was 2.4 months. Twenty patients (80%) received a FOLFOX-based ICT regimen and 5 patients (20%) received irinotecan-based chemotherapy. Two patients had unresectable disease, one was medically inoperable, and surgery was aborted due to intra-operative complications in one patient. Eighteen of the 21 were NED after surgery and metastatectomy (86%) with 24% pathologic complete response rate in the primary tumor; 10 (56%) received adjuvant chemotherapy. None of the patients recurred locally. Six of the 18 (33%) progressed distally, four of whom had received adjuvant chemotherapy. Four distal recurrences were in the lungs. With a median follow-up of 29.6 months, the 3-year OS was 50.4%. Median OS and PFS were 25.1 months and 13.5 months, respectively. Conclusions: ICT prior to CRT is associated with acceptable toxicity, substantial primary tumor regression, and promising clinical outcomes in patients with high-risk LARC with synchronous, resectable metastatic disease.
TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial.
Authors: Robert J. Mayer, Atsushi Ohtsu, Takayuki Yoshino, Alfredo Falcone, Rocio Garcia-Carbonero, Josep Tabernero, Alberto F. Sobrero, Marc Peeters, Fabio Benedetti, Lukas Makris, Hiroshi Ambe, Alberto Zaniboni, Yasuhiro Shimada, Kentaro Yamazaki, Yoshito Komatsu, Howard S. Hochster, Heinz-Josef Lenz, Ben Tran, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2016)

634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial. Original results of RECOURSE based on the cut-off date of January 24, 2014, in which 72% of mortality events had occurred, demonstrated a significant improvement in overall survival (OS) with TAS-102 vs placebo. Here we report results of an updated survival analysis from RECOURSE and a retrospective analysis of OS outcomes based on a clinical prognostic risk index. Methods: Patients were randomized 2:1 to receive TAS-102 or placebo. Study treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was OS; final survival data were collected on October 8, 2014. A clinical OS prognostic risk score was assessed to evaluate OS effect in patients from low to high prognostic score. Prognostic factors contributing to the risk index were from those prespecified in the multivariate modeling assessment of OS outcome. Results: At data cut-off for the final survival analysis, 89% of the 800 patients randomly assigned to TAS-102 or placebo had died, accounting for 138 events in addition to 574 (72%) events included in the original analysis. The updated results for OS are shown in the Table. Conclusions: An updated survival analysis confirmed that OS benefit with TAS-102 was maintained and increased to a full 2 months; improvement in 1-year survival surpassed 10% in these heavily pretreated patients. OS benefit appears to be maintained for all patients in the trial regardless of prognostic status at trial entry. Clinical trial information: NCT01607957. [Table: see text]
Cancer and the renin angiotensin system (RAS): Substantial activation as evidenced by quantification of various RAS peptides and their metabolites in plasma by LC-MS.
Authors: H. Loibner, M. Poglitsch, C. Schwager, S. Stranner, E. Janzek, M. Schuster, T. Bauernhofer, H. Samonigg
Journal: Journal of Clinical Oncology (2011)

e21171 Background: The RAS is known for regulation of blood pressure. However, an activated RAS also supports tumor growth, in particular by its effector peptide Ang II. Elevated Ang II levels were found in plasma and malignant effusions of cancer patients (Samonigg et al. ASCO 2010). We have developed a sensitive LC-MS method to quantify plasma levels of all relevant peptides of the RAS. Utilization of this method for analysis of plasma of cancer patients, resulting in a “RAS peptide fingerprint” gives insight into the activation pattern of the RAS and may be utilized as guidance for novel therapies that re-balance an activated RAS, thereby reverting a tumor growth-promoting environment. Methods: A sensitive method based on LC-MS was developed to quantify Ang peptides and metabolites in plasma in a single run. Plasma was obtained from various patients with solid cancers in advanced stage and levels of Ang I, Ang II, Ang III, Ang IV, Ang1-9, Ang1-7, Ang2-7, Ang3-7 and Ang1-5 assessed. Respective results found in 21 healthy volunteers served as comparison. Results: In all analysed cancer patients (n=13) an activated RAS was seen. Substantially elevated Ang peptide plasma levels were found (in pg/ml): Ang I: mean 1.900, range 90-12.000 (mean healthy 17); Ang II: mean 350, range 5-2.100 (mean healthy 8); Ang1-9: mean 22, range 3-160 (mean healthy 3) Ang1-7: mean 45, range 5-250 (mean healthy 3); Ang1-5: mean 23, range 2-120 (mean healthy 2). Conclusions: Ang peptide levels in cancer patients were massively elevated when compared to healthy controls (up to 100-fold). Highly elevated levels were found for the effector peptide Ang II and its precursor Ang I, indicating overactivity of Renin and ACE. Degradation products of Ang II such as Ang1-7 and Ang1-5 were also elevated. Interestingly, the activation of the RAS did not have obvious impact on blood pressure. Based on these results, a novel therapeutic modality against cancer may consist in re-balancing an activated RAS. In this regard, treatment of cancer patients with recombinant human ACE2 (which efficiently degrades Ang II to Ang1-7 and is in clinical development against diseases with an imbalanced RAS) may be considered.
Noninferiority (NI) phase III trials in oncology: What is the basis for choosing the NI margin?
Authors: M. S. Militao, E. D. Saad
Journal: Journal of Clinical Oncology (2011)

e13070 Background: The choice of the NI margin has become an important aspect of NI cancer trials, but the contemporary practice regarding this choice has not been formally assessed. Methods: We searched PubMed for reports on phase III trials on systemic antineoplastic treatments for advanced breast cancer (BC) or non-small-cell lung cancer (NSCLC) published between 1/1998 and 12/2009 in 11 leading medical journals (Ann Oncol, BCRT, BJC, Cancer, CCR, EJC, JCO, JNCI, Lancet, Lancet Oncol, and NEJM). Results: We retrieved 197 reports (93 on BC, 104 on NSCLC), 23 of which (12%) had a NI primary hypothesis (12 in BC, 11 in NSCLC). There was no trend in the proportion of trials with a NI hypothesis in the two 6-year periods compared. The median (range) sample sizes for NI and superiority trials were 563 (160-1669) and 368 (97-1692) patients, respectively (P=0.011). The primary end point for NI trials was overall survival (OS)/progression-free survival/response in 9/5/9 cases, respectively. The NI margin was reported in all trials, but justified on statistical grounds in only 3 (13%). Among trials with time-dependent end points (N=14), 11 used the hazard ratio to represent the NI margin (3 used 1-year OS), and the lower limit of the confidence interval ranged from 0.75 to 0.86, with mean and median of 0.8. For trials with a response end point, the NI margin ranged from 15% to 25%, with mean of 18% and median of 15%. Conclusions: NI trials represent 13% and 11% of contemporary phase III trials on BC and NSCLC, respectively, with no apparent recent temporal trend in their use. Most trials use similar NI margins but report no justification for their choice.
Response rate and toxicity of primary concomitant radio-chemotherapy in locally advanced cervical cancer: Results of an open prospective, multicenter phase II study of the NOGGO.
Authors: A. Mustea, A. Belau, J. Sehouli, K. Drzewiecki, M. H. R. Eichbaum, K. Bartz, E. Angelidou, S. Saegner, M. O. Langenbruch, P. Ledwon, M. Zygmunt, G. Koehler, D. Koensgen
Journal: Journal of Clinical Oncology (2011)

5038 Background: To determine the response rate and toxicity of primary concomitant radio-chemotherapy (cRCH) consisting of ifosfamide and carboplatin plus external beam radiotherapy with curative intention in locally advanced primary inoperable stage IIB and IIIB squamous cell cervical cancer (CC). Methods: Patients (pts) with CC from 8 institutions were enrolled. Pts received three cycles of Ifosfamide 1,2 mg/m² (+ Mesna 20%) (d1-3) plus Carboplatin AUC 4 (d1), q21d, and concomitant external beam radiotherapy (50.4 Gy: 1.8 Gy/d). Operability and remission was evaluated by clinical gynecological examination in general anesthesia 4 weeks after 3rd cycle cRCH. If operability was achieved, a radical hysterectomy with pelvic lymphadenectomy was performed within 6 weeks after cRCH. If surgery was not done, because of incomplete remission or preferences, vaginal brachytherapy (BT) (15 Gy: 5 Gy/d) was given additionally. Results: Thirty-nine pts were enrolled from January 2003 through July 2008. Median age was 48 years (range, 30 -73). Distribution of FIGO tumor stage was: IIB: 17, IIIB: 23. Median follow-up was 22 months (range, 1-56). All pts completed cRCH. Grade 3/4 hematologic toxicities (in % of all cycles) were moderate: leucopenia 4.3%, thrombocytopenia 2.6% and anaemia 4.3%. In 8.5%, cycles were delayed because of haematological toxicity. Blood transfusions were given in 23.9%, G-CSF in 35.9%. Grade 3/4 non-hematologic toxicities were seldom (< 6%). Response rate was 89.7% (CR: 35.9%, PR: 53.8%, NC: 5.1%). Operability was achieved in 79.5%. Surgery was performed in 92.8%. Complete histological remission was achieved in 61.5%. Conclusions: cRH is a highly effective and tolerable regimen in CC. Partial remission rate and histological tumour residuals indicate the need for further studies.
Recurrent feature after radiofrequency ablation therapy for hepatocelluar carcinoma: Risk of increasing malignant behavior.
Authors: Shinichiro Yamada, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2016)

213 Background: Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, several reports demonstrated the aggressive local recurrence after RFA, suggesting the induction of further malignant transformation of HCC. Methods: Eighty-eight patients with HCC who underwent hepatic resection were included in this study. Hepatectomy was indicated for local recurrence of HCC after RFA (n = 10, RFA group) and for the HCC without prior RFA (n = 78, non-RFA group). Clinicopathological data and patient’s prognosis after hepatectomy were compared between the two groups. Expression levels of HIF-1, EpCAM, CD44, VEGF and EMT markers mRNA in the tumor tissues were examined. We also investigated miR-34a and miR-200c expressions in the two groups. Results: RFA group showed higher frequency of portal vein invasion and less tumor differentiation compared with the non-RFA group (p &lt; 0.05). Overall and disease-free survival rates in the RFA group were significantly worse than those in the non-RFA group (p &lt; 0.05). HIF-1 and EpCAM mRNA expression levels in the RFA group were significantly higher than those in the non-RFA group (p &lt; 0.05). The expressions of TGF-β, Twist and Snail-1 in RFA group were significantly higher than those in non-RFA group (P &lt; 0.05), and Vimentin expression in RFA group tended to be higher than that in non-RFA group (P = 0.07). Regarding to miRNA, miR-200c and miR-34a expressions in RFA group were significantly lower than those in non-RFA group (miR-200c: P = 0.04, miR-34a: P &lt; 0.01). Conclusions: Recurrent HCC after RFA showed the highly malignant potential through the expressions of HIF-1, cancer stem cell and EMT markers.
Analysis of medical expenses according to the stage of gastric cancer during the first year after diagnosis.
Authors: Sung Soo Kim, Jie-Hyun Kim, Dae Young Cheung, Soo-Heon Park
Journal: Journal of Clinical Oncology (2014)

4 Background: Gastric cancer is one of the most common malignant cancer in Korea as 33,000 new patients are being diagnosed annually. Department of Health and Human Services has performed cancer screening project that recommends adults over 40 years old get mandatorily gastrointestinal endoscopy or gastrography for the detection of early gastric cancer every two years for free. This contributes to the discovery of early gastric cancer. However, the effectiveness of gastric cancer screening project is often questioned due to the lack of accurate data of the difference in the medical expenses between early gastric cancer and advanced gastric cancer. This study was aimed to investigate that the detection of early gastric cancer can lead to a reduction in health care costs. Methods: For the patients with newly diagnosed with gastric cancer in nine medical institutions during December 1, 2011 to June 30, 2012, the cost of the initial treatment, a total of one-year costs related to gastric cancer, inpatient and outpatient visits, test costs according to the tumor stage were investigated using a retrospective analysis of the medical records. Results: The cost of the initial treatment ($1,877 USD, $7,749 USD, $8,020 USD, and $6,809 USD, respectively by stage; P=0.000) and a one-year care costs ($1,441 USD, $5,142 USD, $8,444 USD, and $24,950 USD, respectively by stage; P=0.008) were significantly lower in stage I as compared with stage II, stage III, and stage IV. The numbers of hospitalizations, outpatient visits and abdominal CT and PET-CT scans were also significantly fewer in stage I as compared with more advanced stages. There was no difference in the cost of the initial treatment and one year care costs associated with gastric cancer between stage II, III, and IV. Chemotherapy had no effect on the difference in medical expenses. In the treatment of gastric cancer, medical expenses was affected significantly by early stage, whether or not endoscopic resection and complications. Conclusions: Detection of early gastric cancer is valuable not only for the possibility of a complete cure, but also for the reduction of the medical costs that are responsible for the patients and national health insurance.
Genomics of Myeloproliferative Neoplasms
Authors: Katerina Zoi, Nicholas C.P. Cross
Journal: Journal of Clinical Oncology (2017)

Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1-negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.
ADAMTS13 ACTIVITY and VON Willebrand FACTOR LEVELS IN PATIENTS with Livedoid VASCULOPATHY.
Authors: Andrea Fernandes Eloy da Costa França, Bruna de Moraes Mazetto, Fernanda A. Orsi, Erich Vinicius de Paula, Tania F.G.S Machado, Elemir M Souza, Joyce Maria Annichino-Bizzacchi
Journal: Blood (2009)
Investigating parent of origin effects (POE) and anticipation in Irish Lynch Syndrome kindreds.
Authors: Michael P. Farrell, David J. Hughes, Jasmin Schmid, Philip S Boonstra, Bhramar Mukherjee, Margaret B. Walshe, Padraic M. Mac Mathuna, David J Gallagher
Journal: Journal of Clinical Oncology (2012)

e12031 Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. We sought evidence for a specific POE effect in Lynch syndrome families by studying the ages at diagnosis in the offspring of affected parent-child pairs. In addition, a paired t-test and a specifically developed bivariate statistical approach were used to assess a possible role of anticipation. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) with known germline MMR mutations. Differences in the mean age of LS associated cancer diagnosis were compared between various groups via t-tests: all p-values were 2-sided. Different group comparisons include: (1) unique parental ages (mothers vs. fathers) (2) affected offspring ages (mothers vs. fathers (3) age of affected female offspring (mothers vs. fathers (4) age of affected male offspring (mothers vs. fathers. Results: There were no statistically significant differences in diagnosis of offspring or parents. Sons of affected mothers were more likely to be affected than daughters of affected mothers. However, the affected cohort/study number is small and while affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring (39.7 vs 42.5), this finding failed to reach clinical significance. Comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome associated malignancies Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. This study will be expanded to recruit more eligible affected parent child pairs to increase the power of this evaluation. The Veiland &amp; Huang algorithm will be used to compare mean ages of affected parents and children.