Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in ...approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine‐based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000‐000.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Forages are usually inoculated with homofermentative and facultative heterofermentative lactic acid bacteria (LAB) to enhance lactic acid fermentation of forages, but effects of such inoculants on ...silage quality and the performance of dairy cows are unclear. Therefore, we conducted a meta-analysis to examine the effects of LAB inoculation on silage quality and preservation and the performance of dairy cows. A second objective was to examine the factors affecting the response to silage inoculation with LAB. The studies that met the selection criteria included 130 articles that examined the effects of LAB inoculation on silage quality and 31 articles that investigated dairy cow performance responses. The magnitude of the effect (effect size) was evaluated using raw mean differences (RMD) between inoculated and uninoculated treatments. Heterogeneity was explored by meta-regression and subgroup analysis using forage type, LAB species, LAB application rate, and silo scale (laboratory or farm-scale) as covariates for the silage quality response and forage type, LAB species, diet type total mixed ration (TMR) or non-TMR, and the level of milk yield of the control cows as covariates for the performance responses. Inoculation with LAB (≥105 cfu/g as fed) markedly increased silage fermentation and dry matter recovery in temperate and tropical grasses, alfalfa, and other legumes. However, inoculation did not improve the fermentation of corn, sorghum, or sugarcane silages. Inoculation with LAB reduced clostridia and mold growth, butyric acid production, and ammonia-nitrogen in all silages, but it had no effect on aerobic stability. Silage inoculation (≥105 cfu/g as fed) increased milk yield and the response had low heterogeneity. However, inoculation had no effect on diet digestibility and feed efficiency. Inoculation with LAB improved the fermentation of grass and legume silages and the performance of dairy cows but did not affect the fermentation of corn, sorghum, and sugar cane silages or the aerobic stability of any silage. Further research is needed to elucidate how silage inoculated with homofermentative and facultative heterofermentative LAB improves the performance of dairy cows.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Liquid biopsy has several advantages as compared with tissue biopsy.•Liquid biopsy showed prognostic and predictive value in different CRC stages.•Studies of liquid biopsy in CRC have several ...limits.•Prospective studies are required to transfer liquid biopsy in clinical practice.•Analysis of multiple biomarkers might improve liquid biopsy sensitivity/specificity.
The term liquid biopsy refers to the analysis of biomarkers in any body fluid, including blood, urine and cerebrospinal fluid. In cancer, liquid biopsy testing allows the analysis of tumor-derived DNA, RNA, miRNA and proteins that can be either cell-free or contained in circulating tumor cells (CTC), extracellular vesicles (EVs) or platelets. A number of studies suggest that liquid biopsy testing could have a relevant role in the management of colorectal cancer (CRC) patients at different stages of the disease. Analysis of cell-free DNA (cfDNA), CTC and/or miRNA can provide relevant information for the early diagnosis of CRC and the identification of minimal residual disease and, more generally, the evaluation of the risk of recurrence in early CRC patients. In addition, liquid biopsy testing might allow the assessment of prognostic and predictive biomarkers in metastatic CRC patients, and the monitoring of the response to treatment and of the clonal evolution of the disease. While a number of elegant studies have shown the potential of liquid biopsy in CRC, the possibility to use this approach in the daily clinical practice is still limited. The use of non-standardized methods, the small cohorts of patients analyzed, the lack of demonstration of a clear clinical benefit are the main limitations of the studies with liquid biopsy in CRC reported up to now. The potential of this approach and the steps that need still to be taken to translate these preliminary findings in the clinic are discussed in this review.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A meta-analysis of 158 peer-reviewed articles was conducted to examine effects of inoculation with Lactobacillus buchneri (LB)-based inoculants (LBB) that did or did not include homolactic or ...obligate heterolactic bacteria on silage fermentation and aerobic stability. A complementary meta-analysis of 12 articles examined LBB inoculation effects on dairy cow performance. Raw mean differences between inoculant and control treatment means weighted by inverse variance were compared with a hierarchical effects model that included robust variance estimation. Meta-regression and subgrouping analysis were used to identify effects of covariates including forage type, application rate (≤104, 105, 106, or ≥ 107 cfu/g as fed), bacteria type (LB vs. LB plus other bacteria), enzyme inclusion, ensiling duration, and silo type (laboratory or farm scale). Inoculation with LBB increased acetate (62%), 1, 2 propanediol (364%) and propionate (30%) concentration and aerobic stability (73.8%) and reduced lactate concentration (7.2%), yeast counts (7-fold) and mold counts (3-fold). Feeding inoculated silage did not affect milk yield, dry matter intake, and feed efficiency in lactating dairy cows. However, forage type, inoculant composition, and dose effects on silage quality measures were evident. Inoculation with LBB increased aerobic stability of all silages except tropical grasses. Adding obligate homolactic or facultative heterolactic bacteria to LB prevented the small increase in DM losses caused by LB alone. The 105 and 106 cfu/g rates were most effective at minimizing DM losses while aerobic stability was only increased with 105, 106, and ≥ 107 cfu/g rates. Inoculation with LBB increased acetate concentration, reduced yeast counts and improved aerobic stability but did not improve dairy cow performance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving ...a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal ...cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.
We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (
= 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.
Detection of ctDNA was a strong recurrence predictor postoperatively HR = 7.0; 95% confidence interval (CI), 3.7-13.5;
< 0.001 and directly after ACT (HR = 50.76; 95% CI, 15.4-167;
< 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172;
< 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month;
< 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7;
= 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.
Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.
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Abstract
Several studies have evaluated the effects of the dietary application of exogenous alpha-amylase preparations (AMA) as a strategy to increase total tract starch digestibility (TTSD) and milk ...yield (MY) in dairy cows, but the results have been inconsistent. Thus, the objective of this study was to evaluate the effects of the dietary application of AMA on the performance, digestibility, and rumen fermentation of lactating dairy cows using a meta-analytic method. A total of 18 peer-reviewed manuscripts (N = 32 treatment comparisons) from 2003 to 2019 were systematically identified following the PRISMA method. The weighted raw mean differences between dietary AMA and control treatments were compared with a robust variance estimation. Likewise, diet characteristics like crude protein (CP) content, NDF content, starch content, days in milk (DIM), experimental design (Latin square and continuous), and AMA dose (0 to 732 Kilo Novo units KNU/kg TMR) were used as covariates in a meta-regression, subgrouping, and dose–response analysis. Compared to the control, dietary AMA increased (P < 0.05) DM digestibility (69.32% vs. 68.30%), TTSD (94.62% vs. 94.10%), milk protein concentration and yield (3.11% vs. 3.08%; 1.14 vs. 1.10 kg/d) and tended to increase (P = 0.09) fat-corrected milk (35.96 vs. 35.10 kg/d), but no effects were observed on DM intake (22.99 vs. 22.90 kg/d) and feed efficiency (1.50 vs. 1.48). Dietary AMA tended (P = 0.10) to reduce rumen pH (6.27 vs. 6.30). Both the enzyme dose and DIM strongly influenced (P < 0.05) the effects of AMA on digestibility and performance. The dose–response analysis revealed that feeding 600 KNU/kg to high-producing early lactation (< 70 DIM) dairy cows increased FCM and milk protein. Accounting for the type of experimental design was associated with a lower between-studies-variance among comparisons. Overall, this meta-analysis supports the hypothesis that dietary AMA supplementation is associated with a better lactational performance in dairy cows. However, these effects are only suitable for high-producing early lactation dairy cows.
Lay Summary
For more than a decade, starch-degrading enzymes (amylolytic enzymes) have been used as a strategy to increase total-tract starch degradation to increase milk yield of dairy cows. Therefore, we conducted a meta-analysis to evaluate the effectiveness of starch-degrading enzymes on starch digestion and milk yield in dairy cows. Collectively, results across the literature suggest that feeding starch-degrading enzymes increased the degradation of starch in the rumen of dairy cows and tended to increase milk yield. Our results suggest that starch-degrading enzymes could increase milk yield in high-producing early lactation dairy cows.
• Feeding exogenous alpha-amylases to dairy cows is associated with an increase in starch digestibility, milk protein content, and fat-corrected milk.
• Results from this meta-analysis suggest that lactation stage, dietary starch content, and enzyme dose are the main factors associated with the response to dietary supplementation of alpha-amylases.
• Doses of 600 KNU/kg of exogenous alpha-amylase are associated with a greater starch digestibility, milk yield, and protein content in early lactation dairy cows.
Bacterial expansin-like proteins have synergistically increased cellulose hydrolysis by cellulolytic enzymes during the initial stages of biofuel production, but they have not been tested on ...livestock feeds. The objectives of this study were to: isolate and express an expansin-like protein (BsEXLX1), to verify its disruptive activity (expansion) on cotton fibers by immunodetection (Experiment 1), and to determine the effect of dose, pH and temperature for BsEXLX1 and cellulase to synergistically hydrolyze filter paper (FP) and carboxymethyl cellulose (CMC) under laboratory (Experiment 2) and simulated ruminal (Experiment 3) conditions. In addition, we determined the ability of BsEXLX1 to synergistically increase hydrolysis of corn and bermudagrass silages by an exogenous fibrolytic enzyme (EFE) (Experiment 4) and how different doses of BsEXLX1 and EFE affect the gas production (GP), in vitro digestibility and fermentation of a diet for dairy cows (Experiment 5). In Experiment 1, immunofluorescence-based examination of cotton microfiber treated without or with recombinant expansin-like protein expressed from Bacillus subtilis (BsEXLX1) increased the surface area by > 100% compared to the untreated control. In Experiment 2, adding BsEXLX1 (100 μg/g FP) to cellulase (0.0148 FPU) increased release of reducing sugars compared to cellulase alone by more than 40% (P < 0.01) at optimal pH (4.0) and temperature (50°C) after 24 h. In Experiment 3 and 4, adding BsEXLX1 to cellulase or EFE, synergistically increased release of reducing sugars from FP, corn and bermudagrass silages under simulated ruminal conditions (pH 6.0, 39°C). In Experiment 5, increasing the concentration of BsEXLX1 linearly increased (P < 0.01) GP from fermentation of a diet for dairy cows by up to 17.8%. Synergistic effects between BsEXLX1 and EFE increased in vitro NDF digestibility of the diet by 23.3% compared to the control. In vitro digestibility of hemicellulose and butyrate concentration were linearly increased by BsEXLX1 compared to the control. This study demonstrated that BsEXLX1 can improve the efficacy of cellulase and EFE at hydrolyzing pure substrates and dairy cow feeds, respectively.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer.
Patients with operable magnetic resonance imaging-defined high-risk rectal ...cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis.
One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio HR, 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm.
Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.
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