Int J Mol Sci. 2021 Jul 9;22(14):7389. doi: 10.3390/ijms22147389.

ABSTRACT

Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.

PMID:34299006 | DOI:10.3390/ijms22147389

Int J Mol Sci. 2021 Jul 8;22(14):7357. doi: 10.3390/ijms22147357.

ABSTRACT

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

PMID:34298974 | DOI:10.3390/ijms22147357

Front Pharmacol. 2021 Jul 6;12:657287. doi: 10.3389/fphar.2021.657287. eCollection 2021.

ABSTRACT

Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50-9.00) years and the mean weight was 19.64 (range 7.00-42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio (p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries.

PMID:34295246 | PMC:PMC8292113 | DOI:10.3389/fphar.2021.657287

Commun Biol. 2021 Jul 22;4(1):903. doi: 10.1038/s42003-021-02421-6.

ABSTRACT

One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual's biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression.

PMID:34294869 | DOI:10.1038/s42003-021-02421-6

Eur J Endocrinol. 2021 Jul 1:EJE-21-0429.R1. doi: 10.1530/EJE-21-0429. Online ahead of print.

ABSTRACT

PURPOSE: to examine the MRI diagnostic performance in assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH).

DESIGN: prospective longitudinal open cohort.

PATIENTS: 17 children with XLH, average age of 10.2±2.7 years, had a knee MRI at baseline and after one year of burosumab.

INTERVENTION: Children received burosumab at average dose of 1.4±0.5 mg/kg during one year for the treatment of severe rickets [the target serum phosphate >1.2 mmol/l (>3.7 mg/dl)]. The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP).

RESULTS: One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44±29% in transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28±17%. Additionally, MRI parameters after one year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months.

CONCLUSION: We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in clinical setting avoiding repeated exposition to ionizing radiation. Number of registration with ClinicalTrials.gov: NCT04419363, https://clinicaltrials.gov/ct2/show/NCT04419363.

PMID:34292170 | DOI:10.1530/EJE-21-0429

Sci Transl Med. 2021 Jul 21;13(603):eabf3637. doi: 10.1126/scitranslmed.abf3637.

ABSTRACT

Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read amplicon-based sequencing and cytochrome P450 (CYP) 2D6-mediated tamoxifen metabolism data from a prospective study of 561 patients with breast cancer to train a neural network. The model explained 79% of interindividual variability in CYP2D6 activity compared to 54% with the conventional *-allele approach, assigned enzyme activities to known alleles with previously reported effects, and predicted the activity of previously uncharacterized combinations of variants. The results were replicated in an independent cohort of tamoxifen-treated patients (model R 2 adjusted = 0.66 versus *-allele R 2 adjusted = 0.35) and a cohort of patients treated with the CYP2D6 substrate venlafaxine (model R 2 adjusted = 0.64 versus *-allele R 2 adjusted = 0.55). Human embryonic kidney cells were used to confirm the effect of five genetic variants on metabolism of the CYP2D6 substrate bufuralol in vitro. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP2D6 enzyme activity and could potentially enable more accurate prediction of individual drug response.

PMID:34290055 | DOI:10.1126/scitranslmed.abf3637

Cancer Cell Int. 2021 Jul 21;21(1):388. doi: 10.1186/s12935-021-02091-8.

ABSTRACT

Cancers are complex diseases orchestrated by a plethora of extrinsic and intrinsic factors. Research spanning over several decades has provided better understanding of complex molecular interactions responsible for the multifaceted nature of cancer. Recent advances in the field of next generation sequencing and functional genomics have brought us closer towards unravelling the complexities of tumor microenvironment (tumor heterogeneity) and deregulated signaling cascades responsible for proliferation and survival of tumor cells. Phytochemicals have begun to emerge as potent beneficial substances aimed to target deregulated signaling pathways. Isoflavonoid genistein is an essential phytochemical involved in regulation of key biological processes including those in different types of cancer. Emerging preclinical evidence have shown its anti-cancer, anti-inflammatory and anti-oxidant properties. Testing of this substance is in various phases of clinical trials. Comprehensive preclinical and clinical trials data is providing insight on genistein as a modulator of various signaling pathways both at transcription and translation levels. In this review we have explained the mechanistic regulation of several key cellular pathways by genistein. We have also addressed in detail various microRNAs regulated by genistein in different types of cancer. Moreover, application of nano-formulations to increase the efficiency of genistein is also discussed. Understanding the pleiotropic potential of genistein to regulate key cellular pathways and development of efficient drug delivery system will bring us a step towards designing better chemotherapeutics.

PMID:34289845 | DOI:10.1186/s12935-021-02091-8

J Crohns Colitis. 2021 Jul 21:jjab128. doi: 10.1093/ecco-jcc/jjab128. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) compared to conventional venepuncture.

METHODS: We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire.

RESULTS: Therapeutic drug monitoring requests for adalimumab (96.5 [70.5 - 106] per week to 52 [33.5 - 57.0], p < 0.001) but not infliximab (184.5 [161.2 - 214.2] to 161 [135 - 197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding six months.Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab, and ustekinumab drug, and anti-adalimumab and -infliximab antibody levels. The median (IQR) volume of serum obtained using intracapillary sampling was 195µL (130-210). More than 87% (90/103) patients agreed that intracapillary testing was easy and 69% (71/103) preferred it to conventional venepuncture.In routine care, 75.3% (58/77) patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring.

CONCLUSIONS: Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.

PMID:34289028 | DOI:10.1093/ecco-jcc/jjab128

Res Gerontol Nurs. 2021 Jul-Aug;14(4):211-220. doi: 10.3928/19404921-20210428-01. Epub 2021 May 19.

ABSTRACT

Through pharmacogenomics testing, identifying genetic variants that influence how individuals respond to medications could potentially decrease the "trial and error" approach to prescribing medications, maximize beneficial effects, and reduce risks of adverse drug events. Yet, pharmacogenomics testing is still subject to an ongoing debate over its clinical validity and utility. The purpose of the current integrative review was to examine and synthesize evidence on the clinical application of pharmacogenomics in medication management among older adults. Gaps were found, such as lack of studies investigating the prospective use of pharmacogenomics testing to improve clinical outcomes and lack of strong evidence on the clinical validity and utility of pharmacogenomics testing in the medication management of older adults. However, the review identified evidence for the potential benefits of pharmacogenomics testing to improve older adults' clinical outcomes that warrant further investigation. [Research in Gerontological Nursing, 14(4), 211-220.].

PMID:34288783 | DOI:10.3928/19404921-20210428-01

J Gastroenterol. 2021 Jul 21. doi: 10.1007/s00535-021-01805-z. Online ahead of print.

ABSTRACT

The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.

PMID:34287682 | DOI:10.1007/s00535-021-01805-z

Future Healthc J. 2021 Jul;8(2):e237-e242. doi: 10.7861/fhj.2021-0088.

ABSTRACT

Research into ageing covers opportunities and challenges posed by an older population, and research to understand the ageing processes across the lifespan. The evidence base for Comprehensive Geriatric Assessment (CGA) is well established and efforts should now shift to understanding how to implement its principles across different healthcare contexts. Research around syndromes common in older people has progressed with variable success; while effective therapies for falls and cognitive impairment have been identified, older people with advanced frailty have commonly been excluded from Parkinson's disease and continence research. Research to understand the mechanisms of ageing has potential to mitigate against or treat emerging sarcopenia and cognitive impairment, and thus modify frailty trajectories. Pharmacogenetics could individualise therapeutics to reduce polypharmacy. These issues can only be addressed with development of infrastructure, capacity and expertise in ageing research. Commonly used research methodologies must be adapted to take account of frailty, cognitive impairment and functional dependency.

PMID:34286191 | PMC:PMC8285138 | DOI:10.7861/fhj.2021-0088

Pharmacogenomics. 2021 Jul 21. doi: 10.2217/pgs-2021-0085. Online ahead of print.

NO ABSTRACT

PMID:34284600 | DOI:10.2217/pgs-2021-0085

Am J Pharm Educ. 2021 Apr;85(4):8249. doi: 10.5688/ajpe8249. Epub 2020 Dec 31.

ABSTRACT

Objective. Pharmacogenomics, a key tool in personalized medicine, and therapeutic drug management is projected to become an integral part of pharmacy practice. This study describes an innovative pedagogy that used several interactive learning methods to increase learners' competence and perceptions in pharmacogenomics.Methods. First-year student pharmacists at the Medical College of Wisconsin participated in lectures, discussions, and patient care laboratory training on the topic of pharmacogenomics. These students were given the opportunity to undergo personal pharmacogenomics testing. Before and after these activities, participants were surveyed about their attitudes towards the use of pharmacogenomics in current and future practice.Results. Forty-five students participated in this voluntary personal pharmacogenomics testing and completed pre-course and post-course surveys. Significant improvements were seen in 22 of the 27 surveys questions responses from the pre-course to the post-course surveys. Student learning outcomes, competencies, and attitudes towards pharmacogenomics improved from a relatively neutral perception of pharmacogenomics to one of more confidence.Conclusion. This study demonstrated that participation in a novel pedagogy that included voluntarily individual pharmacogenomics testing was beneficial to student pharmacists by improving knowledge, interest, and confidence in pharmacogenomics and its incorporation into their future pharmacy practice.

PMID:34283790 | DOI:10.5688/ajpe8249

Am J Pharm Educ. 2020 Dec;84(12):ajpe8031. doi: 10.5688/ajpe8031. Epub 2020 Oct 2.

ABSTRACT

Objective. To characterize advanced pharmacy practice experiences (APPEs) with a primary focus in pharmacogenomics at schools and colleges of pharmacy in the United States.Methods. This was a cross-sectional, multicenter, observational study of pharmacogenomics APPEs at US pharmacy schools. Directors of experiential education at 146 accredited schools of pharmacy were contacted by phone and asked if their school offered a pharmacogenomics APPE. The preceptors of pharmacogenomics APPEs identified by this phone screen were sent an email with a link to an online survey that asked about their APPE offerings.Results. Of the 142 schools of pharmacy that were successfully reached via phone, 40 (28%) offered an APPE with a primary focus in pharmacogenomics. Thirty unique APPEs with pharmacogenomics as a primary focus were identified. The total number of preceptors involved in the pharmacogenomics APPEs was 33: 19 (58%) faculty preceptors and 14 (42%) non-faculty preceptors. Twenty-three of the 30 pharmacogenomics APPEs completed the survey (77% response rate). The APPE sites were diverse and included academic medical centers, community health systems, pharmacogenomic testing laboratories, and schools of pharmacy. Each pharmacogenomics APPE accommodated an average of six students per year. The APPE activities varied across sites.Conclusion. Only a small number of US pharmacy schools offer an APPE with a primary focus in pharmacogenomics. These rotations are diverse in scope and precepted by faculty or non-faculty pharmacists. The Academy should pursue opportunities to increase experiential education in pharmacogenomics.

PMID:34283786 | DOI:10.5688/ajpe8031

Genet Med. 2021 Jul 19. doi: 10.1038/s41436-021-01269-9. Online ahead of print.

ABSTRACT

PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.

METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.

RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.

CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.

PMID:34282303 | DOI:10.1038/s41436-021-01269-9

Pharmacogenomics. 2021 Jul 20. doi: 10.2217/pgs-2021-0020. Online ahead of print.

ABSTRACT

Chemoresistance is a significant clinical challenge, limiting the drug response in cancer. Several mechanisms associated with drug resistance have been characterized, and the role of epigenetics in generating resistance to platinum-based drugs has been clarified. Epigenetic mechanisms such as DNA methylation, histone modification, long noncoding RNA, and microRNA affect the expression of genes implicated in absorption, distribution, metabolism and excretion (ADME) of drugs, and other non-ADME genes that encode enzymes involved in the processes of cell proliferation, DNA repair, apoptosis and signal transduction key in the development of chemoresistance in cancer, specifically in platinum-based drugs. This review summarizes current discoveries in epigenetic regulation implicated in platinum drug resistance in cancer and the main clinical trials based on epigenetic therapy, evaluating their potential synergy with platinum-based drugs.

PMID:34281355 | DOI:10.2217/pgs-2021-0020

Int J Mol Sci. 2021 Jul 5;22(13):7213. doi: 10.3390/ijms22137213.

ABSTRACT

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease.

METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review.

RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings.

CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.

PMID:34281267 | DOI:10.3390/ijms22137213

Expert Rev Mol Diagn. 2021 Jul 18:1-10. doi: 10.1080/14737159.2021.1943365. Online ahead of print.

ABSTRACT

Introduction: The treatment scenario of lung cancer is rapidly evolving through time. In parallel, growing evidence is accumulating on different mechanisms of treatment resistance. Inter- and intra-tumor heterogeneity define the spatial and temporal tumor clonal evolution, that is at the basis of tumor progression and resistance to anticancer treatments.Areas covered: This review summarizes the available evidence on molecular heterogeneity in lung cancer, from diagnosis to the occurrence of treatment resistance. The application of novel molecular diagnostic methods to detect molecular heterogeneity, and the implications of understanding heterogeneity for drug development strategies are discussed, with focus on clinical relevance and impact on patients' survival.Expert opinion: The current knowledge of molecular heterogeneity allows to identify different molecular subgroups of patients within the same conventional tumor type. Deeper understanding of heterogeneity determinants and the possibility to comprehensively investigate tumor molecular patterns will lead to the development of personalized treatment approaches, with the final goal to overcome resistance and prolong survival in lung cancer patients.

PMID:34278933 | DOI:10.1080/14737159.2021.1943365

Clin Pharmacol Ther. 2021 Jul 18. doi: 10.1002/cpt.2347. Online ahead of print.

NO ABSTRACT

PMID:34278575 | DOI:10.1002/cpt.2347

Ann Transl Med. 2021 Jun;9(12):1027. doi: 10.21037/atm-20-6636.

ABSTRACT

In fit metastatic colorectal cancer (MCRC), multidisciplinary treatment strategy integrating intensive FIr-B/FOx triplet chemotherapy associated to bevacizumab and secondary metastasectomies significantly improved clinical outcomes up to progression-free survival (PFS) 17 months and overall survival (OS) 44 months. A non-elderly woman affected by rectal cancer, lymph nodes involvement, synchronous unresectable liver metastases, was treated with first-line FIr-B/FOx integrated with two-stage liver resections, short course radiotherapy, anterior rectal resection, with a PFS 9 months and progression-free interval (PFI) 4 months off-treatment. After progression characterized by single liver and lymph node inferior mesenteric axis metastases, FIr-B/FOx was re-introduced, liver and lymph node resections were performed, with a PFS 8 months and PFI 3 months. FIr-B/FOx was further proposed due to bilateral lung, and liver metastases with stable disease, PFS 8 months. Patient experienced a limiting toxicity syndrome multiple sites (LTS-ms) with G3 diarrhea, G2 asthenia, nausea, requiring irinotecan reduction and 5-fluorouracil discontinuation, and subsequent oxaliplatin discontinuation, due to infusional hypersensitivity reaction. Overall, integrated first-line medical and surgical treatment strategies gained PFS 26 months. Further lines II-V of treatment obtained a combined PFS 28 months: modulated aflibercept/irinotecan, PFS 8 months; panitumumab, PFS 8 months, proposed due to KRAS/NRAS/BRAF wild-type and EGFR c.2156 G>C (p.G719A) mutation, achieving biomarkers reduction, lung, liver, lymph nodes partial responses; regorafenib, PFS 8 months; trifluridine-tipiracil, PFS 4 months and induced an LTS-ms, with febrile G4 leucopenia, G3 neutropenia, thrombocytopenia, asthenia, G2 anemia, diarrhea, hypotension. After 2 months of palliative care, patient died, at OS 58 months, gained by intensive medical/surgical treatments coupled with patient's resilience. To date, selection of tailored medical treatments, according to clinical (age, performance and comorbidity status) and molecular (RAS/BRAF and pharmacogenomic analyses) evaluations, careful monitoring of individual toxicity syndromes, potential integration of metastasectomies, and furthermore individual resilience as patient life priority need to challenge MCRC long-term survival.

PMID:34277827 | PMC:PMC8267302 | DOI:10.21037/atm-20-6636