Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy.

Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements.

Exploring Gut Microbiome Composition and Circulating Microbial DNA Fragments in Patients with Stage II/III Colorectal Cancer: A Comprehensive Analysis.

BACKGROUND: Colorectal cancer (CRC) significantly contributes to cancer-related mortality, necessitating the exploration of prognostic factors beyond TNM staging. This study investigates the composition of the gut microbiome and microbial DNA fragments in stage II/III CRC. METHODS: A cohort of 142 patients with stage II/III CRC and 91 healthy controls underwent comprehensive microbiome analysis. Fecal samples were collected for 16S rRNA sequencing, and blood samples were tested for the presence of microbial DNA fragments. De novo clustering analysis categorized individuals based on their microbial profiles. Alpha and beta diversity metrics were calculated, and taxonomic profiling was conducted. RESULTS: Patients with CRC exhibited distinct microbial composition compared to controls. Beta diversity analysis confirmed CRC-specific microbial profiles. Taxonomic profiling revealed unique taxonomies in the patient cohort. De novo clustering separated individuals into distinct groups, with specific microbial DNA fragment detection associated with certain patient clusters. CONCLUSIONS: The gut microbiota can differentiate patients with CRC from healthy individuals. Detecting microbial DNA fragments in the bloodstream may be linked to CRC prognosis. These findings suggest that the gut microbiome could serve as a prognostic factor in stage II/III CRC. Identifying specific microbial markers associated with CRC prognosis has potential clinical implications, including personalized treatment strategies and reduced healthcare costs. Further research is needed to validate these findings and uncover underlying mechanisms.

Spinal accessory nerve anatomy in the posterior cervical triangle: A systematic review with meta-analysis.

This study aimed to investigate the anatomy of the spinal accessory nerve (SAN) in the posterior cervical triangle, especially in relation to adjacent anatomical landmarks, along with a systematic review of the current literature with a meta-analysis of the data. Overall, 22 cadaveric and three prospective intraoperative studies, with a total of 1346 heminecks, were included in the analysis. The major landmarks relevant to the entry of the SAN at the posterior border of the SCM muscle (PBSCM) were found to be the mastoid apex, the great auricular point (GAP), the nerve point (NP), and the point where the PBSCM meets the upper border of the clavicle. The SAN was reported to enter the posterior cervical triangle above GAP in 100% of cases and above NP in most cases (97.5%). The mean length of the SAN along its course from the entry point to its exit point from the posterior triangle of the neck was 4.07 ± 1.13 cm. The SAN mainly gave off 1 or 2 branches (32.5% and 31%, respectively) and received either no branches or one branch in most cases (58% and 23%, respectively) from the cervical plexus during its course in the posterior cervical triangle. The major landmarks relevant to the entry of the SAN at the anterior border of the TPZ muscle (ABTPZ) were found to be the point where the ABTPZ meets the upper border of the clavicle and the midpoint of the clavicle, along with the mastoid apex, the acromion, and the transverse distance of the SAN exit point to the PBSCM. The results of the present meta-analysis will be helpful to surgeons operating in the posterior cervical triangle, aiding the avoidance of the iatrogenic injury of the SAN.

Unraveling the Role of Molecular Profiling in Predicting Treatment Response in Stage III Colorectal Cancer Patients: Insights from the IDEA International Study.

BACKGROUND: This study aimed to investigate the molecular profiles of 237 stage III CRC patients from the international IDEA study. It also sought to correlate these profiles with Toll-like and vitamin D receptor polymorphisms, clinicopathological and epidemiological characteristics, and patient outcomes. METHODS: Whole Exome Sequencing and PCR-RFLP on surgical specimens and blood samples, respectively, were performed to identify molecular profiling and the presence of Toll-like and vitamin D polymorphisms. Bioinformatic analysis revealed mutational status. RESULTS: Among the enrolled patients, 63.7% were male, 66.7% had left-sided tumors, and 55.7% received CAPOX as adjuvant chemotherapy. Whole exome sequencing identified 59 mutated genes in 11 different signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) CRC panel. On average, patients had 8 mutated genes (range, 2-21 genes). Mutations in ARAF and MAPK10 emerged as independent prognostic factors for reduced DFS (p = 0.027 and p < 0.001, respectively), while RAC3 and RHOA genes emerged as independent prognostic factors for reduced OS (p = 0.029 and p = 0.006, respectively). Right-sided tumors were also identified as independent prognostic factors for reduced DFS (p = 0.019) and OS (p = 0.043). Additionally, patients with tumors in the transverse colon had mutations in genes related to apoptosis, PIK3-Akt, Wnt, and MAPK signaling pathways. CONCLUSIONS: Molecular characterization of tumor cells can enhance our understanding of the disease course. Mutations may serve as promising prognostic biomarkers, offering improved treatment options. Confirming these findings will require larger patient cohorts and international collaborations to establish correlations between molecular profiling, clinicopathological and epidemiological characteristics and clinical outcomes.

Ultrasound morphometry of the cervical vagus nerve for daily clinical practice: Reference values for cross sectional area and fascicle count.

INTRODUCTION: High resolution ultrasound (US) of the cervical vagus nerve (CVN) is clinically relevant in the diagnostic workup and during neurostimulation therapy of several neurologic diseases. This prospective study aims to provide reference data of the cross-sectional area (CSA) and fascicle count of the normal CVN and to investigate their possible association with anthropometric data in a large cohort of patients. METHODS: A total of 657 CVNs in 330 individuals without history of neurological disease were examined using US (7-15Mhz). The CVN fascicle count and CSA inside the hyperechoic epineurium at the level of the thyroid lobes were measured. Three CSA measurements were performed to calculate the mean value. Anthropometric data were recorded. RESULTS: The mean fascicle count was 2.4 ± 1.1 (right) and 2 ± 1 (left) (paired t- test, p < 0.001). Two CVN patterns were identified: A single hypoechoic fascicular structure (26.2 % right, 36.3 % left) and a honeycomb structure of 2-6 discrete fascicles (72.3 % right, 63.7 % left). Right CVN mean CSA was larger compared to left (2.3 ± 1 mm2 and 1.8 ± 0.8 mm2 respectively, t-test, p-0.000). There was no difference in the CSA values between sex and no correlation to age or height. A positive correlation between the CSA and weight and BMI was found (Pearson's correlation, p = 0.01 right and p = 0.05 left). CONCLUSION: The right CVN has larger CSA and contains more fascicles than the left. CVN is usually mono- or oligo-fascicular with a honeycomb appearance. The CSA increased with increasing BMI but no age and sex specific differences were noted.

Role of telomere length in human carcinogenesis (Review).

Cancer is considered the most important clinical, social and economic issue regarding cause­specific disability­adjusted life years among all human pathologies. Exogenous, endogenous and individual factors, including genetic predisposition, participate in cancer triggering. Telomeres are specific DNA structures positioned at the end of chromosomes and consist of repetitive nucleotide sequences, which, together with shelterin proteins, facilitate the maintenance of chromosome stability, while protecting them from genomic erosion. Even though the connection between telomere status and carcinogenesis has been identified, the absence of a universal or even a cancer­specific trend renders consent even more complex. It is indicative that both short and long telomere lengths have been associated with a high risk of cancer incidence. When evaluating risk associations between cancer and telomere length, a disparity appears to emerge. Even though shorter telomeres have been adopted as a marker of poorer health status and an older biological age, longer telomeres due to increased cell growth potential are associated with the acquirement of cancer­initiating somatic mutations. Therefore, the present review aimed to comprehensively present the multifaceted pattern of telomere length and cancer incidence association.

Achieving a Textbook Outcome in Colon Cancer Surgery Is Associated with Improved Long-Term Survival.

BACKGROUND: Colon cancer surgery is a complex clinical pathway and traditional quality metrics may exhibit significant variability between hospitals and healthcare providers. The Textbook Outcome (TO) is a composite quality marker capturing the fraction of patients, in whom all desired short-term outcomes of care are realised. The aim of the present study was to assess the TO in a series of non-metastatic colon cancer patients treated with curative intent, with emphasis on long-term survival. METHODS: Stage I-III colon cancer patients, who underwent curative colectomy following the Complete Mesocolic Excision principles, were retrospectively identified from the institutional database. TO was defined as (i) hospital survival, (ii) radical resection, (iii) no major complications, (iv) no reintervention, (v) no unplanned stoma and (vi) no prolonged hospital stay or readmission. RESULTS: In total, 128 patients (male 61%, female 39%, mean age 70.7 ± 11.4 years) were included in the final analysis. Overall, 60.2% achieved a TO. The highest rates were observed for "hospital survival" and "no unplanned stoma" (96.9% and 97.7%), while the lowest rates were for "no major complications" and "no prolonged hospital stay" (69.5% and 75%). Older age, left-sided resections and pT4 tumours were factors limiting the chances of a TO. The 5-year overall and 5-year cancer-specific survival were significantly better in the TO versus non-TO subgroup (81% vs. 59%, p = 0.009, and 86% vs. 65%, p = 0.02, respectively). CONCLUSIONS: Outcomes in colon cancer surgery may be affected by patient-, doctor- and hospital-related factors. TO represents those patients who achieve the optimal perioperative results, and is furthermore associated with improved long-term cancer survival.

Cancer-Associated Fibroblasts: The Origin, Biological Characteristics and Role in Cancer-A Glance on Colorectal Cancer.

The therapeutic approaches to cancer remain a considerable target for all scientists around the world. Although new cancer treatments are an everyday phenomenon, cancer still remains one of the leading mortality causes. Colorectal cancer (CRC) remains in this category, although patients with CRC may have better survival compared with other malignancies. Not only the tumor but also its environment, what we call the tumor microenvironment (TME), seem to contribute to cancer progression and resistance to therapy. TME consists of different molecules and cells. Cancer-associated fibroblasts are a major component. They arise from normal fibroblasts and other normal cells through various pathways. Their role seems to contribute to cancer promotion, participating in tumorigenesis, proliferation, growth, invasion, metastasis and resistance to treatment. Different markers, such as a-SMA, FAP, PDGFR-ß, periostin, have been used for the detection of cancer-associated fibroblasts (CAFs). Their detection is important for two main reasons; research has shown that their existence is correlated with prognosis, and they are already under evaluation as a possible target for treatment. However, extensive research is warranted.

Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients.

Gut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk and death rates. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. Peripheral blood was collected from 132 patients for the detection of microbial DNA fragments, and TLR/VDR gene polymorphisms. In the detection of various microbial DNA fragments, TLR and VDR polymorphisms was significantly higher compared to healthy group. Homozygous individuals of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. Mutational and MSI status were significantly correlated with TLR9 and VDR polymorphisms. Significantly shorter disease-free survival was associated with patients with BRAF mutated tumors and ApaI polymorphisms, whereas shorter overall survival was associated with the detection of C. albicans. The detection of B. fragilis, as demonstrated by the multivariate analysis, is an independent poor prognostic factor for shorter disease-free survival. TLR/VDR genetic variants were significantly correlated with the detection of microbial fragments in the blood, and this in turn is significantly associated with tumorigenesis and disease progression.

Renoprotective Effect of Vardenafil and Avanafil in Contrast-Induced Nephropathy: Emerging Evidence from an Animal Model.

The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN.

Sonoanatomy of the ilioinguinal, iliohypogastric, genitofemoral, obturator, and pudendal nerves: a practical guide for US-guided injections.

The ilioinguinal, iliohypogastric, genitofemoral, obturator, and pudendal nerves are the major sensory nerves that may be involved in chronic groin and genital pain with a significant impact on the quality of life of patients. The diagnosis remains clinical, and US-guided diagnostic injections using an anesthetic may aid in confirming the clinical suspicion. The anatomy of the peripheral nerves can be successfully studied using imaging. High-resolution ultrasound is increasingly used in the clinical setting for visualizing small peripheral nerves, and magnetic resonance imaging provides an anatomical overview of the relationship between small nerves and surrounding structures. In this pictorial assay, we review the anatomy and clinical relevance of the ilioinguinal, iliohypogastric, genitofemoral, obturator, and pudendal nerves. We summarize the various techniques for ultrasound identification, and present the ultrasound-guided infiltration techniques for injecting the ilioinguinal, iliohypogastric, genitofemoral, obturator, and pudendal nerves. Corresponding magnetic resonance images and clinical photos of the probe placement technique are provided for anatomical correlation. This paper is aimed to serve as a practical technical guide for physicians to familiarize themselves with the ultrasound anatomy of the major inguinal sensory nerves and to enable successful ultrasound identification and ultrasound-guided diagnostic or therapeutic infiltrations for pain management of the ilioinguinal, iliohypogastric, genitofemoral, obturator, and pudendal nerves.

Morphology of the sulcus of the caudate process (Rouviere's sulcus) in a Greek population and a systematic review with meta-analysis.

The purpose of this study was to determine the prevalence and to investigate the morphology of the sulcus of the caudate process in a Greek population, along with a systematic review and meta-analysis of the literature. Overall, 103 consecutive patients undergoing laparoscopic cholecystectomy were included in the analysis. The sulcus was present in 91% and three morphological variants were identified (groove 69%, slit 21% and scar 10%). The sulcus had a horizontal course in 90% of patients and a mean length of 25 ± 13 mm. The meta-analysis included 27 surgical and 11 cadaveric studies with 6661 cases in total. The pooled prevalence of the sulcus was 80% and did not differ significantly among various geographical regions. Concerning sulcus subtypes, the binary "open/fused" classification was used to unify the heterogeneous data. The "open" type was more frequent than the "fused" (64.5% vs 35.5%). A horizontal course was observed in 53.5% and an oblique in 45.7%. The sulcus contained the right portal pedicle in 38%, the right posterior portal pedicle in 37%, and the right posteroinferior pedicle in 23.5%. In conclusion, the sulcus of the caudate process is a very helpful anatomical landmark in hepatectomy and laparoscopic cholecystectomy and can be identified in the majority of patients. However, various classifications for the morphological variants and diverse terminology cause discrepancy in the literature and create the need for a single classification system. The proposed 3-tier classification (groove, slit, scar) is simple and easy to remember and avoids ambiguous nomenclature.

Microbiota: An Emerging Biomarker in Colorectal Cancer.

This series of 10 articles (four original articles, five literature reviews, and one systematic review) is presented by international experts in the study of microbiota and its relation to colorectal cancer (CRC) [...].

Normal anatomy, variants and factors associated with the cervical vagus nerve topography: a high-resolution ultrasound study.

PURPOSE: To describe the cervical vagus nerve (CVN) topography at the thyroid lobe (TL) level using high-resolution ultrasound and to investigate the possible association with anthropometric data, TL size, and thyroid disease. METHODS: We prospectively examined 550 CVNs in 275 (205 female, 70 male) individuals with normal thyroid (53/275, 19.3%), multinodular disease (167/275, 60.7%), and Hashimoto thyroiditis (55/275, 20%). The CVN location relative to the common carotid artery was recorded as typical (lateral position) and atypical (anterior, medial, and posterior position). The shortest distance between CVN and TL margin, the TL dimensions, and volume were measured. RESULTS: Normal thyroid subjects had lateral-positioned right CVNs in 100% and lateral/anterior/medial left CVNs in 81.1%, 15.1%, and 3.8%, respectively. CVN types did not differ significantly bilaterally between study groups. Asymmetry in CVN topography in all subjects was found in 22.2%, of which anterior CVN was the most common atypical position (64%), especially on the left side (82%). Significant gender, age, body mass, and BMI differences among CVN types were observed on the left side only. Among CVN types, no difference in TL dimensions, volume, and CVN-TL distance was found in all study groups. A weak negative correlation was recorded between CVN-thyroid distance and TL volume only on the left side (r = - 0.147, p = 0.01). CONCLUSION: Asymmetry in CVN topography is mainly due to the increased incidence of the anterior location of CVN on the left side. Age and anthropometric parameters are different on the left side possibly due to the increased prevalence of left CVN variants.

Novel Prognostic Biomarkers in Metastatic and Locally Advanced Colorectal Cancer: Micronuclei Frequency and Telomerase Activity in Peripheral Blood Lymphocytes.

PURPOSE: Due to the current practice on colorectal cancer (CRC) management, chemoresistance is most often recognized at the end of the treatment. Therefore, effective and easy-to-use prognostic biomarkers are needed. EXPERIMENTAL DESIGN: We evaluated the prognostic significance of two novel CRC biomarkers: a) micronuclei frequency (MNf) in 55 metastatic CRC (mCRC) and 21 locally advanced rectal cancer (laRC) patients using cytokinesis block micronucleus assay (CBMN assay) and b) telomerase activity (TA) in 23 mCRC and five laRC patients using TRAP-ELISA. Both biomarkers were evaluated in peripheral blood lymphocytes (PBLs) before, at the middle, and at the end of the therapy (approximately 0, 3, and 6 months) for mCRC patients before, at the end of the therapy, and after surgery for laRC patients. RESULTS: Overall, MNf demonstrated significant prognostic value since a decrease of MNf less than 29% between middle and initial MNf measurements can discriminate between progressive and stable/responsive disease with sensitivity of 36% and specificity of 87.0% while being able to identify responsive disease with sensitivity of 72.7% and specificity of 59.3%. On the other hand, TA presented a significant trend of increase (p = 0.07) in patients with progressive disease at the middle measurement. CONCLUSIONS: The findings of this study suggest that the MN frequency may serve as a promising prognostic biomarker for the monitoring of the treatment response of patients with CRC, while TA should be evaluated in a larger group of patients to further validate its significance.

Detection of Circulating Tumor Cells and Microbial DNA Fragments in Stage III Colorectal Cancer Patients under Three versus Six Months of Adjuvant Treatment.

Oxaliplatin-fluoropyrimidine combination therapy is the gold standard treatment for patients with stage III colorectal cancer (CRC); however, treatment duration is now under re-evaluation. The aim of the study was the evaluation of the non-inferiority of three over six months treatment with FOLFOX or CAPOX, in stage III CRC patients. Peripheral blood samples from 121 patients were collected, at three time points during treatment and evaluated for circulating tumor cells (CTCs) and microbial DNA detection (16S rRNA, Escherichia coli, Bacteroides fragilis, Candida albicans). Of all patients, 41.3% and 58.7% were treated with FOLFOX and CAPOX, respectively. CTCs were significantly decreased and increased after three and six months of treatment, respectively. CAPOX tends to reduce the CTCs after 3 months, whereas there is a statistically significant increase of CTCs in patients under FOLFOX after 6 months. A significant correlation was demonstrated between microbial DNA detection and both CTCs detection at baseline and CTCs increase between baseline and three months of treatment. To conclude, the current study provides additional evidence of non-inferiority of three over 6 months of treatment, mainly in patients under CAPOX.

Anomalous anatomic trajectory of the superior thyroid artery encountered during thyroidectomy. A rare case report.

Superior thyroid artery (STA), which is one of the primary arteries supplying to the thyroid gland, constitutes a severe consideration of both surgeons and interventional radiologists. Knowledge of the origin, the trajectory, the branching patterns and the anatomic aberrations of STA are of paramount clinical significance, due to its proximity to the external branch of the superior laryngeal nerve and the potentiality of accidental hemorrhage. The present manuscript reports for the first time the anomalous trajectory of the left STA, coursing superficially, through the left sternothyroid muscle and underlines the clinical significance of such aberrations.

The Anatomy in Greek Iatrosophia during the Ottoman domination era.

The knowledge of Anatomy during the Ottoman domination in Greece has not been widely studied. Medical knowledge of the time can be retrieved from folk and erudite books called Iatrosophia. The majority of these books focused on empirical diagnostics and therapeutics. However, a small quota of these Iatrosophia includes important information about anatomy. The interest in anatomy appears only after the Neohellenic Enlightenment (1750-1821) and has been associated to the scholarly background of the 1821 revolution against the Ottomans. At the same time, anatomy has been discussed by various authors in diverse contexts. All in all, it appears that a consensus on the importance of anatomy has been established among Greek scholars in the late 18th century, leading to the translation of current anatomical knowledge to the contemporary language and literature.

Revisiting Amyand's Hernia: A 20-Year Systematic Review.

PURPOSE: Protrusion of the appendix within an inguinal hernia is termed an Amyand's hernia. A systematic review of case reports and case series of Amyand's hernia was performed, with emphasis on surgical decision-making. METHODS: The English literature (2000-2019) was reviewed, using PubMed and Embase, combining the terms "hernia", "inguinal", "appendix", "appendicitis" and "Amyand". Overall, 231 studies were included, describing 442 patients. RESULTS: Mean age of patients was 34 ± 32 years (adults 57.5%, children 42.5%). 91% were males, while a left-sided Amyand's hernia was observed in 9.5%. Of 156 elective hernia repairs, 38.5% underwent appendectomy and 61.5% simple reduction of the appendix. 88% of the adult patients had a mesh repair, without complications. Of 281 acute cases, hernial complications (76%) and acute appendicitis (12%) were the most common preoperative surgical indications. Appendectomy was performed in 79%, more extensive operations in 8% and simple reduction in 13% of cases. A mesh was used in 19% of adult patients following any type of resection and in 81% following reduction of the appendix. Among acute cases, mortality was 1.8% and morbidity 9.2%. Surgical site infections were observed in 3.6%, all of which in patients without mesh implantation. CONCLUSION: In elective Amyand's hernia cases, appendectomy may be considered in certain patients, provided faecal spillage is avoided, to prevent mesh infection. In cases of appendicitis, prosthetic mesh may be used, if the surgical field is relatively clean, whereas endogenous tissue repairs are preferred in cases of heavy contamination.