Navigating through novelties concerning mCRC treatment-the role of immunotherapy, chemotherapy, and targeted therapy in mCRC.

Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.

Role of Adipose Tissue Hormones in Pathogenesis of Cryptoglandular Anal Fistula.

The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.

The Role of Chronic Fatigue in Patients with Crohn's Disease.

Crohn's disease (CD) is a chronic, relapsing disorder belonging to inflammatory bowel diseases (IBD). It is manifested by relapsing transmural inflammation found in any segment of the gastrointestinal tract. Chronic fatigue is a common and underrecognized symptom of CD for which the prevalence is much higher in the population of CD patients compared to the healthy population. It stems from an intricate web of interactions between various risk factors, and its pathophysiology is still not fully understood. The implementation of routine screening and a holistic, multidisciplinary approach involving psychological support may be crucial in the management of CD patients with chronic fatigue. There is currently no single intervention aimed at decreasing fatigue alone, and its treatment is especially difficult in patients with fatigue persisting despite clinical and endoscopic remission. Extensive research is still needed in order to be able to predict, prevent, identify, and ultimately treat fatigue associated with CD. The aim of this review is to summarize the knowledge on the etiology, diagnosis, and treatment of chronic fatigue in CD patients.

Rectal Cancer: Are 12 Lymph Nodes the Limit?

Lymph node dissection is a crucial element of oncologic rectal surgery. Many guidelines regard the removal of at least 12 lymph nodes as the quality criterion in rectal cancer. However, this recommendation remains controversial. This study examines the factors influencing the lymph node yield and the validity of the 12-lymph node limit. Patients with rectal cancer who underwent low anterior resection or abdominoperineal amputation between 2000 and 2010 were analyzed. In total, 20,966 patients from 381 hospitals were included. Less than 12 lymph nodes were found in 20.53% of men and 19.31% of women (p = 0.03). The number of lymph nodes yielded increased significantly from 2000, 2005 and 2010 within the quality assurance program for all procedures. The univariate analysis indicated a significant (p < 0.001) correlation between lymph node yield and gender, age, pre-therapeutic T-stage, risk factors and neoadjuvant therapy. The multivariate analyses found T3 stage, female sex, the presence of at least one risk factor and neoadjuvant therapy to have a significant influence on yield. The probability of finding a positive lymph node was proportional to the number of examined nodes with no plateau. There is a proportional relationship between the number of examined lymph nodes and the probability of finding an infiltrated node. Optimal surgical technique and pathological evaluation of the specimen cannot be replaced by a numeric cut-off value.

Squamous Cell Carcinoma of perineal area developed from the Buschke-Löwenstein tumor.

The Buschke-Löwenstein tumor is a rare disease associated with human papillomavirus infection. The condition manifests with an ulcerative, exophytic tumor localized in the perineal area. Generally considered as non-cancerous, the growth may develop malignant transformation. Our manuscript highlights the importance of early diagnosis with histopathological analysis.

Management of Pelvic Pain in Patients with Crohn's Disease-Current Overview.

Crohn's disease (CD) is a subtype of chronic inflammatory bowel diseases (IBD) with characteristic skip lesions and transmural inflammation that may affect the entire gastrointestinal tract from the mouth to the anus. Persistent pain is one of the main symptoms of CD. This pain has multifactorial pathogenesis, but most often arises from intestinal inflammation itself, as well as from gut distention or partial intestinal obstruction. Some current evidence also suggests sensitization of sensory pathways, as well as modulation of those signals by the central nervous system, which highlights the impact of biopsychosocial factors. To date, most studies have focused only on the pain located in the abdomen, while pelvic pain has rarely been explored, despite it being a common symptom. The aim of this study is to provide an abbreviated summary of the current state of knowledge on the origins and treatment of pelvic pain in CD.

Increased GPR35 expression in human colorectal and pancreatic cancer samples: A preliminary clinical validation of a new biomarker.

BACKGROUND: G protein-coupled receptor 35 (GPR35) is involved in carcinogenesis; however, limited experimental data are available on its actual expression in patients with colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC). OBJECTIVES: We aimed to measure the relative expression of GPR35 in samples from patients with CRC or PDAC. MATERIAL AND METHODS: Using real-time polymerase chain reaction (RT-PCR), we have examined GPR35 expression in surgery samples from 40 CRC and 17 PDAC patients, and performed analysis of the results. RESULTS: The analysis of GPR35 expression in patients with CRC revealed correlations between relative GPR35 mRNA expression and several tumor characteristics, with statistical significance for higher American Joint Committee on Cancer (AJCC) stages, T stages and histological grades. GPR35 expression was significantly higher in tumor samples compared to the paired healthy samples collected from the same patient. Similar, although not statistically significant trends were found in PDAC tumor samples for sex (lower expression in women) and for samples with no nodal involvement (lower expression). Samples with higher tumor T stages and higher histological grades or considered inoperable had higher GPR35 expression. CONCLUSIONS: We have identified correlations which confirm our expectation of high GPR35 expression in CRC and PDAC. Our findings suggest the prognostic value of GPR35 testing in patients with an increased risk of CRC or PDAC development, and warrant further clinical confirmation.

Risk factors and clinical characteristics of rectal cancer recurrence after radical surgical treatment.

<b><br>Introduction:</b> Recurrence of rectal cancer affects from 4% to even 50% of patients after surgical treatment. The incidence may be influenced by numerous factors depending on the patient, the characteristics of the tumor and the type and quality of the surgical technique used.</br> <b><br>Aim:</b> The aim of this study was to assess the clinical characteristics of rectal cancer recurrence, identify potential risk factors and role of patient surveillance after primary resection of rectal cancer.</br> <b><br>Materials and methods:</b> The study comprised patients operated on due to recurrence of rectal cancer at the Department of General and Colorectal Surgery of Medical University of Lodz between 2014 and 2020, who were in the follow-up program at the hospital's outpatient clinic after the primary surgery. Risk factors for disease recurrence were sought by analyzing the characteristics of the primary tumor, treatment history and postoperative care.</br> <b><br>Results:</b> Twenty-nine patients were included in the study, the majority (51.7%) of the patients were men. The largest group was represented by patients with stage II and III disease. The most frequently performed primary surgery was low anterior resection (LAR) (62.8%). 35% of patients received neoadjuvant treatment prior to primary surgery. We demonstrated that the lack of neoadjuvant treatment before primary surgery increases the risk of cancer recurrence nine times. Higher stage of disease at the point of primary surgery is associated with nearly seven times the risk of recurrence compared to stage I disease.</br> <b><br>Conclusions:</b> Optimal preoperative staging, reasonable neoadjuvant treatment, proper surgical technique and precise follow-up regimen are essential for further improvement of rectal cancer outcomes.</br>.

Colorectal Cancer: Is it Still a Disease of the Elderly?

<b><br>Introduction:</b> Colorectal cancer is becoming an increasingly significant health issue, being one of the more commonly diagnosed malignancies. Colorectal tumors account for 10% of all malignant cancers in women and 12% in men. Incidence is higher in the male population, especially among younger individuals. It is commonly believed that colorectal cancer is predominantly associated with advanced age. However, colorectal surgeons, who specialize in the treatment of this type of cancer, are observing a growing number of cases among middle-aged and younger individuals.</br> <b><br>Aim:</b> The aim of our study was to investigate whether colorectal cancer still predominantly affects elderly individuals, how frequently it is diagnosed in younger patients, and whether the location of tumors in the intestines of younger patients aligns with data from elderly individuals.</br> <b><br>Materials and methods:</b> The study was conducted retrospectively and included a cohort of 1771 patients who underwent surgical procedures due to colorectal cancer between 2012 and 2015 at the Department of General and Colorectal Surgery at the Medical University of Lódz and between 2014 and 2017 at the Department of General Surgery with a Division of Surgical Oncology at the District Health Center in Brzeziny. Data were analyzed regarding the frequency of colorectal cancer occurrence by age, tumor location in different age groups, and disease stage according to age. Age groups included <40 years, 41-50 years, 51-70 years, and >70 years.</br> <b><br>Results:</b> The study encompassed a total of 1771 patients, with 988 (55.79%) being males and 783 (44.21%) females. The mean age of the patients was 65.27 11.12 years. The highest number of cases was observed in the age range of 60-70 years and 70-80 years. It was found that colorectal tumors in males more frequently occurred on the left side of the colon and rectum, while in females, they were more commonly located on the right side of the colon, which was statistically significant (P = 0.007). Younger age groups of patients (<40 years, 40-50 years) had a similar male-to-female ratio, whereas in age groups above 50 years, males significantly outnumbered females (P = 0.049). The study revealed that in the group of patients below 40 years of age, an advanced stage of colorectal cancer was significantly more common; stage D occurred over twice as often as in the 51-70 age group and over three times as often as in the >70 age group.</br> <b><br>Conclusions:</b> The incidence of colorectal cancer in Poland is steadily increasing, with a growing number of diagnoses in younger individuals. Research findings demonstrate that males, especially those in younger age groups, are at a higher risk of developing colorectal cancer. A higher disease stage is more frequently observed in younger patients, possibly due to delayed diagnosis and symptomatic treatment. Screening programs should be adjusted to the changing age groups at higher risk. Our study underlines the need to raise public awareness regarding colorectal cancer, particularly among the younger population.</br>.

Multiple symmetrical lipomatosis: A literature review and case report of a patient with Madelung's disease.

<b><br>Introduction:</b> Madelung's disease is a rare condition characterised by the symmetric growth of fatty tumours (lipomas) around the neck, shoulders, upper arms and trunk.</br> <b><br>Case report:</b> We present a description of a male patient with extensive adipose tissue overgrowth around the neck. Once the possibility of malignancy was excluded, the patient's history and clinical and radiological findings led to the diagnosis of Madelung's disease. A two-stage surgery was planned and the patient underwent lipectomy of the lipomas around the neck.</br> <b><br>Conclusions:</b> This article analyses the clinical data with Madelung's disease; discusses its aetiology, clinical manifestations, diagnosis and treatment methods; and provides help with clinical diagnosis and treatment.</br>.

Small-molecule inhibitors of the PERK-mediated Unfolded Protein Response signaling pathway in targeted therapy for colorectal cancer.

<b> Introduction:</b> The newest data has reported that endoplasmic reticulum (ER) stress and PERK-dependent Unfolded Protein Response (UPR) signaling pathway may constitute a key factor in colorectal cancer (CRC) pathogenesis on the molecular level. Nowadays used anti-cancer treatment strategies are still insufficient, since patients suffer from various side effects that are directly evoked via therapeutic agents characterized by non-specific action in normal and cancer cells. </br></br> <b>Aim:</b> Thereby, the main aim of the presented research was to analyze the effectiveness of the small-molecule PERK inhibitor NCI 12487 in an in vitro cellular model of CRC. </br></br> <b>Materials and methods:</b> The study was performed on colorectal cancer HT-29 and normal human colon epithelial CCD 841 CoN cell lines. The cytotoxicity was measured by XTT assay, evaluation of apoptosis was performed by caspase-3 assay, whereas cell cycle analysis via the propidium iodide (PI) staining. </br></br> <b>Results:</b> Results obtained have demonstrated that the investigated compound is selective only for HT-29 cancer cells, since at 25 µM concentration it significantly decreased HT-29 cells viability in a dose- and time-dependent manner, evoked increased caspase-3 activity and arrest in the G2/M phase of the cell cycle. Moreover, NCI 12487 compound markedly decreased HT-29 cells viability, increased caspase-3 activity and percentage of cells in sub-G0/G1, thus promoted apoptosis of cancer HT-29 cells with induced ER stress conditions. </br></br> <b>Conclusion:</b> Thus, based on the results obtained in this study it may be concluded that small-molecule modulators of the PERK-dependent UPR signaling pathway may constitute an innovative, targeted treatment strategy against CRC.

Polymorphism association of NIL1, NIL2, CYP1A1 xenobiotic metabolism genes and their expression with the risk of colorectal cancer in the Polish population.

<b>Introduction:</b> Colorectal cancer (CRC), despite intensive research on the improvement of diagnosis and treatment, is still the second most deadly cancer in Poland in terms of mortality. One of the factors predisposing to a higher risk of CRC may be the individual differences in the effectiveness of proteins responsible for the metabolism of xenobiotics - it seems that the removal of potentially harmful exogenous substances significantly reduces the risk of carcinogenesis. </br></br> <b>Aim:</b> In this work, we analyzed the effect of polymorphisms of genes responsible for metabolizing xenobiotics on the risk of CRC - rs72554606 polymorphism of N AT 1 gene, rs1799930 polymorphism of N AT 2 gene and rs1799814 polymorphism of CYP1A1 gene, as well as the level of expression of these genes. </br></br> <b> Conclusions:</b> The results indicate that the GC genotype for N AT 1 and the GA genotype for CYP1A1 may increase the risk of CRC, and in those already diagnosed with colorectal cancer, the expression level of NAT1 is significantly lower than in the control. We believe that these factors may have potential prognostic and diagnostic significance in the treatment of CRC.

Colitis-Associated Colorectal Cancer in Patients with Inflammatory Bowel Diseases in a Tertiary Referral Center: A Propensity Score Matching Analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a risk factor in developing colitis-associated colorectal cancer (CA-CRC). CA-CRC causes the death of about 15% IBD patients and the risk is 1.5-2.4 fold higher among IBD sufferers than in the general population. The dysplasia CA-CRC develops in a different mechanism in comparison to sporadic colorectal cancer (CRC). This study aimed at evaluating the surgical treatment and its outcomes as well as 5-year survival rates in the CA-CRC and sporadic CRC patients. MATERIALS AND METHODS: This single-center, retrospective, propensity score-matched case-control study was conducted with 2204 patients operated on due to primary CRC, who were hospitalized from 2003 to 2019. The CA-CRC group consisted of 49 patients with CRC in the course of IBD. The sporadic CRC group was selected with the propensity score matching technique and comprised 98 patients with sporadic CRC who did not have clinical or histopathological features characteristic for IBD. RESULTS: CA-CRC is characterized by a more aggressive clinical course. Surgical treatment of CA-CRC involves more palliative operations and is related with a higher risk of perioperative and postoperative complications. Further studies of CA-CRC risk factor stratification and the development of molecular markers hold promise in reducing CRC in IBD patients in the future were warranted.

Current Overview on the Use of Mesenchymal Stem Cells for Perianal Fistula Treatment in Patients with Crohn's Disease.

Perianal fistula in patients with Crohn's disease is an extremely challenging condition. The disease tends to reoccur, and with current treatment options, a large number of patients are left with active ailment and experience major morbidity. In recent years, hopeful results regarding local use of mesenchymal stem cells (MSCs) in perianal Crohn's disease have been published. Although to this day there are no clear guidelines determining optimal dosage, injections frequency and culture conditions, their efficiency has proven to be much higher than conventionally used methods. According to studies, they can effectively induce as well as maintain fistula closure. This approach also avoids common side effects related to conventional surgical treatment.

Blockade of fructose transporter protein GLUT5 inhibits proliferation of colon cancer cells: proof of concept for a new class of anti-tumor therapeutics.

BACKGROUND: Despite the fact that colorectal cancer (CRC) is one of the most commonly diagnosed cancers in men and women, its current treatment remains unsatisfactory and therefore novel studies proposing new approaches are necessary. A high sugar diet is believed to promote carcinogenesis. Fructose is absorbed from the gastrointestinal tract by members of the glucose transporter family-GLUT. The aim of the study was to characterize the expression of GLUT5 at mRNA level in CRC patients. Moreover, our goal was to elucidate the molecular role of GLUT5 in CRC and assess whether GLUT5 inhibitor may affect the viability of colon cancer cells. METHODS: The expression of GLUT5 at mRNA level was characterized based on 30 samples from resected colorectal cancers and 30 healthy colonic mucosa specimens from surgical margins. The inhibitory effect of N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSBNA) was assessed on a colon cancer cell line, HT-29, and normal colon epithelium cells-CCD 841 CoN Cells. RESULTS: GLUT5 expression was found in 96.7% of cancer specimens and only in 53.3% of healthy mucosa fragments. In cancer tissue, real-time PCR analysis showed almost 2, fivefold (p< 0.001) increase of GLUT5 mRNA expression level compared with the healthy intestinal mucosa. GLUT5 inhibitor, MSNBA (10 µM) significantly decreased the viability of colon cancer cells, while barely affected the viability of normal colon epithelium cells. CONCLUSIONS: Our study suggests that a strong focus should be put on GLUT5 and its inhibitors for both diagnostic and therapeutic purposes in CRC.

Current Overview on Clinical Management of Chronic Constipation.

Constipation is one of the major gastrointestinal disorders diagnosed in clinical practice in Western countries. Almost 20% of population suffer from this disorder, which means constipation is a substantial utilization of healthcare. Pathophysiology of constipation is complex and multifactorial, where aspects like disturbance in colonic transit, genetic predisposition, lifestyle habits, psychological distress, and many others need to be taken into consideration. Diagnosis of constipation is troublesome and requires thorough accurate examination. A nonpharmacological approach, education of the patient about the importance of lifestyle changes like diet and sport activity state, are the first line of therapy. In case of ineffective treatment, pharmacological treatments such as laxatives, secretagogues, serotonergic agonists, and many other medications should be induced. If pharmacologic treatment fails, the definitive solution for constipation might be surgical approach. Commonness of this disorder, costs of medical care and decrease in quality life cause constipation is a serious issue for many specialists. The aim of this review is to present current knowledge of chronic constipation and management of this disorder.

Current concepts in the pathogenesis of cryptoglandular perianal fistula.

Cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery. A fistula is typically defined as a pathological communication between two epithelialized surfaces. More specifically, perianal fistula manifests as an abnormal tract between the anorectal canal and the perianal skin. Perianal fistulas are often characterized by significantly decreased patient quality of life. The cryptoglandular theory of perianal fistulas suggests their development from the proctodeal glands, which originate from the intersphincteric plane and perforate the internal sphincter with their ducts. Involvement of proctodeal glands in the inflammatory process could play a primary role in the formation of cryptoglandular perianal fistula. The objective of this narrative review was to investigate the current knowledge of the pathogenesis of cryptoglandular perianal fistula with the specific aims of characterizing the potential role of proinflammatory factors responsible for the development of chronic inflammation. Further studies are crucial to improve the therapeutic management of cryptoglandular perianal fistulas.

Association of GEMIN4 gene polymorphisms with the risk of colorectal cancer in the Polish population.

<br><b>Aim:</b> Gem-associated protein 4 (GEMIN4), a member of the GEMIN gene family, is a key compound of the regulating factors responsible for miRNA biogenesis. Genetic variability within this gene can alter the risk for development of colorectal cancer (CRC) as was shown for other genes involved in miRNA biogenesis. Therefore, presented study was intended to identify genetic variants of three single nucleotide polymorphisms (SNPs) in the GEMIN4 gene (rs1062923, rs2740348 and rs910925) and their relationship with CRC.</br> <br><b>Methods:</b> The study comprised 203 patients and 179 age and sex matched controls. Genotyping of GEMIN4 gene variants was done using Taqman® assay. The association of GEMIN4 variants with CRC was done by odds ratio analysis. Haplotype analysis was done to see the combined effect of studied variants on CRC.</br> <br><b>Results:</b> Patients carrying all variant genotypes for GEMIN4 rs1062923 (odds ratio [OR]= 0.205; 95% confidence interval [CI] = 0.1034-0.4065 for CC variant and [OR] = 0.1436; [CI] = 0.0869-0.2373 for CT variant, respectively) and GEMIN4 rs2740348 (odds ratio [OR] = 0.4498; 95% confidence interval [CI] = 0.2342-0.8637 for CC variant and [OR] = 0.3986; [CI] = 0.2043-0.7776 for CG variant, respectively) showed significant association in lower occurrence of cancer, whereas in case of GEMIN4 G/C rs910925 variant genotype, no significance correlation was found.</br> <br><b>Conclusion:</b> Our study gives a substantive support for the association between the GEMIN4 gene variants/miRNA biogenesis and CRC risk.</br>.

Assessment of DNA damage profile and oxidative /antioxidative biomarker level in patients with inflammatory bowel disease.

<b>Aim:</b> The purpose of this study was to investigate the oxidative DNA damage, pro-antioxidant status in Polish patients with inflammatory bowel disease (IBD). <br><b>Methods:</b> Oxidative DNA damage was measured by comet assay techniques; nitric oxide (NO) and plasmatic lipid peroxidation (MDA) as oxidative stress were valuated by colometric methods; superoxide dismutase (SOD1), catalase (CAT) and glutathione peroxidase (GPx1) as antioxidative defense were determined by spectrophotometric methods. <br><b>Results:</b> The level of oxidative DNA damage in IBD patients was significantly higher in relation to controls (P = 0.01). Alike, in control subject as well as in patients with IBD, lymphocytes are characterized by complete repair of DNA damage. A significant decrease of SOD (P = 0.031), CAT (P = 0.006), GPx1 (P = 0.001) activity was seen in IBD patients vs control. MDA (P = 0.001) and NO (P = 0.001) concentrations were significantly increased in IBD patients as compared to healthy subjects. <br><b>Conclusions:</b> Our results may be due to the induction of DNA repair genes which may occur at the stage of the pathological changes (IBD) that may be caused by excessive oxidative stress. However, the cause of this relationship, and whether it is direct or indirect, remains to be explored.

Phantom pain as an adverse effect after maggot (Lucilia sericata) debridement therapy: a case study.

Maggot debridement therapy, also known as larval therapy, is a well known method of treatment for hard-to-heal and intractable wounds. This case study describes severe phantom pain as a rare adverse event of maggot therapy in patients after post-traumatic amputation of the leg. We also hypothesise and discuss the possibility that the phantom pain may be a result of maggot activity, not only through tissue debridement but also through nerve nourishment and nerve regeneration.