Bevacizumab combined with FOLFOX improves outcomes in metastatic colorectal cancer (mCRC), but comprehensive safety evaluations remain limited.

We analyzed adverse drug reactions (ADRs) in the FDA Adverse Event Reporting System (FAERS), comparing FOLFOX monotherapy (366 reports), combination therapy (517 reports), and bevacizumab monotherapy (1,604 reports). Disproportionality analysis using ROR, PRR, BCPNN, and EBGM identified significant ADRs.

Twenty-one ADRs were significantly associated with FOLFOX-bevacizumab combination therapy, predominantly infections (e.g. febrile infection) and gastrointestinal disorders (e.g. anastomotic leak, ulcerative gastritis). The combination exhibited comparable but fewer ADRs than monotherapies, excluding pneumothorax and hypertension. Certain ADRs showed higher incidence and shorter median onset time (3 days post-treatment).

Combination therapy demonstrates manageable safety with early monitoring, though stricter criteria for ADR detection may overlook rare events. Key risks align with monotherapy profiles, emphasizing vigilance for infection-related and gastrointestinal complications. Further studies are warranted to validate these pharmacovigilance findings.

Colorectal cancer (CRC) is a serious public health concern worldwide. Immune checkpoint inhibition medication is likely to remain a crucial part of CRC clinical management. This study aims to create new super paramagnetic iron oxide nano-carrier (SPION) that can effectively transport miRNA to specific CRC cell lines. In addition, evaluate the efficiency of this nano-formulation as a therapeutic candidate for CRC. Bioinformatics tools were used to select a promising tumor suppressor miRNA (mir-497-5p). Green route, using Fusarium oxyporium fungal species, manipulated for the synthesis of SPION@Ag@Cs nanocomposite as a carrier of miR-497-5p. That specifically targets the suppression of PD1/PDL1 and CTLA4pathways for colorectal therapy. UV/visible and FTIR spectroscopy, Zeta potential and MTT were used to confirm the allocation of the miR-497 on SPION@Ag@Cs and its cytotoxicity against CRC cell lines. Immunofluorescence was employed to confirm transfection of cells with miR-497@NPs, and the down- regulation of CTLA4 in HT29, and Caco2 cell lines. On the other hand, PDL1 showed a significant increase in colorectal cell lines (HT-29 and Caco-2) in response to mir497-5p@Nano treatment. The data suggest that the mir-497 -loaded SPION@Ag@Cs nano-formulation could be a good candidate for the suppression of CTLA4in CRC human cell lines. Consequently, the targeting miR-497/CTLA4 axis is a potential immunotherapy treatment strategy for CRC.

The relationship between drug-induced liver injury and liver metastasis of colorectal cancer and the underlying mechanisms are not well understood. In this study, we used carbon tetrachloride to construct a classic mouse liver injury model and injected CT26 colorectal cancer cells into the mouse spleen to simulate the natural route of colorectal cancer liver metastasis. Liver injury significantly increased the number of colorectal cancer liver metastases. Transcriptome sequencing and data-independent acquisition protein quantification identified proteins that were significantly differentially expressed in injured livers, and orosomucoid (ORM) 2 was identified as a target protein for tumor liver metastasis. In vitro experiments showed that exogenous ORM2 protein increased the expression of EMT markers such as Twist, Zeb1, Vim, Snail1 and Snail2 and chemokine ligands to promote CT26 cell migration. In addition, liver-specific overexpression of the ORM2 protein in the mouse model significantly promoted tumor cell liver metastasis without inducing liver injury. Our results indicate that drug-induced liver injury can promote colorectal cancer liver metastasis and that ORM2 can promote cell migration by inducing EMT in tumor cells.

While specific elements of naturopathic medicine, such as botanical medicines and lifestyle interventions, have supporting evidence, there is limited quantitative data confirming its effectiveness as a comprehensive, whole-person medical approach for patients with metastatic colorectal cancer (CRC).

This study aims to retrospectively evaluate the integration of naturopathic modalities, including modulated electrohyperthermia (mEHT), into the standard of care for metastatic CRC. We compare survival outcomes between patients at the Integrated Health Clinic (IHC) and a matched control group from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, a de-identified, publicly available cancer registry in the United States.

A retrospective chart review was conducted for 131 IHC patients diagnosed with stage IV CRC and treated with mEHT between 2010 and 2021. These patients were matched with 262 controls from the SEER database using propensity score matching. The primary outcome was overall survival, with time zero defined as the first IHC treatment date (with controls assigned the time zero of their matched IHC patient) to account for immortal time bias. Survival analysis was conducted using a Kaplan-Meier curve, log-rank test, and Cox proportional-hazards model.

The overall survival analysis did not achieve a statistically significant difference (HR = .76; 95% CI: .57-1.01) between the IHC (median survival time: 29 month) and SEER groups (median survival time: 18 months). Incorporating time-varying effects, the hazard ratio (HR) for the IHC group compared to the SEER group was .63 (95% CI: .46-.86) for survival <36 months, indicating a lower hazard of early mortality in the IHC group. Moreover, IHC patients who initiated treatment within 90 days of diagnosis had significantly improved survival compared to their matched controls (HR = .45; 95% CI: .28-.70).

This study provides evidence that integrative naturopathic treatment, including mEHT, can significantly improve survival outcomes for CRC patients in the first 36 months post-treatment and when initiated within 90 days of diagnosis.

Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) typically have a poor prognosis with historically few treatment options. Cytoreductive surgery (CRS) is the mainstay of treatment to remove macrometastases into the peritoneum, but residual micrometastases are often left behind. Systemic chemotherapy remains a cornerstone of treatment for micrometastases, but intraperitoneal therapy offers advantages including higher local dose concentration with fewer systemic side effects from treatment.

This review covers advancements in the routes and types of pharmacotherapies for PM in CRC.

More evidence is needed to justify HIPEC with CRS as the standard of care treatment modality for patients with resectable PM in CRC. New therapies such as oncolytic viruses, biologics, and small-molecule inhibitors may become additional treatment modalities for PM.

Colorectal cancer (CRC) ranks as the second deadliest cancer globally and the third most common malignant tumor. While surgery remains the primary treatment for CRC, alternative therapies such as chemotherapy, molecular targeted therapy, and immunotherapy are also commonly used. The significant side effects and toxicity of conventional drugs drive the search for novel targeted therapies, including the design of advanced drug delivery systems. Polysaccharide-based biopolymers, with their low toxicity, non-immunogenic behavior, synergistic interactions with other biopolymers, and tissue and cell compatibility, emerge as excellent drug carriers for this application. This review aims to provide an in-depth overview of recent advancements in developing polysaccharide-based biopolymeric carriers for anticancer compounds in the treatment of CRC. We highlight the multifunctional nature of polysaccharides, showcasing their potential as standalone drug carriers or as integral components of intelligent robotic devices for biomedical therapeutic applications. In addition to exploring the opportunities for using carbohydrate polymers in CRC treatment, we address the challenges and failures that may limit their applicability in biomedical research, as well as summarize the recent preclinical and clinical trials, resulting in several commercialization attempts. This comprehensive overview critically summarizes the potential of polysaccharide-based biomaterials in CRC treatment.

One of the most famous and heterogeneous cancers worldwide is breast cancer (BC). Owing to differences in the gene expression profiles and clinical features of distinct BC subtypes, different treatments are prescribed for patients. However, even with more thorough pathological evaluations of tumors than in the past, available treatments do not perform equally well for all individuals. Precision medicine is a new approach that considers the effects of patients' genes, lifestyle, and environment to choose the right treatment for an individual patient. As a powerful tool, the organoid culture system can maintain the morphological and genetic characteristics of patients' tumors. Evidence also shows that organoids have high predictive value for patient treatment. In this review, a variety of BC studies performed on organoid culture systems are evaluated. Additionally, the potential of using organoid models in BC translational research, especially in immunotherapy, drug screening, and precision medicine, has been reported.

Colorectal cancer (CRC) with hepatic (CRLM) and pulmonary metastases (CRLU) presents a significant clinical challenge, leading to poor prognosis. Surgical resection of these metastases remains controversial because of limited evidence supporting its long-term benefits. To evaluate the impact of surgical resection of both hepatic and pulmonary metastases on long-term survival in patients with multivisceral metastatic colorectal cancer, this retrospective cohort study included 192 patients with UICC stage IV CRC treated at a high-volume academic center.

Patients were divided into two groups: those who underwent surgical resection of both hepatic and pulmonary metastases (n = 100) and those who received non-surgical treatment (n = 92). Propensity score matching was used to adjust for baseline differences. The primary outcome was overall survival (OS).

Unadjusted analysis showed a significant OS benefit in the surgical group (median OS: 6.97 years) compared with the conservative group (median OS: 2.17 years). After propensity score matching, this survival advantage persisted (median OS: 5.58 years vs. 2.35 years; HR: 0.3, 95% CI: 0.18-0.47, p < 0.0001).

Surgical resection of hepatic and pulmonary metastases in multivisceral metastatic CRC significantly improves long-term survival, supporting an aggressive surgical approach in selected patients.

Metastatic CRC is considered as a heterogenous disease. Its management is therefore complex and dynamic. In order the give a ready reference to community oncologists, we developed this real world recommendations.

A group of experts with academic background and real world experience in mCRC got together. We reviewed the current literature and the insights gained from our real world experience. Based on the same we put together these recommendations.

Molecular testing should be done wherever possible. Most of these patients will be treated with a palliative approach. Doublet chemotherapy is a long-standing standard of care. Triplet therapy may be offered where a more aggressive approach is indicated. Combination with anti -vascular endothelial growth factor antibodies and/or anti EGFR antibodies is also considered standard. In the first-line setting, pembrolizumab can be used for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumours; Left and right sided tumours are distinct entities. Combination of chemotherapy and targeted therapy is used as per individual patient and tumour characteristics.Oligometastatic disease can be approached with potentially curative intent. Cytoreductive surgery plus chemotherapy can be offered to selected patients with peritoneal only metastases. Stereotactic body radiation therapy can be used as local therapy for patients with oligometastatic liver only disease who cannot be taken up for surgery. New strategies include induction-maintenance chemotherapy and perioperative chemotherapy. All drugs/ regimen included as standard of care in the first line can also be used in subsequent lines. Specific targetable driver mutation tumours can be treated accordingly with their complementary biological therapy.

Multidisciplinary team management and shared decision making are possible when patient and caregivers choose to become active participants.

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.

Abdominal aortic aneurysmal (AAA) repair in patients with concomitant cancer is controversial due to increased comorbidity and reduced life expectancy in this specific patient group. This literature review aims to investigate the evidence supporting one treatment modality over another (endovascular aortic repair (EVAR) or open repair (OR)), as well as treatment strategy (staged AAA-, cancer first or simultaneous procedures) in patients with AAA and concomitant cancer.

Literature review, including studies published from 2000 to 2021 on surgical treatment in patients with AAA and concomitant cancer and related outcomes (30-day morbidity/complications as well as 30-day and 3-year mortality).

24 studies comprising 560 patients undergoing surgical treatment of AAA and concomitant cancer were included. Of these, 220 cases were treated with EVAR and 340 with OR. Simultaneous procedures were performed in 190 cases, 370 received staged procedures. The 30-day mortality for EVAR versus OR was 1% and 8%, corresponding to a relative risk (RR) of 0.11 (95% CI: 0.03-0.46, p = 0.002). No difference in mortality was observed between staged versus simultaneous procedure nor between AAA-first versus cancer-first strategy, RR 0.59 (95% CI: 0.29-1.1, p = 0.13) and 0.88 (95% CI 0.34-2.31, p = 0.80), respectively. Overall, 3-year mortality was 21% for EVAR and 39% for OR from 2000-2021, while the mortality up to 3 years after EVAR within recent years (2015-2021) was 16%.

This review supports EVAR treatment as first choice if suitable. No consensus was established on treating either the aneurysm or the cancer first or simultaneously. Long-term mortality after EVAR was comparable to non-cancer patients within recent years.

The adsorption of 5-fluorouracil (5FU) on Watson-Crick (WC) base pairs and Hoogsteen (HT) base pairs has been studied using the dispersion-corrected density functional theory (DFT). The adsorption, binding energy, and thermochemistry for the drug 5FU on the WC and HT base pairs were determined. The most stable geometries were near planar geometry, and 5FU has a higher preference for WC than HT base pairs. The adsorption energies of 5FU on nucleobase pairs are consistently higher than pristine nucleobase pairs, indicating that nucleobase pair cleavage is less likely during the adsorption of the 5FU drug. The enthalpy change for the formation of 5FU-DNA base pairs is higher than that for the formation of 5FU-nucleobases and is enthalpy-driven. The E gap of AT base pairs is higher, suggesting that their chemical reactivity toward further reaction would be less than that of GC base pairs. The electron density difference (EDD) analysis shows a significant decrease in electron density in aromatic regions on the purine bases (adenine/guanine) compared to the pyrimidine bases. The MESP diagram of the stable 5FU-nucleobase pair complexes shows a directional interaction, with the positive regions in a molecule interacting with the negative region of other molecules. The atoms in molecule analysis show that the ρ(r) values of C=O···H-N are higher than those of N···H/N-H···O. The N···H intermolecular bonds between the base pair/drug and nucleobases are weak, closed shell interactions and are electrostatic in nature. The noncovalent interaction analysis shows that several new spikes are engendered along with an increase in their strength, which indicates that the H-bonding interactions are stronger and play a dominant role in stabilizing the complexes. Energy decomposition analysis shows that the drug-nucleobase pair complex has a marginal increase in the electrostatic contributions compared to nucleobase pair complexes.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

Colorectal cancer remains the third leading cause of cancer-related mortality in the United States. This study evaluates the causes of death in patients operated on for colorectal cancer and their determinants.

An Instructional Review Board-approved database containing patients who underwent surgical resection for colorectal cancer from 2004 to 2018 (last followed up in December 2020) in a tertiary care institution. Data on the underlying cause of death was extracted from the Registry of Vital Records and Statistics in Massachusetts.

A total of 576 deaths were recorded in the database, of which 290 (50.35%) patients died of colorectal cancer. Deaths from colorectal cancer gradually decreased over time, whereas deaths from other cancers increased, and deaths from cardiovascular diseases remained stable. Patients who died from colorectal cancer were younger, died earlier in the disease course, had fewer comorbidities, higher rates of stage IV disease, rectal cancer, neoadjuvant therapy, extramural vascular invasion, perineural invasion, R0 resection, and preserved mismatch repair protein status. On multivariate analysis, age (adjusted odds ratio for 10-year increase = 0.79, 95% confidence interval 0.65-0.95), American Society of Anesthesiologists score (adjusted odds ratio = 0.64, confidence interval 0.42-0.98), stage IV disease (adjusted odds ratio = 3.02, confidence interval 1.59-5.9), neoadjuvant therapy (adjusted odds ratio = 7.91, confidence interval 2.64-28.13), extramural vascular invasion (adjusted odds ratio = 2.3, confidence interval 1.36-3.91) & time from diagnosis to death (adjusted odds ratio = 0.76, confidence interval 0.68-0.83) predicted death due to colorectal cancer versus other causes, whereas tumor location, perineural invasion, R0 resection, and mismatch repair protein status did not.

There is a declining trend of deaths from colorectal cancer, presumably reflecting advances in colorectal cancer management strategies and better screening over time. However, younger patients disproportionately contribute to death due to colorectal cancer and need aggressive screening and management strategies.

Randomized clinical trials have defined the survival advantage with the addition of biologic drugs to chemotherapy in patients with metastatic colorectal cancer (mCRC). Under representation of Hispanics contributes to poorly defined outcomes in this group. We aim to determine whether the real-world benefit of biologics extends to Hispanics using a comparative effectiveness research approach.

This retrospective cohort study included all treatment centers contributing to SEER registry with available claims in the SEER-Medicare linked database (2001-2011) and 2 hospitals (2004-2016) catering to minorities. Metastatic CRC patients were classified as receiving chemotherapy or biochemotherapy (CT plus biologics; if initiated within 3 months of chemotherapy). The primary outcome was overall survival (OS) among the Hispanic patients calculated from time of administration of first dose of chemotherapy to death or last follow-up. A weighted Cox regression model was used to assess differences in survival.

We identified 182 Hispanic patients with mCRC from the Patient Entitlement and Diagnosis Summary (PEDSF) file (n = 101) and hospital database (n = 81). Overall, 52% were women and 72% received biologics. The median OS was 11.3 and 17.0 months in chemotherapy and biochemotherapy group, respectively. Biochemotherapy offered a survival benefit compared with chemotherapy alone, with an average hazard rate reduction of 39% (95% CI 6%-60%, p = .0236) using inverse probability of treatment weighting (IPTW) based analysis.

In this cohort of Hispanic patients with mCRC, biochemotherapy was associated with longer survival. Clinicians may offer biochemotherapy therapy to all patients regardless of race/ethnicity to maximize clinical benefit.

Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient-derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d-bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient-derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient-derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.

Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab.

This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity.

Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed.

Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Colorectal cancer (CRC) is a common and deadly form of cancer, leading to the need for new therapeutic targets and strategies for treatment. Recent studies have shown the cGAS-STING pathway to be a promising target for cancer therapy. The cGAS-STING pathway is a part of the innate immune system and serves to identify DNA damage and viral infection, promoting an immune response. Activation of this pathway leads to the production of immune mediators, such as type I interferons, that activate immune cells to attack cancer cells. Research has identified the cGAS-STING pathway as a frequently dysregulated component in CRC, promoting tumor growth and metastasis, or leading to chronic inflammation and tissue damage. The modulation of this pathway presents a potential therapeutic approach, either activating or inhibiting the pathway to enhance the immune response and prevent inflammation, respectively. Developing drugs that can modulate the cGAS-STING pathway offers promise for improving treatment outcomes for CRC patients. The present review explores recent research on the role of cGAS-STING in CRC and highlights the potential therapeutic benefits of targeting this pathway.

While chemotherapy alone or in combination with radiotherapy and surgery are important modalities in the treatment of colorectal cancer, their widespread use is not paired with an abundance of diagnostic tools to match individual patients with the most effective standard-of-care chemo- or radiotherapy regimens. Patient-derived organoids are tumour-derived structures that have been shown to retain certain aspects of the tissue of origin. We present here a systematic review of studies that have tested the performance of patient derived organoids to predict the effect of anti-cancer therapies in colorectal cancer, for chemotherapies, targeted drugs, and radiation therapy, and we found overall a positive predictive value of 68% and a negative predictive value of 78% for organoid informed treatment, which outperforms response rates observed with empirically guided treatment selection.

Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer.

Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment depends on the drugs used in first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR/MSI-H, TMB-H, and HER2 statuses have been established in clinical practice, and the corresponding molecularly targeted therapeutic agents are selected based on the biomarker status. Given the frequency of biomarkers, it is assumed that when patients move on to second-line treatment, an angiogenesis inhibitor is selected in many cases. For second-line treatment, three angiogenesis inhibitors, bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are available, and one of them is combined with cytotoxic agents. These three angiogenesis inhibitors are known to inhibit angiogenesis through different mechanisms of action. Although no useful biomarkers have been established for the selection of angiogenesis inhibitors, previous biomarker studies have suggested that angiogenesis-related factors such as VEGF-A and VEGF-D might be predictors of the therapeutic efficacy of angiogenesis inhibitors. These biomarkers are measured as protein levels in plasma and are considered to be promising biomarkers. We consider that the rationale for selecting among these three angiogenesis inhibitors should be clarified to benefit patients.

Sensitization of mismatch repair (MMR)-deficient colorectal cancer (CRC) cells by 5-Fluorouracil (5-FU) is well-documented. But not much is known about the treatment of MMR-proficient CRC cancer stem cells (CRC-CSCs). Here, we investigated whether a PARP inhibitor (ABT-888) can enhance the 5-FU-mediated apoptosis in CRC-CSCs through MMR pathway inhibition.

The anti-cancer action of 5-FU+ABT-888 combination in CRC-CSCs has been studied by using in vitro, ex vivo, and in vivo preclinical model systems.

5-FU caused DNA damage in CRC-CSCs, and ABT-888 enhanced the accumulation of DNA mismatches by downregulating the MMR pathway, triggering S-phase arrest, and finally apoptosis and cell death in 5-FU-pre-treated MMR-proficient-CRC-CSCs at much lower concentrations than their individual treatments. After 5-FU treatment, PARylated-PARP1 activated MMR pathway by interacting with MSH6. But, upon ABT-888 treatment in 5-FU-pre-exposed CSCs, PARylation was inhibited, as a result of which PARP1 could not interact with MSH6, and other MMR proteins were downregulated. The role of MSH6 in PARP1-mediated MMR activation, was confirmed by silencing MSH6 gene, which resulted in MMR pathway shutdown. Similar results were obtained in ex vivo and in vivo model systems.

5-FU+ABT-888 combination enhanced CRC-CSCs death by increasing DNA damage accumulation and simultaneously inhibiting the MMR pathway in MMR-proficient cells. But this study does not discuss whether the combination treatment will increase the sensitivity of MMR-deficient CSCs, for which further research will be performed in the future.

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

We preformed a Phase IV non-interventional study to assess KRAS, NRAS and BRAF status in metastatic colorectal cancer (mCRC) patients suitable for 1^st line treatment and to evaluate the decisions for 1^st line treatment considering the treatment goals in the RAS wild type (wt) patients. The aim of our study was also to evaluate the influence of a waiting period for biomarkers analysis on the start of first-line treatment.

Patients with histologically confirmed mCRC adenocarcinoma suitable for first-line treatment fulfilling all inclusion criteria were included in the study. The KRAS, NRAS and BRAF analysis was performed from tissue samples of primary tumor site or metastatic site. All included patients have given consent to participate in the study by signing the informed consent form.

From April 2013 to March 2018 at the Institute of Oncology Ljubljana 650 patients were included, 637 of them were treated with first- line systemic treatment according to RAS and BRAF status. Remaining 13 patients with mCRC did not receive systemic first-line treatment. The distribution of patients with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively, 89 % of the patients had wt NRAS tumours and 86.1% had wt BRAF tumours. The most frequently prescribed treatment was bevacizumab-based therapy (53.1%), either in combination with doublet chemotherapy or with mono-chemotherapy. EGFR inhibitors cetuximab and panitumumab were prescribed in wt RAS mCRC patients (30.9%). The waiting period for biomarkers analysis was two weeks.

Our real-world data, single centre 5-year analysis showed that the distribution between wild type and mutated type tumors of the patients with mCRC was approximately the same, as worldwide, so the Slovenian population with mCRC has the same ratio distribution of KRAS, NRAS and BRAF wild and mutated genes. We concluded that a two-week waiting period for biomarkers analysis did not influence the first line treatment decision, so it was in the accordance with the worldwide treatment guidelines based on evidence-based medicine.

To evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites.

We conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020.

In total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74-90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31-6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59-1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85-1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases.

Oxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.

Various prognostic factors have been reported for bone metastases from different primary tumor sites. However, bone metastases from colorectal cancer are very rare, and the prognostic factors have not been investigated in detail.

This study aimed to identify prognostic factors of bone metastases from colorectal cancer.

This is a retrospective cohort study using data from a prospectively collected database.

This study was conducted at a single tertiary care cancer center in Japan.

Patients who developed bone metastases from colorectal cancer during the study period among all patients who received initial treatment for colorectal cancer at our hospital between 2005 and 2016 (n = 4538) were included.

Overall survival after diagnosis of bone metastases from colorectal cancer was the main outcome measure.

Ninety-four patients developed bone metastases during the study period. The 5-year overall survival rate was 11.0%. Multivariable analysis identified the following independent risk factors associated with poor prognosis: ≥70 years of age at diagnosis of bone metastases (HR, 2.48; 95% CI, 1.24-4.95; p < 0.01), curative surgery not performed as initial treatment (HR, 2.54; 95% CI, 1.24-5.19; p = 0.01), multiple bone metastases (HR, 2.44; 95% CI, 1.30-4.57; p < 0.01), albumin level <3.7 g/dL (HR, 3.80; 95% CI, 1.95-7.39; p < 0.01), CEA ≥30 ng/mL (HR, 1.94; 95% CI, 1.09-3.46; p = 0.02), and less than 3 chemotherapy options remaining at diagnosis of bone metastases (HR, 2.83; 95% CI, 1.51-5.30; p < 0.01). The median survival times for patients with 0-2, 3, and 4-6 risk factors were 25.0, 8.8, and 4.3 months, respectively.

The main limitation is the single-center, retrospective design of this study.

Our results may facilitate multidisciplinary decision-making in patients with bone metastases from colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B930 .

ANTECEDENTES:Se han reportado varios factores pronósticos para las metástasis óseas de diferentes sitios de tumores primarios. Sin embargo, las metástasis óseas del cáncer colorrectal son muy raras y los factores pronósticos no se han investigado en detalle.OBJETIVO:Identificar los factores pronósticos de las metástasis óseas del cáncer colorrectal.DISEÑO:Estudio de cohorte retrospectivo utilizando datos de una base de datos recolectada prospectivamente.ENTORNO CLINICO:Un solo centro oncológico de atención terciaria en Japón.PACIENTES:Se seleccionaron pacientes que desarrollaron metástasis óseas de cáncer colorrectal durante el período de estudio entre todos los pacientes que recibieron tratamiento inicial para el cáncer colorrectal en nuestro hospital entre 2005 y 2016 (n = 4538).MEDIDA DE RESULTADO PRINCIPAL:Supervivencia general después del diagnóstico de metástasis óseas por cáncer colorrectal.RESULTADOS:Noventa y cuatro pacientes desarrollaron metástasis óseas, lo que representa el 2,0% de todos los pacientes con cáncer colorrectal que comenzaron el tratamiento durante el período de estudio. La tasa de supervivencia global a 5 años fue del 11,0 %. El análisis multivariable identificó los siguientes factores de riesgo independientes asociados con mal pronóstico: edad ≥70 años al momento del diagnóstico de metástasis óseas (hazard ratio 2,48, CI del 95 % 1,24-4,95, p < 0,01), cirugía curativa no realizada como tratamiento inicial (hazard ratio 2,54, CI 95 % 1,24-5,19, p = 0,01), metástasis óseas múltiples (hazard ratio 2,44, CI del 95 % 1,30-4,57, p < 0,01), nivel de albúmina <3,7 g/dL (hazard ratio 3,80, CI del 95 % 1,95 -7,39, p < 0,01), antígeno carcinoembrionario ≥30 ng/mL (hazard ratio 1,94, CI del 95 % 1,09-3,46, p = 0,02) y menos de 3 opciones de quimioterapia restantes al momento del diagnóstico de metástasis óseas (hazard ratio 2,83, 95 % CI 1,51-5,30, p < 0,01). La mediana de los tiempos de supervivencia para los pacientes con 0-2, 3 y 4-6 factores de riesgo fue de 25,0, 8,8 y 4,3 meses, respectivamente.LIMITACIONES:Diseño retrospectivo de un solo centro.CONCLUSIÓN:Nuestros resultados pueden facilitar la toma de decisiones multidisciplinares en pacientes con metástasis óseas de cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B930 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) combined with or without anti-VEGF therapy represents one of the primary first-line treatment options for metastatic colorectal carcinoma (mCRC). However, there is limited comparative data on the impact of anti-VEGF therapy on treatment effectiveness, survival outcomes, and tumor location.

This retrospective, comparative study utilized data from the AIM Cancer Care Quality Program and commercially insured patients treated at medical oncology clinics in the US. We analyzed 1652 mCRC patients who received FOLFOX, of which 1015 (61.4%) were also treated with anti-VEGF therapy (VEGF cohort).

Patients in the VEGF cohort exhibited a higher frequency of lung (33% vs 23%; P < .001) and liver metastases (74% vs 62%; P < .001), underwent fewer liver surgeries prior to treatment (1.2% vs 3.6%; P = .002), and had a higher proportion of right-sided tumors (27% vs 18%; P = .001). Adjusted analysis revealed no significant difference in overall survival (OS) between patients treated with and without anti-VEGF (median survival: 25.4 vs 26.0 months; P = .4). FOLFOX-only treated patients experienced higher rates of post-treatment hospitalizations (22% vs 15%; P < .001). Notably, left-sided tumors treated with anti-VEGF showed a trend toward decreased OS (median survival: 26.8 vs 33 months; P = .09).

Our real-world data analysis suggests that the addition of anti-VEGF to FOLFOX offers limited and short-lived benefits in the context of mCRC and may provide differential survival benefit based on tumor sidedness.

Colorectal cancer (CRC) is the third most common malignancy and the second most common deadly cancer worldwide as of 2020. Unusual presentation of this cancer with locally advanced disease is rare and seen in only 5% to 22% of cases. We present the case of a 53-year-old male who had invasive cecal adenocarcinoma with phlegmon of the abdominal wall musculature at presentation and an aggressive course that did not respond to the standard lines of therapy. In the current era of ongoing tremendous developments in colorectal cancer diagnosis and treatment, this uncommon case reminds us that locally advanced CRC is still a challenge to manage. Precision medicine with treatment strategies tailored to an individual's genetic, environmental and lifestyle factors is the current need.

There is no effective method to predict chemotherapy response and postoperative prognosis of colorectal cancer liver metastasis (CRLM) patients. Patient-derived organoid (PDO) has become an important preclinical model. Herein, a living biobank with 50 CRLM organoids derived from primary tumors and paired liver metastatic lesions is successfully constructed. CRLM PDOs from the multiomics levels (histopathology, genome, transcriptome and single-cell sequencing) are comprehensively analyzed and confirmed that this organoid platform for CRLM could capture intra- and interpatient heterogeneity. The chemosensitivity data in vitro reveal the potential value of clinical application for PDOs to predict chemotherapy response (FOLFOX or FOLFIRI) and clinical prognosis of CRLM patients. Taken together, CRLM PDOs can be utilized to deliver a potential application for personalized medicine.

Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.

Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking.

This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method.

This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings.

NCT03914820.

At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine.