Use of genetic variants in c-MET to predict clinical outcome in localized gastric cancer (GC) patients (pts) treated with surgery.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 50-50
Author(s):  
Yu Sunakawa ◽  
Takeru Wakatsuki ◽  
Wu Zhang ◽  
Dongyun Yang ◽  
Mizutomo Azuma ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Univariate Analysis ◽  
Candidate Snps ◽  
Prognostic Impact ◽  
Wide Range ◽  
The Impact

50 Background: Dysregulation of the c-MET signaling pathway occurs in a wide range of human cancers including GC. Such derangements result from various molecular mechanisms, including mutations, amplification and overexpression of c-MET. Overexpression and amplification of c-MET have been correlated with poor clinical outcomes in pts with GC. However, the association between c-MET polymorphisms and prognosis in GC is not well defined. We examined the prognostic impact of c-MET polymorphisms on clinical outcomes in pts with localized GC treated with surgery. Methods: One-hundred and sixty-one Japanese pts were included, with localized GC (stage Ib-IV) treated with surgery alone (n=58), or surgery plus adjuvant therapy (n=103) between 2002 and 2010. Median follow up was 4 years. Genomic DNA was extracted from the pts’ blood or tissue. Six functionally significant c-MET SNPs (rs1621, rs40239, rs41736, rs41739, rs184953, rs10234854) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with disease free survival (DFS) and overall survival (OS) by uni- and multivariate analyses, adjusting for age, sex, stage and type of adjuvant therapy. Results: The MET rs40239 variant was associated with favorable clinical outcomes. Univariate analysis showed pts with any G (AG/GG) allele had significantly longer DFS and OS compared to those with the AA genotype (HR: 0.43; 95% CI: 0.25-0.74; P=0.001, HR: 0.47; 95% CI: 0.27-0.81; P=0.006, log-rank test, respectively); this remained significant upon multivariate analysis (HR: 0.48; 95% CI: 0.27-0.83; P=0.009, HR: 0.50; 95% CI: 0.28-0.88; P=0.017, respectively). In the subgroup analysis by gender, men, but not women, with the AG/GG genotypes maintained a DFS and OS benefit. Conclusions: Our results show for the first time that the c-MET polymorphism, rs40239, may serve as a prognostic marker in pts with localized GC treated with surgery. There also appears to be a gender-related difference in the impact on clinical outcome by genetic variants of c-MET. Prospective validation of this study is warranted.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

P5472Social economic deprivation and adverse clinical outcomes after acute coronary syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y C Lau ◽  
J Latter ◽  
A Jong ◽  
R Weir
Keyword(s):  
Clinical Outcome ◽  
Secondary Prevention ◽  
Clinical Outcomes ◽  
Statistical Difference ◽  
Independent Predictor ◽  
Composite Endpoint ◽  
Socioeconomic Deprivation ◽  
Angiotensin Ii Receptor Blocker ◽  
The Impact

Abstract Background NHS was created in 1948 to redress the healthcare inequality through provision of universal healthcare service in the UK. However even of late, significant health inequality persists. Socioeconomic deprivation is known to result in increased overall morbidity and mortality. Aim To assess the impact of socioeconomic deprivation (as categorised by Scottish Index of Multiple Deprivation, SIMD) on the medical management and clinical outcomes of patients with ACS (NSTEMI/STEMI) who were treated with PCI Methods A retrospective study of NSTEMI/NSTEMI patients after inpatient treatment with coronary angiogram and PCI. The parameters include basic demographics, risk factors, LV EF on echocardiogram, lipid profile and discharge medication. Individual's socioeconomic deprivation index, as described SIMD was also recorded (1 – most deprived and 10 – least deprived), and accordingly placed into quintile (SIMD 1–2, 3–4, 5–6,7 –8, 9–10). Follow-up for 24 months. Clinical outcome assessed was composite endpoint event of MACE. Results 357 from the lowest quintile (SIMD 1–2), 319 from SIMD 3–4, 191 from SIMD 5–6, 120 from SIMD 7–8, and 99 from the highest quintile (SIMD 9–10) were included. No statistical difference exists between age or gender. No difference in past medical history (inclusive of hypertension, diabetes, dyslipidemia, family history. No difference in incidence of nicotine use. Prescription of aspirin, P2Y12 inhibitors (clopidogrel, ticagrelor or prasugrel) as well as secondary prevention medications (such as ace inhibitor/angiotensin II receptor blocker, beta blocker, statin and GTN) were good and not statistically different between all groups. No statistical difference exists between all groups relating to pre-discharge LV ejection fraction on echocardiogram or random cholesterol level check on admission. 24 months follow-up demonstrated composite endpoint of MACE was statistically higher among patients of lowest socioeconomic quintile (Kaplan Meier plot, p<0.001). Step-wise multiple regression analysis also confirmed multiple socioeconomic deprivation as an independent predictor for more adverse clinical outcomes (p<0.001, R2=14.5%). Patients from the least deprived quintile possess survival advantage almost 14-folds as compared to those of most deprived group (Odd-ratio 13.8 (95% CI: 39.4–48.5)). Summary After an ACS event, despite initial coronary intervention and subsequent optimal prescription of prognostically beneficial secondary prevention medications, patients from the lower socioeconomic group (as described by SIMD) are still more likely to experience readmission for cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Socioeconomic deprivation has been shown to be an independent predictor of adverse clinical outcome for those who survived initial ACS. Acknowledgement/Funding None

scholarly journals Prognostic Impact of Stromal Immune Infiltration before and after Neoadjuvant Chemotherapy (NAC) in Triple Negative Inflammatory Breast Cancers (TNIBC) Treated with Dose-Dense Dose-Intense NAC

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2657
Author(s):  
Luca Campedel ◽  
Paul Blanc-Durand ◽  
Asker Bin Asker ◽  
Jacqueline Lehmann-Che ◽  
Caroline Cuvier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative ◽  
Univariate Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
Prognostic Impact ◽  
Breast Cancers ◽  
Dose Dense ◽  
The Impact

Inflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13–3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07–3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36–3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05–3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment.

scholarly journals Mechanical Thrombectomy for Middle Cerebral Artery Division Occlusions: A Systematic Review and Meta-Analysis

2017 ◽  
Vol 6 (3-4) ◽  
pp. 242-253 ◽  
Author(s):  
Hisham Salahuddin ◽  
Aixa Espinosa ◽  
Mark Buehler ◽  
Sadik A. Khuder ◽  
Abdur R. Khan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Outcome ◽  
Middle Cerebral Artery ◽  
Clinical Outcomes ◽  
Cerebral Artery ◽  
Mechanical Thrombectomy ◽  
Meta Analysis ◽  
Total N ◽  
Clinical Databases ◽  
The Impact

Background: Middle cerebral artery division (M2) occlusion was significantly underrepresented in recent mechanical thrombectomy (MT) randomized controlled trials, and the approach to this disease remains heterogeneous. Objective: To conduct a systematic review and meta-analysis of outcomes at 90 days among patients undergoing MT for M2 middle cerebral artery (MCA) occlusions. Methods: Five clinical databases were searched from inception through September 2016. Observational studies reporting 90-day modified Rankin Scale scores for patients undergoing MT for M2 MCA occlusions with an M1 MCA control group were selected. The primary outcome of interest was good clinical outcome 90 days after MT of an M1 or M2 MCA occlusion. Secondary outcomes of interest included mortality and excellent clinical outcome, recanalization rates, significant intracerebral hemorrhage, and procedural complications. Results: A total of 323 publications were identified, and 237 potentially relevant articles were screened. Six studies were included in the analysis (M1 = 1,203, M2 = 258; total n = 1,461). We found no significant differences in good clinical outcomes (1.10 [95% CI, 0.83-1.44]), excellent clinical outcomes (1.07 [0.65-1.79]), mortality at 3 months (0.85 [0.58-1.24]), recanalization rates (1.06 [0.32-3.48]), and significant intracranial hemorrhage (1.19 [0.61-2.30]). Conclusions: MT of M2 MCA occlusions is as safe as that of main trunk MCA occlusions, and comparable in terms of clinical outcomes and hemorrhagic complications. Randomized clinical trials are needed to assess the impact of MT in patients with M2 occlusions, given that M1 MCA occlusions have different natural histories than M2 occlusions.

Prognostic Impact of Hematopoietic Recovery After Fludarabine, IV Busulfan and Antithymocyte Globulins (FB2 regimen) Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4483-4483
Author(s):  
Amandine Lebourgeois ◽  
Marion Loirat ◽  
Benoit Tessoulin ◽  
Elsa Lestang ◽  
Pierre Peterlin ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Prognostic Impact ◽  
Immune Recovery ◽  
Post Transplant ◽  
Factors Associated ◽  
Before And After ◽  
Circulating Lymphocytes ◽  
The Impact

Abstract Abstract 4483 Introduction: RIC regimens are increasingly used prior to allo-SCT. The FB2 regimen (Fludarabine 120–150 mg/m2 + IV Busulfan 6.4 mg/Kg + ATG Thymoglobuline 5mg/Kg) is currently the most widely used RIC regimen in many European centres. This retrospective analysis aimed to assess the hematopoietic and immune recovery in a homogeneously treated cohort of 53 patients (males: n=33; median age: 59 years (range: 22–70)) who received the FB2 regimen between January 2007 and October 2010 in our department. Patients and Methods: Diagnoses were as follow: AML n=23; ALL n=1; biphenotypic leukemia n=1; lymphoma n=16; myelodysplastic syndrome n=9; multiple myeloma n=3. Nineteen patients (36%) had received a prior autologous SCT. The majority of patients (n=40, 75.5%) were transplanted in complete remission. Thirty patients received a graft from a matched sibling donor (56.5%). All patients, but one (who received unmanipulated bone marrow) received G-CSF-mobilized PBSCs. GVHD prophylaxis consisted of cyclosporine (CsA) alone in patients transplanted with an HLA-identical sibling, and CsA+ mycophenolate mofetyl in other cases. None of the patients received G-CSF during aplasia following transplant while nine patients received erythropoietin before day+100. Results: Engraftment was achieved in 96% of patients (n=51). Median times for neutrophils (n=51) and platelets (n=22) recovery were 17 days (range: 0–39) and 10 days (range: 4–186), respectively. The majority of patients (n=31, 58%) did not receive platelet support during aplasia. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 30% and 15%, respectively, while overall incidence of chronic extensive GVHD was 33%. With a median follow-up of 19 months (range: 2–53), the 2-year OS, DFS, relapse incidence, and NRM were 63%, 59.5%, 35% and 6%, respectively. In univariate analysis, when regarding pre-transplant factors associated with outcome, the only factor correlated with a significantly higher 2-year OS and DFS was a higher total circulating lymphocytes count at transplant (> 730/mm3) (OS: 81.5% vs 43.2%, p=0.01; DFS: 73.2% vs 45.5%, p=0.03). Regarding post-transplant factors, we found that higher recovery of leukocytes (>5000/mm3) (2-year OS: 78% vs 46%, p=0.007; 2-year DFS: 70% vs 48%, p=0.08), neutrophils (>3230/mm3) (2-year OS: 76% vs 50%, p=0.02; 2-year DFS: 67.5% vs 52.0%, p=0.09), and monocytes (>590/mm3) (2-year OS: 80% vs 47%, p=0.004; 2-year DFS: 75% vs 42%, p=0.007) at day+30 post-transplant were the most significant factors associated with outcome. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm3; HR 0.22; 95%CI: 0.08–0.63, p=0.005; and HR: 0.29; 95%CI: 0.12–0.71, p=0.006, respectively) and a higher monocytes count at day+30 post-transplant (>590/mm3) (HR: 0.24; 95%CI: 0.08–0.66, p=0.006; and HR: 0.28; 95%CI: 0.11– 0.68, p=0.005; respectively). Conclusion: These results suggest that hematopoietic status and recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Regulation of Erythropoiesis by Histone Methyltransferase EZH2 Inhibitor 3-Deazaneplanocin A (DZNep)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 982-982
Author(s):  
Tohru Fujiwara ◽  
Haruka Saitoh ◽  
Yoko Okitsu ◽  
Noriko Fukuhara ◽  
Yasushi Onishi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Mrna Levels ◽  
Wide Range ◽  
The Impact ◽  
Chip Analysis

Abstract Abstract 982 Background. EZH2, a core component of Polycomb repressive complex 2 (PRC2), plays a role in transcriptional repression through mediating trimethylation of histone H3 at lysine 27 (H3K27), and is involved in various biological processes, including hematopoiesis. Overexpression of EZH2 has been identified in a wide range of solid tumors as well as hematological malignancies. Recent studies indicated that 3-deazaneplanocin A (DZNep), an inhibitor of EZH2, preferentially induces apoptosis in cancer cells, including acute myeloid leukemia and myelodysplastic syndromes, implying that EZH2 may be a potential new target for epigenetic treatment. On the other hand, whereas PRC2 complex has been reported to participate in epigenetic silencing of a subset of GATA-1 target genes during erythroid differentiation (Yu et al. Mol Cell 2009; Ross et al. MCB 2012), the impact of DZNep on erythropoiesis has not been evaluated. Method. The K562 erythroid cell line was used for the analysis. The cells were treated with DZNep at doses of 0.2 and 1 microM for 72 h. Quantitative ChIP analysis was performed using antibodies to acetylated H3K9 and GATA-1 (Abcam). siRNA-mediated knockdown of EZH2 was conducted using Amaxa nucleofection technology™ (Amaxa Inc.). For transcription profiling, SurePrint G3 Human GE 8 × 60K (Agilent) and Human Oligo chip 25K (Toray) were used for DZNep-treated and EZH2 knockdown K562 cells, respectively. Gene Ontology was analyzed using the DAVID Bioinformatics Program (http://david.abcc.ncifcrf.gov/). Results. We first confirmed that DZNep treatment decreased EZH2 protein expression without significantly affecting EZH2 mRNA levels, suggesting that EZH2 was inhibited at the posttranscriptional level. We also confirmed that DZNep treatment significantly inhibited cell growth. Interestingly, the treatment significantly induced erythroid differentiation of K562 cells, as determined by benzidine staining. Transcriptional profiling with untreated and DZNep-treated K562 cells (1 microM) revealed that 789 and 698 genes were upregulated and downregulated (> 2-fold), respectively. The DZNep-induced gene ensemble included prototypical GATA-1 targets, such as SLC4A1, EPB42, ALAS2, HBA, HBG, and HBB. Concomitantly, DZNep treatment at both 0.2 and 1 microM upregulated GATA-1 protein level as determined by Western blotting, whereas the effect on its mRNA levels was weak (1.02- and 1.43-fold induction with 0.2 and 1 microM DZNep treatment, P = 0.73 and 0.026, respectively). Furthermore, analysis using cycloheximide treatment, which blocks protein synthesis, indicated that DZNep treatment could prolong the half-life of GATA-1 protein, suggesting that DZNep may stabilize GATA-1 protein, possibly by affecting proteolytic pathways. Quantitative ChIP analysis confirmed significantly increased GATA-1 occupancy as well as increased acetylated H3K9 levels at the regulatory regions of these target genes. Next, to examine whether the observed results of DZNep treatment were due to the direct inhibition of EZH2 or hitherto unrecognized effects of the compound, we conducted siRNA-mediated transient knockdown of EZH2 in K562 cells. Quantitative RT-PCR analysis demonstrated that siRNA-mediated EZH2 knockdown had no significant effect on the expression of GATA-1 as well as erythroid-lineage related genes. Furthermore, transcription profiles of the genes in the quantitative range of the array were quite similar between control and EZH2 siRNA-treated K562 cells, with a correlation efficient of 0.977. Based on our profiling results, we are currently exploring the molecular mechanisms by which DZNep promotes erythroid differentiation of K562 cells. Conclusion. DZNep promotes erythroid differentiation of K562 cells, presumably through a mechanism not directly related to EZH2 inhibition. Our microarray analysis of DZNep-treated K562 cells may provide a better understanding of the mechanism of action of DZNep. Disclosures: No relevant conflicts of interest to declare.

Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10581-10581 ◽  
Author(s):  
C. Sotiriou ◽  
C. Desmedt ◽  
B. Haibe-Kains ◽  
A. Harris ◽  
D. Larsimont ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Clinical Outcome ◽  
Tumor Size ◽  
Tumor Invasion ◽  
Molecular Mechanisms ◽  
Molecular Subtypes ◽  
Proliferation Index ◽  
P Value ◽  
Prognostic Impact

10581 Background: We have recently developed several gene expression indices related to hallmarks of breast cancer involving various biological processes such as tumor invasion, impairment of immune response, sustained angiogenesis, evasion of apoptosis and self- sufficiency in growth signal, and investigated their impact on clinical outcome. Here, we aim to refine our biological understanding and the prognostic impact of these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors. Methods: Each of these indices were developed in a series of 581 BC samples and then computed on several publicly available microarray studies totaling over 2100 BC patients. Multivariate analyses were used to study the dependency patterns between these indices, the molecular subtypes and their impact on survival. Results: ER-/ERBB2- and ERBB2+ subgroups were significantly associated with high expression levels of the proliferation, tumor invasion, angiogenesis and immune response indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup, only tumor size and the proliferation and tumor invasion indices were significantly associated with clinical outcome, with the proliferation index having the largest HR and most significant p-value (HR 3.25; CI 2.31–4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only tumor size (HR 2.08; CI 1.14–3.81; p=0.01) and immune response index (HR 0.66; CI 0.46–0.95; p=0.02) were associated with prognosis whereas in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96–12.10; p=0.05) and tumor invasion index (HR 3.03; CI 1.32–6.95; p=0.009) showed significant association with survival. Of interest, proliferation index lost its significance as almost all ER- /ERBB2- and ERBB2 + tumors showed high proliferation levels. Conclusions: Although proliferation seems to be the strongest parameter predicting clinical outcome in ER+/ERBB2- subtype, immune response and tumor invasion appear to be the main molecular mechanisms associated with prognosis in the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these clinico-genomic models in the specific molecular subgroups will be the key to success for personalized medicine. No significant financial relationships to disclose.

Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3590-3590 ◽  
Author(s):  
Hagen F. Kennecke ◽  
Jason Yu ◽  
Sharlene Gill ◽  
Winson Y. Cheung ◽  
Charles Davic Blanke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Primary Tumor ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
Primary Tumors ◽  
7Th Edition ◽  
The Impact

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]

Association between single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC) and clinical outcomes in advanced gastric cancer (AGC) patients (pts) treated with taxane-based chemotherapy.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 79-79
Author(s):  
Shinichi Yamauchi ◽  
Satoshi Okazaki ◽  
Afsaneh Barzi ◽  
Wu Zhang ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Spindle Assembly Checkpoint ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Nucleotide Polymorphisms ◽  
Tissue Samples ◽  
Significant Difference ◽  
Validation Set ◽  
The Impact

79 Background: Taxanes which disrupt the microtubule function and inhibit the process of cell division have shown encouraging activity in the treatment of AGC. Resistance to these agents often becomes a problem in clinical settings and its mechanism hasn’t been dissolved conclusively. SAC is a safety device ensures the proper chromosome segregation in mitosis and is required for taxane-induced cell death. We hypothesized genetic variants in SAC genes may be associated with clinical outcomes in pts with AGC treated with taxane. Methods: Genomic DNA was isolated from blood or tissue samples of 39 U.S. pts (median age 57; median follow-up 6.4 months) for evaluation set and 39 Japanese (JPN) pts (median age 63; median follow-up 9.4 months) for validation set, with AGC treated with taxane. Twenty-five functionally significant SNPs in SAC genes (MAD1, MAD2, BUB3, BUBR1, RAN, TPX2, CDC20, AURKA, AURKB, RCC1, ANAPC10, ANAPC13) were analyzed by PCR-based direct sequencing and evaluated for association with outcomes. Results: In univariate analysis, rs4236271 (MAD1), rs6954673 (MAD1), and rs2064863 (AURKA) showed a significant difference in 6-month (mo) progression-free survival (PFS) rate [(C/C 42%, C/T 12%; HR 2.66, P=0.008), (C/C 75%, C/T or T/T 24%; HR 5.10, P=0.008), and (T/T 50%, T/G 15%, G/G 57%; HR1.55, P=0.046), respectively] and 18-mo overall survival (OS) rate [(C/C 40%, C/T 8%; HR3.69, P<0.001), (C/C 56%, C/T or T/T 19%; HR3.60, P=0.004), and (T/T 59%, T/G 15%, G/G 29%; HR 2.02, P=0.047), respectively] in evaluation set. In multivariate analysis, rs4236271 and rs6954673 remained significant in PFS (HR 7.24, P=0.005, HR 14.49, P=0.015, respectively) and OS (HR 7.39, P=0.001, HR 6.37, P=0.002, respectively). In validation set, rs6954763 showed a significant difference in 18-mo OS rate (C/C 16%, C/T or T/T 47%, HR 3.55, P=0.014), but the impact of C/C genotype on OS in the JPN pts was the opposite to the U.S. pts. Conclusions: These results suggest that MAD1 polymorphisms may serve as a prognostic marker in pts with AGC. Further studies using larger population are needed to corroborate our results.

Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 635-635
Author(s):  
Satoshi Matsusaka ◽  
Fotios Loupakis ◽  
Wu Zhang ◽  
Shu Cao ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Candidate Snps ◽  
First Line ◽  
Significant Difference

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.

Sign in / Sign up

Export Citation Format

Share Document