Tissue engineering and regenerative medicine (TERM) is an emerging field that has provided new therapeutic opportunities by delivering innovative solutions. The development of nontraditional therapies for previously unsolvable diseases and conditions has brought hope and excitement to countless individuals globally. Many regenerative medicine therapies have been developed and delivered to patients clinically. The technology platforms developed in regenerative medicine have been expanded to various medical areas; however, their applications in colorectal surgery remain limited. Applying TERM technologies to engineer biological tissue and organ substitutes may address the current therapeutic challenges and overcome some complications in colorectal surgery, such as inflammatory bowel diseases, short bowel syndrome, and diseases of motility and neuromuscular function. This review provides a comprehensive overview of TERM applications in colorectal surgery, highlighting the current state of the art, including preclinical and clinical studies, current challenges, and future perspectives. This article synthesizes the latest findings, providing a valuable resource for clinicians and researchers aiming to integrate TERM into colorectal surgical practice.
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From the Editor: Uniting expertise, a new era of global collaboration in coloproctology In Ja Park Annals of Coloproctology.2024; 40(4): 285. CrossRef
Hyo Seon Ryu, Hyun Jung Kim, Woong Bae Ji, Byung Chang Kim, Ji Hun Kim, Sung Kyung Moon, Sung Il Kang, Han Deok Kwak, Eun Sun Kim, Chang Hyun Kim, Tae Hyung Kim, Gyoung Tae Noh, Byung-Soo Park, Hyeung-Min Park, Jeong Mo Bae, Jung Hoon Bae, Ni Eun Seo, Chang Hoon Song, Mi Sun Ahn, Jae Seon Eo, Young Chul Yoon, Joon-Kee Yoon, Kyung Ha Lee, Kyung Hee Lee, Kil-Yong Lee, Myung Su Lee, Sung Hak Lee, Jong Min Lee, Ji Eun Lee, Han Hee Lee, Myong Hoon Ihn, Je-Ho Jang, Sun Kyung Jeon, Kum Ju Chae, Jin-Ho Choi, Dae Hee Pyo, Gi Won Ha, Kyung Su Han, Young Ki Hong, Chang Won Hong, Jung-Myun Kwak, Korean Colon Cancer Multidisciplinary Committee
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Colorectal cancer is the third most common cancer in Korea and the third leading cause of death from cancer. Treatment outcomes for colon cancer are steadily improving due to national health screening programs with advances in diagnostic methods, surgical techniques, and therapeutic agents.. The Korea Colon Cancer Multidisciplinary (KCCM) Committee intends to provide professionals who treat colon cancer with the most up-to-date, evidence-based practice guidelines to improve outcomes and help them make decisions that reflect their patients’ values and preferences. These guidelines have been established by consensus reached by the KCCM Guideline Committee based on a systematic literature review and evidence synthesis and by considering the national health insurance system in real clinical practice settings. Each recommendation is presented with a recommendation strength and level of evidence based on the consensus of the committee.
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Colitis caused by vasculitis is a rare and poorly understood pathology. Little evidence exists on its clinical presentation, path to diagnosis, and surgical management. In this report, we present a case report and literature review. A healthy 20-year-old male patient presented with hemorrhagic colitis requiring total colectomy with end ileostomy. Pathological examination showed pancolitis with multiple ulcers, transmural inflammation, hemorrhage, and microvascular thrombosis. Extensive serological testing revealed elevated cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and eosinophilia, leading to a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) and vasculitis-induced colitis. A literature review was subsequently conducted. Nineteen studies were found documenting vasculitis-induced colitis in the absence of inflammatory bowel disease (IBD). Systemic signs of vasculitis, hemorrhagic colitis, and progression to fulminant colitis were present. Of all patients, 40.0% required colorectal surgery and 62.5% of those patients received a stoma; 25% underwent emergency surgery following failed immunosuppression. All cases relied on clinical correlation with serology and/or histopathology to reach a final diagnosis. We report a case of vasculitis-induced colitis caused by c-ANCA−positive EGPA. The review shows that vasculitis-induced colitis without IBD is an important differential that clinicians should be aware of in patients presenting with colitis.
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Purpose Intestinal fibrosis is a common complication of inflammatory bowel diseases. However, the possible involvement of epithelial-mesenchymal transition (EMT) has been scarcely investigated. This systematic review aims to search through research papers that are focusing on messenger RNA (mRNA) and protein expression profile in EMT in fistula or in intestinal fibrosis.
Methods Electronic exploration was performed until April 24, 2019 through PubMed, Ovid, Science Direct, and Scopus databases with the terms of “fistula” OR “intestinal fibrosis” AND “epithelial-mesenchymal transition”. Two independent reviewers scrutinized the suitability of the title and abstract before examining the full text that met the inclusion criteria. For each study, the sample types that were used, methods for analysis, and genes expressed were identified. The list of genes was further analyzed using DAVID (Database for Annotation, Visualization, and Integrated Discovery) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway.
Results There were 896 citations found; however, only 3 studies fulfilled the requirements. Among the EMT-related genes, 5 were upregulated genes at mRNA level while 6 were at protein level. However, only 2 downregulated genes were found at each mRNA and protein level. Of the 4 inflammation-related genes found, 3 genes were upregulated at mRNA level and 1 at protein level. These genes were confirmed to be involved in the development of inflammatory induced fibrosis and fistula through EMT. Results from quantitative real-time polymerase chain reaction analysis were consistent with the process of EMT, confirmed by the western blot protein analysis.
Conclusion Many significant genes which are involved in the process of EMT in fistula and intestinal fibrosis have been identified. With high-end technology many more genes could be identified. These genes will be good molecular targets in the development of biomarkers for precision drug targeting in the future treatment of intestinal fibrosis and fistula.
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Hermansky-Pudlak syndrome (HPS) is a rare genetic disease consisting of the triad of oculocutaneous albinism, bleeding diathesis, and pigmented reticuloendothelial cells. In HPS patients’ granulomatous colitis could be an additional feature and perianal abscess could be seen in such patients. We report a patient with HPS-associated granulomatous colitis, refractory to medical treatment, and perianal involvement. Patients with HPS-associated granulomatous colitis and perianal involvement may require multiple surgical interventions and there is no consensus yet for treatment in such patients.
Purpose Ulcerative colitis (UC) is known to have an association with the increased risk of colorectal cancer (CRC), and UC-associated CRC does not follow the typical progress pattern of adenoma-carcinoma. The aim of this study is to investigate molecular characteristics of UC-associated CRC and further our understanding of the association between UC and CRC.
Methods From 5 patients with UC-associated CRC, matched normal, dysplasia, and tumor specimens were obtained from formalin-fixed paraffin-embedded (FFPE) samples for analysis. Genomic DNA was extracted and whole exome sequencing was conducted to identify somatic variations in dysplasia and tumor samples. Statistical analysis was performed to identify somatic variations with significantly higher frequencies in dysplasia-initiated tumors, and their relevant functions were investigated.
Results Total of 104 tumor mutation genes were identified with higher mutation frequencies in dysplasia-initiated tumors. Four of the 5 dysplasia-initiated tumors (80.0%) have TP53 mutations with frequent stop-gain mutations that were originated from matched dysplasia. APC and KRAS are known to be frequently mutated in general CRC, while none of the 5 patients have APC or KRAS mutation in their dysplasia and tumor samples. Glycoproteins including mucins were also frequently mutated in dysplasia-initiated tumors.
Conclusion UC-associated CRC tumors have distinct mutational characteristics compared to typical adenoma-carcinoma tumors and may have different cancer-driving molecular mechanisms that are initiated from earlier dysplasia status.
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Purpose Perianal fistula is one of the most common anorectal diseases in adult patients, especially men. A relationship between pyogenic perianal abscess and fistula formation is established in multiple domains. This is the first exploration of such association among patients in the country as no related study has been published in Bahrain. We expect this study to be a foundation for future protocols and evidence-based practice.
Methods A retrospective study was conducted in Salmaniya Medical Complex of Bahrain. A total of 109 patients with a diagnosis of anal abscess were included between 2015 and 2018. Data were collected from the electronic files database used in Salmaniya Medical Complex (iSeha) as well as phone calls to the patients. Collected data were analyzed using statistical software.
Results The most predominant presentation of perianal abscess was pain. Over 50% of abscesses were classified as perianal (56.9%) and among those, left-sided abscesses were more common, followed by right-, posterior-, and anterior-sited, respectively. No recurrence of abscess was recorded among 80% of patients. A fistula developed following abscess drainage in 33.9% of patients. Most fistulas (37.8%) were diagnosed within 6 months or less from abscess drainage. Posterior fistulas were the most common, followed by anterior and left-sided fistulas.
Conclusion The incidence of anal fistula in Bahrain after perianal abscess was 33.9%. Most of the patients who developed a fistula following pyogenic abscess drainage were males and above the age of 40 years. The most common site for fistula was posterior.
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We report a case of a 66-year-old male who presented with a locally advanced primary mucinous adenocarcinoma arising from a fistula-in-ano. The presentation was typical for perianal sepsis and fistula-in-ano with anal pain and chronic discharge. Initial treatments with fistula debridement and seton were performed. Subsequent review of histology revealed underlying adenocarcinoma, while magnetic resonance imaging (MRI) showed local invasion into the prostate. The patient received neoadjuvant chemoradiotherapy followed by pelvic exenteration to maximize the chance of achieving cure. Features of this case are discussed together with its implications, including treatment guidelines and typical MRI findings.
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Purpose Animal models show a strong relationship between lymphangiogenesis and lymph node metastasis. However, the clinical significance of lymphangiogenesis in patients with colorectal cancer (CRC) remains uncertain. This study aimed to evaluate the association between c-Met and lymphangiogenic factors and to elucidate the prognostic significance of c-Met in patients with CRC.
Methods A total of 379 tissue samples were obtained from surgically resected specimens from patients with CRC at Soonchunhyang University Cheonan Hospital between January 2002 and December 2010. The expressions of c-Met, vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, and podoplanin were examined using immunohistochemistry. The expression of c-Met and clinical factors were analyzed.
Results Of the 379 tissues, 301 (79.4%) had c-Met expression. High expression of c-Met in tumor cells was significantly associated with high expression of VEGF-C (P < 0.001) and VEGFR-3 (P = 0.001). However, no statistically significant association with podoplanin (P = 0.587) or VEGF-D (P = 0.096) was found. Of the 103 evaluable patients, expression of c-Met in tumor cells was significantly associated with advanced clinical stage (P = 0.020), positive lymph node status (P = 0.038), and high expression of VEGF-C (P = 0.020). However, no statistically significant association with podoplanin (P = 0.518), VEGFR-3 (P = 0.085), VEGF-D (P = 0.203), or overall survival (P = 0.360) was found.
Conclusion Our results provide indirect evidence for an association and possible regulatory link of c-Met with the lymphangiogenic markers, but c-Met expression in patients with CRC is not a prognostic indicator for overall survival.
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Future medical technology breakthroughs will build from the incredible progress made in computers, biotechnology, and nanotechnology and from the information learned from the human genome. With such technology and information, computer-aided diagnoses, organ replacement, gene therapy, personalized drugs, and even age reversal will become possible. True 3-dimensional system technology will enable surgeons to envision key clinical features and will help them in planning complex surgery. Surgeons will enter surgical instructions in a virtual space from a remote medical center, order a medical robot to perform the operation, and review the operation in real time on a monitor. Surgeons will be better than artificial intelligence or automated robots when surgeons (or we) love patients and ask questions for a better future. The purpose of this paper is looking at the future medical science and the changes of colorectal surgeons.
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The activity of epithelial lactase (LCT) is associated with a polymorphism 13910 bp upstream in the lactase encoding gene. Because the association between the LCT-13910 polymorphism and the risk for colorectal cancer is not clear, we investigated the role of the LCT-13910 polymorphism as a potential risk factor for colorectal cancer and colorectal polyps in the Turkish population.
Methods
One hundred sixty-six subjects (74 with polyps, 44 with colorectal cancer, 48 controls), who had undergone a total colonoscopy between January 2012 and November 2012 in our endoscopy unit were genotyped for the LCT-13910 polymorphism by using the polymerase chain reaction and minisequencing.
Results
The CC genotype in the lactose gene 13910 locus, which is accepted as the genetic indicator of lactase deficiency, was determined as 83.7%. The CC genotype rate was determined as 89.1% in patients who had a history of lactose intolerance and 81.5% in those without a history of lactose intolerance (P = 0.236). No difference was detected between the patients who had colorectal polyp(s) and/or cancer and the controls with regard to the LCT-13910 polymorphism. No differences were determined between groups when they were compared with regard to the C or the T allele.
Conclusion
No differences were detected between the patients who had colorectal polyp(s) and/or cancer and those with normal colonoscopy findings with regard to lactase gene polymorphisms. No differences were determined between the groups when they were compared with regard to the C or the T allele.
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This experimental study verified the effect of adipose-tissue-derived stem cells (ASCs) on the healing of ischemic colonic anastomoses in rats.
Methods
ASCs were isolated from the subcutaneous fat tissue of rats and identified as mesenchymal stem cells by identification of different potentials. An animal model of colonic ischemic anastomosis was induced by modifying Nagahata's method. Sixty male Sprague-Dawley rats (10-week-old, 370 ± 50 g) were divided into two groups (n = 30 each): a control group in which the anastomosis was sutured in a single layer with 6-0 polypropylene without any treatment and an ASCtreated group (ASC group) in which the anastomosis was sutured as in the control group, but then ASCs were locally transplanted into the bowel wall around the anastomosis. The rats were sacrificed on postoperative day 7. Healing of the anastomoses was assessed by measuring loss of body weight, wound infection, anastomotic leakage, mortality, adhesion formation, ileus, anastomotic stricture, anastomotic bursting pressure, histopathological features, and microvascular density.
Results
No differences in wound infection, anastomotic leakage, or mortality between the two groups were observed. The ASC group had significantly more favorable anastomotic healing, including less body weight lost, less ileus, and fewer ulcers and strictures, than the control group. ASCs augmented bursting pressure and collagen deposition. The histopathological features were significantly more favorable in the ASC group, and microvascular density was significantly higher than it was in the control group.
Conclusion
Locally-transplanted ASCs enhanced healing of ischemic colonic anastomoses by increasing angiogenesis. ASCs could be a novel strategy for accelerating healing of colonic ischemic risk anastomoses.
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Effects of adipose stem cell sheets on colon anastomotic leakage in an experimental model: Proof of principle Panithi Sukho, Geesien S.A. Boersema, Abigael Cohen, Nicole Kops, Johan F. Lange, Jolle Kirpensteijn, Jan Willem Hesselink, Yvonne M. Bastiaansen-Jenniskens, Femke Verseijden Biomaterials.2017; 140: 69. CrossRef
Novel therapy for pancreatic fistula using adipose-derived stem cell sheets treated with mannose Hirokazu Kaneko, Toshio Kokuryo, Yukihiro Yokoyama, Junpei Yamaguchi, Tokunori Yamamoto, Rei Shibata, Momokazu Gotoh, Toyoaki Murohara, Akira Ito, Masato Nagino Surgery.2017; 161(6): 1561. CrossRef
Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases Lina Zhao, Takerra Johnson, Dong Liu Stem Cell Research & Therapy.2017;[Epub] CrossRef
PURPOSE Colorectal cancer (CRC) is one of the leading causes of cancer death in South Korea. Angiogenesis has been associated with invasion and metastasis of tumors and with the secretion of various growth factors. Bevacizumab is a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor (VEGF) and that targets integrin alphaVbeta3 and matrix metalloproteinases (MMPs) as angiogensis inhibitors. The aims of this study were identification of the mechanism of target molecules related to angiogenesis and demonstration of identifiable invasion by using chemotherapeutic regimens in vitro. METHODS The five colorectal cancer cell lines were treated with bevacizumab using standard or combined regimens. The expression of integrin alphaVbeta3 was detected and the investigation of apoptosis was done by using flow cytometry.
The activations of MMP-2 and MMP-9 were measured by using gelatin zymography. RESULTS The apoptotic cell death was significantly increased for the combined regimens, especially for FOLFOX (5-FU, leucovorin, and oxaliplatin) with bevacizumab.
Bevacizumab inhibited the expression of integrin alphaVbeta3 in the HT29 (59%), LoVo (67%), and SW480 (17%) cell lines, but did not in the AMC5 and the RKO cell lines. The activations of MMP-2 and MMP-9 were significantly reduced by treatment with bevacizumab in the HT29 and the LoVo cell lines. In the HT29 and the LoVo cell lines, thus, bevacizumab inhibited invasion and metastasis activity through down-regulation of integrin alphaVbeta3 and MMPs. CONCLUSION Our results provide biological evidence of potent angiogenic activity and indicate that angiogenesis is a complex process that involves multiple factors, including VEGF, integrin alphaVbeta3, and MMPs.
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RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions Hossein Javid, Mahsa Akbari Oryani, Nastaran Rezagholinejad, Ali Esparham, Mahboubeh Tajaldini, Mehdi Karimi‐Shahri Cancer Medicine.2024;[Epub] CrossRef
PURPOSE Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family and play an important role in cellular growth. Recent reports suggest that exogenous bone morphogenetic protein-2 (BMP-2) acts as an antiproliferative agent in a variety of cell lines. We will study whether BMP-2 is altered in human colorectal cancer. METHODS We analyzed 40 colorectal cancer cases and 6 colorectal cancer cell lines by using reverse transcription-polymerase chain reaction (RT-PCR) to determine the expression of BMP-2. RESULTS Thirteen of 40 colorectal cancers (33%) and 3 of 6 colorectal cancer cell lines (50%) revealed decreased expression of BMP-2. The rates of decreased expression were 0% (0/7), 42.1% (8/19), 28.6% (2/7), 33.3% (2/6), and 100% (1/1) in stages I, II, III, and IV, respectively.
Histologically, the rates were 33.3% (2/6), 32.2% (10/21), 50% (1/2), and 0% (0/1) in well-differentiated, moderately-differentiated, poorly-differentiated and mucinous cancers, respectively. As for location, the rates for colon and rectal cancers were 27.8% (5/18) and 36.4% (8/22), respectively. We identified methylation in the CpG island of the BMP-2 gene in 60% of colorectal cancer cells and in 50% of colorectal cancer cell lines. The 13 cases without BMP-2 gene expression showed no significant correlation with clinicopathological factors. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. CONCLUSION We found, through an analysis using the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in colorectal cancer. Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to colorectal carcinogenesis.
Fecal incontinence remains a socially isolating condition, which can have a profound impact on all aspects of quality of life. It affects 2% to 17% of people living in the community and is an iatrogenic disease that develops after a restorative proctectomy for rectal cancer. Conservative management, such as biofeedback and medication, or surgical therapy may be ineffective, the symptomatic benefit being disappointing. In a few recent reports, autologous myoblasts injected into the urinary or anal sphincter were used successfully for the treatment of incontinence, and these cells improved the muscle function. These autologous cell therapies can avoid adverse events, such as tumor formation, compared to the use of embryonic stem cells. However, the limited regenerative capacity of cell therapy has prompted the development of replacing dysfunctional muscle tissue.
Regenerative medicine for functioning muscles may be a therapeutic tool for fecal incontinence in the future. Now, many challenges remain to be overcome prior to reaching the ultimate goal of a fully functional 3-D vascularized engineered muscle: These include development of highly organized 3-D scaffolds, development of scaffolds that specifically direct cellular differentiation, development of co-culture systems of multiple cell types on smart surfaces, development of vascularized constructs, reduction of serum dependence, and innervation into constructed muscle. The successful generation of functional muscle tissues requires an in-depth knowledge of both muscle tissue physiology and advanced engineering practices. The recent advances in tissue engineering technique and cell biology suggest that artificially-derived muscle constructs may be used in clinical settings in the near future.
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Feasibility of Neurovascular Antropylorus Perineal Transposition With Pudendal Nerve Anastomosis Following Anorectal Excision: A Cadaveric Study for Neoanal Reconstruction Abhijit Chandra, Ashok Kumar, M Noushif, Nitish Gupta, Vijay Kumar, Navneet Kumar Chauhan, Vishal Gupta Annals of Coloproctology.2013; 29(1): 7. CrossRef
Functional New Sphincter Ani Reconstruction by Using Neurovascualr Antropylorus Transposition After an Anorectal Excision Bong Hwa Lee, Min Jung Kim, Hyoung Chul Park Annals of Coloproctology.2013; 29(1): 5. CrossRef
Injection of porous polycaprolactone beads containing autologous myoblasts in a dog model of fecal incontinence Sung-Bum Kang, Hye Seung Lee, Jae-Young Lim, Se Heang Oh, Sang Joon Kim, Sa-Min Hong, Je-Ho Jang, Jeong-Eun Cho, Sung-Min Lee, Jin Ho Lee Journal of the Korean Surgical Society.2013; 84(4): 216. CrossRef