tbuckley/cabot-search huggingface dataset:
Relevance of <i>PIG-A </i>mutation in aplastic anemia and myelodysplastic syndromes.
Authors: J. J. Pu, R. Hu, G. Mukhina, R. A. Brodsky
Journal: Journal of Clinical Oncology (2011)

6596 Background: Aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS) are acquired bone marrow failure diseases. About 15% AA eventually transform to classical PNH; however, MDS almost never evolve to classical PNH. PNH originates from a multipotent HSC that acquires a PIG-A mutation. PIG-A mutations lead to absence of glycosylphosphatidylinositol-anchor proteins (GPI-AP). About 50% AA and 10~30% MDS harbor PNH granulocytes. Methods: A prospective study of 16 AA patients and 20 MDS patients was conducted. The median age for AA patients was 49. The median age for MDS patients was 66. The PNH cells were measured by flow cytometry. Bone marrow CD34+ cells were isolated via Ficoll-Paque separation and magnetic selection. Aerolysin-containing methylcellulose culture was used to select PNH colony-forming cells (CFC). Novel T cell enrichment culture under aerolysin selection was performed to enrich PNH T cells. Genomic DNAs were extracted from individual aerolysin resistant CFC and T cell colonies and were PCR amplified and sequenced for PIG-A mutation analysis. Results: Of 12 AA patients bearing a PNH granulocyte population, the median PIG-A mutation frequency in CFC assay was 1.07%, and median CD34+ cell was 0.05%. All AA patients had normal karyotypes. PIG-A mutation analysis on 3 of them showed that all of them harboring matched PIG-A mutation in both myeloid lineage and lymphoid lineage, which suggested that PIG-A mutations occurred at multipotent HSC level. Of 20 MDS patients, 18 had hypercellular bone marrow, and 11 had abnormal karyotypes. Three (15%) had detectable PNH granulocytes, which disappeared later during 4 months of observation. The median PIG-A mutation frequency in CFC assay was 0.035%. PIG-A mutation studies identified point mutation in those PNH CFCs. However, no PNH T cells were detected in any of those MDS patients. These data suggested that PIG-A mutation in MDS arose at progenitor level and was transient. Conclusions: PIG-A mutations in AA are clonal and arise from multipotent HSC. However, PIG-A mutations in MDS arise from progenitor cells, which explains why PNH cells in MDS are transient and seldom evolve into classical PNH. Proaerolysin-selected T cell enrichment assay is a powerful measure to distinguish them.
Molecular prognostic markers in oropharyngeal squamous cell carcinoma: The role of phospho-Akt
Authors: Z. Yu, P. M. Weinberger, C. T. Sasaki, B. Haffty, R. Camp, D. Rimm, B. Burtness, A. Psyrri
Journal: Journal of Clinical Oncology (2005)

5517 Background: The serine/threonine protein kinase Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K) and has been shown to be a key regulator of various cellular processes linked to tumorigenesis, including cell cycle progression, cell survival, cell motility, angiogenesis as well as regulation of mTOR (mammalian target of rapamycin) signaling pathway. Although persistent activation of Akt Pathway in HNSCC has been reported, the prognostic significance of Akt activation in this tumor type has not been determined. We have previously reported that high EGFR tumor expression was associated with increased five-year local recurrence rate and inferior five-year disease-free survival. In the present study we investigated the relationship between phospho-Akt expression and outcome in patients with SCC of the oropharynx. We also compared phospho-Akt with previously determined EGFR expression levels. Methods: A tissue microarray including 84 specimens from primary oropharyngeal SCC cases has been constructed. Protein expression levels for phospho-Akt were analyzed using a novel system of in-situ protein expression analysis (AQUA). In this system, an anti-cytokeratin antibody conjugated to Cy3 is used to define pixels as tumor within each tissue spot. The intensity of c-Met expression is then measured using Cy5 conjugated antibody with signal amplification. Results: The top quartile of phospho-Akt expression was associated with increased local recurrence (p=0.008), inferior disease-specific mortality (p=0.0232), and overall survival (p=0.0357). In multivariate Cox regression, high phospho-Akt tumor expression was an independent predictor for local recurrence, disease-free survival and overall survival at 5 years. A significant correlation was also found between phospho-Akt and EGFR nuclear expression levels (p=0.035). Conclusions: Our results indicate that quantitative assessment of phospho-Akt tumor expression level by AQUA analysis is a strong predictor for outcome in oropharyngeal squamous cell carcinoma. We also demonstrated a correlation between phospho-Akt and EGFR nuclear expression, strengthening the evidence for a relationship between these two pathways. No significant financial relationships to disclose.
Final result of a phase I/II trial of the oral anti-angiogenesis inhibitor TSU-68 in patients with advanced hepatocellular carcinoma
Authors: F. Kanai, H. Yoshida, R. Tateishi, S. Shiina, M. Ikeda, T. Okusaka, Y. Kondo, K. Tagawa, M. Omata
Journal: Journal of Clinical Oncology (2008)

4589 Background: Advanced hepatocellular carcinoma (HCC) has a poor prognosis. Liver function needs to be considered in a clinical trial, since most patients (pts) with HCC have cirrhosis or hepatitis. Previously, we proposed a feasibility study design based on hepatic function to evaluate TSU-68, an oral multikinase inhibitor (VEGFR, PDGFR, FGFR), and determined that 400 mg/d of TSU-68, which is half of the dose for other types of cancer, was the recommended dose for phase II (Kanai et al., A4145, ASCO 2006). Here, we show the efficacy of TSU-68 in phase II and confirmed the validity of the study design. Methods: Pts previously treated with surgery, radiofrequency ablation, transcatheter arterial embolization, chemotherapy, or radiotherapy, were eligible. The primary endpoint of phase II was the objective response rate using RECIST. Nine plasma angiogenic markers were evaluated at baseline and on day 28. Results: 35 pts (12 pts in phase I and 23 pts in phase II) were enrolled: median age = 68 years, male/female = 29/6, chronic hepatitis/Child-Pugh A/B = 4/23/8, HCV/HBV/nBnC = 26/5/4, and the pts were pretreated 8.1 times on average by different modalities. Common adverse events were hypoalbuminemia, diarrhea, abdominal pain, fever, and AST/ALT elevation, and most of them were grade 1 or 2. Only one patient (pt) discontinued administration due to toxicities. One pt achieved CR, 2 pts achieved PR, 15 pts had SD, 16 pts had PD, and 1 pt was not evaluable. The response rate (CR+PR) was 8.6%, and the disease control rate (CR+PR+SD) was 51.4% (6 pts for over 6 months). Tumor necrosis was observed in 9 pts (25.7%). While the PDGF levels in the non-PD group (18 pts) did not change from baseline to day 28 (median 1,980 to 1,960 pg/ml), those of the PD group (16 pts) were significantly elevated (median 1,265 to 3,470 pg/ml). Conclusions: TSU-68 showed promising efficacy with a high safety profile, even in heavily pretreated HCC pts with Child-Pugh B liver cirrhosis. This study design with stepwise adjustment of doses based on liver function constitutes an appropriate approach for HCC. No significant financial relationships to disclose.
In silico and ex vivo approaches identify a role for toll-like receptor 4 in the biology of sporadic colorectal cancer.
Authors: D. A. Sussman, R. Santaolalla, J. Clarke, M. T. Abreu
Journal: Journal of Clinical Oncology (2011)

460 Background: Several lines of evidence suggest that the host response to bacteria plays a role in the development of colorectal cancer (CRC). Work on innate immune signaling has shown that toll-like receptor-4 (TLR4) is required for colitis-associated neoplasia in a mouse model, suggesting that TLRs may be a critical link between colonic bacteria and the development of colon cancer. The objective of the present study was to test the hypothesis that dysregulated TLR4 expression occurs in a subset of sporadic colorectal cancers. Methods: Bioinformatic and immunohistochemical approaches were used to test the hypothesis. Publicly available, online microarray data sets of gene expression data (Oncomine and Gene Expression Omnibus) were searched for information relevant to CRC. Searches were included if data sets contained human patient data with paired samples, ≥ 20 subjects per study, and use of standardized microarray platforms. Excluded searches contained patients with genetic cancer syndromes or colitis. Associations were investigated between TLR4 expression and oncogenic pathways. Staining of human CRCs for TLR4 was performed in a consecutive series of 10 patients at the University of Miami. Intensity of staining for TLR4 was calculated using immunofluorescence and NIH's ImageJ software. 5 different areas per 10x-field were quantified per tumor. Results: Heat maps were generated from the microarray data and demonstrated an increased expression of TLR4 in colon adenomas and CRCs when compared to matched samples of normal colonic mucosa. In silico, expression of TLR4 was positively correlated with expression of COX-2, β-catenin, and EGFR. By IHC, 30% of CRCs have increased TLR4 expression compared with histologically normal epithelium obtained from the tumor margins. ImageJ analysis revealed that CRC's could be segregated based on fluorescent intensity into negative, intermediate, and strongly positive samples. Conclusions: TLR4 receptor expression defines a subset of patients with sporadic CRC and is associated with expression of key oncogenic pathways. Further study is needed to establish the relationship between TLR4 and CRC outcomes. No significant financial relationships to disclose.
Sentinel lymph node biopsy for early cervical cancer. Results of a diagnostic, prospective, multicenter study
Authors: F. Lecuru, A. Bats, P. Mathevet, D. Querleu, E. Leblanc, P. Morice, E. Darai, H. Marret
Journal: Journal of Clinical Oncology (2008)

11012 Background: Sentinel lymph node (SLN) biopsy is now part of management of small solid tumors such as cutaneous melanoma or breast cancer. This approach avoids dissection of regional lymph nodes and its complications with an acceptable false-negative rate (<7%).It could be applied to cervical cancer which is the most common gynecologic cancer in the world. Methods: A multicenter prospective study has been carried out between January 2005 and June 2007. The primary objective was to assess the negative predictive value (NPV) of sentinel node biopsy in early-stage cervical cancer. Secondary objectives were to report the anatomical distribution of SLN, and the micrometastases rate in SLN. Inclusion criteria were : 1) clinical FIGO stage IA/IB1 cervical cancer, 2) histology : squamous, adenocarcinoma and adenosquamous, patients aged > 18. Non-inclusion criteria were : 1) other histological sub- types, 2) pregnancy. Patients underwent SLN identification with a combined method (technetium + Patent blue) followed by full pelvic ± para- aortic lymphadenectomy. All the procedures were performed by laparoscopy. The protocol was funded by the French National Institute of Cancer and reviewed by an IRB. Results: 145 patients were included and 18 were excluded due to deviation to the protocol, leaving 127 patients for the analysis. The detection rates (at least one sentinel node) were 122/127 (96.1%) per patient (95%CI: 91.1 to 98.7%) and 213/254 (83.9 %) per side (95%CI: 78.8 to 88.2%) with the combined detection method. The median number of SLN was 3 per patient and 1 per side. Anatomic distribution of SLN was 83.5 % external iliac, 8.5 % common iliac, 5.1% presacral and paraaortic and 2.7 % parametrial. Seven patients (5.5%) were found to have metastatic tumor to the lymph nodes (6 macro-metastases and 1 micro-metastasis). One other patient had multiple metastastic nodes, without SLN detected. There was no false-negative. Conclusion: With a very low false-negative rate, SLN biopsy detects abnormal lymphatic pathways in 16.3% of patients. In patients with positive nodes, 1/7 (14%) had only micrometastases. SLN may improve the management of early cervical cancer. This study may lead to morbidity-sparing approaches in cervical cancer treatment. No significant financial relationships to disclose.
How many patients could have a salvage local treatment after radiotherapy/brachytherapy for prostate cancer?
Authors: Christophe Hennequin, Pierre Mongiat-Artus, Eric De Kerviler, Laetitia Vercellino, Vincent Ravery, Paul Meria, Stephane Culine, Francois Desgrandchamps, Laurent Quero
Journal: Journal of Clinical Oncology (2016)

23 Background: In our institution, as soon as biochemical relapse (BR; nadir PSA + 2 ng/ml) occurred after external beam radiotherapy (EBRT) or brachytherapy (BT), 18-fluorocholine-PET-CT (18-FCH-PET) with or without multiparametric prostate MRI are performed. The aim is to select patients for a salvage local treatment (SLT) with a curative intent. We presented here the results of this approach. Methods: Records of patients with BR, without clinical evidence of relapsing disease and with at least a18-FCH-PET performed, were retrospectively reviewed. Patients were considered eligible for SLT if the relapse was only local or in case of nodal relapse reasonably encompass in a RT field. Results: Between 2010 and 2014, 89 pts were included, 23 initially treated with BT and 66 with EBRT. Prognostic group at diagnosis were: favourable: 25 (28%), intermediate: 35 (39%), unfavourable: 29 (33%). At the time of relapse, mean age was 72 yrs and mean PSA level: 6.2 ng/ml. After 18-FCH-PET ± MRI, patients were classified as: no target lesion identified: 20 (22.5%); local relapse: 35 (39%); nodal relapse: 22 (25%); distant metastases: 12 (13%.5%). Among 35 pts with a local relapse, 14 had SLT (cryotherapy:13; cyberknife:1). Reasons to not performed SLT were: advanced age or poor performance status: 10; Gleason 8-10: 2; T3 on MRI: 2; Patient refusal (fear of incontinence): 7. Among 22 pts with a nodal relapse, only 3 could have salvage EBRT. Reasons to not performed SLT were: old age or poor PS: 5; extensive nodal relapse: 8; local and nodal relapse: 6. At the end, 57 pts (64%) are potentially eligible for SLT and 17 (19%) could have it. Conclusions: In routine practice, in a population of 89 pts with a BR, 64% are eligible for SLT but 19% could have it. Main reasons for not having SLT were absence of target lesions, extensive disease, or advanced age. This result justified the realisation of an extensive staging at the time of BR after EBRT or brachytherapy.
C-reactive protein as an independent prognostic factor for metastatic gastric cancer.
Authors: Mika Kitagawa, Takaya Shimura, Tomonori Yamada, Keisuke Itoh, Chihiro Hasegawa, Takashi Kawai
Journal: Journal of Clinical Oncology (2013)

110 Background: S-1 plus cisplatin has been recognized as the standard chemotherapy for metastatic gastric cancer (MGC). Inflammation is considered to be a critical component of tumor progression. C-reactive protein (CRP) has been associated with the development of many cancers, but the significance of CRP remains unclear for MGC. The present study assessed the relationship between serum levels CRP and antitumor effects in MGC. Methods: Among 109 MGC patients who received S-1 plus cisplatin as first-line chemotherapy from January 2006 to December 2011 in 3 Japanese institutions, we retrospectively identified 70 patients who fulfilled eligibility criteria of this study. Patients were categorized into 2 groups depending on serum CRP level before chemotherapy: 43 patients with CRP &lt;1.0 mg/dl (CRP &lt;1.0 group) and 27 patients with CRP ≥1.0 mg/dl (CRP ≥1.0 group). Results: Median overall survival was significantly shorter in the CRP ≥1.0 group than in the CRP &lt;1.0 group [267 days (95% CI, 208 to 326) versus 416 days (95% CI, 325 to 507); p = 0.0007]. Moreover, progression-free survival (PFS) was significantly shorter in the CRP ≥1.0 group than in the CRP &lt;1.0 group (median PFS 126 days [95% CI, 63 to 189) versus 188 days (95% CI, 159 to 217); p = 0.0050]. Meanwhile, response rate was determined in 58 patients with target lesions. No significant differences were noted between the CRP &lt;1.0 group and the CRP ≥1.0 group (10/33, 30.3% versus 7/25, 28.0%; p = 0.663). In a multivariate analysis, serum CRP level before chemotherapy was an only independent prognostic factor for MGC (hazard ratio 3.09 (95% CI, 1.46 to 6.54); p = 0.003). Conclusions: Serum CRP level before chemotherapy might be an independent and potential prognostic factor for MGC. Stringent follow-up during chemotherapy is expected for patients with MGC and a high CRP level.
Understanding the drivers of cancer care at the regional, state, and local levels.
Authors: Ken Williams, Sarah Donovan, Eleanor Fitall, Tilithia McBride
Journal: Journal of Clinical Oncology (2012)

142 Background: Regional, state, and local variations in cancer care necessitate a more thorough understanding of the key drivers of quality at these levels. In this study, Avalere sought to understand how local quality and health information technology (HIT) infrastructures may influence the quality of care to which a cancer patient has access. Methods: Avalere conducted an analysis of the primary influencers of quality and value in each state, cataloguing over 500 public and private quality improvement organizations, including payers; employer groups; and hospitals and alternative care delivery models, such as accountable care organizations and patient-centered medical homes, among others. Recognizing the critical role that health information technology (HIT) plays in underpinning quality improvement efforts, Avalere also catalogued the primary HIT organizations in each state. From this, Avalere conducted a sub-analysis of those initiatives with a specific focus on cancer care to determine how the number of cancer-related initiatives relates to the sophistication of a region’s or state’s quality and HIT sophistication. Results: Avalere found that the sophistication of the quality and HIT infrastructures varied widely from state-to-state and region-to-region, with some areas being significantly less developed than others. Similarly, the number of cancer-related quality initiatives also varied widely, with fewer initiatives found in areas with less sophisticated quality and HIT infrastructures. In addition, major urban areas tend to have significantly more sophisticated infrastructures—and an associated higher number of cancer-related initiatives—than non-urban areas, regardless of regional or state quality or HIT trends, more generally. Conclusions: While national quality improvement efforts receive the most media attention and funding, patient care, including cancer care, is delivered at the local level. As such, in order to improve the quality and value of care cancer patients receive, it is imperative to understand and improve local quality and HIT infrastructures and the barriers to quality associated therewith. This is particularly important in locales without major urban access, such as found in large parts of the Midwest and West.
Comparison of prognosis and specific features according to tumor size in small-sized breast cancer with extensive lymph node involvement.
Authors: Hong-Seok Han, Hyun-June Paik, Jai Min Ryu, Sungmin Park, Ha Woo Yi, Suyeon Bae, Sekyung Lee, Won Ho Kil, Jeong Eon Lee, Seok Jin Nam, Seok Won Kim
Journal: Journal of Clinical Oncology (2015)

81 Background: As known, larger tumor size and more extensive lymph node (LN) involvement have been considered an independent factor for poor prognosis of breast cancer. We evaluated if very small tumor size may be a factor of worse prognosis compared to larger tumor in small sized breast cancer with LN involvement. Methods: A retrospective analysis was made in a single center of all 1400 patients with small (below 2cm, T1) sized and LN involved (N1~N3) breast cancer without metastasis diagnosed between 2004 and 2014. Their ages ranged from 23 to 88 years (mean age 49.1 ± 9.9 years) and mean follow-up was 31 months. All patients were performed with surgery including axillary LN dissection without neo-adjuvant chemotherapy. We subdivided their tumor size to 4 group (T1m, T1a, T1b and T1c) grading by 7th AJCC cancer staging. The number of patients in each group is as follows: T1m = 17, T1a = 63, T1b = 214, T1c = 1106. The specific features related to mortality were analyzed according to the minor groups and they were compared with one another by Chi-square test and Kaplan-Meier analysis. Results: Total expired patients were 39 (2.8%) and the number (the rate in each group) of the minor groups is as follows: T1m = 1 (5.9%), T1a = 1 (1.6%), T1b = 7 (3.3%), T1c = 22 (2.0%). Overall survival of smaller sized tumor groups ( ≤ 1cm, T1m+T1a+T1b) are significantly decreased than the other larger sized group T1c in T1N1 staged patients (p = 0.004). There are significant differences in estrogen receptor, progesterone receptor, nuclear grade, recurrence among the 4 minor groups in whole patients group. In the analysis of nuclear grade, the results show higher grade in T1m than T1a, T1m than T1b, T1b than T1c. Especially, recurrence of T1m is significantly more frequent than T1a (17.6% vs 3.2%, P = 0.03) or T1b (17.6% vs 4.2%, p = 0.016). Conclusions: In conclusion, this study indicates smaller sized tumor with LN involvement can progress worse compared to larger tumor. This result supports very small size can be another predictive factor for prognosis in small sized breast cancer with LN involvement.
A retrospective cohort study to determine the prognostic factors in metastatic colorectal cancer (mCRC) patients (pts) undergoing lung metastatectomy.
Authors: Francisco Socola, Dao M. Nguyen, Roberto Enrique Ochoa, Caio Max S. Rocha Lima, Peter Joel Hosein
Journal: Journal of Clinical Oncology (2013)

565 Background: Resection of liver metastases is now accepted as a potentially curative strategy in some pts with mCRC. Resection of lung metastases (LMs) may also be beneficial but this is not well established. We hypothesized that resection of LMs may lead to prolonged survival in highly selected pts with mCRC. Methods: In this IRB-approved retrospective cohort study, cases were defined as mCRC pts with LMs as their only site of disease who underwent metastatectomy. Controls consisted of mCRC pts who had LMs but did not undergo resection. Charts were reviewed for clinical characteristics; survival data was obtained from the institutional tumor registry. The primary endpoint was overall survival (OS) in the cases versus controls. The secondary endpoint was to determine prognostic factors associated with better survival. Results: We included 26 consecutive cases of mCRC undergoing resection of LMs and randomly selected 26 controls. All pts in the both groups were treated with contemporary chemotherapy, as well as bevacizumab and anti-EGFR monoclonals when appropriate. The median OS from the time of diagnosis with LMs was 29.8 months (95% CI 22.9-36.6) in the control group versus 56.6 months (95% CI 47.3-65.8) for the cases who underwent resection (log rank p=0.04). A number of baseline factors were significantly different between the cases and controls. The control group contained more pts with poorly differentiated tumors (p=0.016); had more pts with synchronous versus metachronous presentation of LM's (p=0.001); had more pts with multiple vs solitary LM's (p&lt;0.001); and had more pts with bilateral vs unilateral LMs (p&lt;0.001). The interval from initial diagnosis to the onset of LMs was significantly longer in the resection group vs controls (22.9 vs 2.9 months, p&lt;0.001). Conclusions: In this retrospective study, pts with mCRC to the lung who were referred for resection were more likely to have well differentiated, solitary, unilateral tumors, with a long interval between the original diagnosis and the onset of LMs. Pts selected using these criteria may have a significant survival benefit from surgical resection of their LMs.