Histopathological, Clinical, And Molecular (HICAM) score for patients with colorectal liver metastases.

BACKGROUND: Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation ('GAME') score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases. METHODS: Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular ('HICAM') score. RESULTS: Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20 ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001). CONCLUSION: The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection.

Local and systemic replicative fitness for viruses in specialist, generalist, and non-specialist interactions with salmonid hosts.

Host tissues represent diverse resources or barriers for pathogen replicative fitness. We tested whether viruses in specialist, generalist, and non-specialist interactions replicate differently in local entry tissue (fin), and systemic target tissue (kidney) using infectious hematopoietic necrosis virus (IHNV) and three salmonid fish hosts. Virus tissue replication was host specific, but one feature was shared by specialists and the generalist which was uncommon in the non-specialist interactions: high host entry and replication capacity in the local tissue after contact. Moreover, specialists showed increased replication in systemic target tissues early after host contact. By comparing ancestral and derived IHNV viruses, we also characterized replication tradeoffs associated with specialist and generalist evolution. Compared with the ancestral virus, a derived specialist gained early local replicative fitness in the new host but lost replicative fitness in the ancestral host. By contrast, a derived generalist showed small replication losses relative to the ancestral virus in the ancestral host but increased early replication in the local tissue of novel hosts. This study shows that the mechanisms of specialism and generalism are host specific and that local and systemic replication can contribute differently to overall within host replicative fitness for specialist and generalist viruses.

Medical oncology workload, workforce census, and needs in Spain: two nationwide studies by the Spanish Society of medical oncology

Purpose Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. Methods Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. Results Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87–110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110–130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). Conclusions Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing (AU)

Medical oncology workload, workforce census, and needs in Spain: two nationwide studies by the Spanish Society of medical oncology.

PURPOSE: Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. METHODS: Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. RESULTS: Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87-110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110-130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). CONCLUSIONS: Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing.

Measuring under-5 mortality and fertility through mobile phone surveys: an assessment of selection bias in 34 low-income and middle-income countries.

OBJECTIVES: This study aims to assess sample selection bias in mobile phone survey estimates of fertility and under-5 mortality. DESIGN: With data from the Demographic and Health Surveys, we use logistic regressions to identify sociodemographic correlates of mobile phone ownership and access, and Poisson regressions to estimate the association between mobile phone ownership (or access) and fertility and under-5 mortality estimates. We evaluate the potential reasons why estimates by mobile phone ownership differ using a set of behavioural characteristics. SETTING: 34 low-income and middle-income countries, mostly in sub-Saharan Africa. PARTICIPANTS: 534 536 women between the ages of 15 and 49. OUTCOME MEASURES: Under-5 mortality rate (U5MR) and total fertility rate (TFR). RESULTS: Mobile phone ownership ranges from 23.6% in Burundi to 96.7% in Armenia. The median TFR ratio and U5MR ratio between the non-owners and the owners of a mobile phone are 1.48 and 1.29, respectively. Fertility and mortality rates would be biased downwards if estimates are only based on women who own or have access to mobile phones. Estimates of U5MR can be adjusted through poststratification using age, educational level, area of residence, wealth and marital status as weights. However, estimates of TFR remain biased even after adjusting for these covariates. This difference is associated with behavioural factors (eg, contraceptive use) that are not captured by the poststratification variables, but for which there are also differences between mobile phone owners and non-owners. CONCLUSIONS: Mobile phone surveys need to collect data on sociodemographic background characteristics to be able to weight and adjust mortality estimates ex post facto. Fertility estimates from mobile phone surveys will be biased unless further research uncovers the mechanisms driving the bias.

Mass transfer vectors for nitric oxide removal through biological treatments.

The reduction of nitric oxide (NO) emissions to atmosphere has been recently addressed using biological technologies. However, NO removal through bioprocesses is quite challenging due to the low solubility of NO in water. Therefore, the abatement of NO emissions might be improved by adding a chelating agent or a mass transfer vector (MTV) to increase the solubility of this pollutant into the aqueous phase where the bioprocess takes place. This research seeks to assess the performance of different non-aqueous phase liquids (NAPs): n-hexadecane (HEX), diethyl sebacate (DSE), 1,1,1,3,5,5,5-heptamethyl-trisiloxane (HTX), 2,2,4,4,6,8,8-heptamethylnonane (HNO), and high temperature silicone oil (SO) in chemical absorption-biological reduction (CABR) integrated systems. The results showed that HNO and HTX had the maximum gas-liquid mass transfer capacity, being 0.32 mol NO/kmol NAP and 0.29 mol NO/kmol NAP, respectively. When an aqueous phase was added to the system, the mass transfer gas-liquid of NO was increased, with HTX reaching a removal efficiency of 82 ± 3% NO with water, and 88 ± 6% with a phosphate buffer solution. All NAPs were tested for short-term toxicity assessment and resulted neither toxic nor inhibitory for the biological activity (denitrification). DSE was found to be biodegradable, which could limit its applicability in biological processes for gas treatment. Finally, in the CABR system tests, it was shown that NO elimination improved in a short time (30 min) when the three mass transfer vectors (HEX, HTX, HNO) were added to enriched denitrifying bacteria.

Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain.

PURPOSE: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers. METHODS: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. RESULTS: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. CONCLUSION: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved. TRIAL REGISTRATION: Not applicable.

Male Fertility and Internal Migration in Rural and Urban Sub-Saharan Africa.

Subnational differences in male fertility within sub-Saharan African countries have not been explored, nor the differences in male fertility according to migration status been sufficiently probed. We study divergences in rural and urban male fertility and investigate the relationship between male fertility and migration across 30 sub-Saharan African countries. We employ 67 Demographic and Health Surveys to estimate completed cohort fertility among men aged 50-64 according to migration status. Overall, we find that urban male fertility has declined faster than rural male fertility, widening the gap between the sectors. Rural-urban migrant men have lower fertility than their rural non-migrant counterparts. Men migrating within the rural sector have similarly high fertility as rural non-migrants, while urban-urban migrant men have even lower fertility than non-migrant urban men. Using country-fixed effects models, we find that among men with at least secondary education, differences in completed cohort fertility by migration status are widest. When we consider the timing of migration in relation to the timing of the birth of the last child, we observe that migrant men are a select group, having around two children less than non-migrant rural men. There is also evidence of adaptation to destination, though to a lesser extent. Furthermore, migration within the rural sector does not seem to be disruptive to fathering. These results indicate that rural-to-urban migration has the potential to delay rural fertility decline, and that urban male fertility is likely to decline further, especially as the proportion of urban-to-urban migration increases.

Current professional standing of young medical oncologists in Spain a nationwide survey by the Spanish Society of Medical Oncology + MIR section

Background There is a lack of knowledge about the career paths and employment situation of young medical oncologists. The aim of our study was to evaluate the current professional standing of these professionals in Spain. Methods The Spanish Society of Medical Oncology + MIR section conducted a national online survey in May 2021 of young medical oncology consultants (< 6 years of expertise) and final year medical oncology residents. Results A total of 162 responses were eligible for analysis and included participants from 16 autonomous communities; 64% were women, 80% were consultants, and 20% were residents. More than half of the participants performed routine healthcare activity and only 7% research activity. Almost three quarters (73%) were subspecialized in a main area of interest and almost half of these chose this area because it was the only option available after residency. Half of the respondents (51%) considered working abroad and 81% believed the professional standing in Spain was worse than in other countries. After finishing their residency, only 22 were offered a job at their training hospital. Just 16% of participants had a permanent employment contract and 87% were concerned (score of ≥ 5 on a scale of 1–10) about their job stability. In addition, one quarter of the participants in our study showed an interest in increasing their research activity. Conclusions The choice of subspecialty in medical oncology may depend on job opportunities after residency rather than personal interest. The abundance of temporary contracts may have influenced the job stability concerns observed. Future mentoring strategies should engage in building a long-term career path for young medical oncologists (AU)

Coproduction and modeling spatial contact networks prevent bias about infectious hematopoietic necrosis virus transmission for Snake River Basin salmonids.

Much remains unknown about variation in pathogen transmission across the geographic range of a free-ranging fish or animal species and about the influence of movement (associated with husbandry practices or animal behavior) on pathogen transmission. Salmonid hatcheries are an ideal system in which to study these processes. Salmonid hatcheries are managed for endangered species recovery, supplementation of threatened or at-risk fish stocks, support of fisheries, and ecosystem stability. Infectious hematopoietic necrosis virus (IHNV) is a rhabdovirus of significant concern to salmon aquaculture. Landscape IHNV transmission dynamics previously had been estimated only for salmonid hatcheries in the Lower Columbia River Basin (LCRB). The objectives of this study were to estimate IHNV transmission dynamics in a unique geographic region, the Snake River Basin (SRB), and to quantitatively estimate the effect of model coproduction on inference because previous assessments of coproduction have been qualitative. In contrast to the LCRB, the SRB has hatchery complexes consisting of a main hatchery and ≥1 satellite facility. Knowledge about hatchery complexes was held by a subset of project researchers but would not have been available to project modelers without coproduction. Project modelers generated and tested multiple versions of Bayesian susceptible-exposedinfected models to realistically represent the SRB and estimate the effect of coproduction. Models estimated the frequency of transmission routes, route-specific infection probabilities, and infection probabilities for combinations of salmonid hosts and IHNV lineages. Model results indicated that in the SRB, avoiding exposure to IHNV-positive adult salmonids is the most important action to prevent juvenile infections. Migrating adult salmonids exposed juvenile cohort-sites most frequently, and the infection probability was greatest following exposure to migrating adults. Without coproduction, the frequency of exposure by migrating adults would have been overestimated by 70 cohort-sites, and the infection probability following exposure to migrating adults would have been underestimated by∼0.09. The coproduced model had less uncertainty in the infection probability if no transmission route could be identified (Bayesian credible interval (BCI) width = 0.12) compared to the model without coproduction (BCI width = 0.34). Evidence for virus lineage MD specialization on steelhead and rainbow trout (both Oncorhynchus mykiss) was apparent without model coproduction. In the SRB, we found a greater probability of virus lineage UC infection in Chinook salmon (Oncorhynchus tshawytscha) compared to in O. mykiss, whereas in the LCRB, UC more clearly exhibited a generalist approach. Coproduction influenced estimates that depended on transmission routes, which operated differently at main hatcheries and satellite sites within hatchery complexes. Hatchery complexes are found outside of the SRB and are not specific to salmonid hatcheries alone. There is great potential for coproduction and modeling spatial contact networks to advance understanding about infectious disease transmission in complex production systems and surrounding free-ranging animal populations.

Liquid Biopsy Detects Early Molecular Response and Predicts Benefit to First-Line Chemotherapy plus Cetuximab in Metastatic Colorectal Cancer: PLATFORM-B Study.

PURPOSE: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy. EXPERIMENTAL DESIGN: Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. RESULTS: One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with "early molecular response" (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with "early molecular progression" (increase in trunk and/or increase in resistant mutations). CONCLUSIONS: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations. See related commentary by Eluri et al., p. 302.

Current professional standing of young medical oncologists in Spain: a nationwide survey by the Spanish Society of Medical Oncology + MIR section.

BACKGROUND: There is a lack of knowledge about the career paths and employment situation of young medical oncologists. The aim of our study was to evaluate the current professional standing of these professionals in Spain. METHODS: The Spanish Society of Medical Oncology + MIR section conducted a national online survey in May 2021 of young medical oncology consultants (< 6 years of expertise) and final year medical oncology residents. RESULTS: A total of 162 responses were eligible for analysis and included participants from 16 autonomous communities; 64% were women, 80% were consultants, and 20% were residents. More than half of the participants performed routine healthcare activity and only 7% research activity. Almost three quarters (73%) were subspecialized in a main area of interest and almost half of these chose this area because it was the only option available after residency. Half of the respondents (51%) considered working abroad and 81% believed the professional standing in Spain was worse than in other countries. After finishing their residency, only 22 were offered a job at their training hospital. Just 16% of participants had a permanent employment contract and 87% were concerned (score of ≥ 5 on a scale of 1-10) about their job stability. In addition, one quarter of the participants in our study showed an interest in increasing their research activity. CONCLUSIONS: The choice of subspecialty in medical oncology may depend on job opportunities after residency rather than personal interest. The abundance of temporary contracts may have influenced the job stability concerns observed. Future mentoring strategies should engage in building a long-term career path for young medical oncologists.

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01)

Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB).MethodsIn this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38).ResultsBetween February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B.ConclusionsThe BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation. (AU)

Variation in within-host replication kinetics among virus genotypes provides evidence of specialist and generalist infection strategies across three salmonid host species.

Theory of the evolution of pathogen specialization suggests that a specialist pathogen gains high fitness in one host, but this comes with fitness loss in other hosts. By contrast, a generalist pathogen does not achieve high fitness in any host, but gains ecological fitness by exploiting different hosts, and has higher fitness than specialists in nonspecialized hosts. As a result, specialist pathogens are predicted to have greater variation in fitness across hosts, and generalists would have lower fitness variation across hosts. We test these hypotheses by measuring pathogen replicative fitness as within-host viral loads from the onset of infection to the beginning of virus clearance, using the rhabdovirus infectious hematopoietic necrosis virus (IHNV) in salmonid fish. Based on field prevalence and virulence studies, the IHNV subgroups UP, MD, and L are specialists, causing infection and mortality in sockeye salmon, steelhead, and Chinook salmon juveniles, respectively. The UC subgroup evolved naturally from a UP ancestor and is a generalist infecting all three host species but without causing severe disease. We show that the specialist subgroups had the highest peak and mean viral loads in the hosts in which they are specialized, and they had low viral loads in nonspecialized hosts, resulting in large variation in viral load across hosts. Viral kinetics show that the mechanisms of specialization involve the ability to both maximize early virus replication and avoid clearance at later times, with different mechanisms of specialization evident in different host-virus combinations. Additional nuances in the data included different fitness levels for nonspecialist interactions, reflecting different trade-offs for specialist viruses in other hosts. The generalist UC subgroup reached intermediate viral loads in all hosts and showed the smallest variation in fitness across hosts. The evolution of the UC generalist from an ancestral UP sockeye specialist was associated with fitness increases in steelhead and Chinook salmon, but only slight decreases in fitness in sockeye salmon, consistent with low- or no-cost generalism. Our results support major elements of the specialist-generalist theory, providing evidence of a specialist-generalist continuum in a vertebrate pathogen. These results also quantify within-host replicative fitness trade-offs resulting from the natural evolution of specialist and generalist virus lineages in multi-host ecosystems.

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01).

PURPOSE: Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). METHODS: In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). RESULTS: Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. CONCLUSIONS: The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

SEOM-GEMCAD-TTD clinical guidelines for localized rectal cancer (2021)

The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined.

SEOM-GEMCAD-TTD clinical guidelines for localized rectal cancer (2021).

The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined.

Elucidating the role of pharmacogenetics in irinotecan efficacy and adverse events in metastatic colorectal cancer patients.

INTRODUCTION: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking. AREAS COVERED: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients. EXPERT OPINION: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.