scholarly journals An Insight into Deficient Mismatch Repair Colorectal Cancer Screening in a Romanian Population—A Bi-Institutional Pilot Study

Medicina ◽  
2021 ◽  
Vol 57 (8) ◽  
pp. 847
Author(s):  
Cristina Lungulescu ◽  
Vlad Mihai Croitoru ◽  
Simona Ruxandra Volovat ◽  
Irina Mihaela Cazacu ◽  
Adina Turcu-Stiolica ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Univariate Analysis ◽  
Tumor Stage ◽  
Immune Checkpoints ◽  
P Value ◽  
Regional Variability ◽  
Formalin Fixed Paraffin Embedded

Background and Objectives: Colorectal cancer (CRC) can be classified as mismatch-repair-deficient (dMMR) with high levels of microsatellite instability (MSI-H), or mismatch-repair-proficient (pMMR) and microsatellite stable (MSS). Approximately 15% of patients have microsatellite instability (MSI). MSI-H tumors are associated with a high mutation burden. Monoclonal antibodies that block immune checkpoints can induce long-term durable responses in some patients. Pembrolizumab is the first checkpoint inhibitor approved in the EU to treat dMMR–MSI-H metastatic CRC. Materials and Methods: Our study assesses the regional variability of MSI-H colorectal cancer tumors in Romania. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumor samples from 90 patients diagnosed with colorectal cancer were collected from two tertiary referral Oncology Centers from Romania. Tissues were examined for the expression loss of MMR proteins (MLH1, PMS2, MSH2, MSH6) using immunohistochemistry or MSI status using polymerase chain reaction (PCR), respectively. Results: MSI-H was detected in 19 (21.1%) patients. MSI-H was located more in ascending colon (36.8% vs. 9.9%, p-value = 0.0039) and less in sigmoid (5.3% vs. 33.8%, p-value = 0.0136) than MSS patients. Most patients were stage II for MSI-H (42.1%) as well as for MSS (56.3%), with significant more G1 (40.9% vs. 15.8%, p-value = 0.0427) for MSS patients. Gender, N stage, and M stage were identified as significant prognostic factors in multivariate analysis. MSI status was not a statistically significant predictor neither in univariate analysis nor multivariate analysis. Conclusion: Considering the efficacy of PD-1 inhibitor in metastatic CRC with MSI-H or dMMR, and its recent approval in EU, it is increasingly important to understand the prevalence across tumor stage, histology, and demographics, since our study displayed higher regional MSI-H prevalence (21%) compared to the literature.

Predictive factors for early mortality after initiation of regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3560-3560
Author(s):  
Toshiki Masuishi ◽  
Toshikazu Moriwaki ◽  
Shota Fukuoka ◽  
Atsuo Takashima ◽  
Yosuke Kumekawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Mortality Rate ◽  
Metastatic Colorectal Cancer ◽  
Predictive Factors ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Early Mortality ◽  
Cox Proportional Hazards Model ◽  
P Value

3560 Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been recognized as standard treatments for patients (pts) with refractory metastatic colorectal cancer (mCRC). Because these drugs have limits on efficacy benefit for some pts, we are necessary to select pts who may be better not to receive REG or FTD/TPI. However, no reports are available on how to predict pts with early mortality after initiation of these drugs. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG or FTD/TPI. Predictive factors for early mortality (≤ 12 weeks from initiation of REG or FTD/TPI) were evaluated by multivariate analysis for survival with all variables with P values of <0.05 from the univariate analysis, using the Cox proportional hazards model. In this analysis, the pts who lived at first 15 weeks were defined as censored case. Results: A total of 523 pts (REG, 212; FTD/TPI, 311) were eligible. Predictive factors for early mortality were without primary tumor resection [adjusted hazard ratio (aHR), 1.56; p = 0.02], the low level of albumin (aHR, 2.31; p < 0.0001), the high level of CRP (aHR, 2.31; p < 0.0001), and short time from diagnosis of mCRC (aHR, 1.77; p = 0.002) by multivariate analysis. The pts harboring all these poor factors were classified into the high (H) risk of early mortality group. Two groups of pts with H and non-H were identified, with 12-week mortality rate of 39 and 14%, with 14-week mortality rate of 70 and 18%, and with median survival time (MST) of 2.9 and 7.8 months, respectively (HR of H/non-H, 4.02; p value < 0.0001). In pts treated with REG, H and non-H groups had 12-week mortality rate of 38 and 16%, 14-week mortality rate of 79 and 18%, and MST of 2.8 and 7.8 months, respectively. In pts treated with FTD/TPI, H and non-H groups had 12-week mortality rate of 41 and 13%, 14-week mortality rate of 63 and 18%, and MST of 3.2 and 7.7 months, respectively. Conclusions: Our predictive model for early mortality after initiation of REG or FTD/TPI might be useful for selecting pts who should not receive either these drugs.

Association between primary tumor site, perioperative CEA ratio, and overall survival in patients with colorectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 518-518
Author(s):  
Thomas A Odeny ◽  
Nicole Farha ◽  
Wilfred Vazquez ◽  
Amna Batool ◽  
Anwaar Saeed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Smoking Status ◽  
Tumor Stage ◽  
Tumor Location ◽  
Effect Modification ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Primary Tumor Site

518 Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on the tumor location. Emerging research suggests that the perioperative carcinoembryonic antigen (CEA) ratio is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, perioperative CEA ratio, and 5-year survival among patients with CRC. Methods: We analyzed 111 patients who underwent resection for CRC at KUMC. After excluding patients without pre- or post-operative CEA data, 62 patients for whom we could calculate a CEA ratio (post-op/pre-op CEA) were classified as either high ( ≥ 0.5) or low ( < 0.5) ratio. The primary outcomes were: 1) overall survival (OS) stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether there was effect modification by tumor location, of the association between perioperative CEA ratio and OS, after adjusting for tumor stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 61 years, 54% male, 31% smokers, 74% left-sided tumors, median pre-operative CEA was 3.3, and 60% had CEA ratio ≥ 0.5. The OS rates were 89.1% and 81.3% in patients with left-sided versus right-sided tumors respectively (p-value = 0.4). The OS rates were 83.8% and 92.0% in patients with high versus low CEA ratios respectively (p-value = 0.3). There was effect modification by tumor location on association between CEA ratio and OS, after adjusting for smoking status and tumor stage (p-value < 0.001). However, in the stratified analysis, the n was too small to permit inferential analysis. In multivariate analysis, both tumor location (HR 0.4; p = 0.3) and perioperative CEA ratio (HR 2.7; p = 0.3) were not significantly associated with OS after adjusting for smoking status and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between perioperative CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left versus right warrants validation in a larger cohort as our sample size was limited.

Association between primary tumor site, perioperative CEA ratio, smoking status, and overall survival in patients with colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15156-e15156
Author(s):  
Thomas A Odeny ◽  
Nicole Farha ◽  
Hannah Hildebrand ◽  
Jessica Allen ◽  
Wilfred Vazquez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Proportional Hazards ◽  
Smoking Status ◽  
Tumor Stage ◽  
Tumor Location ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Primary Tumor Site

e15156 Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, CEA ratio, smoking status and overall survival (OS) among patients with CRC. Methods: We analysed 323 patients who underwent resection for CRC at KUMC. After excluding those without pre- or post-operative CEA data, 162 patients were classified as either high ( > = 0.5) or low ( < 0.5) ratio. Primary outcomes were: 1) OS stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether the association between CEA ratio and OS differed by tumor location, after adjusting for stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 63 years (inter-quartile range 53-72), 61% male, 43% smokers, 73% left-sided tumors, median pre-operative CEA was 3.0 (IQR 1.5-7), and 64% had CEA ratio > = 0.5. The OS rates were 85.7% and 91.9% in patients with left-sided vs right-sided tumors respectively (log-rank p-value = 0.9). The OS rates were 83.5% and 91.5% in patients with high vs low CEA ratios respectively (log-rank p-value = 0.3). The effect of CEA ratio on OS was significantly different when stratified by tumor location (p-value for interaction < 0.001). However, in the stratified analysis, the n was too small to permit further inferential analysis. In multivariate analysis, both tumor location (HR 0.6; p = 0.5) and CEA ratio (HR 1.5; p = 0.5) were not significantly associated with OS after adjusting for smoking status and tumor stage. Smoking was significantly associated with higher rates of death (HR 3.9; p = 0.04) when adjusted for tumor location, CEA ratio, and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left vs right warrants validation in a larger cohort as our sample size was limited. Smoking increases mortality irrespective of right vs left sided CRC.

scholarly journals Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

2021 ◽  
Vol 22 (8) ◽  
Author(s):  
Federica Pecci ◽  
Luca Cantini ◽  
Alessandro Bittoni ◽  
Edoardo Lenci ◽  
Alessio Lupi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Tnm Classification ◽  
Standard Of Care ◽  
First Line Therapy ◽  
Combination Strategies ◽  
The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

scholarly journals Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

ESMO Open ◽  
2021 ◽  
Vol 6 (3) ◽  
pp. 100120
Author(s):  
A. Guyot D'Asnières De Salins ◽  
G. Tachon ◽  
R. Cohen ◽  
L. Karayan-Tapon ◽  
A. Junca ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Molecular Testing ◽  
Mismatch Repair Proteins

P1018Evolution of atrioventricular conduction disorders after TAVI

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Irles ◽  
F Salerno ◽  
R Cassagneau ◽  
R Eschallier ◽  
C Maupain ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Primary Endpoint ◽  
Univariate Analysis ◽  
P Value ◽  
Conduction Disorders ◽  
Av Conduction ◽  
One Year ◽  
The One ◽  
Valve Implantation

Abstract Background The evolution of atrioventricular block (AVB) after Trans Aortic Valve Implantation (TAVI) is poorly understood, and indications of pacemaker (PM) implantation after TAVI not well defined. Modern PM algorithms can help studying the evolution of these AV conduction disorders after TAVI. SafeR® mode (Sorin® PM) allows to monitor precisely the AV conduction and to store AVB episodes in the PM memory as intracardiac electrograms, which can be re-read and validated afterwards. Methods From November 2015 and January 2017, all patients implanted in one of the 19 French enrolling centers with a Sorin® PM set in SafeR® mode after TAVI could be prospectively included in the study. All the PM interrogation files were centrally collected. The primary endpoint (PE) was the presence of at least one episode of high grade AVB (HG-AVB) beyond day 7 (D7) to one year after the TAVI. It could be validated either by the presence of a HG-AVB on EKG or telemetry, or by the confirmation of a HG-AVB in the PM memory files. Results 273 patients were included in the study, the PE was assessable in 197 patients. PE was validated in 74.6% patients. In univariate analysis, the use of an oversized prothesis or balloon, and all early episodes of HG-AVB (all those occurring up to D7) influence the validation of the PE. Other AV conduction disorders have no influence on the PE (Table). In multivariate analysis, only HG-AVB occurring between D2 and D7 has a significant influence on the PE. Factors influencing HG-AVB after TAVI Studied factor HG-AVB episode(s) during the one year follow up No HG-AVB episode during the one year follow up p value RBBB before TAVI (%) 41 34 0,346 Low implantation (>6mm) (%) 59 37 0,156 Use of Autoexpansive Valve (%) 62 62 0,990 Oversizing (%) 19 6 0,022 HG-AVB per TAVI (%) 56 30 0,001 HG-AVB D0-D1 (%) 53 24 0,001 HG-AVB D2-D7 (%) 68 34 0,001 New or wiser LBBB and improvement of PR interval after TAVI (%) 30 39 0,253 Influence of predefined factors on the Primary Endpoint. Conclusion The analysis of the SafeR® algorithm files in patients implanted with a PM after TAVI show a high incidence of HG-AVB during the one year follow up. In multivariate analysis, only HG-AVB occurring between D2 and D7 significantly influence the PE, confirming that AV conduction disorders occurring during the first 24 hours may spontaneously normalize. Acknowledgement/Funding Microport CRM

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