tbuckley/cabot-search huggingface dataset:
MTX and VBL treatment for patients with desmoid tumors resistant to meloxicam treatment: Relationship between efficacy and CTNNB1 mutation status.
Authors: Yoshihiro Nishida, Shunsuke Hamada, Satoshi Tsukushi, Hiroshi Urakawa, Naoki Ishiguro, Yuichi Ando
Journal: Journal of Clinical Oncology (2014)

e21525 Background: Treatment modalities for desmoid tumors have been changed because of the high recurrence rate even after wide resection. Since 2003, meloxicam, which is a selective COX-2 inhibitor, has been applied consecutively as a first line treatment. Although not a few patients were resistant to this treatment, we applied low-dose chemotherapy following the treatment with meloxicam. The aim of this study was to reveal the clinical outcome of successive treatment with low-dose chemotherapy for patients with extra-peritoneal desmoid tumors resistant to treatment with meloxicam, and relationship between efficacy and CTNNB1 mutation status. Methods: Since 2003, 51 consecutive cases were diagnosed as desmoid tumors arising in extra-peritoneal regions, prospectively treated with meloxicam (10mg/day). Effects of meloxicam were evaluated with MRI and/or CT every 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST). Patients evaluated as progressive disease (PD) were subjected to low-dose chemotherapy composed of methotrexate (MTX) (30mg/M2) and vinblastine (VBL) (6mg/M2) every two weeks. Clinical outcome of successive treatment following meloxicam treatment was investigated. Frozen specimens obtained at biopsy or formalin embedded tissues were subjected to the analyses for CTNNB1 mutation status. Results: Among 51 patients with treatment of meloxicam, PD was in 15. Among them, 9 patients with PD status received treatment with MTX + VBL. Among them, 8 (89%) patients revealed PR or SD (5 patients; PR, 3; SD), and only 1 patient had PD status. Three tumors were with 45A mutation (one each with PR, SD, and PD), 5 with 45F (2 each with PR and SD, one with PD), and one each with 45P (PR) and wild type (PR), suggesting the mutation status does not affect the efficacy of MTX + VBL. Conclusions: Considering the functional impairment with surgery with negative surgical margin, effective treatment modality with fewer complications is desired. Not a few patients revealed resistant to treatment with meloxicam. However, successive treatment with low-dose chemotherapy of MTX + VBL could favorably control desmoid tumors regardless of CTNNB1 mutation status.
Anti Müllerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity: From the bench to the bedside.
Authors: Irit Ben-Aharon, Mattan Levi, Noa Hasky, Salomon M. Stemmer, Ruth Shalgi
Journal: Journal of Clinical Oncology (2015)

e20624 Background: Due to increased numbers of young cancer patients, the impact of anti-cancer treatments on fertility has become a major public health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. We aimed to characterize the role of AMH as a marker for chemotherapy-induced testicular toxicity in both preclinical and clinical settings. Methods: Male patients ( < 45y) who were candidate for chemotherapy were enrolled into the study. Serum AMH and a panel of gonadal hormones were measured at baseline and post-treatment. In the preclinical setting, pubertal mice were injected with saline or various classes of chemotherapies and were sacrificed after 1week or 1/3/6 months post treatment. We evaluated compartments of spermatogenesis by AMH (both proteomics and real-time PCR), as well as qualitative and quantitative sperm parameters. Results: Nineteen patients were enrolled, median age was 38y (21-44y).Serum AMH was correlated with increased FSH and testosterone and decreased inhibin-B levels in gonadotoxic protocols (as cisplatin and busulfan), and remained unchanged in non-gonadotoxic protocols (as capecitabine). In mice, serum and testicular AMH levels exhibited the same pattern and were negatively correlated with testicular and epididymal weight and sperm motility. The increase in AMH expression in the testes was also correlated with enhanced staining of markers of apoptosis and repair (TUNEL, Ki67 and PCNA). Severely damaged tested demonstrated a marked co-staining of AMH and GATA-4, a Sertoli cell marker that resembled the pattern of Sertoli-cell only condition. Conclusions: Our study indicates that the pattern of serum AMH, in combination with other hormones may delineate testicular damage, as determined in both preclinical and clinical settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity.
Identification of Common Neural Circuit Disruptions in Cognitive Control Across Psychiatric Disorders
Authors: Lisa M. McTeague, Julia Huemer, David M. Carreon, Ying Jiang, Simon B. Eickhoff, Amit Etkin
Journal: American Journal of Psychiatry (2017)

Objective: Cognitive deficits are a common feature of psychiatric disorders. The authors investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis. Method: A PubMed search was conducted for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with axis I disorders and matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates. Results: The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with various disorders (schizophrenia, bipolar or unipolar depression, anxiety disorders, and substance use disorders). Transdiagnostically abnormal activation was evident in the left prefrontal cortex as well as the anterior insula, the right ventrolateral prefrontal cortex, the right intraparietal sulcus, and the midcingulate/presupplementary motor area. Disruption was also observed in a more anterior cluster in the dorsal cingulate cortex, which overlapped with a network of structural perturbation that the authors previously reported in a transdiagnostic meta-analysis of gray matter volume. Conclusions: These findings demonstrate a common pattern of disruption across major psychiatric disorders that parallels the “multiple-demand network” observed in intact cognition. This network interfaces with the anterior-cingulo-insular or “salience network” demonstrated to be transdiagnostically vulnerable to gray matter reduction. Thus, networks intrinsic to adaptive, flexible cognition are vulnerable to broad-spectrum psychopathology. Dysfunction in these networks may reflect an intermediate transdiagnostic phenotype, which could be leveraged to advance therapeutics.
piRNA-651 as a prognostic marker in surgically resected non-small-cell lung cancer.
Authors: Nuria Vinolas, Francisco Aya, Alfons Navarro, Ramon M Marrades, Anna Cordeiro, Aranzazu Fernandez, Nuria Chic, Josep M Gimferrer, Jose Ramirez, Laureano Molins, Mariano Monzo
Journal: Journal of Clinical Oncology (2015)

11043 Background: Piwi-RNAs (piRNAs) are small non-coding RNAs (24-32 nt) required to protect the genome in germline cells. Initially they were thought to be expressed only in germline cells, but they have recently been found to be expressed in several tumours. piRNA-651 has been identified as an oncogene in gastric cancer. However, its role in non-small-cell lung cancer (NSCLC) as well as its potential as a prognostic marker have not yet been examined. Methods: piRNA-651 expression levels were assessed in tumour and paired normal tissue samples from NSCLC patients. piRNA-651 expression was analyzed from formalin-fixed paraffin-embedded samples by real-time PCR and by chromogenic in situ hybridization. Disease-free survival (DFS) and overall survival (OS) were studied by means of Kaplan-Meier, Log Rank and Cox methods. Results: A total of 70 patients with stage I-III surgically resected NSCLC between March 1996 and June 2007 in a single institution were prospectively registered. The median follow-up of living patients was 79 months. None of these patients received preoperative or adjuvant treatment. piRNA-651 was overexpressed in tumour tissue compared to normal tissue, and tumour cells showed a marked cytoplasmic expression. Low piRNA-651 expression was associated with shorter disease-free survival (86.8 Vs 25.4 months, p = 0.045) and shorter overall survival (116 Vs 59.1 months, p = 0.044). The multivariate analysis identified piRNA-651 as an independent prognostic factor for DFS (p = 0.031) and for OS (p = 0.050). Conclusions: piRNA-651 expression may well influence prognosis in NSCLC. To our knowledge, this is the first study to find evidence for a prognostic role for piRNAs in cancer.
Prevalence and survival benefit of adjuvant chemotherapy in stage III colon cancer patients: Comparison of overall and age-stratified results by multivariable modeling and propensity score methodology in a population-based cohort.
Authors: Robert Brooks Hines, Milan Bimali, Asal Johnson, Rana Bayakly, Tracie Collins
Journal: Journal of Clinical Oncology (2017)

649 Background: Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort. Methods: Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000–07 were eligible (final N = 3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM). Results: Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate - ACT rate] 25.4 deaths/ 1000 person-years [py], 95% confidence interval [CI]: 19.1–32.7 deaths/1000 py) and relative (MM HR = 0.67, 95% CI: 0.59–0.76) survival benefit. The survival benefit was demonstrated across age groups. mm and propensity score methods yielded highly similar HRs. Conclusions: Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease.
Evaluation of the knowledge about breast cancer in Brazilian women seeking assistance in basic health care units.
Authors: Juliana Giacomazzi, Aishameriane Venes Schmidt, Edenir Inez Palmero, Fernanda Lenara Roth, Maira Caleffi, Suzi Alves Camey, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2014)

e20573 Background: Although breast cancer incidence, mortality, and survival rates vary in different continents, the overall data suggest that breast cancer incidence is increasing, and in regions without early and efficient breast cancer screening programs, mortality may be increasing as well. In these scenatios, knowledge about the disease and awareness towards risk reducing interventions are essential tools. Fear and misinformation generate myths about breast cancer and may result in lower demand and/or adherence to breast cancer screening. The objectives are to report on misconceptions about risk, treatment and prevention of breast cancer among women seeing assistance in basic health care units in Southern Brazil. Methods: The sample consisted of 589 cancer-unaffected women aged 15-69 years enrolled in the Nucleo Mama Porto Alegre Cohort (NMPOA). All answered a questionnaire with 19 questions about their knowledge about breast cancer. For this study, we considered only the first 10 questions of the instrument, relating to risk factors, detection and treatment of breast cancer. Results: The questions with the highest percentage of error or no response were:
Targeted therapies (TT) in metastatic renal cell carcinoma (mRCC): An Italian survey of 902 pts.
Authors: Felice Pasini, Anna Paola Fraccon, Carmen Barile, Cosimo Sacco, Teodoro Sava, Francesco Valduga, Umberto Basso, Emanuela Vattemi, Giovanni Rosti, Emilia Durante, Maurizio Nicodemo, Giovanni Lo Re, Rita Cengarle, Paola Bertocchi, Daniele Bernardi, Donata Sartori, Donatella Donati, Cristina Pegoraro, Alessandro Inno, Franco Bassan
Journal: Journal of Clinical Oncology (2013)

e15514 Background: TT have improved the outcome in mRCC; however, definite data regarding their efficacy when used in the community setting are still insufficient. This survey was aimed to evaluate survival in subsequent lines of treatment (tx) in mRCC pts treated outside clinical trials. Methods: Individual data from the clinical records of 902 pts treated with TT from mid 2007 to December 2012 were obtained from 28 Italian Institutions, through a questionnaire sent after approval by local ethical committees. Results: Median follow up was 26 mo (range 1-85), median age was 60 yrs (range 25-89), 75% were male. At onset metastatic sites were lung (62%), lymph nodes (38%), bone (31%); each of the other sites &lt;10%. Median overall survival (mOS) was 24 mo (range 1-85) without statistical difference among the various centres. Sunitinib was the 1 st line tx in 693 pts (76.6%), sorafenib in 124 (13.7%) , temsirolimus in 35 (4%), bevacizumab in 26 (3%), pazopanib in 19 (1.5%), others 5. Median PFS of 1 st line (mPFS1) sunitinib was 11 mo and that of sorafenib 7 mo. Type of response: CR 32 (3.5%), PR 274 (30%), SD 275 (30%); PD 265 (29%), not evaluable 33 (3.5%), tx ongoing 23 (2.5%). Dose reduction of sunitinib and sorafenib was required in 49% and 39% of the cycles administered, respectively; 137 pts (15%) received only 1 cycle of sunitinib mostly for rapid progression and/or deterioration. 2 nd line tx was performed in 46% of the pts: sorafenib 143 (16%), everolimus 121 (13%), sunitinib 100 (11%), temsirolimus 25 (3%), chemo-immunotherapy 26 (3%), others 1%. mPFS2 was 6 mo with sunitinib and about 4 mo with the other tx (p=0.001). 155 pts (17%) received 3 lines of tx: mOS of TKI-TKI-mTOR (A), TKI-mTOR-TKI (B) and other (C) triplets were 48, 37 and 33 mo, respectively; A vs B p= 0.06; A vs C p= 0.01. Overall PFS3 was 6 mo. Conclusions: i) This survey shows that data of clinical trials were reproduced in the real world setting; ii) a good proportion of pts achieved long OS after subsequent lines of tx; iii) on the other hand, a similar percentage of pts experienced rapid progression; iv) further studies are needed to better identify the different subsets of pts in order to improve the efficacy of TT.
Comprehensive genomic profiling of urethral cancer to reveal distinctive features compared to bladder cancer.
Authors: Tanya B. Dorff, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti Ramkissoon, Siraj Mahamed Ali, Alexa Betzig Schrock, Hugh A.G. Fisher, Badar Mian, Tipu Nazeer, David Fabrizio, Garrett Michael Frampton, Vincent A. Miller, Phil Stephens, Laurie M. Gay, Jeffrey S. Ross, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

429 Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of &gt;500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p&lt;0.0001 for all comparisons) In addition, mUrethC featured as significantly lower frequency of TMB &gt; 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. [Table: see text]
Correlation of acute myeloid leukemia (AML) stem cell phenotype with cytogenetic/molecular features and prognosis.
Authors: Jonathan Michael Gerber, Joshua F. Zeidner, Sarah Morse, Amanda Blackford, Brandy Perkins, Breann Yanagisawa, Hao Zhang, Laura Morsberger, Judith E. Karp, Yi Ning, Christopher D Gocke, Gary L. Rosner, B. Douglas Smith, Richard J. Jones
Journal: Journal of Clinical Oncology (2015)

7000 Background: Emerging evidence supports the clinical significance of leukemia stem cells (LSCs).We previously found that patients with AML exhibited 1 of 3 distinct LSC phenotypes based on CD34, CD38, and aldehyde dehydrogenase (ALDH): 1. CD34-, 2. CD34+CD38-ALDHintermediate (ALDHint), or 3. CD34+CD38-ALDHhigh (ALDHhigh) [Gerber, et al. Blood, 2012]. We hypothesized that LSC phenotypes might correlate with cytogenetic/molecular features and treatment outcomes. Methods: Diagnostic samples from 98 patients with newly diagnosed normal or unfavorable cytogenetic AML, enrolled on clinical protocol NCT01413880, were analyzed by FACS. Sorted cell populations were assayed by FISH and/or PCR for leukemia-specific abnormalities. Fisher’s exact and Mantel-Haenszel tests were used to analyze differences in risk factors and outcomes by LSC phenotype. Results: LSCs were CD34- in 21 cases; ALDHint in 44; and ALDHhigh in the remaining 33. Poor risk cytogenetics and/or FLT3-ITD mutations were uncommon in the CD34- (4/21 = 19%) and ALDHint (17/44 = 39%) cases, but were frequent in the ALDHhigh cases (28/33 = 85%, p < 0.001). NPM1 mutations were detected in 14/21 (67%) of the CD34- LSC patients vs. just 8/77 (10%) of the patients with CD34+ LSCs ( p < 0.001). Both patients with t(9;11) had CD34- LSCs (p < 0.001), while antecedent MDS or MPN (p = 0.04) were more common in patients with ALDHhigh LSCs. Only 15/33 patients (45%) with ALDHhigh LSCs achieved complete remission, compared to 29/43 patients (69%) with ALDHint LSCs and 19/22 patients (86%) with CD34- LSCs (p < 0.01). Among patients who did not undergo allogeneic stem cell transplant, long term disease-free survival was 0% (0/6) in patients with ALDHhigh LSCs vs. 31% (4/13) with ALDHint and 62% (8/13) with CD34- LSCs (p = 0.04). Conclusions: LSC phenotype correlates with cytogenetic/molecular risk factors and response, permitting rapid risk-stratification of AML patients. This may be of particular use for patients with ALDHhigh LSCs, who appear to be at high risk – more likely to harbor adverse cytogenetic/molecular features and prove refractory to chemotherapy. Earlier identification would facilitate access to clinical trials of novel induction approaches.
Aprepitant for preventing chemotherapy-induced nausea and vomiting (CINV) in children.
Authors: Hyoung Jin Kang, Susan Loftus, Arlene Taylor, Cara DiCristina, Christian M. Zwaan, Stuart Green
Journal: Journal of Clinical Oncology (2014)

e20674 Background: The NK1 receptor antagonist aprepitant, in combination with a 5HT3-antagonist and a corticosteroid, is indicated for prevention of CINV due to highly/moderately emetogenic chemotherapy (chemo) in adults. To evaluate aprepitant for CINV prevention in children, a global, phase III, randomized, double-blind, active-comparator study was conducted in patients 6 months to 17 years (y) of age (NCT01362530). Methods: Patients 12-17 y old undergoing emetogenic chemo received aprepitant capsule 125 mg + ondansetron before chemo (Day 1) + aprepitant capsule 80 mg (Days 2-3) OR placebo (Days 1-3) + ondansetron (Day 1). Patients <12 y old received aprepitant powder-for-suspension (PFS) 3 mg/kg (up to 125 mg) + ondansetron (Day 1) + aprepitant PFS 2 mg/kg (up to 80 mg) (Days 2-3) OR placebo (Days 1-3) + ondansetron (Day 1). Dexamethasone was added at investigator discretion to either treatment regimen. The primary objective was to compare the aprepitant regimen vs the control regimen in eliciting a complete response (CR: no vomiting/retching/rescue medication) 25-120 hours (h) after chemo initiation (delayed phase) in Cycle 1. Secondary objectives included CR in the acute (0-24 h) and overall phases (0-120 h), no vomiting (NV) in the overall phase, and safety. Results: Efficacy and safety were evaluated in 152 aprepitant and 150 control patients. The proportion of patients achieving CR in the delayed phase was significantly higher for aprepitant than controls (50.7% vs 26.0%, P<0.01). A significantly greater proportion of aprepitant patients also showed CR during acute (66.4% vs 52.0%, P<0.05) and overall (40.1% vs 20.0%, P<0.01) phases, and NV in the overall phase (46.7% vs 21.3%, P<0.01). The aprepitant regimen was well tolerated; adverse events (AEs) were similar between regimens and consistent with AEs in patients undergoing chemo. Conclusions: In pediatric cancer patients 6 months to 17 y of age treated with emetogenic chemo, the 3-day regimen containing aprepitant was well tolerated and significantly more effective than the control regimen for prevention of CINV. Clinical trial information: NCT01362530.