Colorectal cancer (CRC), the third most prevalent cancer globally, shows a diminished 5‑year survival rate compared with patients at early stages of the disease, underscoring the urgency for early diagnostic biomarker identification. The C‑X‑C motif chemokine ligand (CXCL) family plays a significant role in immune modulation and cancer progression. the present study constructed a prognostic model for CXCL family in CRC and conducted an in‑depth investigation of the hub gene CXCL9 within the model. CXCL9 is highly expressed in CRC while high expression levels of CXCL9 in patients with CRC often indicates an improved prognosis. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis enrichment analysis, it was discovered that CXCL9 is not only associated with immune modulation but also closely related to pathways that affect the occurrence and development of cancer. CXCL9 is closely related to mitophagy and blocks autophagy flow by altering the expression of autophagy‑related genes. Additionally, it was found that CXCL9 is a downstream gene modified by ALKBH5 and can partially restore the tumor‑suppressive effects induced by the knockdown of ALKBH5. These studies indicated that CXCL9 is a prognostic marker in CRC and plays a dual role in cancer progression: It activates immune responses on one hand and promotes the malignant characteristics of cancer on the other hand.

Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated.

Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity.

Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo.

Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo.

Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

Targeted therapy has significantly transformed the treatment landscape of colorectal cancer (CRC), enabling personalized treatment approaches and improving patient prognosis. This study employs bibliometric analysis to explore the research hotspots and development trends in the field of CRC-targeted therapy from 2000 to 2023.

Based on the Web of Science Core Collection, this study collected literature related to CRC-targeted therapy published between 2000 and 2023. CiteSpace and VOSviewer were used for data analysis, with a focus on publication trends, key contributors, and keyword co-occurrence patterns.

A total of 2252 relevant articles were included, demonstrating a steady growth trend in research output. China ranked first in terms of the number of publications, while the University of Texas MD Anderson Cancer Center was identified as the institution with the highest research output. Josep Tabernero was the most prolific author in this field. Among journals, Cancers had the highest impact, while Clinical Cancer Research held a significant advantage in citation frequency. Keyword co-occurrence and clustering analysis indicated that research primarily focused on treatment strategies and precision medicine, with emerging technologies such as cell therapy and liquid biopsy garnering increasing attention.

This study reveals the research trends, core hotspots, and emerging directions in the field of CRC-targeted therapy, providing valuable insights for future research.

To assess biomarker testing utilization, treatment patterns, and clinical outcomes in previously treated proficient mismatch repair deficient (pMMR) or non-microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients.

Using the iKnowMed electronic health record database, this study included pMMR/non-MSI-H adult mCRC patients previously treated with standard-of-care (SoC) chemotherapies between 1 January 2016 and 31 December 2021. Patients were censored for overall survival (OS) and real-world progression-free survival (rwPFS) at their last visit date or the end of study period, 31 August 2022.

MSI/MMR testing was conducted in 70.9% of mCRC patients. In 292 previously treated mCRC patients, 69.5% received SACT (regorafenib:14.8%, trifluridine+tipiracil (TAS-102):12.3%, other SACT:72.9%), 28.8% received BSC and 1.7% received no BSC/SACT. The most common other SACT included irinotecan- (37.4%) and oxaliplatin-based (14.8%) therapies. The most patients were tested for KRAS (89%) and BRAF (81%). Overall, the median (95% CI) OS and rwPFS was 7.4(5.8,8.8) and 3.5(3.2,4.3) months, respectively.

Only 70.9% of mCRC patients received guideline-recommended MSI/MMR testing, indicating a need for improved testing rates. Additionally, only 27.1% of previously treated mCRC patients received SoC options (regorafenib/TAS-102). The real-world variability in treatment choices and a high rate of chemotherapy rechallenge in subsequent lines highlight an unmet need in this patient population.

To evaluate the effect of intraocularly applied epidermal growth factor receptor (EGFR) antibody panitumumab on axial elongation.

This is a preclinical, safety, and efficacy experimental study. Guinea pigs aged 2-3 weeks were fitted with bilateral plano lenses (Group I; n = 10) or underwent bilateral lens-induced myopization (LIM) (Group II; n = 10) with no intravitreal injections. Animals with LIM of Groups III (n = 15), IV (n = 15) and V (n = 15) received three 4-weekly intravitreal injections of panitumumab at doses of 25, 50 and 100 μg, respectively, into their right eyes, and of phosphate-buffered saline into their left eyes.

Inter-eye differences in axial elongation (right eye minus left eye at study end) decreased (p < 0.001) from 0.00 ± 0.02 mm (Group I) and - 0.01 ± 0.02 mm (Group II) to -0.09 ± 0.03 mm (Group III), -0.12 ± 0.03 mm (Group IV) and - 0.17 ± 0.05 mm (Group V). Interocular choroidal thickness differences (measured by optical coherence tomography) increased (p < 0.01) from Groups I and II to Groups III-V. Western blot analysis showed an increase (p < 0.05) in expression levels of EGFR and its downstream phosphorylated signalling molecule, p-PI3K, in Group II compared to Group I and a decrease in Groups III-V compared to Group II (all p < 0.01). Interocular differences in retinal thickness did not differ significantly (p > 0.05) between the groups. TUNEL staining revealed no significant differences in retinal apoptotic cell density among any groups (all p > 0.05).

Intravitreally administered panitumumab in young guinea pigs with LIM resulted in a dose-dependent and treatment frequency-dependent reduction in axial elongation, supporting the role of EGFR signalling in axial elongation.

We have made steady gains in improving overall survival in patients with metastatic, unresectable, colon cancer in the last 5 to 10 years. The backbone of systemic treatment for most patients remains combination chemotherapy, but the field is becoming increasingly biomarker driven, with exciting new targeted therapies on the horizon. This review is organized in sections corresponding to currently relevant biomarkers in colon cancer and will summarize first-, second-, and third-line standard of care for metastatic, unresectable, colon cancer. The last section is intended to introduce the reader to promising agents and novel therapeutic strategies currently under investigation.

Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.

In the era of precision oncology, systemic therapies for colon cancer are becoming increasingly biomarker-led, with implications for patients in the neoadjuvant, adjuvant and metastatic settings. As the landscape for colon cancer treatment evolves and becomes more complex, it is important that all members of the multidisciplinary team keep abreast of developments to ensure the most effective care is delivered to patients. As core members of the colorectal multidisciplinary team, Radiologists play a central role throughout the patient journey. This review serves as an educational summary of current and emerging treatment pathways in colon cancer, standards for biomarker testing, mechanisms of action for key drugs, important treatment-related complications, relevant tumour biology that underpins patterns of disease and treatment response, and the specific implications systemic therapies have for cancer imaging and Radiologists. We also highlight the increasing role for radiology in patient stratification and the importance of imaging biomarkers. It is crucial that Radiologists understand the current landscape of colon cancer treatment and emerging strategies on the horizon in clinical trials. Only through engagement across the wider multidisciplinary team will we deliver true personalised medicine for patients with colon cancer.

Glioblastoma (GBM), the most common malignant tumor of the central nervous system (CNS) in adults, continues to result in poor survival rates despite standard treatment. Advancements in understanding GBM's molecular complexity have increased interest in targeted therapeutic approaches. This retrospective, single-center, single-arm study combined nimotuzumab and bevacizumab with radiotherapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed GBM. The objectives were to determine the efficacy of this treatment combination and the associated toxicity.

A retrospective analysis of clinical data of GBM patients treated at our institution from September 2021 to May 2023 with postoperative combination therapy of nimotuzumab, bevacizumab, and TMZ concurrent with RT, as well as maintenance therapy with bevacizumab and TMZ. Follow-ups were performed every 3 to 6 months via hospital visits and telephone interviews. The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoint was the incidence of adverse events (AEs).

A total of 18 patients were included. The median follow-up time was 23 months. The one-year PFS rate was 77.8%, and the one-year OS rate was 94.4%. The median PFS was 18 months (95%CI, 15.9-20.1), and the median OS was 28 months (95%CI, 18.9-37.1). All AEs were controllable.

The combination of nimotuzumab and bevacizumab with TMZ and RT appears to demonstrate efficacy and safety in newly diagnosed GBM patients, providing a reference for clinical treatment. Further prospective studies are needed to confirm our results.

Despite apparently curative treatment, many patients with colorectal cancer develop subsequent metastatic disease. Current prognostic models are criticised because they are based on standard staging and omit novel biomarkers. Improved prognostication is an unmet need.

To improve prognostication for colorectal cancer by developing a baseline multivariable model of standard clinicopathological predictors, and to then improve prediction via addition of promising novel imaging, genetic and immunohistochemical biomarkers.

Prospective multicentre cohort.

Thirteen National Health Service hospitals.

Consecutive adult patients with colorectal cancer.

Collection of prespecified standard clinicopathological variables and more novel imaging, genetic and immunohistochemical biomarkers, followed by 3-year follow-up to identify postoperative metastasis.

Best multivariable prognostic model including perfusion computed tomography compared with tumour/node staging. Secondary outcomes: Additive benefit of perfusion computed tomography and other biomarkers to best baseline model comprising standard clinicopathological predictors; measurement variability between local and central review; biological relationships between perfusion computed tomography and pathology variables.

Between 2011 and 2016, 448 participants were recruited; 122 (27%) were withdrawn, leaving 326 (226 male, 100 female; mean ± standard deviation 66 ± 10.7 years); 183 (56%) had rectal cancer. Most cancers were locally advanced [≥ T3 stage, 227 (70%)]; 151 (46%) were node-positive (≥ N1 stage); 306 (94%) had surgery; 79 (24%) had neoadjuvant therapy. The resection margin was positive in 15 (5%); 93 (28%) had venous invasion; 125 (38%) had postoperative adjuvant chemotherapy; 81 (25%, 57 male) developed recurrent disease. Prediction of recurrent disease by the baseline clinicopathological time-to-event Weibull multivariable model (age, sex, tumour/node stage, tumour size and location, treatment, venous invasion) was superior to tumour/node staging: sensitivity: 0.57 (95% confidence interval 0.45 to 0.68), specificity 0.74 (95% confidence interval 0.68 to 0.79) versus sensitivity 0.56 (95% confidence interval 0.44 to 0.67), specificity 0.58 (95% confidence interval 0.51 to 0.64), respectively. Addition of perfusion computed tomography variables did not improve prediction significantly: c-statistic: 0.77 (95% confidence interval 0.71 to 0.83) versus 0.76 (95% confidence interval 0.70 to 0.82). Perfusion computed tomography parameters did not differ significantly between patients with and without recurrence (e.g. mean ± standard deviation blood flow of 60.3 ± 24.2 vs. 61.7 ± 34.2 ml/minute/100 ml). Furthermore, baseline model prediction was not improved significantly by the addition of any novel genetic or immunohistochemical biomarkers. We observed variation between local and central computed tomography measurements but neither improved model prediction significantly. We found no clear association between perfusion computed tomography variables and any immunohistochemical measurement or genetic expression.

The number of patients developing metastasis was lower than expected from historical data. Our findings should not be overinterpreted. While the baseline model was superior to tumour/node staging, any clinical utility needs definition in daily practice.

A prognostic model of standard clinicopathological variables outperformed tumour/node staging, but novel biomarkers did not improve prediction significantly. Biomarkers that appear promising in small single-centre studies may contribute nothing substantial to prognostication when evaluated rigorously.

It would be desirable for other researchers to externally evaluate the baseline model.

This trial is registered as ISRCTN95037515.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/22/49) and is published in full in Health Technology Assessment; Vol. 29, No. 8. See the NIHR Funding and Awards website for further award information.

This review article aims to address the challenges associated with targeted therapy for the treatment of metastatic colorectal cancer (mCRC). We will first provide an overview of approved targeted therapies for treating mCRC, which include antiangiogenic therapy, as well as inhibitors of EGFR, BRAFV600E, HER2 inhibitors, and immune checkpoints. Second, we discuss the different mechanisms of primary resistance, including tumor heterogeneity, both as inter-patient and intra-patient heterogeneity, and mechanisms of secondary resistance which include: driver oncogene alterations, downstream or parallel bypass signaling, presence of co-dominant driver oncogenes, tumor lineage plasticity, and epithelial to mesenchymal transition. Resistance mechanisms towards the different drug classes targeting mCRC are discussed in detail. Strategies to overcome resistance primarily involve combination of therapies, although this approach is typically linked to increased drug toxicity, manifesting as on and off-target effects. Moreover, the cost and accessibility of targeted therapies pose significant challenges for diverse populations. Addressing these challenges necessitates further research efforts aimed at optimizing the use of targeted therapy in mCRC. Integration of genomic biomarkers, such as sequencing and liquid biopsy, into routine clinical practice holds promise in enhancing treatment outcomes. In conclusion, this comprehensive review underscores the complex challenges encountered in targeted therapy for mCRC.

The combination of anti-epidermal growth factor receptor (EGFR) therapy and chemotherapy is currently a preferred first-line treatment for patients with unresectable, RAS and BRAF wild-type, left-sided metastatic colorectal cancer (mCRC). Several studies have also demonstrated the benefit of anti-EGFR therapy in subsequent line settings for this patient population. However, direct evidence comparing the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited, leaving a crucial gap in guiding optimal treatment strategies.

To compare overall survival (OS) between frontline and subsequent anti-EGFR treatment in patients with unresectable, RAS and BRAF wild-type, left-sided mCRC.

We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital, Thailand, between January 2013 and April 2023. Patients were classified into two groups based on the sequence of their anti-EGFR treatment. The primary endpoint was OS.

Among 222 patients with a median follow-up of 29 months, no significant difference in OS was observed between the frontline and subsequent-line groups (HR 1.03, 95%CI: 0.73-1.46, P = 0.878). The median OS was 35.53 months (95%CI: 26.59-44.47) for the frontline group and 31.60 months (95%CI: 27.83-35.37) for the subsequent-line group. In the subsequent-line group, 71 patients (32.4%) who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months (95%CI: 12.87-26.53).

Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable, RAS/BRAF wild-type, left-sided mCRC patients, but early exposure is vital for those unlikely to receive subsequent therapy.

Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.

Skin disorders are major adverse events associated with necitumumab plus gemcitabine and cisplatin (Neci + GC) administration. However, the prognostic effect of skin disorders in patients with lung squamous cell carcinoma (LSCC) administered Neci + GC is unclear.

We examined this prognostic effect in patients with LSCC, and the usefulness of minocycline administration.

This was a sub-analysis of the retrospective multicenter NINJA study.

We performed a landmark survival analysis according to the presence of skin disorders at Day 30 of treatment and examined the usefulness of minocycline for treating skin disorders.

Among the 93 patients, 62 (66.7%) had a skin disorder at Day 30. Nineteen, 30, and 13 patients experienced Grade 1, 2, and 3 skin disorders, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with skin disorders at Day 30 were longer than those of patients without skin disorders (median OS: 434 vs 278 days, p = 0.0201; median PFS: 148 vs 82 days, p = 0.0835). Multivariable analysis showed that a skin disorder at Day 30 was an independent prognostic factor for both OS (p = 0.0044) and PFS (p = 0.0514). Of the 62 patients with skin disorders at Day 30, 38 (61.3%) were taking minocycline, and their time to treatment failure (TTF) was better than that in patients not taking minocycline (median TTF: 148 vs 101 days, p = 0.0495).

A skin disorder within 30 days was a favorable prognostic factor for patients with LSCC administered Neci + GC. Additionally, minocycline administration may be beneficial in patients who develop skin disorders within 30 days.

FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment.

The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation.

From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63 years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3 months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2 months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment.

FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.

Fatal anaphylactic reactions to cetuximab remain a clinical issue, although they are associated with preexisting immunoglobulin E (IgE) directed against the galactose-α1,3-galactose epitope (α3Gal). We aimed to compare the clinical usefulness of the two assays and determine the prevalence of preexisting anti-α3Gal IgE.

An anti-α3Gal IgE assay was developed (70BP assay) and compared with a commercial assay [bovine thyroglobulin (bTG) assay]. Both assays were applied to two cohorts: 299 healthy blood donors and 41 patients with head and neck cancer treated with cetuximab, including four patients with a history of anaphylactic reaction (9.8%).

The prevalence of anti-α3Gal IgE was 6% and 5% using 70BP and bTG assays, respectively, in healthy blood donors. Among the head and neck cancer patients, the four who had an anaphylactic reaction were included in the seven (17.1%) and six (14.6%) patients with a signal above the detection threshold using the 70BP and bTG assays, respectively. This resulted in a sensitivity and negative predictive value of 100% for both assays, with a specificity of 91.9% and 94.6%, respectively, and a positive predictive value of 57.1% and 66.6% for the 70BP and bTG assays, respectively. Using an optimized threshold in the bTG assay, the prevalence of anti-α3Gal IgE in blood donors decreased to 1.3%, and five patients (12.2%) were eventually considered positive, giving a specificity of 97.3% and a positive predictive value of 80%.

The predictive value of anti-α3Gal IgE using these two assays was excellent and useful in clinical practice.

The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated.

PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses.

Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses.

Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer.

A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS).

A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET.

In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.

The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality.

Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.

BRAF mutations occur in 5-10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear.

This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods.

BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors.

These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.

Colorectal carcinomas (CRCs) are seldom eradicated by cytotoxic chemotherapy. Cancer cells with stem-like functional properties, often referred to as "cancer stem cells" (CSCs), display preferential resistance to several anti-tumor agents used in cancer chemotherapy, but the molecular mechanisms underpinning their selective survival remain only partially understood.

In this study, we used Transcription Factor Target Genes (TFTG) enrichment analysis to identify transcriptional regulators (activators or repressors) that undergo preferential activation by chemotherapy in CRC cells with a "bottom-of-the-crypt" phenotype (EPCAM+/CD44+/CD166+; CSC-enriched) as compared to CRC cells with a "top-of-the-crypt" phenotype (EPCAM+/CD44neg/CD166neg; CSC-depleted). The two cell populations were purified in parallel by fluorescence-activated cell sorting (FACS) from a patient-derived xenograft (PDX) line representative of a moderately differentiated human CRC, following in vivo chemotherapy with irinotecan (CPT-11). The transcriptional regulators identified as differentially activated were tested for differential expression in normal vs. cancer tissues, and in cell populations enriched in stem/progenitor cell-types as compared to differentiated lineages (goblet cells, enterocytes) in the mouse colon epithelium. Finally, the top candidate was tested for mechanistic contribution to drug-resistance by selective down-regulation using short-hairpin RNAs (shRNAs).

Our analysis identified E2F4 and TFDP1, two core components of the DREAM transcriptional repression complex, as transcriptional modulators preferentially activated by irinotecan in EPCAM+/CD44+/CD166+ as compared to EPCAM+/CD44neg/CD166neg cancer cells. The expression levels of both genes (E2F4, TFDP1) were found up-regulated in CRCs as compared to human normal colon tissues, and in a sub-population of mouse colon epithelial cells enriched in stem/progenitor elements (Epcam+/Cd44+/Cd66alow/Kitneg) as compared to other sub-populations enriched in either goblet cells (Epcam+/Cd44+/Cd66alow/Kit+) or enterocytes (Epcam+/Cd44neg/Cd66ahigh). Most importantly, E2F4 down-regulation using shRNAs dramatically enhanced the sensitivity of human CRCs to in vivo treatment with irinotecan, across three independent PDX models.

Our data identified E2F4 and the DREAM repressor complex as critical regulators of human CRC resistance to irinotecan, and as candidate targets for the development of chemo-sensitizing agents.

Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancers worldwide. The majority of the new cases were from Asia and are the leading cause of cancer in China. The main treatment is surgery and radiotherapy with chemotherapy for advanced cases. With the advancement of targeted therapies, the objective of this study was to investigate the efficacy and safety of targeted therapies in NPC.

Databases were searched from inception to Aug 2023, comparing molecular targeted therapies (MTT) with conventional chemotherapy, chemotherapy or surgery. Study screening, data extraction, and data analysis were conducted independently by two investigators. The Cochrane Risk of Bias tool 1.0 was used for the quality of the studies.

There was a total of ten eligible studies with 471 participants in the treatment arm and 469 participants in the control arm. Most studies had an unclear risk of bias assessment. Upon network meta-analysis, cetuximab was found to be the most effective regimen for complete response (CR), bevacizumab was found to be the most effective regimen for partial response (PR), nimotuzumab was found to be the most effective regimen for overall survival rate (OS) and progression-free survival (PFS). Pairwise meta-analysis showed that MTT had a significantly better response than conventional therapies in complete response. GRADE analysis reported low certainty of evidence for CR and very low certainty of evidence for other efficacy outcomes. There was a higher chance of bleeding with MTT and was statistically significant.

It was observed that targeted therapies were found to be a promising strategy for NPC especially recurrent and/or metastatic NPC, but the most appropriate therapy still needs to be evaluated.

This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) with a registration number of INPLASY202380024.

Immunotherapy is a cutting-edge approach that leverages sophisticated technology to target tumor-specific antibodies and modulate the immune system to eradicate cancer and enhance patients' quality of life. Bioinformatics and genetic science advancements have made it possible to diagnose and treat cancer patients using immunotherapy technology. However, current immunotherapies against cancer have limited clinical benefits due to cancer-associated antigens, which often fail to interact with immune cells and exhibit insufficient therapeutic targeting with unintended side effects. To surmount this challenge, nanoparticle systems have emerged as a potential strategy for transporting immunotherapeutic agents to cancer cells and activating immune cells to combat tumors. Consequently, this process potentially generates an antigen-specific T cells response that effectively suppresses cancer growth. Furthermore, nanoplatforms have high specificity, efficacy, diagnostic potential, and imaging capabilities, making them promising tools for cancer treatment. However, this informative paper delves into the various available immunotherapies, including CAR T cells therapy and immune checkpoint blockade, cytokines, cancer vaccines, and monoclonal antibodies. Furthermore, the paper delves into the concept of theragnostic nanotechnology, which integrates therapy and diagnostics for a more personalized treatment approach for cancer therapy. Additionally, the paper covers the potential benefits of different nanocarrier systems, including marketed immunotherapy products, clinical trials, regulatory considerations, and future prospects for cancer immunotherapy.

Colorectal cancer (CRC) is widely recognized as the third most prevalent malignancy globally and the second leading cause of cancer-related mortality. Traditional treatment modalities for CRC, including surgery, chemotherapy, and radiotherapy, can be utilized either individually or in combination. However, these treatments frequently result in significant side effects due to their non-specificity and cytotoxicity affecting all cells. Moreover, a considerable number of patients face relapses following these treatments. Consequently, it is imperative to explore more efficacious treatment interventions for CRC patients. Immunotherapy, an emerging frontier in oncology, represents a novel therapeutic approach that leverages the body's immune system to target cancer cells. The principal advantage of immunotherapy is its capacity to selectively target cancer cells while minimizing damage to healthy cells. Its recent adoption as a neoadjuvant therapy presents significant potential to transform the treatment landscape for both primary resectable and metastatic CRC. This review endeavors to offer a comprehensive overview of current strategies in CRC immunotherapy, critically analyze existing literature, underscore anticipated outcomes from ongoing clinical trials, and deliberate on the challenges and impediments encountered within the field of immunotherapy.

New cases and deaths of gastrointestinal cancers are predicted to increase significantly by 2040. This study aims to explore cross-country inequalities and trends in global burdens of colon and rectum cancer (CRC), esophageal cancer (EC) and gastric cancer (GC).

Data from the Global Burden of Diseases Study 2019 were analyzed to examine trends in disability-adjusted life-years (DALYs) for three gastrointestinal cancers with estimated annual percentage change (EAPC) and Joinpoint analysis. Inequality in their DALYs rates was assessed with the slope index of inequality and the concentration index, based on the Socio-Demographic Index (SDI).

From 1990 to 2019, the age standardized DALYs rate of CRC decreased in these countries from high and high-middle SDI regions, with the EAPC values of - 1.018% and - 0.161%, respectively, but increased among low, low-middle and middle SDI regions (EAPC = 1.035%, 0.926% and 0.406%, respectively). The age standardized DALYs rates of EC and GC decreased in all SDI regions. Moreover, the slope index changed from 358.42 (95% confidence interval 343.28 to 370.49) to 245.13 (217.47 to 271.24) for CRC, from - 63.88 (- 87.48 to - 48.28) to - 1.36 (- 32.44 to 25.87) for EC, and from 126.37 (101.97 to 146.47) to 58.04 (20.54 to 96.12) for GC. The concentration index for CRC moved from 29.56 (28.99 to 29.84) to 23.90 (23.19 to 24.26), from - 9.47 (- 10.30 to - 9.24) to - 14.64 (- 15.35 to - 14.24) for EC, and from 8.44 (7.85 to 8.72) to - 6.42 (- 7.65 to - 6.12) for GC.

This study suggests strong heterogeneity in global DALYs for gastrointestinal cancers across different SDI regions. Higher SDI regions faced a greater burden of CRC, while the burdens of EC and GC were more prevalent in lower SDI regions.

There is evidence that adding cetuximab can overcome resistance to irinotecan, but a similar analysis with Panitumumab isn't readily available. This study evaluated the activity of each anti-EGFR plus irinotecan as a salvage third-line treatment for metastatic colorectal cancer.

This is a retrospective cohort of metastatic colorectal cancer patients who progressed to irinotecan monotherapy and were exposed to an anti-EGFR antibody as a third line of treatment. This study was conducted at a single cancer center in Brazil. The primary outcome was overall survival. The secondary outcomes were objective response rate, stratified by primary tumor sidedness, progression-free survival, and toxicity.

This analysis included 412 patients who had progressed on irinotecan and were KRAS wild-type. One hundred eighty-two received Irinotecan plus Cetuximab (I + C group) and 230 Irinotecan plus Panitumumab (I + P group). There was no significant difference in median overall survival between treatment groups (9.1 months [I + C] vs 10.1 months [I + P]; p = 0.76). There was also no difference in progression-free survival (3.63 months [I + C] vs 3.73 months [I + P]; p = 0.19) and objective response rate (23.0 % [I + C] vs 22.3 % [I + P]; p = 0.97). Patients with right-sided tumors had worse overall survival than left-sided (6.2 months vs 10.1 months; p = 0.003) but presented a better objective response rate with panitumumab (8.3 % [I + P] vs 3.3 % [I + C]). There were more infusion reactions with cetuximab.

Panitumumab and cetuximab have similar activity when combined with irinotecan as treatment for patients with disease progression with an irinotecan regimen, potentially rescuing the irinotecan activity.

Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance.

ErbB3 is markedly overexpressed in breast cancer cells and is associated with resistance and metastasis. Additionally, ErbB3 expression levels are positively correlated with low densities of tumor-infiltrating lymphocytes, a marker of poor prognosis. Consequently, ErbB3 is a promising therapeutic target for cancer immunotherapy. Here, we report the generation of ErbB3-targeted chimeric antigen receptor (CAR)-modified natural killer (NK) cells by transducing cord blood-derived primary NK cells using vsv-g envelope-pseudotyped lentiviral vectors. Transduced cells displayed stable CAR-expressing activity and increased cytotoxicity against ErbB3-positive breast cancer cell lines. Furthermore, anti-ErbB3 (aErbB3) CAR-NK cells strongly reduced the tumor burden in the SK-BR-3 xenograft mouse model without observable side effects. These findings underscore the potential of aErbB3 CAR-NK cells as targeted immunotherapy for ErbB3-positive breast cancer, suggesting a promising alternative to conventional treatments.

The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC.

Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine-tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine-tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRASG12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium.

This study aims to develop a thermoresponsive biomaterial system of irinotecan (IRT) and curcumin (CUR) nano-transferosomal gel (IRT-CUR-NTG) for targeting colorectal cancer (CRC). The IRT-CUR-NTs were statistically optimized and loaded into poloxamer-based thermosensitive gel. Transmission electron microscopy (TEM), Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) of the IRT-CUR-NTs were performed, whereas pH, gelation time, gelation temperature, gel and mucoadhesive strength of the IRT-CUR-NTG were investigated. In-vitro release and anticancer analyses were explored using HT29 cells. Additionally, in-vivo pharmacokinetics study was investigated followed by histopathological examination and in-vivo anticancer analysis. The PS, PDI, ZP, %EE of IRT and %EE of CUR were found to be 136.15 nm, 0.143, -15.5 mV, 95.05% and 85.12%, respectively. IRT-CUR-NTs exhibited spherical shape with no chemical interactions among the constituents. Similarly, IRT-CUR-NTG was homogenous gel suitable for rectal administration. IRT-CUR-NTG manifested prolonged release profiles of IRT and CUR. Moreover, a significantly enhanced (4-fold) bioavailability and no toxicity of IRT-CUR-NTG was observed when compared with conventional gel. IRT-CUR-NTs were found to be more effective against HT29 cell lines. In-vivo antitumor analysis demonstrated significantly reduced tumor volume and tumor mass after treatment with IRT-CUT-NTG, indicating improved antitumor effect. It can be concluded that IRT-CUR-NTG is suitable biomaterial system for colorectal cancer.

Population-based data on the incidence of frequent colorectal metastases are fairly scarce, while that on rare metastatic sites are lacking.

The aim of this study was to provide epidemiological indicators of metastatic sites frequency in patients with colorectal cancer.

Incidence was modelled using Poisson and Joinpoint regressions in a population-based cancer registry study including metastatic colorectal cancers diagnosed between 1991 and 2020 (N = 5,199). Tumor molecular markers were collected for the [2016-2020] period.

Liver, peritoneum, lung and bone were the most frequent metastatic sites. Among frequent sites, incidence of liver and lung sites decreased in men respectively since 1999 and 2010, whereas in women incidence of liver and peritoneum sites increased steadily throughout the whole period. Each of the other sites concerned less than 3% of metastatic colorectal cancer cases and presented standardized incidence rates between 0.19 and 1.39 per 1,000,000. Among rare sites, incidence of adrenal glands, supraclavicular lymph node, mediastinum and ascites had doubled in [2016-2020] as compared to the 25 previous years. BRAFV600E variant was more frequent in presence of carcinomatosis, and absence of liver and lung metastasis while KRAS variant was more frequent in presence of lung metastasis.

This study provides unprecedented incidence indicators for rare synchronous metastases of colorectal cancer.

Despite advances in targeted therapies, primary and acquired resistance make the treatment of colorectal cancer (CRC) a pressing issue to be resolved. According to reports, the development of CRC is linked to miRNA dysregulation. Multiple studies have demonstrated that miR-135b-5p has an aberrant expression level between CRC tissues and adjacent tissues. However, it is unclear whether there is a correlation between miR-135b-5p and cetuximab (CTx) resistance in CRC. Use the GEO database to measure miR-135b-5p expression in CRC. Additionally, RT-qPCR was applied to ascertain the production level of miR-135b-5p in three human CRC cells and NCM460 cells. The capacity of cells to migrate and invade was examined utilizing the wound-healing and transwell assays, while the CCK-8 assay served for evaluating cell viability, as well as colony formation assays for proliferation. The expected target protein of miR-135b-5p in CRC cell cetuximab resistance has been investigated using western blot. Suppression of miR-135b-5p could increase the CTx sensitivity of CTx-resistant CRC cells, as manifested by the attenuation of proliferation, migration, and invasion ability. Mechanistic studies revealed miR-135b-5p regulates the epithelial-to-mesenchymal transition (EMT) process and Wnt/β-catenin signaling pathway through downgulating FOXN3. In short, knockdowning miR-135b-5p could increase FOXN3 expression in CRC cells, promote the EMT process, and simultaneously activate the Wnt/β-catenin signaling pathway to elevate CTx resistance in CRC cells.

MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA.

Patients with chemotherapy refractory mCRC and MET amp detected by cfDNA were treated with savolitinib until unacceptable toxicity or disease progression. The primary endpoint was objective response rate. Secondary endpoints were clinical activity and safety.

Five patients were enrolled and treated. Best overall response was stable disease (SD) in two patients, progressive disease (PD) in two patients, and one patient unevaluable for response. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common TEAEs included fatigue (n = 3) and nausea (n = 3). There were no grade 4 or 5 TEAEs.

Savolitinib was well tolerated; however, in this small group of biomarker-selected patients, we observed no evidence of anti-tumor activity.

Clinicaltrials.gov Identifier: NCT03592641. Registered on July 17, 2018.