Differential expression of TIM-3 in circulation and tumor microenvironment of colorectal cancer patients.

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is an inhibitory immune checkpoint, which suppresses anti-tumor immune responses. TIM-3 expression on different immune cells in periphery and tumor microenvironment (TME) of colorectal cancer (CRC) patients has not been fully investigated. We found that TIM-3 was mainly expressed on monocytic myeloid cells (MMCs) and antigen-presenting cells (APCs) in circulation but was mainly expressed on T cells and APCs in the TME. Additionally, TIM-3- T cells co-expressed higher levels of PD-1 than TIM-3+ T cells in normal tissue. In contrast, TIM-3+ T cells in the TME showed significantly higher PD-1 expression. Interestingly, there was a trend towards increased levels of TIM-3+ APCs with disease stages; however, levels of TIM-3+ T cells were decreased with disease stages in the TME. This study shows the differential expression of TIM-3 on different immune cells in circulation and TME of CRC patients, and their associations with disease stages.

Transanal minimally invasive surgery for benign and malignant rectal lesions: midterm outcomes from a tertiary center.

BACKGROUND: Although transanal minimally invasive surgery (TAMIS) for rectal neoplasia has gained wide acceptance, the mid-term and long-term outcomes are not widely reported in the literature. OBJECTIVE: Describe the mid-term outcomes of patients who underwent TAMIS for benign and malignant rectal lesions in a single center. DESIGN: Retrospective cohort study. SETTINGS: Tertiary referral center. PATIENTS AND METHODS: Demographic, clinical, and oncological outcomes of patients who underwent TAMIS between January 2015 and December 2022 were prospectively collected. The indication for TAMIS was based on the National Comprehensive Cancer Network guidelines. The follow up for the cancer patients included clinical examination, tumor markers every 6 months and MRI rectum at the end of one year. In addition, colonoscopy and CT scan at years one and three and a final CT scan and colonoscopy at year five. MAIN OUTCOME MEASURES: Mid-term oncological and clinical outcome. RESULTS: Thirty elective TAMIS procedures included adenocarcinoma for 33.3% (n=10) of the patients, 20% (n=6) neuroendocrine tumor and the 40% (n=12) were adenomatous lesions. Negative resection margins were achieved in all malignant lesions. Perioperative complications occurred in 2 patients (6.6%), one patient had breaching into the peritoneal cavity, and postoperative hypotension occurred in another patient. The median follow-up time was 23 months (range: 5-72 months). Two patients with adenoma and positive margins developed recurrent adenoma (6.6%) and one patient with initial polypectomy biopsy of adenocarcinoma, had TAMIS with histopathology of adenoma and distant metastasis had developed. CONCLUSIONS: TAMIS for local excision of rectal neoplasia is a valid option with favorable mid-term outcomes provided there is adherence to careful selection criteria. LIMITATIONS: Retrospective nature and small number of the patients.

Colonic medullary carcinoma: an exceedingly rare type of colorectal malignancy: a case report and review of the literature.

BACKGROUND: Medullary carcinoma of the colon is a rare subtype of colorectal cancer that has a unique, and sometimes varied, clinical and histologic profile. It usually presents in adult patients older than 50 years. Here, we report a unique case of young male patient who initially presented with abdominal pain followed by a large bowel obstruction. CASE PRESENTATION: A 40-year-old SriLankan male presented with right-sided abdominal pain and on examination, there was a palpable right iliac fossa mass. Colonoscopy and a computed tomography scan revealed cecal mass. Later, while waiting for elective resection, the patient developed symptoms and signs of a large bowel obstruction. He underwent a laparoscopic right hemicolectomy with an uneventful postoperative course. The histopathologic evaluation of the resected specimens showed invasive carcinoma with syncytial growth pattern, foci of lymphoid host response, and dirty necrosis, in keeping with a medullary carcinoma pT4a pN2b. Unlike most reported medullary carcinoma cases, this patient was young and caudal-related homeobox transcription factor 2 positive. CONCLUSION: We have reported another case of medullary carcinoma of the colon in a young patient with unique histologic characteristics. Reporting such cases helps in refine understanding of the histologic and genetic, as well as clinical, phenotypes of medullary carcinoma of the colon.

Elective surgical removal of migrated intrauterine contraceptive devices from within the peritoneal cavity: a comparison between open and laparoscopic removal.

BACKGROUND: Intrauterine contraceptive devices (IUCDs) comprise the most popular form of reversible contraception. Uterine perforation is a rare but potentially serious complication associated with their use. We examined all reported cases of elective surgical removal of peritoneally migrated IUCDs, to compare laparoscopic and open approaches, and to identify beneficial surgical techniques. DATABASE: MEDLINE and Embase were searched using the following medical subject heading terms: (IUCD or IUD or IUS or intrauterine device or intrauterine devices, copper or intrauterine devices, medicated) AND (migrated or displaced or foreign-body migration or intrauterine device migration) AND (peritoneal or peritoneal cavity). The Cochrane Library was searched using the terms IUCD, IUD, IUS, and intrauterine device. Additional studies were identified by manually searching the reference lists of the studies found through database search. Studies were included irrespective of language or publication type. DISCUSSION: We identified 129 cases, reported in 30 studies. In the majority of cases (93.0% [120/129]), surgery was attempted laparoscopically; however 22.5% (27/120) of surgeries were converted to open operations, giving an overall rate of open surgery of 27.9% (36/129). This systematic review supports the use of laparoscopic surgery for elective removal of migrated IUCDs from the peritoneal cavity. With complications rarely reported, it is also likely the procedure could be undertaken in an outpatient setting. The use of intraoperative adjuncts (ie, cystoscopy) and the rate of conversion to open surgery are influenced by the site of the IUCD. Therefore, accurate preoperative localization of the device is advised.

Visceral Basidiobolomycosis Causing Bowel Ischemia.

Basidiobolomycosis is a rare fungal infection caused by saprophyte Basidiobolus ranarum. It is rarely seen in healthy adult patients; however, it usually affects children. The commonly involved sites are skin and subcutaneous tissue, mostly found in the Middle East and the southwestern United States. The diagnosis is challenging because of the lack of specific clinical presentation and the absence of predisposing factors. In our case report, we discuss a 38-year-old male patient who presented with a 2-months history of right lower quadrant pain. Initially, his pain was intermittent and gradually increased in intensity; it localized to the right lower quadrant and radiated to the right flank region. No relieving or aggravating factors were noted. In addition, the patient mentioned a history of constipation, weight loss, decreased appetite, and vomiting-however, no history of fever, night sweats, trauma, or recent travel. The diagnosis was made based on computerized tomography (CT) guided biopsy of the mass, illustrating the findings of fungal hyphae with a gradual increase in the eosinophilic count since admission. The patient was managed using a combined medical and surgical approach, including surgical debulking of the mass and a well-monitored course of anti-fungal therapy. Gastrointestinal basidiobolomycosis infection (GBI) can present in many forms, with an increasing potential to invade the colon, ultimately forming an inflamed mass. Nonetheless, the presence of a mass invading the colon, adjacent vessels, and a retroperitoneal area, along with an increase in the number of eosinophil count in the Middle East region, should raise the suspicion of basidiobolomycosis fungal infection.

Towards development of a tele-mentoring framework for minimally invasive surgeries.

BACKGROUND: Tele-mentoring facilitates the transfer of surgical knowledge. The objective of this work is to develop a tele-mentoring framework that enables a specialist surgeon to mentor an operating surgeon by transferring information in a form of surgical instruments' motion required during a minimally invasive surgery. METHOD: A tele-mentoring framework is developed to transfer video stream of the surgical field, poses of the scope and port placement from the operating room to a remote location. From the remote location, the motion of virtual surgical instruments augmented onto the surgical field is sent to the operating room. RESULTS: The proposed framework is suitable to be integrated with laparoscopic as well as robotic surgeries. It takes on average 1.56 s to send information from the operating room to the remote location and 0.089 s for vice versa over a local area network. CONCLUSIONS: The work demonstrates a tele-mentoring framework that enables a specialist surgeon to mentor an operating surgeon during a minimally invasive surgery.

Transcriptome of Tumor-Infiltrating T Cells in Colorectal Cancer Patients Uncovered a Unique Gene Signature in CD4+ T Cells Associated with Poor Disease-Specific Survival.

Colorectal cancer (CRC) is influenced by infiltration of immune cell populations in the tumor microenvironment. While elevated levels of cytotoxic T cells are associated with improved prognosis, limited studies have reported associations between CD4+ T cells and disease outcomes. We recently performed transcriptomic profiling and comparative analyses of sorted CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from bulk tumors of CRC patients with varying disease stages. In this study, we compared the transcriptomes of CD4+ with CD8+ TILs. Functional annotation pathway analyses revealed the downregulation of inflammatory response-related genes, while T cell activation and angiogenesis-related genes were upregulated in CD4+ TILs. The top 200 deregulated genes in CD4+ TILs were aligned with the cancer genome atlas (TCGA) CRC dataset to identify a unique gene signature associated with poor prognosis. Moreover, 69 upregulated and 20 downregulated genes showed similar trends of up/downregulation in the TCGA dataset and were used to calculate "poor prognosis score" (ppScore), which was significantly associated with disease-specific survival. High ppScore patients showed lower expression of Treg-, Th1-, and Th17-related genes, and higher expression of Th2-related genes. Our data highlight the significance of T cells within the TME and identify a unique candidate prognostic gene signature for CD4+ TILs in CRC patients.

Left iliac fossa mini-incision sigmoidectomy for treatment of sigmoid volvulus. Case series of six patients from Qatar.

BACKGROUND: Midline laparotomy is the definitive treatment for sigmoid volvulus after initial colonoscopic detorsion. We successfully adopted another technique at our center on 6 patients, treating sigmoid volvulus by left iliac fossa mini-incision. PRESENTATION OF CASES: We report our experience of six non-consecutive cases of sigmoid volvulus treated by left iliac fossa mini-incision. The cases were a 33 year old Egyptian female, a 21 year old Bangladeshi male, a 58 year old Qatari male, a 30 year old Ethiopian male, a 36 year old Ugandan male, and a 58 year old Indian male. The six cases are unique in the surgical technique employed in their management. This is possibly the second case series of left iliac fossa mini-incision for sigmoid volvulus in the Middle East and North Africa Region. DISCUSSION: All patients underwent initial colonoscopic detorsion followed by sigmoidectomy and anastomosis. The procedure was successful in treating the volvulus in five patients with no complication or recurrence over a mean follow up of 8 months (range: 1-36 months). One patient required further laparotomy and resection with anastomosis due to incompletely removed sigmoid colon. CONCLUSIONS: Left iliac fossa mini-incision for sigmoid volvulus is safe, feasible, cosmetically appealing and with low morbidity.

Differential gene expression of tumor-infiltrating CD4+ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis.

Tumor-infiltrating lymphocytes (TILs) play indispensable roles in the progression and response to treatment of solid tumors. However, the prognostic significance of CD4+ TILs is not fully disclosed in cancers generally and in CRC in particular, mainly due to the existence of different functional subsets of CD4+ T cells. We performed transcriptomic profiling of CD4+ TILs isolated from CRC patients in order to identify differentially expressed genes and their functional pathways in early versus advanced disease stages. We found that in advanced stages, genes related to immune and inflammatory responses, in particular Th1-mediated immune response and cytotoxicity-mediated genes, were downregulated; while epigenetic-mediated silencing genes were upregulated. Interestingly, we identified genes, which were steadily upregulated or downregulated in CD4+ TILs with CRC progression from stage I to IV. Additionally, of the top 200 deregulated genes, 43 upregulated and 64 downregulated genes showed similar deregulation trends in the cancer genome atlas CRC dataset. From these 97 deregulated genes, we identified a "poor prognosis CD4 gene signature (ppCD4sig)". Patients with high ppCD4sig score showed shorter disease-specific survival (DSS) and progression-free interval (PFI). The ppCD4sig was an independent prognostic indicator for DSS (HR = 1.73, 95% CI 1.32-2.27, P = 0.0001) and PFI (HR = 1.75, 95% CI 1.3-2.35, P = 0.0016). Additionally, patients at advanced stages and at a younger age (<55 years) were more likely to have a high ppCD4sig score. Altogether, our data provide novel insights and a unique prognostic gene signature of CD4+ TILs in the CRC microenvironment.

Epigenetic regulation of immune checkpoints and T cell exhaustion markers in tumor-infiltrating T cells of colorectal cancer patients.

Aim: To elucidate the epigenetic alterations behind the upregulation of immune checkpoints and T cell exhaustion markers in colorectal cancer (CRC) patients. Materials & methods: mRNA expressions of different immune checkpoint/exhaustion markers were analyzed by quantitative real-time reverse transcriptase PCR and epigenetic investigations were performed using bisulfite sequencing and chromatin immunoprecipitation quantitative PCR. Results: mRNA expressions of PD-1, TIM-3, CTLA-4, PD-L1 and TOX2 were significantly upregulated in CD4+ and CD8+ tumor-infiltrating lymphocytes and bulk CRC tumor tissues. Histone 3 lysine 9 trimethylation was downregulated and histone 3 lysine 4 trimethylation was upregulated in PD-L1 and TOX2 promoters in tumor tissues, suggesting that PD-L1 and TOX2 upregulation in CRC tumors could be mediated by activating histone 3 lysine 4 trimethylation. Conclusion: Epigenetic modifications in promoters of immune checkpoint and T cell exhaustion genes could induce their upregulation, and potentially implicate the use of epigenetic modifiers to enhance antitumor immunity in CRC patients.

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients.

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4- (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3- counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer.

BACKGROUND: Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs). METHODS: Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. RESULTS: We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. CONCLUSIONS: This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits.

Laparoscopic repair of abdominal intercostal hernia: a case report and review of the literature.

Abdominal intercostal herniation occurs rarely, with only 27 previous cases reported in the literature. An 84-year-old man presented with a painful large thoraco-abdominal mass. He had no history of trauma or surgery to the chest or abdomen. A thoraco-abdominal computerized tomography scan revealed a protrusion of intra-abdominal omental fat into a sac between the left eighth and ninth ribs. We present a novel technique for the repair of this uncommon condition. There were no peri-operative complications and the patient was asymptomatic on review 9 months later. We suggest that a laparoscopic approach may be used for treatment of an uncomplicated abdominal intercostal hernia.

An Unusual Presentation of Gallstone Ileus: A Red-Herring or Missed Diagnosis.

BACKGROUND: Gallstone ileus is a rare complication of chronic calcular cholecystitis and an uncommon etiological entity responsible for mechanical intestinal obstruction. The most common obstructed part is the narrow terminal ileum, whereas the jejunum is rarely affected. The gallstone is postulated to reach the small bowel by gradual erosion from the gall bladder, most commonly into the duodenum, forming a cholecysto-duodenal fistula. CASE REPORT: Herein, we report a 72-year-old male who presented with intestinal obstruction of a 5-day duration, with a clinical diagnosis of an irreducible inguinal hernia. However, the patient continued to be symptomatic following an uncomplicated hernioplasty. A computerized tomography (CT) scan of the abdomen revealed a small bowel lesion, which intra-operatively was confirmed to be an impacted gallstone in the jejunum with a cholecysto-duodenal fistula. CONCLUSIONS: Despite gallstone is uncommon cause of intestinal obstruction, a high index of suspicion with a careful CT scan interpretation is the key to the diagnosis, especially when there is a red-herring distracting the attention, like irreducible hernia in this case.

Solitary caecal diverticulitis as an unusual cause of a right iliac fossa mass: a case report.

Inflammation of a solitary caecal diverticulum is an uncommon pathological condition. Preoperatively the condition is almost indistinguishable from appendicitis, and is often confused with carcinoma of the caecum during operation. The typical patient with this condition is male, Asian, and in the fourth decade of life. This case is unusual in that the patient was a 26-year-old Caucasian man.