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Background and Aims: The best adjuvant chemotherapy for resected biliary tract cancer (BTC) is under debate, with capecitabine supported by weak evidence. Aim of this network meta‐analysis is to estimate the efficacy of different phase II/III regimens, comparing monotherapies (gemcitabine or fluoropyrimidines) head‐to‐head, against observation and combination regimens. Methods: A comprehensive literature search was conducted on PubMed and EMBASE for phase II/III randomized clinical trials (RCTs) available as of December 2023, reporting hazard ratios (HRs) of overall survival (OS) and event‐free survival (EFS). A frequentist framework employing a random‐effects model was applied; treatment rankings were outlined according to P‐score, based on direct and indirect evidence. Exploratory subgroup analyses for OS were also performed (primary site, resected margin status and nodal involvement). Results: Six RCTs (1979 total patients) were identified. Fluoropyrimidine monotherapy showed significantly better OS (HR.84 [.72–.97]) and EFS (HR.79 [.69–.91]) than observation, as any monotherapy did (HR.84 [.74–.96]; HR.79 [.70–.89]). In the head‐to‐head comparison for OS, only S1 confirmed to be superior to observation alone (HR.69 [.49–.98]) while fluoropyrimidines achieved the best P score (.81), similarly to any monotherapy (0.92). Combinations failed to prove superior to monotherapies with respect both to OS and EFS. Subgroup analyses were inconclusive due to results' inconsistency and limited sample size. Conclusions: Our work confirmed that adjuvant chemotherapy grants OS and EFS benefit for resected BTC patients. Fluoropyrimidines appeared the most effective option, confirming capecitabine as the preferred choice for the Western population. Key points: The administration of chemotherapy after surgery in primary liver cancers arising from biliary cells is needed to reduce the risk of disease relapse. Different chemotherapy regimens are available. From our study, we confirmed that capecitabine is the most effective option compared to doublet regimens in terms of disease‐free patients' survival and overall survival. [ABSTRACT FROM AUTHOR]

PURPOSE: Patient outcomes may differ from randomized trial averages. We aimed to predict benefit from FOLFOXIRI versus infusional fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (FOLFOX/FOLFIRI), both plus bevacizumab, in patients with metastatic colorectal cancer (mCRC). METHODS: A Cox model with prespecified clinical, molecular, and laboratory variables was developed in 639 patients from the TRIBE2 trial for predicting 2-year mortality. Data from the CHARTA (n = 232), TRIBE1 (n = 504), and CAIRO5 (liver-only mCRC, n = 287) trials were used for external validation and heterogeneity of treatment effects (HTE) analysis. This involves categorizing patients into risk groups and assessing treatment effects across these groups. Performance was assessed by the C-index and calibration plots. The C-for-benefit was calculated to assess evidence for HTE. The c-for-benefit is specifically designed for HTE analysis. Like the commonly known c-statistic, it summarizes the discrimination of a model. Values over 0.5 indicate evidence for HTE. RESULTS: In TRIBE2, the overoptimism-corrected C-index was 0.66 (95% CI, 0.63 to 0.69). At external validation, the C-index was 0.69 (95% CI, 0.64 to 0.75), 0.68 (95% CI, 0.64 to 0.72), and 0.65 (95% CI, 0.65 to 0.66), in CHARTA, TRIBE1, and CAIRO5, respectively. Calibration plots indicated slight underestimation of mortality. The c-for-benefit indicated evidence for HTE in CHARTA (0.56, 95% CI, 0.48 to 0.65), but not in TRIBE1 (0.49, 95% CI, 0.44 to 0.55) and CAIRO5 (0.40, 95% CI, 0.32 to 0.48). CONCLUSION: Although 2-year mortality could be reasonably estimated, the HTE analysis showed that clinically available variables did not reliably identify which patients with mCRC benefit from FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab, across the three studies. [ABSTRACT FROM AUTHOR]

PURPOSE: Patient outcomes may differ from randomized trial averages. We aimed to predict benefit from FOLFOXIRI versus infusional fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (FOLFOX/FOLFIRI), both plus bevacizumab, in patients with metastatic colorectal cancer (mCRC). METHODS: A Cox model with prespecified clinical, molecular, and laboratory variables was developed in 639 patients from the TRIBE2 trial for predicting 2-year mortality. Data from the CHARTA (n = 232), TRIBE1 (n = 504), and CAIRO5 (liver-only mCRC, n = 287) trials were used for external validation and heterogeneity of treatment effects (HTE) analysis. This involves categorizing patients into risk groups and assessing treatment effects across these groups. Performance was assessed by the C-index and calibration plots. The C-for-benefit was calculated to assess evidence for HTE. The c-for-benefit is specifically designed for HTE analysis. Like the commonly known c-statistic, it summarizes the discrimination of a model. Values over 0.5 indicate evidence for HTE. RESULTS: In TRIBE2, the overoptimism-corrected C-index was 0.66 (95% CI, 0.63 to 0.69). At external validation, the C-index was 0.69 (95% CI, 0.64 to 0.75), 0.68 (95% CI, 0.64 to 0.72), and 0.65 (95% CI, 0.65 to 0.66), in CHARTA, TRIBE1, and CAIRO5, respectively. Calibration plots indicated slight underestimation of mortality. The c-for-benefit indicated evidence for HTE in CHARTA (0.56, 95% CI, 0.48 to 0.65), but not in TRIBE1 (0.49, 95% CI, 0.44 to 0.55) and CAIRO5 (0.40, 95% CI, 0.32 to 0.48). CONCLUSION: Although 2-year mortality could be reasonably estimated, the HTE analysis showed that clinically available variables did not reliably identify which patients with mCRC benefit from FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab, across the three studies. Predict heterogeneity of treatment effects with risk modeling in metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The management of primary tumors in metastatic colorectal cancer patients is still a broad and controversial scenario. While in the case of symptomatic primary tumors, the indication for surgery is a need rather than a choice, in the case of asymptomatic patients, literature data are conflicting about the benefit of primary tumor resection in terms of survival. This pooled analysis of patients enrolled in TRIBE and TRIBE2 studies revealed that primary tumor resection at baseline was independently associated with good prognosis and with lower incidence of serious gastrointestinal and surgical adverse events during upfront chemotherapy plus bevacizumab. Moreover, we observed that the benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of the primary tumor resection. In the absence of strong evidence from randomized trials and considering the failure of many studies in this field, our results support the choice of primary tumor resection in selected asymptomatic patients. Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm. Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months (p < 0.001) and 26.6 vs. 22.5 (p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS (p = 0.032) and OS (p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea (p = 0.055) and lower incidence of anemia (p = 0.053), perforation (p = 0.015), and serious gastrointestinal and surgical AEs (p < 0.001). No statistically significant differences were noted in incidence of bleeding (p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS (p for interaction: 0.46), OS (p for interaction: 0.80), ORR (p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR. Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR. [ABSTRACT FROM AUTHOR]

2nd-line target therapy outperforms chemotherapy in patients with BRAFV600E-mut mCRC regardless of RNF43 status. PURPOSE: Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with BRAFV600E -mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in RNF43 , encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) BRAFV600E -mut mCRC treated with TT. Here, we explored the effect of RNF43 mutations on the efficacy of second-line TT versus standard chemotherapy (CT). METHODS: A retrospective cohort of patients with pMMR/MSS BRAFV600E -mut tumors, available RNF43 mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed. RESULTS: One hundred thirty-two patients with pMMR/MSS BRAFV600E -mut mCRC were included. RNF43 was found mut in 34 (26%) cases. Among RNF43 mutants, TT was associated with longer PFS (7.7 v 3.0 months; P =.002) and higher overall response rate (ORR; 45% v 0%; P =.009) compared with CT. Conversely, among RNF43 wild-type (wt) patients, only a trend for longer PFS (4.5 v 3.7 months; P =.064) favoring TT, with no differences in ORR (P =.14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 v 10.1 months; P =.022) and a numerically OS advantage (10.6 v 6.6 months; P =.068) were reported for TT both in the RNF43 -mut and in the RNF43 wt groups. However, no interaction effect was reported between RNF43 mutational status and treatment in ORR (P interaction =.96), PFS (P interaction =.13), and OS (P interaction =.44). CONCLUSION: Patients with pMMR/MSS BRAFV600E -mut mCRC achieve benefit from TT versus CT independently of RNF43 mutational status, although a higher magnitude of benefit from TT is observed in RNF43 -mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Up to 80% of disease relapse within 2 years after resection of colorectal cancer liver metastases occurs in patients with high burden of disease. Increase in life expectancy with new chemotherapy protocols opens the new challenge of maintaining quality of life after disease relapse and of offering subsequent surgical options when feasible. First-order glissonean-pedicles division recurrence should be absolutely avoided since it may hamper the subsequent administration of systemic treatments and worsen patient's quality of life due to biliary involvement. To this end, selected cases of metastases at the hepatocaval-confluence were treated with vessel-guided mesohepatectomy of segments 1 and 4 en-bloc with the middle hepatic vein. This minor liver resection induces a major hepatic scaffold modification, transforming the liver into a paired organ. This novelty led us to use for the first time liver augmentation techniques in a parenchyma-sparing context, observing a liver regeneration never described before. Based on our results, this surgical approach may represent a new option for patients affected by colorectal liver metastases selected in the frame of an experienced multidisciplinary environment including dedicated oncologists, anesthesiologists, radiologists, pathologists and surgeons. Background. R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods. We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0–67) lesions with a median diameter of 3.5 cm (range: 0.0–8.0), bilateral in 73% of cases. Results. Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6–62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7–20%) up to 41% (range: 37–69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions. Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient. [ABSTRACT FROM AUTHOR]

Aims: Evaluating the prognostic role of radiomic features in liver-limited metastatic colorectal cancer treated with first-line therapy at baseline and best response among patients undergoing resection. Patients & methods: Among patients enrolled in TRIBE2 (NCT02339116), the association of clinical and radiomic data, extracted by SOPHiA-DDM™ with progression-free and overall survival (OS) in the overall population and with disease-free survival/postresection OS in those undergoing resection was investigated. Results: Among 98 patients, radiomic parameters improved the prediction accuracy of our model for OS (area under the curve: 0.83; sensitivity: 0.85; specificity: 0.73; accuracy: 0.78), but not progression-free survival. Of 46 resected patients, small-distance high gray-level emphasis was associated with shorter disease-free survival and high gray-level zone emphasis/higher kurtosis with shorter postresection OS. Conclusion: Radiomic features should be implemented as tools of outcome prediction for liver-limited metastatic colorectal cancer. In colorectal liver metastases, radiomics could be a valid tool for predicting prognosis in patients receiving first-line treatment and for stratification of patients based on the risk of relapse after curative resection. [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. Methods: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. Results: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. Conclusions: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours. [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0.Methods: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples.Results: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population.Conclusions: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours. [ABSTRACT FROM AUTHOR]

Background: Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown.Methods: Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided.Results: Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P  < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P  < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P  < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm.Conclusions: HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation. [ABSTRACT FROM AUTHOR]

Background: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC.Methods: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided.Results: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002).Conclusion: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Background: In mCRC, CEA is used to monitor response to systemic therapy together with imaging. After the end of induction, no major improvement in tumour shrinkage is expected, and the availability of a marker able to predict progressive disease (PD) versus no-PD might allow avoiding CT scans.Methods: We pooled data from patients with baseline CEA ≥ 10 ng/mL included in TRIBE and TRIBE2 studies with the aim of identifying a threshold for percent increase of CEA from nadir able to predict PD after the end of the induction therapy.Results: In total, 1178 paired CEA and radiological assessments from 434 patients were included. According to the optimal cut-off determined by ROC, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of CT scans. However, CEA cut-off of 120% was not able to detect radiological PD in 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as a threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected.Conclusions: In mCRC with baseline CEA ≥ 10 ng/mL, CEA values can accurately predict PD versus no-PD after the end of the first-line induction therapy. [ABSTRACT FROM AUTHOR]

Background: Doublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC. Materials and Methods: We selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab. Results: A total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p =.11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p =.14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p =.001). Conclusion: Although randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC. Implications for Practice: A propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients' preference and potential impact on quality of life. This article reports a propensity score‐based analysis of data from five randomized clinical trials, comparing the efficacy and safety of FOLFOXIRI‐bevacizumab versus FOLFOX‐panitumumab in the subgroup of patients with left‐sided RAS and BRAF wild‐type metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression.Methods: We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction.Results: Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045).Conclusions: First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation.Methods: AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee.Discussion: The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status.Trial Registration: AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017-000977-35), Februray 28th, 2017. [ABSTRACT FROM AUTHOR]

Purpose: In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. Methods: 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. Results: Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70–1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5–51.4) and 62.4% (95% CI 58.4–66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. Conclusion: Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate. [ABSTRACT FROM AUTHOR]

PURPOSE: To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At- RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. MATERIALS AND METHODS: By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At- RAS mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At- RAS –positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS: At- RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At- RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS /BRAF V600E mutations and NF1 mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At- RAS , typical RAS , or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (P <.001). No significant OS difference (P =.240) was found between patients with At- RAS versus typical RAS -mutated mCRC. Only one of six patients evaluable for primary resistance to anti–epidermal growth factor receptors achieved tumor response. CONCLUSION: At- RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations. [ABSTRACT FROM AUTHOR]

Sentence embeddings are the suitable input vectors for the neural learning of a number of inferences about content and meaning. Similarity estimation, classification, emotional characterization of sentences as well as pragmatic tasks, such as question answering or dialogue, have largely demonstrated the effectiveness of vector embeddings to model semantics. Unfortunately, most of the above decisions are epistemologically opaque as for the limited interpretability of the acquired neural models based on the involved embeddings. We think that any effective approach to meaning representation should be at least epistemologically coherent. In this paper, we concentrate on the readability of neural models, as a core property of any embedding technique consistent and effective in representing sentence meaning. In this perspective, this paper discusses a novel embedding technique (the Nyström methodology) that corresponds to the reconstruction of a sentence in a kernel space, inspired by rich semantic similarity metrics (a semantic kernel) rather than by a language model. In addition to being based on a kernel that captures grammatical and lexical semantic information, the proposed embedding can be used as the input vector of an effective neural learning architecture, called Kernel-based deep architectures (KDA). Finally, it also characterizes by design the KDA explanatory capability, as the proposed embedding is derived from examples that are both human readable and labeled. This property is obtained by the integration of KDAs with an explanation methodology, called layer-wise relevance propagation (LRP) , already proposed in image processing. The Nyström embeddings support here the automatic compilation of argumentations in favor or against a KDA inference, in form of an explanation: each decision can in fact be linked through LRP back to the real examples, that is, the landmarks linguistically related to the input instance. The KDA network output is explained via the analogy with the activated landmarks. Quantitative evaluation of the explanations shows that richer explanations based on semantic and syntagmatic structures characterize convincing arguments, as they effectively help the user in assessing whether or not to trust the machine decisions in different tasks, for example, Question Classification or Semantic Role Labeling. This confirms the epistemological benefit that Nyström embeddings may bring, as linguistically rich and meaningful representations for a variety of inference tasks. [ABSTRACT FROM AUTHOR]

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Background: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.Methods: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.Results: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).Conclusions: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents. [ABSTRACT FROM AUTHOR]

Ultra-high-performance liquid chromatography coupled with high-resolution quadrupole-time of flight mass spectrometry with both negative and positive ionization was used for comprehensively investigating the phenolic and polyphenolic compounds in berries from three spontaneous or cultivated Vaccinium species (i.e., Vaccinium myrtillus, Vaccinium uliginosum subsp. gaultherioides, and Vaccinium corymbosum). More than 200 analytes, among phenolic and polyphenolic compounds belonging to the classes of anthocyanins, monomeric and oligomeric flavonols, flavanols, dihydrochalcones, phenolic acids, together with other polyphenolic compounds of mixed structural characteristics, were identified. Some of the polyphenols herein investigated, such as anthocyanidin glucuronides and malvidin-feruloyl-hexosides in V. myrtillus, or anthocyanindin aldopentosides and coumaroyl-hexosides in V. uliginosum subsp. gaultherioides and a large number of proanthocyanidins with high molecular weight in all species, were described for the first time in these berries. Principal component analysis applied on original LC-TOF data, acquired in survey scan mode, successfully discriminated the three Vaccinium berry species investigated, on the basis of their polyphenolic composition, underlying one more time the fundamental role of mass spectrometry for food characterization. [ABSTRACT FROM AUTHOR]

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09-7.53;p < .0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. [ABSTRACT FROM AUTHOR]

Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated.Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05-19.92), female gender (OR: 2.90, 95% CI 1.14-7.37) and mucinous histology (OR: 4.95, 95% CI 1.90-12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2%; specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy.Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity. [ABSTRACT FROM AUTHOR]

The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally administered combination of the nucleoside analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. In a randomized trial of 800 patients who had received at least two other treatments previously (most patients had received more than four treatments). TAS-102 demonstrated a significant prolongation of overall survival compared with placebo (median survival 7.1 vs. 5.3 months; hazard ratio 0 · 68, 95%CI: 0 · 58–0 · 81; p < 0 · 001). The toxicity was manageable, grade 3 or higher events occurred in 69% of patients in the TAS-102 group versus 52% in the placebo group, with neutropenia the most common event. [ABSTRACT FROM PUBLISHER]

Merkel cell carcinoma (MCC) is an extremely rare primary neuroendocrine neoplasm of the skin that shows aggressive behavior and a poor prognosis. We report a case of a 67-year-old male with aMerkel cell carcinoma which initially presented itself as a large retroperitoneal mass. Pathological and immunohistochemical analysis revealed tissue consistent with neuroendocrine carcinoma. Despite completemedical workup, no other primaryMCC could be detected. While being an atypical presentation, the tumormass showed an excellent response to the combination of chemotherapy followed by radiotherapy. [ABSTRACT FROM AUTHOR]

Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7–34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95–1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3–18.1) and 12.7 (95%CI: 8.8–17.5) months, respectively (HR= 1.31 (95%CI: 0.89–1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02–2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99–2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed. [ABSTRACT FROM AUTHOR]

Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29–0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option. [ABSTRACT FROM AUTHOR]