tbuckley/cabot-search huggingface dataset:
Prediction of response of locally advanced breast cancer (LABC) to neoadjuvant anthracycline chemotherapy using <sup>99m</sup>Tc-sestamibi
Authors: P. Ang, C. Balram, P. H. Tan, E. E. S. Ang, S. C. Ong, Z. W. Wong, E. Lim, Q. Y. Zhou, G. H. Ho
Journal: Journal of Clinical Oncology (2005)

2100 Background: P-glycoprotein (Pgp) is an ATP-dependent efflux membrane transporter that confers multidrug resistance in cancer cells. It has been shown that the efflux rate of technetium 99mTc-sestamibi, a transport substrate of Pgp, is directly correlated with Pgp levels in untreated breast carcinoma. We performed an exploratory study to investigate whether efflux rates of 99mTc-sestamibi correlates with response to neoadjuvant anthracycline chemotherapy in LABC. Methods: Following IV 25 mCi of 99mTc-sestamibi, pixel counts of both tumor (T) and corresponding normal contralateral breast (B) were acquired at 10 (B10,T10) and 120 (B120, T120) mins. The retention index (RI) was calculated as the ratio of (B120/T120) and (B10/T10). Neoadjuvant doxorubicin/epirubicin and cyclophosphamide given 3 weekly was administered following a baseline 99mTc-sestamibi scan. Response was evaluated after at least 3 cycles of anthracycline chemotherapy. Results: 23 patients with LABC were accrued. The median age was 50 years (range 29 to 74). The median tumor size was 7.5cm (range 5 to 13 cm). A good response to anthracycline chemotherapy was achieved in 57% of pt (4 CR, 9 PR, 9 SD, 1 PD). The median RI was 0.873 (range: 0.318 to 1.000). The RI were similar in patients with CR, PR and SD (0.829, 0.839 and 0.865, respectively). The lowest RI (0.318) was found in a patient with PD. Conclusions: This exploratory study shows that the RI of 99mTc-sestamibi may be used to predict, at least in part, for poor response to neoadjuvant anthracycline chemotherapy in LABC patients. However, in patients achieving CR, PR or SD, the RI of 99mTc-sestamibi does not seem to be distinctly predictive of the type of response achieved. No significant financial relationships to disclose.
Molecular profiling of triple-negative endometrial cancers (TNEC) and triple-negative breast cancers (TNBC) to reveal unique expression profiles.
Authors: Nathaniel L. Jones, Joanne Xiu, Sandeep K. Reddy, Jason Dennis Wright, William M. Burke, Ana Isabel Tergas, June YiJuan Hou
Journal: Journal of Clinical Oncology (2015)

159 Background: “Triple negative” has been used to characterize a subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. They are aggressive cancers with limited treatment options. It’s unknown if similar phenotype found in other cancer types, like endometrial cancer, harbor similar molecular alterations and prognosis. We aim to compare molecular features between TNEC and TNBC. Methods: A total of 3133 endometrial cancer samples were evaluated by Caris Life Sciences (Phoenix, AZ) from Mar, 2011 to Jul, 2014 by multiplatform profiling, which included a combination of sequencing (Sanger or NGS), protein expression (IHC), and/or gene amplification (CISH or FISH). 545 TNEC and 2049 TNBC were identified based on reported pathology and compared using Fisher exact tests. Results: Compared to an incidence of 15-20% TNBC in breast cancer, 17% (545/3133) TNEC was seen in our cohort, of which 13% were endometrioid, 22% serous, 26% carcinosarcoma, 7% clear cell, and 22% other. Compared with TNBC, TNEC showed 1.9 exonic mutations per case while TNBC showed 1.2 mutations per case. As shown in the table, AR expression is lower in TNEC than TNBC. TP53 mutation was common in both but more frequent in TNBC. While BRCA1/2 mutation rates were similar, low MGMT and ERCC1 were more common in TNEC, suggesting increased aberrant DNA repair. DNA synthesis protein expression was higher in TNEC including TS, RRM1, and TOPO2A, although TNBC had higher TOPO1. PD-1 expression was more common in TNEC suggesting immune pathway involvement. PI3K/AKT/mTor, MAPK and Wnt pathways were more involved in TNEC with greater PTEN, PIK3CA, FBXW7, KRAS and CTNNB1 mutations. Conclusions: Our study reveals significantly higher overall mutation rates in TNEC than TNBC, and specifically higher activations of multiple molecular pathways including PI3K/Akt/mTor, MAPK and Wnt. Further studies are warranted to validate these findings in clinical trials.
C-Type Lectin Receptor Mediated Immune Recognition of ADAMTS13 Promotes HLA-DRB1*11 Dependent Presentation of CUB1-2 Derived Peptides by Dendritic Cells
Authors: Nicoletta Sorvillo, Simon D van Haren, Wouter Pos, Eszter Herczenik, Rob Fijnheer, Luisa Martinez-Pomares, Teunis B Geijtenbeek, Alexander B Meijer, Jan Voorberg
Journal: Blood (2011)
Results of a phase I/II trial of amrubicin (AMR) in combination with cisplatin (CDDP) as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC).
Authors: T. Seto, Y. Ichinose, N. Yamamoto, K. Kaira, S. Negoro, T. Hida, K. Takeda, N. Masuda, S. Yokota, M. Fukuoka
Journal: Journal of Clinical Oncology (2010)

7586 Background: Amrubicin (AMR), a totally synthetic 9-aminoanthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. We investigate the recommended doses (RD) of AMR in combination with CDDP in a phase I trial, and assess the efficacy and safety in a phase II trial in Japanese patients with advanced NSCLC. Methods: In the phase I trial, patients with advanced NSCLC, with no history of previous chemotherapy, an ECOG performance status (PS) 0–1 and adequate organ functions were eligible. Patients were to receive AMR 35 mg/m2 for 3 successive days IV and CDDP 60 mg/m2 on day 1 (level 1) and AMR 35 mg/m2 for 3 successive days IV and CDDP 80 mg/m2 on day 1 (level 2) every 3 weeks. In the phase II trial, the primary endpoint was objective tumor response rate (ORR, by RECIST). Secondary endpoints included time to progression (TTP) and overall survival (OS). Results: In the phase I trial, six patients were enrolled in each of the level 1 and level 2. treatments. The RD was AMR 35 mg/m2 × 3 days and CDDP 80 mg/m2 (level 2) every 3 weeks. In the phase II trial, the ORR was 23.4% (11/47, CR in 0%, PR in 23.4%). The median TTP was 6.2 months, and the 1-year survival rate was 73.5%. In the safety population (n = 47), the most common grade 3 or 4 adverse events were neutropenia (93.6%) and febrile neutropenia (29.8%). Conclusions: AMR delivers a significant improvement on ORR of 23.4 %, and promising activity on TTP, and on the 1-year survival rate. Furthermore, it has an acceptable safety profile in advanced NSCLC patients at the dose of AMR 35 mg/m2x3 days IV and CDDP 80 mg/m2 on day 1 every 3 weeks. No significant financial relationships to disclose.
Effect of helicobacter pylori on prognosis of curatively resected gastric cancers in a population with high prevalence: Short-term results of a prospective study.
Authors: H. Hur, J. Y. Kim, Y. B. Kim, Y. A. Lim, Y. K. Cho, S. U. Han
Journal: Journal of Clinical Oncology (2011)

152b Background: Although two prospective studies reported that negative H pylori is associated with good prognosis in Western countries, these results are not generally acceptable due to regional differences in H pylori virulence and incidence of gastric cancer. Here, we prospectively assessed the correlation between H pylori status of patients who underwent curative resection for treatment of gastric adenocarcinoma and their prognosis in Korea, where H pylori is highly prevalent in the population. Methods: Between 2006 and 2007, 192 patients who had undergone curative resection for treatment of gastric adenocarcinoma were prospectively enrolled. Of these patients, 18 patients were excluded due to inexact evaluation of H pylori status, and 174 patients were finally analyzed. Serologic testing for H pylori was assessed using an enzyme-linked immunosorbent assay kit for IgG, and histological presence was identified using Giemsa stain. Results: Of 174 patients, 111 patients (63.8%) who showed both serologically and histologically positive results were confirmed as having positive H pylori infection. H pylori status was not correlated with overall or disease-free survival. In term of patients who were diagnosed with AJCC stage III or IV, disease-free survival of patients with positive H pylori status was a significant predicting factor for recurrence longer than that of negative patients (p = 0.019). Negative H pylori status became a predicting factor for recurrence in multivariable analysis (RR = 2.724, 95% C.I.: 1.192-6.228). Conclusions: H pylori status did not show correlation with clinicopathologic factors of gastric adenocarcinoma in Korea. However, negative H pylori may be a predictive factor for recurrence in patients diagnosed with gastric adenocarcinoma of advanced status. Therefore, in H pylori endemic areas, patients diagnosed with locally advanced gastric cancer accompanied by negative H pylori status should be considered for an aggressive treatment strategy and close follow-up. In addition, correlation in an early stage should be confirmative through the results of longer follow-up. No significant financial relationships to disclose.
Cyclin-dependent kinase 4/6 inhibition for the treatment of mature teratoma germ cell tumor: Long-term follow-up of a phase II study.
Authors: Vivek Narayan, Wei-Ting Hwang, Priti Lal, Mark Alan Rosen, Maryann Gallagher, Peter J. O'Dwyer, David J. Vaughn
Journal: Journal of Clinical Oncology (2016)

474 Background: We have previously reported the results of a phase II clinical trial evaluating the safety and efficacy of palbociclib for the treatment of patients with unresectable germ cell tumors, including mature teratoma, teratoma with malignant transformation, and non-teratomatous tumors. In an effort to better assess the efficacy of palbociclib, we now report long-term follow-up of a more homogeneous population of patients with unresectable mature teratoma treated on the phase II clinical trial, with an emphasis on clinically-relevant endpoints for this incurable patient population. Methods: This was a retrospective analysis with long-term follow-up of the patient cohort with mature teratoma treated on the phase II study of palbociclib for the treatment of retinoblastoma protein-expressing germ cell tumors. Patient clinical data was obtained from the medical records and from communication with the enrolled patients and referring medical providers. Major medical events for the treatment of germ cell tumor, including before, during, and after study treatment, were recorded. Clinical events of interest included the initiation of systemic therapy, radiation therapy, surgical debulking, or other invasive procedures. Study endpoints included pre-study and post-study clinical event rates, event-free survival, and radiographic progression-free survival. Results: Long-term follow-up was obtained for 12 patients with mature teratoma. The median pre-study follow-up time was 19.7 months, and the median post-study follow-up time was 38.0 months. The median number of palbociclib treatment cycles was 11. The pre-study clinical event rate was 2.27 events/year (95% CI 1.66 – 3.13), and the post-study event rate was 0.62 events/year (95% CI 0.36 – 1.09). The median progression-free survival was 5.3 months (95% CI 1.8 – 22.6), and the median event-free survival was 16.2 months (95% CI 3.0 – 24.3). Conclusions: The initiation of palbociclib resulted in a clinically-meaningful delay in disease-related major clinical events and radiographic progression. These findings lend further support to the therapeutic activity of CDK4/6 inhibition in this incurable patient population.
Variations in treatment modality use for the definitive management of prostate cancer in the United States.
Authors: Jay P. Ciezki, Chandana A. Reddy, James Ulchaker, Kenneth Angermeier, Kevin L. Stephans, Rahul D. Tendulkar, Andrew J. Stephenson, Nabil Chehade, Andrew Altman, Eric A. Klein
Journal: Journal of Clinical Oncology (2013)

174 Background: No prospective, randomized comparative efficacy trial exists to guide treatment of definitively managed prostate cancer patients. Despite this, treatment selection varies nationally and we attempt to assess these patterns of use. Methods: The SEER database was queried to identify cases of prostate cancer diagnosed between 1998-2008. The modalities identified were brachytherapy (brachy), combination of brachytherapy and external beam radiation (CombRT), external beam radiotherapy (EBRT), radical prostatectomy and external beam radiotherapy (RP+RT), and radical prostatectomy (RP). The number of cases by year, patient age and SEER region was computed. Results: There were 361,135 men in this analysis: 12.4% brachy, 6.8% CombRT, 27.5% EBRT, 3.1% RP+RT, and 50.3% RP. As expected, treatment modality varied by age with younger men more likely to receive RP and older man more likely to receive EBRT or brachy. There was some variation in choice of treatment modality over time: 6.6% for brachy; 4.2% for CombRT; 1.9% for EBRT; 2.0% for RP+RT; and 7.8% for RP. The variation in treatment modality by region was surprisingly wide (table): 14.4% for brachy; 25.5% for CombRT; 28.5% for EBRT; 3.8% for RP+RT; and 26.8% for RP. Conclusions: Choice of prostate cancer treatment modality varies by age, year of treatment, and most notably geographical region. Surprisingly the changes in reimbursement rates over the study period seem to have had minimal impact on choice of treatment modality. The regional variation implies that affiliations among healthcare providers significantly impact treatment. [Table: see text]
Association of adiponectin in <i>patatin-like phospholipase domain-containing 3 (PNPLA3</i>) associated hepatic steatosis.
Authors: Muhammad Shaalan Beg, Amit G. Singal, Colby Ayers, Sadia Saleem, Jorge A. Marrero, Adam C. Yopp, Philipp Scherer, Aslan Turer
Journal: Journal of Clinical Oncology (2014)

184 Background: The I148M polymorphism (rs738409) of the patatin-like phospholipase domain-containing 3 (PNPLA3) gene is strongly associated with hepatic triglyceride content (HTGC) and the development of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), which are themselves risk factors for hepatocellular cancer (HCC). Serum adiponectin affects insulin resistance and carcinogenesis and has also been associated with HTGC. Whether these risk factors are additive in predisposing to HTGC is unknown. We evaluated the impact of adiponectin and PNPLA3 genotypes on HTGC in a large community cohort. Methods: The Dallas Heart Study (DHS) is a multi-ethnic population based study of Dallas County residents. HTGC was quantified using H-MR spectroscopy. Univariate and multivariable logistic and linear regression models were generated to test the association between HTGC and log adiponectin stratified by PNPLA3 genotype (CC, CG and GG). Models were adjusted for age, gender, race, hypertension, diabetes, HOMA-IR and BMI. Results: There were 2,259 patients who had complete clinical, biochemical, imaging, and genotyping data and were included in this analysis. Median age was 44 and 47% were male. Race distribution was 48% Black, 32% White, and 18% Hispanic. The prevalences of PNPLA3 genotypes were 61% CC (wild type), 32% GC and 7% GG. The median concentration of adiponectin was 6.6 ug/ml. Adiponectin was an independent predictor HTCG across all genotypes after adjusting for covariates (CC b=-0.34, GC b=-0.42, GG b=-0.38, p&lt;0.005 for each). HTGC decreased across gender and race-stratified quartiles of adiponectin for each PNPLA3 genotype, and the qualitative effect was greatest in the I148M homozygotes (table). Conclusions: Adiponectin is independently associated with hepatic steatosis across all three PNPLA3 genotypes. The combination of at-risk PNPLA3 genotypes and hypoadiponectemia is associated with a high risk of hepatic steatosis. Future studies will need to address downstream HCC risk and whether manipulation of adiponectin level may be of clinical benefit. [Table: see text]
In vitro and in vivo evaluation of sunitinib eluting beads.
Authors: Pierre E. Bize, Olivier Jordan, Katrin Fuchs, Olivier Dormond, Rafael Duran, Eric Doelker, Thierry De Baere, Alban Denys
Journal: Journal of Clinical Oncology (2013)

246 Background: Chemoembolization is used to treat liver malignancies. However recurrence occurs frequently, possibly because of neoangiogenesis triggered by ischemia caused by the embolic agent. In this context, the combination of an embolic agent with an anti-angiogenic drug seems appealing. This study characterizes the in vitro loading and release profile of sunitinib eluting beads of different sizes and their pharmacokinetic profile in a rabbit model. Methods: 70-150 μm and 100-300 μm drug eluting beads (DC Bead, Biocompatibles UK) were loaded by incubation in a sunitinib hydrochloride solution. Drug was quantified by spectrophotometry at 430 nm. Drug release was measured over one-week periods and normalized using an internal standard in 30% ethanol in NaCl 0.9%. New-Zealand white rabbits were used. Eight animals received 0.2 ml of 100-300 μm DC Bead loaded with 6 mg of sunitinib in the hepatic artery (group 1) and 4 animals received 6 mg of sunitinib p.o. (group 2). Half of the animals were sacrificed after 6 hours and half after24 hours. Liver enzymes were measured at 0, 6 and 24 hours in both groups. Plasmatic sunitinib concentration was determined by tandem mass spectroscopy (LC MS/MS) at 0, 1, 2, 3, 4, 5, 6 and 24 hours. At sacrifice, the livers were harvested and sunitinib concentration in liver tissue was assessed by LC MS/MS. Results: High drug loading was obtained for both microsphere bead sizes. Particle shrinking was observed with adsorption of sunitinib. Almost complete release of sunitinib was detected under physiological conditions, with very similar release for 70-150 μm and 100-300 μm (t 50% =1.2 h) DC Bead. Conclusions: Sunitinib eluting beads are well tolerated by rabbits when administered in the hepatic artery. No unexpected toxicity was observed. Very high drug concentration can be obtained at the site of embolization with minimal systemic passage.
Toxin-positive <i>Clostridium difficile</i> latently infect mouse colonies and protect against highly pathogenic <i>C. difficile</i>
Authors: Lucie Etienne-Mesmin, Benoit Chassaing, Oluwaseyi Adekunle, Lisa M Mattei, Frederic D Bushman, Andrew T Gewirtz
Journal: Gut (2017)

Objective Clostridium difficile is a toxin-producing bacterium and a leading cause of antibiotic-associated disease. The ability of C. difficile to form spores and infect antibiotic-treated persons at low multiplicity of infection (MOI) underlies its large disease burden. However, C. difficile -induced disease might also result from long-harboured C. difficile that blooms in individuals administered antibiotics. Design Mice purchased from multiple vendors and repeatedly testing negative for this pathogen by quantitative PCR bloomed C. difficile following antibiotic treatment. This endogenous C. difficile strain, herein termed LEM1, which formed spores and produced toxin, was compared with highly pathogenic C. difficile strain VPI10463. Results Whole-genome sequencing revealed that LEM1 and VPI10463 shared 95% of their genes, including all known virulence genes. In contrast to VPI10463, LEM1 did not induce overt disease when administered to antibiotic-treated or germ-free mice, even at high doses. Rather, blooms of LEM1 correlated with survival following VPI10463 inoculation, and exogenous administration of LEM1 before or shortly following VPI10463 inoculation prevented C. difficile -induced death. Accordingly, despite similar growth properties in vitro, LEM1 strongly outcompeted VPI10463 in mice even at 100-fold lower inocula. Conclusions These results highlight the difficulty of determining whether individual cases of C. difficile infection resulted from a bloom of endogenous C. difficile or a new exposure to this pathogen. In addition to impacting the design of studies using mouse models of C. difficile -induced disease, this study identified, isolated and characterised an endogenous murine spore-forming C. difficile strain able to decrease colonisation, associated disease and death induced by a pathogenic C. difficile strain.
Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence of menopausal status and age on treatment effects.
Authors: Helen Marshall, Walter Gregory, Richard Bell, David A. Cameron, David John Dodwell, Maccon M. Keane, Miguel J. Gil Gil, Claire Davies, Robert Edward Coleman
Journal: Journal of Clinical Oncology (2012)

502 Background: The AZURE trial evaluated the use of zoledronic acid (ZOL) in addition to standard adjuvant therapy in patients with stage II/III breast cancer. Although analysis of the primary endpoint in the total study population showed no significant effects on disease outcomes, pre-specified subgroup analyses identified significant benefit in both invasive disease-free survival (IDFS) and overall survival (OS) in women &gt;5years postmenopause (Coleman et al. NESM. 2011;365:1396–1405). Here we evaluate the treatment modifying effects of both menopausal status and age. Methods: 3360 patients were randomized to receive standard (neo) adjuvant systemic therapy +/- ZOL 4mg iv every 3-4 weeks for 6 doses, then at reduced frequency to complete 5 years treatment. Results: ZOL had no overall effect on IDFS or OS at a median follow-up of 59 months. Pre-specified subgroup analyses showed significant heterogeneity of treatment effect (chi 2 1 =7.91; p=.0049) on IDFS between those who were &gt;5 years post-menopause (n=1041; adjusted HR= 0.75; 95% CI 0.59-0.96, p=0.02) and all other (pre, peri and unknown status) menopausal groups (n=2318; adjusted HR= 1.15; 95% CI 0.97-1.36, p=0.11). The treatment interaction between the two menopausal groups was related to differences in first extra-skeletal IDFS events (chi 2 1 = 14.00, p=0.0002), rather than first recurrence in bone (chi 2 1 = 0.14, p=0.70). In women aged &lt;40, a significant worsening in extra-skeletal IDFS events was seen (HR = 1.68; 95% CI = 1.14-2.47, p=.008). Although the ZOL effect on IDFS improved by age from a negative effect in younger patients (&lt;40) to a beneficial effect for those aged 54 and over (chi 2 1 (trend) = 5.96, p=0.015, using Cox model analysis to test for an interaction effect between age, menopausal status and treatment for IDFS (using age 55 as a cut-off) showed that the age effect is reversed by menopausal status, with this model providing a significantly better fit (chi 2 2 = 22.8, p=.00001) than the aforementioned linear model. Conclusions: These results suggest menopausal status is more informative than age in the selection of patients for treatment with ZOL. In women aged &lt;40, ZOL may increase extra-skeletal recurrence.