Impact of primary tumor side on clinical outcomes of first-line cetuximab plus FOLFOX-4 in RAS wild-type metastatic colorectal cancer.

Aim: To examine the impact of tumor sidedness on clinical outcomes in Chinese patients with metastatic colorectal cancer treated with folinic acid/fluorouracil/oxaliplatin (FOLFOX-4) ± cetuximab in the TAILOR trial. Patients & methods: Clinical data from 391 patients were evaluated for tumor sidedness. Results: Patients with left-sided tumors who received cetuximab plus FOLFOX-4 had a significantly longer overall survival (medians: 22.0 vs 18.3 months; p = 0.007) and progression-free survival (medians: 9.3 vs 7.9 months; p = 0.006) compared with FOLFOX-4 alone. Overall survival (medians: 11.5 vs 9.4 months; p = 0.664) and progression-free survival (medians: 7.4 vs 4.5 months; p = 0.068) also improved in patients with right-sided tumors. Conclusion: Adding cetuximab to first-line FOLFOX-4 in patients with metastatic colorectal cancer improved clinical outcomes irrespective of primary tumor side.

Cetuximab is a drug used to treat people with advanced metastatic colorectal cancer (mCRC) with a gene called RAS wild-type (wt) and is given along with standard chemotherapy. The TAILOR study showed that in people with RAS wt mCRC cetuximab together with chemotherapy worked better than chemotherapy alone and had similar side effects. This analysis of the TAILOR study looked at whether Chinese people with RAS wt mCRC responded differently to treatment with cetuximab plus chemotherapy depending on the primary tumor location (whether left or right side of the colon). This analysis found that people with left- or right-sided primary tumors who received cetuximab plus chemotherapy lived longer and their cancer progressed more slowly compared with those who received chemotherapy alone.

[SENP1 induced protein deSUMO modification increased the chemotherapy sensitivity of endometrial cancer side population cells].

Objective: To inhibit the stemness maintenance potential of endometrial cancer and increase the sensitivity of endometrial cancer side population cells to chemotherapy drugs by inducing extensive deSUMOylation modification of proteins. Methods: Flow cytometry was used to sort and culture CD133(+) CD44(+) KLE endometrial cancer cell clone spheres. Protein expression level of small ubiquitin-related modifier 1 (SUMO1) and two stemness maintenance genes of tumor side population cells, octamer binding transcription factor-4 (Oct4) and sex determining region Y-box2 (Sox2), were detected by western blotting method. Lentivirus-mediated Sentrin/SUMO-specific proteases 1 (SENP1) gene was stably transfected into KLE side population cells. Western blotting was used to detect the protein expressions of SENP1, SUMO1, Oct4 and Sox2. The clone formation rate was compared between KLE side population cells with or without SENP1 overexpression. Flow cytometry was applied to detect cell cycle changes. 3-(4, 5-Dimethylthiazole-2)-2, 5-diphenyl-tetrazolium bromide (MTT) experiment and flow cytometry apoptosis method were used to detect the chemosensitivity of the side population of endometrial cancer cells to cisplatin. Tumor-bearing mouse models of endometrial cancer were established to detect the effect of SENP1 overexpression on the chemotherapy sensitivity of cisplatin. Results: Compared with CD133(-)CD44(-) KLE cells, CD133(+) CD44(+) KLE side population cells could form clonal spheres and express higher levels of SUMO1, Oct4 and Sox2 proteins (P<0.05). Compared with KLE side population cells that were not transfected with SENP1 gene, the expression level of SENP1 protein in KLE side population cells overexpressing SUMO1、Oct4 and Sox2 were lower. The clonal sphere formation rate was reduced from (25.67±5.44)% to (7.46±1.42)%, and cell cycle shifted from G(0)/G(1) phase to G(2) phase. IC(50) of cisplatin decreased from (55.46±6.14) µg/ml to (11.55±3.12) µg/ml, and cell apoptosis rate increased from (9.76±2.09)% to (16.79±3.44)%. Overexpression of SENP1 could reduce the tumorigenesis rate of KLE side population cells in vivo and increase their chemotherapy sensitivity to cisplatin (P<0.05). Conclusion: Overexpression of SENP1 can induce protein deSUMOylation modification, inhibit the stemness maintenance potential of endometrial cancer side population cells, and enhance their chemotherapy sensitivity, which provides a new reference for gene therapy of endometrial cancer.

Efficacy of 90Y-Radioembolization in Metastatic Colorectal Cancer Depending on the Primary Tumor Side.

BACKGROUND: Metastatic colorectal cancer (mCRC) is associated with different molecular biology, clinical characteristics, and outcome depending on the primary tumor localization. We aimed to evaluate the effectiveness of 90Y-radioembolization (RE) for therapy of colorectal liver metastases depending on the primary tumor side. METHODS: We performed a retrospective analysis of n = 73 patients with mCRC and RE in our university liver center between 2009 and 2018. Patients were stratified according to the primary tumor side (left vs. right hemicolon), treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) at follow-up after 3 months. Kaplan-Meier analysis was performed to analyze survival followed by Cox regression to determine independent prognostic factors for survival. RESULTS: Prior to RE, all patients had received systemic therapy, with either stable or progressive disease, but no partial or complete response. In n = 22/73 (30.1%) patients, the primary tumor side was in the right colon; in n = 51/73 (69.9%) patients, in the left colon. Hepatic tumor burden was ≤25% in n = 36/73 (49.3%) patients and >25% in n = 37/73 (50.7%) patients. At 3 months, n = 21 (33.8%) patients showed treatment response (n = 2 [3.2%]; complete response, n = 19 [30.6%]; partial response), n = 13 (21.0%) stable disease, and n = 28 (45.2%) progressive disease after RE. The median survival in case of primary tumor side in the left colon was significantly higher than for primary tumors in the right colon (8.7 vs. 6.0 months, p = 0.033). The median survival for a hepatic tumor burden ≤25% was significantly higher than that of >25% (13.9 vs. 4.3 months, p < 0.001). The median overall survival was 6.1 months. CONCLUSION: The median survival after RE in hepatic-mCRC depends on the primary tumor side and the preprocedural hepatic tumor burden.

Colon cancer survival differs from right side to left side and lymph node harvest number matter.

BACKGROUND: Right-sided colorectal cancer (CRC) has worse survival than does left-sided CRC. The objective of this study was to further assess the impact of right-side location on survival and the role of the extent of lymphadenectomy. METHODS: All CRCs diagnosed between 2000 and 2012 in Emilia-Romagna Region, Italy, were included. Data for stage, grade, histology, screening history, and number of removed lymph nodes (LN) were collected. Multivariable Cox regression models were used to estimate hazard ratios (HR), with relative 95% confidence intervals (95%CI), of right vs. left colon and of removing < 12, 12-21 or > 21 lymph nodes by cancer site. RESULTS: During the study period, 29,358 patients were registered (8828 right colon, 18,852 left colon, 1678 transverse). Patients with right cancer were more often older, females, with advanced stage and high grade, and higher number of removed LNs. Five-year survival was lower in the right than in the left colon (55.2% vs 59.7%). In multivariable analysis, right colon showed a lower survival when adjusting for age, sex, and screening status (HR 1.12, 95%CI 1.04-1.21). Stratification by number of lymph nodes removed (12-21 or > 21) was associated with better survival in right colon (HR 0.54, 95%CI 0.40-0.72 and HR 0.40, 95%CI 0.30-0.55, respectively) compared to left colon (HR 0.89, 95%CI 0.76-1.06 and HR 0.83, 95%CI 0.69-1.01, respectively). CONCLUSIONS: This study confirms that right CRC has worse survival; the association is not due to screening status. An adequate removal of lymph nodes is associated with better survival, although the direction of the association in terms of causal links is not clear.

The Effects of Primary Tumor Location on Survival after Liver Resection for Colorectal Liver Metastasis in the Mediterranean Population.

(1) Background: There is an abundance of literature available on predictors of survival for patients with colorectal liver metastases (CRLM) but minimal information available on the relationship between the primary tumor location and CRLM survival. The studies that focus on the primary tumor location and CRLM survival exhibit a great deal of controversy and inconsistency with regard to their results (some studies show statistically significant connections between the primary tumor location and prognosis versus other studies that find no significant relationship between these two factors). Furthermore, the majority of these studies have been conducted in the West and have studied more diverse and heterogenous populations, which may be a contributing factor to the conflicting results. (2) Methods: We included patients who underwent liver resection for CRLM between December 2004 and January 2019 at two university-affiliated medical centers in Israel: Carmel Medical Center (Haifa) and Rabin Medical Center (Petach Tikvah). Primary tumors located from the cecum up to and including the splenic flexure were labeled as right-sided primary tumors, whereas tumors located from the splenic flexure down to the anal verge were labeled as left-sided primary tumors. (3) Results: We identified a total of 501 patients. Of these patients, 225 had right-sided primary tumors and 276 had left-sided primary tumors. Patients with right-sided tumors were significantly older at the time of liver surgery compared to those with left-sided tumors (66.1 + 12.7 vs. 62 + 13.1, p = 0.002). Patients with left-sided tumors had slightly better overall survival rates than those with right-sided tumors. However, the differences were not statistically significant (57 vs. 50 months, p = 0.37 after liver surgery). (4) Conclusions: The primary tumor location does not significantly affect patient survival after liver resection for colorectal liver metastasis in the Mediterranean population.

Primary tumor side is associated with prognosis of colorectal cancer patients with brain metastases.

BACKGROUND: Brain metastases (BM) are a rare complication in colorectal cancer (CRC) patients and associated with an unfavorable survival prognosis. Primary tumor side (PTS) was shown to act as a prognostic and predictive biomarker in several trials including metastatic CRC (mCRC) patients. Here, we aim to investigate whether PTS is also associated with the outcome of CRC patients with BM. METHODS: Patients treated for CRC BM between 1988 and 2017 at an academic care center were included. Right-sided CRC was defined as located in the appendix, cecum and ascending colon and left-sided CRC was defined as located in the descending colon, sigma and rectum. RESULTS: Two hundred and eighty-one CRC BM patients were available for this analysis with 239/281 patients (85.1%) presenting with a left-sided and 42/281 patients (14.9%) with a right-sided primary CRC. BM-free survival (BMFS) was significantly longer in left-sided compared with right-sided CRC patients (33 versus 20 months, P = 0.009). Overall survival from CRC diagnosis as well as from diagnosis of BM was significantly longer in patients with a left-sided primary (42 versus 25 months, P = 0.002 and 5 versus 4 months, P = 0.005, respectively). In a multivariate analysis including graded prognostic assessment, PTS remained significantly associated with prognosis after BM (hazard ratio 0.65; 95% confidence interval: 0.46-0.92 months, P = 0.0016). CONCLUSIONS: PTS was associated with survival times after the rare event of BM development in CRC patients. Therefore, its prognostic value remains significant even thereafter.

Impact of Tumor Side on Clinical Outcomes in Stage II and III Colon Cancer With Known Microsatellite Instability Status.

BACKGROUND: Tumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied. METHODS: The National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan-Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received. RESULTS: A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18-90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left vs right (5-year OS 76.2 vs 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in the left vs right (5-year OS 73.2 vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 vs 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) vs 48.4% (n = 6,905), and survival was better in the left vs right (5-year OS 67.0 vs 54.4%, p < 0.001). CONCLUSION: Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.

Appraisal of Prognostic Interaction between Sidedness and Mucinous Histology in Colon Cancer: A Population-Based Study Using Inverse Probability Propensity Score Weighting.

Introduction: Colon cancer with different sidedness (right vs. left) and histology (mucinous vs. non-mucinous) may represent different disease entities. We investigated whether the prognostic values of sidedness and histology differed according to each other. Materials and Methods: We analyzed 81342 patients with stage II-IV colon cancer from the Surveillance, Epidemiology, and End Results database between 2004 and 2012. Patients were divided into four subgroups on the basis of sidedness and histology: non-mucinous right-sided, non-mucinous left-sided, mucinous right-sided, and mucinous left-sided subgroups. Among each tumor stage, median overall survival (mOS) was compared between these subgroups after inverse probability propensity score weighting to handle confounding factors. Results: In the stage IV subgroup, the prognosis for non-mucinous left-sided tumors (weighted mOS, 24.5 months) was significantly better than that for non-mucinous right-sided tumors (weighted mOS, 16.5 months; P<0.001) and that for mucinous left-sided tumors (weighted mOS, 16.5 months; P<0.001), whereas the survival was similar between left-sided and right-sided tumors with the mucinous subtype (weighted mOS, 16.5 months for both; P=0.570; test for interaction between sidedness and histology, Pinteraction <0.001), and between mucinous and non-mucinous tumors in the right-sided colon (weighted mOS, 16.5 months for both; P=0.207). Similar findings were detected in the stage III subgroup (Pinteraction <0.001). In the stage II subgroup, the survival was comparable among the four sidedness-histology subgroups (P=0.159 and Pinteraction =0.466). Conclusions: In stage III/IV colon cancer, the prognostic value of sidedness differed according to histology, and vice versa. By contrast, neither should be considered in risk stratification for stage II colon cancer.

Impact of primary tumor side on the outcomes of patients with non-metastatic colon cancer; a patient-level pooled analysis of two clinical trials.

OBJECTIVE: To assess the impact of primary tumor side on the outcomes of non-metastatic colon cancer patients included in two clinical trials. METHODS: Overall and disease-free survivals were assessed according to the side of the tumor, through Kaplan-Meier analysis. Univariate and Multivariate analysis of predictors of disease-free survival was performed through Cox regression analysis. RESULTS: Kaplan-Meier analysis of disease-free survival according to the side of the primary tumor was conducted. In the overall cohort, the right-sided disease has longer disease-free survival compared to left-sided disease (p = 0.005). When the analysis was repeated among different treatment strata (observation, adjuvant 5FU/LCV, adjuvant edrecolomab), right-sided colon cancer has longer disease-free survival among observation-treated patients only (p = 0.020). Multivariate analysis was conducted among the three subsets of adjuvant treatment. The left side of the primary tumor was predictive of worse disease-free survival in patients treated with observation only (p = 0.005) but not in patients treated with adjuvant 5FU/LCV (p = 0.345) or patients treated with adjuvant edrecolomab (p = 0.661). CONCLUSION: Stage II right-sided colon cancer patients have better disease-free survival compared to stage II left-sided colon cancer patients when treated with surgery only. This survival difference disappears if patients were treated with adjuvant fluoropyrimidines.

Does the Site of the Primary Affect Outcomes When Ablating Colorectal Liver Metastases with Radiofrequency Ablation?

PURPOSE: To determine whether primary tumor side was a predictor of radiofrequency ablation (RFA) outcome in colorectal liver metastases (CRLM). MATERIALS AND METHODS: The institutional review board approved this retrospective study. Written informed consent was obtained from all patients. From January 2007 to December 2013, 102 patients underwent RFA of metachronous CRLM were enrolled in this study with propensity score matching method. Recurrence rate (RR) and overall survival (OS) were analyzed between two patients cohorts with primary left-side colorectal cancer (LSCRC) or primary right-side colon cancer (RSCC). RESULTS: The total RR was 59.8% in all patients. Patients in LSCRC cohort had lower RR and non-local recurrence (NLR) rate than those in RSCC patients' cohort (49.0 vs 70.6%, p = 0.026 and 21.6 vs 41.2%, p = 0.033). Five-year OS was 14 and 30% for RSCC and LSCRC, respectively. There was a significant difference between two cohorts in median OS (29.4 vs 40.3 months for RSCC and LSCRC, respectively, p = 0.042). Univariate analysis showed that primary tumor side, the number of liver metastases, tumor size, carcinoembryonic antigen level, differentiation, TNM stage, active chemotherapy and RFA boundary were significant in predicting OS. When these variables were subsequently entered in a multivariate model, RSCC (p < 0.001; hazard ratio [HR], 6.2) and tumor size (> 3 cm) (p = 0.006; HR, 3.9) were significant. CONCLUSION: LSCRC and tumor size (≤ 3 cm) are independent predictors of RFA in CRLM and yield the better oncologic outcomes.

Effect of primary tumor side on survival outcomes in metastatic colorectal cancer patients after hepatic arterial infusion chemotherapy.

AIM: To analyze the survival data between patients diagnosed with right-sided primary (RSP) tumors and patients diagnosed with left-sided primary (LSP) tumors after hepatic arterial infusion chemotherapy (HAIC) at our center. METHODS: A retrospective analysis of pretreated metastatic colorectal cancer patients who received HAIC from May 2006 to August 2015 was conducted. A Cox proportional hazard regression analysis was used to assess the long-term survival outcomes. The mean and median age of patients was 61 years (range 27-85 years). There were 115 males and 53 females in our study. RESULTS: One hundred sixty-eight patients were enrolled in this study. The overall response rate was 28.9% in LSP patients and 27.3% in RSP patients. The disease control rate was 76.3% in LSP patients and 69.7% in RSP patients. The median overall survival in response to HAIC was 16.3 mo in the LSP arm and 9.3 mo in the RSP arm (P = 0.164). The median progression-free survival was 5.7 mo in the LSP arm and 4.2 mo in the RSP arm (P = 0.851). CONCLUSION: There was no significant difference in survival between LSP patients and RSP patients after HAIC. Further prospective studies are needed to confirm these findings.

DNA mismatch repair and CD133-marked cancer stem cells in colorectal carcinoma.

BACKGROUND: Except for a few studies with contradictory observations, information is lacking on the possibility of association between DNA mismatch repair (MMR) status and the presence of cancer stem cells in colorectal carcinoma (CRC), two important aspects in colorectal carcinogenesis. METHODS: Eighty (40 right-sided and 40 left-sided) formalin-fixed, paraffin-embedded primary CRC were immunohistochemically studied for CD133, a putative CRC stem cell marker, and MMR proteins MLH1, MSH2, MSH6 and PMS2. CD133 expression was semi-quantitated for proportion of tumor immunopositivity on a scale of 0-5 and staining intensity on a scale of 0-3 with a final score (units) being the product of proportion and intensity of tumor staining. The tumor was considered immunopositive only when the tumor demonstrated moderate to strong intensity of CD133 staining (a decision made after analysis of CD133 expression in normal colon). Deficient MMR (dMMR) was interpreted as unequivocal loss of tumor nuclear staining for any MMR protein despite immunoreactivity in the internal positive controls. RESULTS: CD133 was expressed in 36 (90.0%) left-sided and 28 (70.0%) right-sided tumors (p < 0.05) and CD133 score was significantly higher in left- (mean ± SD = 9.6 ± 5.3 units) compared with right-sided tumors (mean ± SD = 6.8 ± 5.6 units) p < 0.05). dMMR was noted in 14 (35%) right-sided and no (0%) left-sided CRC. When stratified according to MMR status, dMMR cases showed a lower frequency of CD133 expression (42.9%) and CD133 score (mean ± SD = 2.5 ± 3.6 units) compared with pMMR tumors on the right (frequency = 84.6%; mean score ± SD = 9.2 ± 5.0 units) as well as pMMR tumors on the left (frequency = 90.0%; mean score ± SD = 9.6 ± 5.3 units) (p < 0.05). Interestingly, frequencies of CD133 immunoreactivity and CD133 scores did not differ between pMMR CRC on the right versus the left (p > 0.05). CONCLUSION: Proficient MMR correlated with high levels of CD133-marked putative cancer stem cells in both right- and left-sided tumors, whereas significantly lower levels of CD133-marked putative cancer stem cells were associated with deficient MMR status in colorectal carcinomas found on the right.

Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls.

BACKGROUND: Brain stereotactic biopsy (SB) followed by conventional histopathology and immunohistochemistry (IHC) is the gold standard approach for primary central nervous system lymphoma (PCNSL) diagnosis. Flow cytometry (FCM) characterization of fine-needle aspiration cytology and core needle biopsies are increasingly utilized to diagnose lymphomas however, no biological data have been published on FCM characterization of fresh single cell suspension from PCNSL SB. The aim of this study was to establish the feasibility and utility of FCM for the diagnosis and characterization of brain lymphomas from a tissue samples obtained by a single SB disaggregation. METHODS: Twenty-nine patients with a magnetic resonance suggestive for PCNSL entered the study. A median of 6 SB were performed for each patient. A cell suspension generated from manual tissue disaggregation of a single, unfixed, brain SB, was characterized by FCM. The FCM versus standard approach was prospectively compared. RESULTS: FCM and IHC showed an high degree of agreement (89 %) in brain lymphoma identification. By FCM, 16 out of 18 PCNSL were identified within 2 h from biopsy. All were of B cell type, with a heterogeneous CD20 mean fluorescence intensity (MFI), CD10 positive in 3 cases (19 %) with surface Ig light chain restriction documented in 11 cases (69 %). No false positive lymphomas cases were observed. Up to 38 % of the brain leukocyte population consisted of CD8 reactive T cells, in contrast with the CD4 positive lymphocytes of the peripheral blood samples (P < 0.001). By histopathology, 18 B-PCNSL, only one CD10 positive (5 %), 1 primitive neuroectodermal tumor (PNET) and 10 gliomas were diagnosed. A median of 6 days was required for IHC diagnosis. CONCLUSION: Complementary to histopathology FCM can contribute to a better characterization of PCNSL, although necrosis and previous steroid treatment can represent a pitfall of this approach. A single brain SB is a valid source for accurate FCM characterization of both lymphoma and reactive lymphocyte population, routinely applicable for antigen intensity quantification and consistently documenting an active mechanism of reactive CD8 T-lymphocytes migration in brain lymphomas. Moreover, FCM confirmed to be more sensitive than IHC for the identification of selected markers.