Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers.

The detailed association between tumor DNA methylation, including CpG island methylation, and tumor immunity is poorly understood. CpG island methylator phenotype (CIMP) is observed typically in sporadic colorectal cancers (CRCs) with microsatellite instability-high (MSI-H). Here, we investigated the differential features of the tumor immune microenvironment according to CIMP status in MSI-H CRCs. CIMP-high (CIMP-H) or CIMP-low/negative (CIMP-L/0) status was determined using MethyLight assay in 133 MSI-H CRCs. All MSI-H CRCs were subjected to digital pathology-based quantification of CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + tumor-infiltrating immune cells using whole-slide immunohistochemistry. Programmed death-ligand 1 (PD-L1) immunohistochemistry was evaluated using the tumor proportion score (TPS) and combined positive score (CPS). Representative cases were analyzed using whole-exome and RNA-sequencing. In 133 MSI-H CRCs, significantly higher densities of CD8 + tumor-infiltrating lymphocytes (TILs) were observed in CIMP-H tumors compared with CIMP-L/0 tumors. PD-L1 TPS and CPS in CIMP-H tumors were higher than in CIMP-L/0 tumors. Next-generation sequencing revealed that, compared with CIMP-L/0 tumors, CIMP-H tumors had higher fractions of CD8 + T cells/cytotoxic lymphocytes, higher cytolytic activity scores, and activated immune-mediated cell killing pathways. In contrast to CIMP-L/0 tumors, most CIMP-H tumors were identified as consensus molecular subtype 1, an immunogenic transcriptomic subtype of CRC. However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.

The prognostic significance of growth pattern, tumor budding, poorly differentiated clusters, desmoplastic reaction pattern and tumor-stroma ratio in colorectal cancer and an evaluation of their relationship with KRAS, NRAS, BRAF mutations.

Growth pattern (GP), tumor budding (TB), poorly differentiated clusters (PDC), desmoplastic reaction pattern (DRP) and tumor-stroma ratio (TSR) are prognostic histomorphological parameters in colorectal cancer (CRC). Correlations between these parameters, their individual prognostic values, and their relationship with KRAS/NRAS/BRAF mutations have not been comprehensively examined. We aimed to investigate these associations, which have not been previously explored in this combination. 126 CRC cases were included. GP, TB, PDC, DRP and TSR were evaluated by two experienced pathologists. KRAS/NRAS/BRAF mutation profile were determined using qPCR. Demographic, clinicopathological and survival data were recorded. Interrelations were investigated by statistical analysis. Infiltrative GP was more frequent in high-score TB, PDC-G3, and stroma-high tumors (p < 0.05). High-score TB was more common in PDC-G3 and stroma-high tumors (p < 0.05). Immature DRP was more frequent in stroma-high tumors (p = 0.014). Among histomorphological parameters, a significant relationship was found only between infiltrative GP and the presence of KRAS mutation (p = 0.023). Moreover, GP was significantly associated with pT, lymphatic invasion, perineural invasion (p < 0.05). Effects on survival were assessed using Kaplan-Meier method and Cox proportional hazards model. TB and PDC were identified as independent predictors of overall survival. Higher TB score (p = 0.008) and higher PDC grade (p = 0.013) lead to worse survival. Interestingly, GP, DRP, TSR or KRAS/NRAS/BRAF mutations were not associated with overall survival. Our results highlight the prognostic significance of TB and PDC. We suggest incorporating TB and PDC into routine CRC reports. The association of KRAS mutation with infiltrative GP supports its role in the acquisition of invasive behavior.

To study the utility of HER2 and Ki-67 as immunohistochemical prognostic markers in comparison to histopathological parameters and tumour, node and metastasis staging in colorectal carcinoma.

Colorectal Carcinoma (CRC) ranks among the most prevalent cancers globally, with significant variability in incidence rates across different regions. A shift towards a Westernized diet has been implicated in rising cancer rates, particularly in emerging nations. By 2020, CRC is projected to represent a notable proportion of global cancer cases and deaths. In India, CRC primarily affects individuals aged 45 to 84, with a higher incidence in males, commonly occurring in the rectum and sigmoid colon. Risk factors such as obesity, dietary factors, sedentary lifestyle, smoking, and alcohol use contribute to CRC development, especially in aging populations. Diagnosis involves various imaging modalities and histological assessments using Tumour, node and metastasis (TNM) and American Joint Committee on Cancer classifications. Recent advancements in targeted therapies like monoclonal antibodies against HER2 have shown promise in treating metastatic CRC. Immunohistochemistry markers like Ki-67 and HER2 play crucial roles in prognostic assessment and treatment planning. This study aims to investigate Ki-67 and HER2 expression in CRC, correlating with histological characteristics and prognostic factors.

Fusobacterium Nucleatum Promotes Microsatellite Instability in Colorectal Carcinoma Through Up-regulation of miRNA-155-5p-Targeted Inhibition of MSH6 via the TLR4/NF-κB Signaling Pathway.

Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells.

Local TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in colorectal carcinoma.

BACKGROUND: Dysfunction of CD8+ T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid-stimulating hormone (TSH)/thyroid-stimulating hormone receptor (TSHR) signaling in CD8+ T cell exhaustion and tumor immune evasion remain poorly understood. This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8+ T cells and immune evasion in colorectal cancer (CRC). METHODS: TSHR expression levels in CD8+ T cells were assessed with immunofluorescence and flow cytometry. Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8+ T cells. Mechanistic insights were mainly gained through RNA-sequencing, Western blotting, chromatin immunoprecipitation and luciferase activity assay. Immunofluorescence, flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues. RESULTS: TSHR was highly expressed in cancer cells and CD8+ T cells in CRC tissues. TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8+ T cell exhaustion. Conditional deletion of TSHR in CD8+ tumor-infiltrating lymphocytes (TILs) improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1 (PD-1) and hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3) through the protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway. CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8+ T cells, resulting in immunosuppression in the TME. Myeloid-derived suppressor cells (MDSCs) was the main source of TSH within the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response. CONCLUSIONS: The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8+ T cell exhaustion and immune evasion in CRC. TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.

The 3-Biomarker Classifier-A Novel and Simple Molecular Risk Score Predicting Overall Survival in Patients with Colorectal Cancer.

INTRODUCTION: Several new molecular markers in colorectal carcinomas have been discovered; however, classical histopathological predictors are still being used to predict survival in patients. We present a novel risk score, which uses molecular markers, to predict outcomes in patients with colorectal carcinoma. METHODS: The immunohistochemistry of tissue micro arrays was used to detect and quantify H2BUB1, RBM3 and Ki-67. Different intensities of staining were categorized for these markers and a score was established. A multivariate analysis was performed and survival curves were established. RESULTS: 1791 patients were evaluated, and multivariate analysis revealed that our risk score, the 3-biomarker classifier, is an independent marker to predict survival. We found a high risk-score to be associated with dismal median survival for the patients. CONCLUSIONS: A more personalized score might be able to better discriminate low- and high-risk patients and suggest adjuvant treatment compared to classical pathological staging. Our score can serve as a tool to predict outcomes in patients suffering from colorectal carcinoma.

The Value of C-Reactive Protein and Peritoneal Cytokines as Early Predictors of Anastomotic Leak after Colorectal Surgery.

OBJECTIVES: The aim of this study was to evaluate the accuracy of serum C-reactive protein (CRP) and intraperitoneal CRP, interleukin-6, and tumor necrosis factor-alpha in early diagnostics of anastomotic leakage in the first 4 postoperative days after colorectal surgery. METHODS: Between January 2023 and June 2023, one hundred patients with colorectal carcinoma were operated on with primary anastomosis. Ten patients had anastomotic leak (10%). RESULTS: Based on serum CRP, a patient with a leak will be detected with a 78% probability on postoperative day 3 with values above 169.0 mg/L and on postoperative day 4 with values equal to 159.0 mg/L and above. Intraperitoneal CRP values greater than 56 mg/L on the fourth postoperative day indicate a 78% probability of a diagnosis of leakage. An anastomotic leak will be detected with a 70.0% probability based on an IL-6 value on the first day, at a cut-off value of 42,150. The accuracy of TNF-alpha in predicting anastomotic leak in the first two days is 70% at values higher than 78.00 on the first and 58.50 on the second postoperative day. CONCLUSION: In this study serum CRP proved to be the most accurate in predicting anastomotic dehiscence after colorectal surgery.

Molecular genetic analysis of colorectal carcinoma with an aggressive extraintestinal immunohistochemical phenotype.

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

Non-clinical evaluation of pmIL12 gene therapy for approval of the phase I clinical study.

Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.

Integrated molecular profiling of RAS, BRAF mutations, and mismatch repair status in advanced colorectal carcinoma: insights from gender and tumor laterality.

Background: Colorectal carcinoma (CRC) is one of the most frequently diagnosed forms of cancer worldwide. The RAS (KRAS, NRAS) and BRAF genes encode proteins that are important therapeutic targets for the treatment of CRC and, together with the mismatch repair (MMR) system, are closely related to patient prognosis and survival in advanced CRC. Here we evaluate the mutational profile and the frequency of mutations in the KRAS, NRAS and BRAF genes, along with the expression of MMR in advanced CRC, at a tertiary hospital in southern Brazil. Methods: A cross-sectional retrospective study was carried out, where molecular analysis of mutations in the KRAS, NRAS and BRAF genes was carried out, as well as immunohistochemistry for MMR proteins. Results: Next-generation sequencing (NGS) analysis of 310 tumors revealed that 202 patients (65.2%) had mutations. The KRAS gene (53.2%) was the most frequently mutated in our sample, with G12D being the most frequent, representing 30.5% of the mutations in this gene. The most frequent mutation found in BRAF was V600E (n=25; 89.3%) and differed significantly in women and in the right colon in patients with MMR deficiency. Among the 283 patients tested for MMR, the rate of loss of expression was 8.8% (25/283). Conclusions: Deficiency in the MMR system is associated with the presence of the BRAF V600E mutation, tumors located in the right colon, and the female sex. In our case series, more than 60% of patients had at least one mutation in KRAS, NRAS, or BRAF. The presence of mutations in these genes is closely related to CRC prognosis and helps define the best therapeutic approach in patients with metastatic CRC.

Revisiting Luteolin Against the Mediators of Human Metastatic Colorectal Carcinoma: A Biomolecular Approach.

Metastatic colorectal carcinoma (mCRC) is one of the prevalent subtypes of human cancers and is caused by the alterations of various lifestyle and diet-associated factors. ß-catenin, GSK-3ß, PI3K-α, AKT1, and NF-κB p50 are known to be the critical regulators of tumorigenesis and immunopathogenesis of mCRC. Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti-mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti-mCRC agent through a five-targets (ß-catenin, GSK-3ß, PI3K-α, AKT1, and p50)-based and three-tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti-inflammatory/anti-mCRC efficacy alongside 5-fluorouracil (FU), a reference drug. Luteolin (a phyto-flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT-15, HCT-116, DLD-1, and HT-29) without hampering the viability of non-tumorigenic ones (RWPE-1). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit ß-catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3-ß and ceasing its activation by inactivating AKT1 and PI3K-α. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC-associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.

Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience.

Background: Most gastrointestinal polyps are asymptomatic; therefore, assessing symptoms associated with cancer and precancerous polyps is essential. Objectives: The aim of this study was to study the histopathology, number, distribution, and degree of polyps' dysplasia in terms of age, gender, and clinical presentation. Methods: This study was performed on patients who underwent endoscopy from July 2015 to August 2021 in Sulaimaniyah, Iraq. Surgical pathology records of patients were analyzed for age, sex, nature of the polyps, number, site, histopathology, degree of dysplasia, resection margins and patients' presented clinical data. Results: The mean patients' age was 51.4 ± 17.1 years, and most were males (51.9%). The most common indications for endoscopy were screening (28.62%), and the least common was weight loss (4.46%). Neoplastic polyps were common among patients with hematemesis (75%), while non-neoplastic were common among those with dyspepsia (60%). Most polyps were solitary in upper (80.8%) and lower gastrointestinal tract (GIT). Most polyps in the upper GIT were non-neoplastic (87.3%), while most lower proximal/distal GIT polyps were neoplastic. Most neoplastic polyps showed low-grade dysplasia (94.4%), and most high-grade dysplasia was a villous type (24.1%). Conclusions: Initiation of the screening program is highly recommended as a facilitating method for the early detection of multiple and high-grade gastrointestinal polyps. Thus, screening programs can reduce the rate of mortality of carcinoma in this locality.

N-palmitoyl-d-glucosamine limits mucosal damage and VEGF-mediated angiogenesis by PPARα-dependent suppression of pAkt/mTOR/HIF1α pathway and increase in PEA levels in AOM/DSS colorectal carcinoma in mice.

Chronic intestinal inflammation and neo-angiogenesis are interconnected in colorectal carcinoma (CRC) pathogenesis. Molecules reducing inflammation and angiogenesis hold promise for CRC prevention and treatment. N-Palmitoyl-d-glucosamine (PGA), a natural glycolipid analog with anti-inflammatory properties, has shown efficacy against acute colitis. Micronized PGA (mPGA) formulations exhibit superior anti-inflammatory activity. This study investigates the in vivo anti-angiogenic and protective effects of mPGA in a mouse model of colitis-associated CRC induced by azoxymethane/dextran sodium sulfate (AOM/DSS). CRC was induced in C57BL/6J mice using intraperitoneal azoxymethane followed by three cycles of 2.5% dextran sodium sulfate (DSS) in drinking water. Mice were treated with mPGA (30-150 mg/kg) with or without the PPARα inhibitor MK886 (10 mg/kg). At Day 70 post-azoxymethane injection, mice underwent anesthetized endoscopic colon evaluation. Post-mortem analysis of tumorigenesis and angiogenesis was performed using histological, immunohistochemical, and immunoblotting techniques. mPGA improved disease progression and survival rates in a dose- and PPARα-dependent manner in AOM/DSS-exposed mice. It reduced polyp formation, decreased pro-angiogenic CD31, pro-proliferative Ki67, and pro-inflammatory TLR4 expression levels, and inhibited VEGF and MMP-9 secretion by disrupting the pAkt/mTOR/HIF1α pathway. mPGA increased colon PEA levels, restoring anti-tumoral PPARα and wtp53 protein expression. Given its lack of toxicity, mPGA shows potential as a nutritional intervention to counteract inflammation-related angiogenesis in CRC.

Diagnostic application of the ColonFlag AI tool in combination with faecal immunochemical test in patients on an urgent lower gastrointestinal cancer pathway.

OBJECTIVE: Colorectal cancer (CRC) is the fourth most common cancer in the UK. Patients with symptoms suggestive of CRC should be referred for urgent investigation. However, gastrointestinal symptoms are often non-specific and there is a need for suitable triage tools to enable prioritisation of investigations. In this study, the performance of the faecal immunochemical test (FIT), anaemia and the artificial intelligence algorithm ColonFlag were retrospectively examined and evaluated for their potential clinical benefits in patients who had been referred on an urgent lower gastrointestinal cancer pathway. DESIGN: All patients aged over 40 years referred in a 12-month period were included. After 6 months, clinical outcomes were determined and the performance of the triage tests was evaluated. RESULTS: A total of 3822 patients completed investigations and received a diagnosis. 143 had CRC, 126 high-risk adenomas (HRA). ColonFlag would have missed 27 CRC and 29 HRA. Faecal haemoglobin (f-Hb) at a cut-off of 10 µg/g would have missed 10 CRC and 26 HRA; f-Hb in combination with anaemia would have missed 2 CRC and 14 HRA. Using f-Hb in combination with ColonFlag would have missed only 1 CRC and 5 HRA and would have reduced the need for urgent referral by over 400 patients. CONCLUSION: ColonFlag has potential to assist detection of CRC and HRA, alone where no faecal sample is present and in combination with FIT and to reduce the need for urgent referral.

Colorectal Carcinoma-An Anomalous Trigger of Adult Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but often fatal condition characterized by a hyperinflammatory immune response leading to multiorgan failure. It is predominantly observed in the pediatric population and can be classified as familial or acquired HLH. The latter is more common in adults, often associated with malignancy, infection, or autoimmune diseases. Among acquired HLH cases, hematologic neoplasms account for the majority, with only a few isolated reports documenting solid neoplasms as the cause. Herein, we present a case of adult HLH associated with colorectal adenocarcinoma, which, to the best of our knowledge, is only the second reported case of HLH associated with this type of cancer.

TROP2 in colorectal carcinoma: associations with histopathology, molecular phenotype, and patient prognosis.

Antibody-drug conjugates (ADCs) directed to trophoblast cell surface antigen 2 (TROP2) have gained approval as a therapeutic option for advanced triple-negative breast cancer, and TROP2 expression has been linked to unfavourable outcomes in various malignancies. In colorectal carcinoma (CRC), there is still a lack of comprehensive studies on its expression frequency and its prognostic implications in relation to the main clinicopathological parameters. We examined the expression of TROP2 in a large cohort of 1,052 CRC cases and correlated our findings with histopathological and molecular parameters, tumour stage, and patient outcomes. TROP2 was heterogeneously expressed in 214/1,052 CRCs (20.3%), with only a fraction of strongly positive tumours. TROP2 expression significantly correlated with an invasive histological phenotype (e.g. increased tumour budding/aggressive histopathological subtypes), advanced tumour stage, microsatellite stable tumours, and p53 alterations. While TROP2 expression was prognostic in univariable analyses of the overall cohort (e.g. for disease-free survival, p < 0.001), it exhibited distinct variations among important clinicopathological subgroups (e.g. right- versus left-sided CRC, microsatellite stable versus unstable CRC, Union for International Cancer Control [UICC] stages) and lost its significance in multivariable analyses that included stage and CRC histopathology. In summary, TROP2 is quite frequently expressed in CRC and associated with an aggressive histopathological phenotype and microsatellite stable tumours. Future clinical trials investigating anti-TROP2 ADCs should acknowledge the observed intratumoural heterogeneity, given that only a subset of TROP2-expressing CRC show strong positivity. The prognostic implications of TROP2 are complex and show substantial variations across crucial clinicopathological subgroups, thus indicating that TROP2 is a suboptimal parameter to predict patient prognosis.

Multi-institutional analysis of extracranial oligometastatic colorectal cancer patients treated with stereotactic body radiation therapy: TROD 02-008 study.

PURPOSE: To investigate the treatment outcomes of extracranial oligometastatic colorectal cancer (CRC) patients treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: The clinical data of 388 extra-cranial oligometastatic CRC (≤ 5 lesions) patients and 463 lesions treated with SBRT at 19 cancer institutions were retrospectively analyzed. The prognostic factors predicting overall survival (OS), progression-free survival (PFS), and local control (LC) were assessed in uni- and multivariable analyses. RESULTS: The median age was 62 years (range, 29-92 years). The majority of the patients (90.5%) received surgery and systemic treatment for their primary tumor, had ≤ 2 metastasis (83.3%), had single organ involvement (90.3%), and staged using flouro-deoxyglucose positron emission tomography (FDG-PET/CT) (76%). The median fraction and total radiation doses were 10 Gy (range: 6-34 Gy) and 50 Gy (range: 8-64 Gy), respectively, delivered in a median of 4 fractions (range: 1-8). The median follow-up time for the entire cohort was 30.7 months (interquartile range: 27.0-34.3 months). The 3­year OS, PFS, and LC rates were 64.0%, 42.3%, and 72.7%, respectively. The 3­year LC rate was significantly higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (76.0% vs. 67.3%; p = 0.04). The 3­year PFS and OS rates were higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (33.2% vs. 25.2%; p = 0.03; 53.7% vs.  44.8%; p = 0.02). Single metastasis and complete response after SBRT were independent prognostic factors for survival in multivariable analysis. CONCLUSIONS: In this multi-center study, we demonstrated that SBRT is an effective treatment option of metastatic lesions in oligometastatic CRC patients by providing promising LC rates. Higher SBRT doses beyond BED10 ≥ 100 Gy were associated with improved LC and survival. LC of treated lesion and lower tumor burden after SBRT were associated with better outcomes.

Surgical management of rare tumors (Part 1).

With an annual cumulative occurrence of approximately 15,000 in North America, all childhood cancers are rare. Very rare cancers as defined by both the European Cooperative Study Group for Rare Pediatric Cancers and the Children's Oncology Group fall into two principal categories: those so uncommon (fewer than 2 cases/million) that their study is challenging even through cooperative group efforts (e.g., pleuropulmonary blastoma and desmoplastic small round cell tumor) and those that are far more common in adults and therefore rarely studied in children (e.g., thyroid, melanoma, and gastrointestinal stromal tumor). Treatment strategies for these latter tumors are typically based on adult guidelines, although the pediatric variants of these tumors may harbor different genetic signatures and demonstrate different behavior. If melanoma and differentiated thyroid cancer are excluded, other rare cancer types account for only 2% of the cancers in children aged 0 to 14. This article highlights several of the most common rare tumor types.

Association of KRAS Mutation and Gene Pathways in Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study and Potential Implications for Therapy.

Kirsten Rat Sarcoma (KRAS) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti-CDKN2A therapy with Villosol in KRAS-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.

Outcomes of noncurative endoscopic submucosal dissection for T1 colorectal cancer: Prospective, multicenter, cohort study in Japan.

OBJECTIVES: This study investigated the incidence of lymph node metastasis and long-term outcomes in patients with T1 colorectal cancer where endoscopic submucosal dissection (ESD) resulted in noncurative treatment. It is focused on those with deep submucosal invasion, a factor considered a weak predictor of lymph node metastasis in the absence of other risk factors. METHODS: This nationwide, multicenter, prospective study conducted a post-hoc analysis of 141 patients with T1 colorectal cancer ≥20 mm where ESD of the lesion resulted in noncurative outcomes, characterized by poor differentiation, deep submucosal invasion (≥1000 µm), lymphovascular invasion, high-grade tumor budding, or positive vertical margins. Clinicopathologic features and patient prognoses focusing on lesion sites and additional surgery requirements were evaluated. Lymph node metastasis incidence in the low-risk T1 group, identified by deep submucosal invasion as the sole high-risk histological feature, was assessed. RESULTS: Lymph node metastasis occurred in 14% of patients undergoing additional surgery post-noncurative endoscopic submucosal dissection for T1 colorectal cancer. In the low-risk T1 group, in the absence of other risk factors, the frequency was 9.7%. The lymph node metastasis rates in patients with T1 colon and rectal cancers did not differ significantly (14% vs. 16%). Distant recurrence was observed in one patient (2.3%) in the ESD only group and in one (1.0%) in the additional surgery group, both of whom had had rectal cancer removed. CONCLUSION: The risk of lymph node metastasis or distant occurrence was not negligible, even in the low-risk T1 group. The findings suggest the need for considering additional surgery, particularly for rectal lesions (Clinical Trial Registration: UMIN000010136).