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  • 1
    In: Aging Clinical and Experimental Research, Springer Science and Business Media LLC, Vol. 35, No. 10 ( 2023-08-25), p. 2219-2225
    Type of Medium: Online Resource
    ISSN: 1720-8319
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2119282-0
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  • 2
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 29, No. 3 ( 2023-03), p. 605-614
    Abstract: Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 ( KRAS G12 ) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS G12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS / RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial ( n  = 800 patients) and found that KRAS G12 mutations ( n  = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P  = 0.0031, adjusted interaction P  = 0.015). For patients with KRAS G12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo ( n  = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P  = 0.85). In contrast, patients with KRAS G13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo ( n  = 60; HR = 0.29; 95% CI = 0.15–0.55; P   〈  0.001). In isogenic cell lines and patient-derived organoids, KRAS G12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS G12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1484517-9
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  • 3
    In: Cancers, MDPI AG, Vol. 14, No. 22 ( 2022-11-09), p. 5513-
    Abstract: Colorectal cancer (CRC) patients frequently develop liver metastases. Different treatment strategies are available according to the timing of appearance, the burden of metastatic disease, and the performance status of the patient. Systemic treatment (ST) represents the cornerstone of metastatic disease management. However, in select cases, combined ST and surgical resection can lead to remarkable survival outcomes. In the present multicentric cohort study, we explored the efficacy of a conversion strategy in a selected population of left-sided RAS/BRAF wild-type CRC patients with liver-limited metastatic disease. Methods: The primary endpoint was to compare survival outcomes of patients undergoing ST not leading to surgery, liver resection after conversion ST, and hepatic resection with perioperative ST. Furthermore, we explored survival outcomes depending on whether the case was discussed within a multidisciplinary team. Results: Between 2012 and 2020, data from 690 patients respecting the inclusion criteria were collected. Among these, 272 patients were deemed eligible for the analysis. The conversion rate was 24.1% of cases. Fifty-six (20.6%) patients undergoing surgical resection after induction treatment (i.e., ultimately resectable) had a significant survival advantage compared to those receiving systemic treatment not leading to surgery (176 pts, 64.7%) (5-year OS 60.8% and 11.7%, respectively, Log Rank test p 〈 0.001; HR = 0.273; 95% CI: 0.16–0.46; p 〈 0.001; 5-year PFS 22.2% and 6.3%, respectively, Log Rank test p 〈 0.001; HR = 0.447; 95% CI: 0.32–0.63; p 〈 0.001). There was no difference in survival between ultimately resectable patients and those who had liver resection with perioperative systemic treatment (potentially resectable—40 pts) (5-year OS 71.1%, Log Rank test p = 0.311. HR = 0.671; 95% CI: 0.31–1.46; p = 0.314; 5-year PFS 25.7%, Log Rank test p = 0.305. HR = 0.782; 95% CI: 0.49–1.25; p = 0.306). Conclusions: In our selected population of left-sided RAS/BRAF wild-type colorectal cancer patients with liver-limited disease, a conversion strategy was confirmed to provide a survival benefit. Patients not deemed surgical candidates at the time of diagnosis and patients judged resectable with perioperative systemic treatment have similar survival outcomes.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 4
    In: Cancers, MDPI AG, Vol. 12, No. 7 ( 2020-07-01), p. 1749-
    Abstract: Background: Guidelines recommend a perioperative approach in patients with stage II/III gastric cancer, but in real-life many patients receive immediate surgery followed by adjuvant chemotherapy (aCT). Although histologic subtypes may have different response to CT, no study has explored the influence of histotype on the efficacy of perioperative CT (pCT) or aCT. Materials and methods: The objective of the study was to evaluate the impact of clinicopathological features and histology (intestinal or diffuse) on survival according to strategy (pCT vs. aCT). The primary endpoint was overall survival (OS) and the secondary endpoint was event-free survival (EFS). Results: Out of 203 patients affected by LAGC, 83 received pCT and 120 aCT. At multivariate, histology and LVI in pCT cohort and positive resection margin in the aCT influenced both OS and EFS. No difference in EFS and OS was observed in relation to strategy. However, in the intestinal-type of pCT cohort survival outcomes were significantly higher compared to the aCT cohort, whereas in the diffuse-type were significantly worse in patients receiving pCT compared to those receiving aCT. Conclusions: Although retrospective and small-sized, this study suggests that the benefit of pCT might be limited to the intestinal-type. This hypothesis needs to be confirmed in prospective series.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 5
    In: Cancers, MDPI AG, Vol. 13, No. 9 ( 2021-04-27), p. 2098-
    Abstract: Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age 〈 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 4082-4082
    Abstract: 4082 Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, which a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to primary tumor site in third line. Methods: Pts affected by RAS/BRAF wt mCRC treated with third-line anti-EGFR-based tx or R/T were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to tumor site. Primary endpoint was PFS; secondary endpoints were OS and RR. PFS and OS analyses were performed using Kaplan-Meier method, and survival curves were compared using the log-rank test. RR was evaluated according to RECIST criteria and it was compared in the two groups using Fisher’s exact test. Statistical significance was set at p = 0.05 for a bilateral test. Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 76 RAS/BRAF wt mCRC pts, treated with third-line anti-EGFR-based tx or R/T, were enrolled. Of those, 19 (25%) pts had R-sided tumor (9 pts received anti-EGFR tx and 10 pts received R/T) and 57 (75%) pts had L-sided tumor (30 pts received anti-EGFR tx and 27 pts received R/T). As shown in the table, a significant PFS and OS benefit in favor of anti-EGFR tx vs R/T was observed in L-sided pts, while no difference both in PFS and OS was observed in R-sided pts. RR was significantly higher in L-sided pts treated with anti-EGFR vs R/T, no difference was shown in R-sided pts. At the multivariate analysis, tx regimen was indipendently associated with PFS in L-sided pts, but not in R-sided pts. Conclusions: Our study confirmed the results deriving from the retrospective analysis of the phase III study 20020408. Our results demonstrated a different benefit from third-line anti-EGFR tx according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T, while no difference was observed in R-sided tumors. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 8_suppl ( 2019-03-10), p. 44-44
    Abstract: 44 Background: The emerging role of immunotherapy (IT) in cancer treatments has increased the research about tumor microenvironment (TME), tumor infiltrating lymphocytes (TILs) function and their TME regulation. Nowadays ongoing trial are showing conflicting preliminary data about the efficacy of IT in advanced gastric cancer (GC). Therefore, we performed this exploratory analysis to evaluate the correlation between histology, TILs density (reported as CD4/CD8 tissue ratio), neutrophil-lymphocytes ratio (NLR) and response outcome in GC patients who underwent cytotoxic neoadjuvant treatment (NAD). Methods: CD4+ and CD8+ expression was assessed by immunohistochemistry (IHC) in pre-NAD biopsies. NLR was calculated on baseline complete blood count. A cut-off value to define low or high NLR has been selected on 3.0, based on literature data. X 2 test was used to explore the correlation between histology, CD4/CD8 ratio, NLR and response. Results: We analyzed 10 diffuse and 10 intestinal GC histotypes. In the intestinal-type CD4/CD8 ratio was lower (ratio range 1:15 - 1:20) with a predominant count of CD8+ suggesting a hot and inflamed TME compared to the diffuse cohort (ratio range 1:3 -1:5) where both CD8+ and CD4+ density was lower (p=0.03). Baseline NLR was calculated in 18 out of 20 pts. All intestinal GCs showed a low NLR ( 〈 3) while all diffuse GCs displayed a high cutoff (p=0.03). CD4/CD8 ratio resulted associated to histology (p=0.025) and response outcome (p=0.0003). NLR was statistically related to histology (p=0.03) and CD4/CD8 tissue ratio (p=0.03), confirming a different systemic inflammatory status and TME according to histology. Conclusions: Despite the small sample size, our exploratory analysis shows a possible correlation between histology, systemic inflammation and TME behavior (“hot” vs“cold”) described by NLR and TILs concentration (CD4/CD8 ratio) respectively and response to NAD. Intestinal-type seems to be a “hot” tumor whereas diffuse-type appears “cold”. Future clinical trial should analyze the impact of histology and TME features on IT efficacy and the appropriate strategy to convert “cold” tumor increasing TILs density.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3558-3558
    Abstract: 3558 Background: Target therapies and new surgical strategies deeply modify the history of CCLM patients (pts). Several prognostic scoring systems have been developed but no one is able to identify pts who should be excluded from a potentially useless surgery. Currently research is committed in identifying early biomarkers able to discern pts who could benefit from an aggressive approach. Exosomes are arising as promising biomarkers in cancer. The aim of this pivotal study was to analyze the association among exosome levels during CCLM-pts treatment, clinical outcomes and the KRAS status. Methods: We enrolled 22 pts with CCLM candidate to preoperative chemotherapy (pCT) and subsequent liver surgery. A blood sample was collected before pCT, after surgery, monthly during follow-up and at progression (PD). Exosomes were isolated by ultracentrifugation and characterized by standard methods. Exosomes concentration was assessed by Bradford assay. We adopted ddPCR™ KRAS G12/G13 Screening Kit to evaluate the KRAS status in exosomal DNA (e-DNA). Results: 22 CCLM pts received pCT and underwent liver surgery: 5 major hepatectomies and 17 multiple liver resections. Changes in exosomes plasma levels were found to correlate with each treatment step,resulting reduced after pCT and surgery and increased at PD, respectively (p = 0.0026). Pts with higher baseline exosome levels experimented shorter PFS than those with lower levels (p = 0.0033 HR 0.2). No association was found between exosome levels after liver surgery and disease free interval nor overall survival. KRAS status on e-DNA was evaluated on 10 pts in baseline, in pCT, after surgery, and in PD samples. In 8 out of 10 pts e-DNA displayed the same mutational status than the one detected on tumor DNA. Changes in e-DNA KRAS copies were found statistically significant in pCT vs surgery and pCT vs PD (p = 0.039; p = 0.04). Conclusions: Our study suggests a prognostic role of exosome levels in CCLM pts. Moreover, we showed that KRAS mutational status could be monitored during the post-surgery follow up by analyzing e-DNA. Overall, our data confirm the potential role of exosomes in liquid biopsy tool to monitor molecular changes during the treatment of CCLM pts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-8-12)
    Abstract: The aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens. Study design and methods Clinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age ( & lt; vs. ≥70 years old), overweight (body mass index, BMI & lt; vs. ≥25), underweight (BMI & lt; vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1–2), and intensity of chemotherapy regimen (doublet vs. triplet). Results Among 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users. Conclusion In patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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  • 10
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-10-27)
    Abstract: Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. Methods This multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). Results At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively ( p & lt; 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively ( p & lt; 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p & lt; 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. Conclusion Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2649216-7
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