Cranial transposition and revascularization of autologous omentum: a novel surgical technique for resection of recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system. The study aims to assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM. Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study. Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients.

Immunohistochemical examination of immune cells in adipose tissue of rainbow trout (Oncorhynchus mykiss) following intraperitoneal vaccination.

Mammalian perivisceral adipose has been shown to play an important role in the regulation of the peritoneal immune responses. Recently it has been demonstrated that peritoneal antigens are collected by leukocytes within the visceral adipose mass, and a broad range of immunomodulatory genes are differentially expressed in adipose tissue after intraperitoneal vaccination in rainbow trout. To assess the immune cell component in adipose, immunohistochemical analysis was used to examine B-cell, T-cell and antigen presenting cell (APC) numbers and distribution in rainbow trout adipose tissue 24 and 72 h post vaccination in comparison to control fish. The results of this study support previous work on mammals with omental milky spots in naïve fish found to contain APCs and T-cells which then increased in size, number and complexity following vaccination. It suggests that following peritoneal stimulation the visceral adipose mass in fish likely plays an important role in vaccine antigen uptake and presentation by APCs, as well as subsequent T-cell activation and differentiation.

Comparative analysis of human omental milky spots between the patients with colon cancer and the control group.

AIM: Morphological description of milky spots (MSs) in the human greater omentum. METHOD: Samples of the greater omentum collected during surgical procedures were subjected to further histological analysis. Two groups of patients were studied. Group A consisted of patients with colon cancer and peritonitis (stimulated MSs), group B consisted of patients without colon cancer and without peritonitis (unstimulated MSs). In the research, we focused on the cellular composition and differences between stimulated and unstimulated MSs. RESULTS: MSs detected in the study were predominantly oval (67 %), round (12 %) or irregular in shape (21 %). The average number of immune cells found in one milky spot (MS) in the group A was 454 (209-694), consisted of T cells in 44.7 % (27-55 %), B cells in 26.8 % (16-34 %), macrophages in 18.3 % (12-27 %) and other immune cells in 10.2 % (6-18 %). The average number of immune cells found in one MS in the group B was 58 (42-100 %), consisted of T cells in 21.1 % (16-22 %), B cells in 18.7 % (13-22 %), macrophages in 46.9 % (33-60 %) and other immune cells in 13.3 % (1-22 %). The average size of MSs in the group A was significantly higher than in the group B: 768 µm (313-1075) to 293 µm (197-421). The results showed that there were significant differences in terms of strong predominance of macrophages in unstimulated milky spots and strong predominance of T cells in stimulated milky spots. CONCLUSION: MSs are specific immune active lymphatic structures on the greater omentum. They play a key role in defense mechanism, especially in peritonitis. Their function is not completely clear in cancer, some authors suggest they might play a significant role in omental metastasis. Further analysing of the morphology and cells interactions of MSs is needed (Tab. 2, Fig. 6, Ref. 20).

Milky spots: omental functional units and hotbeds for peritoneal cancer metastasis.

As the most common metastatic disease of abdomen pelvic cavity cancer, peritoneal carcinomatosis (PC) renders significant negative impact on patient survival and quality of life. Invasive peritoneal exfoliated cancer cells (PECCs) preferentially select the omentum as a predominant target site for cancer cell colonization and proliferation compared with other tissues in the abdominal cavity. The precise pathogenic mechanism remains to be determined. As omental milky spots (MSs) are the major implantation site for malignant cells in peritoneal dissemination, researches on mechanisms of PC have been mainly focused on MS, primitive lymphoid tissues with unique structural features, and functional characteristics. To date, extensive biophysical and biochemical methods have been manipulated to investigate the MS exact function in the peritoneal cavity. This review summarized MS as hotbeds for PECC. The anatomical distribution was briefly described first. Then, MS histology was systematically reviewed, including morphological features, cellular constituents, and histological staining methods. At last, the roles of MS in PC pathological process were summarized with special emphasis on the distinct roles of macrophages.

Peritoneal milky spots serve as a hypoxic niche and favor gastric cancer stem/progenitor cell peritoneal dissemination through hypoxia-inducible factor 1α.

Peritoneal dissemination is the most common cause of death in gastric cancer patients. The hypoxic microenvironment plays a major role in controlling the tumor stem cell phenotype and is associated with patients' prognosis through hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor that responds to hypoxic stimuli. During the peritoneal dissemination process, gastric cancer stem/progenitor cells (GCSPCs) are thought to enter into and maintained in peritoneal milky spots (PMSs), which have hypoxic microenvironments. However, the mechanism through which the hypoxic environment of PMSs regulated GCSPC maintenance is still poorly understood. Here, we investigated whether hypoxic PMSs were an ideal cancer stem cell niche suitable for GCSPC engraftment. We also evaluated the mechanisms through which the HIF-1α-mediated hypoxic microenvironment regulated GCSPC fate. We observed a positive correlation between HIF-1α expression and gastric cancer peritoneal dissemination (GCPD) in gastric cancer patients. Furthermore, the GCSPC population expanded in primary gastric cancer cells under hypoxic condition in vitro, and hypoxic GCSPCs showed enhanced self-renewal ability, but reduced differentiation capacity, mediated by HIF-1α. In an animal model, GCSPCs preferentially resided in the hypoxic zone of PMSs; moreover, when the hypoxic microenvironment in PMSs was destroyed, GCPD was significantly alleviated. In conclusion, our results demonstrated that PMSs served as a hypoxic niche and favored GCSPCs peritoneal dissemination through HIF-1α both in vitro and in vivo. These results provided new insights into the GCPD process and may lead to advancements in the clinical treatment of gastric cancer.

Involvement of transforming growth factor-ß3 and betaglycan in the cytoarchitecture of postoperative omental adhesions.

BACKGROUND: Adhesions commonly appear in patients after abdominal surgery, with considerable individual variation in adhesion composition and severity of the repair process. Here, we address the influence of transforming growth factor (TGF)-ß3 and betaglycan in this response, in relation to TGF-ß1, in an adhesiogenic rabbit model. MATERIALS AND METHODS: Omental adhesions were recovered 3, 7, 14, and 90 d after the implantation of a polypropylene mesh on the parietal peritoneum in New Zealand White rabbits. Omentum from nonoperated animals served as control. Tissue specimens were examined for TGF-ß3 and TGF-ß1 (Western blotting, reverse transcription-polymerase chain reaction), and TGF-ß1:TGF-ß3 messenger RNA and protein expression ratios were analyzed. Immunohistochemical detection of TGF-ß3 and betaglycan was performed. RESULTS: Injury to the omentum led to mobilization of TGF-ß3 and betaglycan-expressing cells from milky spots. Fibrous zones in adhesions were simultaneous to the presence of TGF-ß1 and the membrane-bound form of betaglycan (7-d adhesions), whereas soluble betaglycan appeared in TGF-ß1-positive areas showing limited fibrosis (3-d adhesions). The elevated expression of TGF-ß3 concurrent with the presence of membrane-bound form of betaglycan was observed in zones of adipose regeneration (14-d adhesions), whereas zones of fibrous consistency were negative for TGF-ß3. CONCLUSIONS: Milky spots on the omentum contain inflammatory/immune cells positive for TGF-ß3, TGF-ß1, and betaglycan, playing a role in the damaged omentum repair. Our observations support the contribution of TGF-ß3 to tissue repair through adipose tissue regeneration and the profibrotic role of TGF-ß1 and suggest that these effects on the local wound repair response could be driven by the expression of betaglycan in its soluble or membrane-bound form.

Recent insights into the pathophysiology of omental metastases.

Although, useful in inflammatory conditions, the greater omentum represents an important site of metastasis in peritoneal carcinomatosis and is therefore frequently removed as a staging or therapeutic tool. Apart from the milky spots, omental adipose stem cells, and adipocytes have recently been identified to play a role in the preferential homing of tumor cells to the omentum. The extent of omentectomy and whether a routine omentectomy should be done are still known unknowns.

Exosomes secreted by ST3GAL5high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment.

Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid-binding Ig-like lectin 1 (CD169; also known as SIGLEC1). ST3G5high -cExos induced pro-inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial-mesenchymal transition (MMT) in PMCs, thereby generating αSMA+ myofibroblasts. ST3G5high -cExos also increased the expression of immune checkpoint molecules and T-cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5high -cExos upregulated chemokines, including CC-chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5high -cExo-mediated MMT, T-cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo-mediated peritoneal dissemination.

Morphological differences between the lesser and the greater omenta in albino rats.

BACKGROUND: Publications report that all mammals have two omenta, namely, lesser omentum and greater omentum. Basically, these organs, which share the same name except for the adjective "lesser" or "greater," should not differ from each other. However, no clear description of the structure of the lesser omentum, as well as comparative morphological analysis between the lesser and greater omenta have been found in the literature, which necessitates a thorough investigation. Therefore, the aim of our study was to analyze the morphofunctional differences between the greater and lesser omenta in albino rats. METHOD: The experiment involved 20 mature male albino rats, weighing 298,28±7,36 grams. The material for our study were preparations of lesser and greater omenta, fixed in 10 % of neutral buffered formalin. Paraffin sections were stained with hematoxylin-eosin and Van Gieson stain. RESULTS: The findings of the study showed that the greater omentum in albino rats, unlike other derivatives of the omentum (ligaments and mesenteries), represents a free extension (mostly from the greater curvature of the stomach), in the form of an "apron," into a specific depth of the peritoneal cavity, duplicating the serous membrane. This duplication is characterized by the composition of two structurally interdependent formations. These include vascular-fatty arcades, associated with lymphoid nodules known as milky spots, and binding serous-reticular membranes. The findings of the study of the lesser omentum have established that in all cases it is located beneath the liver and becomes visualized only after hepatolifting. It is presented in the form of two ligaments: hepatoduodenal and hepatogastric, which contain two main structured formations, which we called vascular-fatty spurs, between these spurs, serous-reticular membranes are located. CONCLUSION: despite having similar names, the lesser omentum, a derivative of the peritoneum, is fundamentally different. As it is well known, the lesser omentum is represented by ligaments that extend from the liver hilus to the lesser curvature of the stomach and the duodenum. Due to this arrangement, the lesser omentum lacks the mobile activity characteristic of the greater omentum, which plays a crucial role in rapid response to damage in the gastrointestinal tract. Despite sharing the same names, both formations differ in shape, morphological structure, development and function.

The role of dendritic cells in the immune niche of the peritoneum.

Dendritic cells (DCs) are professional antigen presenting cells that play an important role in the induction of T cell responses. Different subsets (cDC1s, cDC2s, pDCs, and moDCs) were described based on the expression of different surface markers and functions. In the context of peritoneum, DCs are also a key population cell orchestrating immune responses against pathogens, malignant cells and tissue-damage. Furthermore, they play an important role in the promotion of an anti-inflammatory microenvironment, which is necessary to maintain tolerance and adipocyte homeostasis. The aim of this review is to summarize the current knowledge of the functional and phenotypic features of peritoneal DCs and shed some light on the importance of these cells within this unique cavity and its associated components: the omentum, the mesentery and gut-associated lymphoid tissue (GALT).

Potential Role of Diabetes Mellitus-Associated T Cell Senescence in Epithelial Ovarian Cancer Omental Metastasis.

Epithelial ovarian cancer (EOC) is one of the most common causes of cancer-related deaths among women and is associated with age and age-related diseases. With increasing evidence of risks associated with metabolic inflammatory conditions, such as obesity and type 2 diabetes mellitus (T2DM), it is important to understand the complex pathophysiological mechanisms underlying cancer progression and metastasis. Age-related conditions can lead to both genotypic and phenotypic immune function alterations, such as induction of senescence, which can contribute to disease progression. Immune senescence is a common phenomenon in the ageing population, which is now known to play a role in multiple diseases, often detrimentally. EOC progression and metastasis, with the highest rates in the 75-79 age group in women, have been shown to be influenced by immune cells within the "milky spots" or immune clusters of the omentum. As T2DM has been reported to cause T cell senescence in both prediabetic and diabetic patients, there is a possibility that poor prognosis in EOC patients with T2DM is partly due to the accumulation of senescent T cells in the omentum. In this review, we explore this hypothesis with recent findings, potential therapeutic approaches, and future directions.

The Essential Involvement of the Omentum in the Peritoneal Defensive Mechanisms During Intra-Abdominal Sepsis.

Although the abilities of the omentum to alleviate inflammation and prevent infection have been revealed over the past decades, the underlying mechanisms remain largely unelucidated. Here, we demonstrated that the mortality of mice exposed to cecal ligation and puncture (CLP) and omentectomy was remarkably increased compared to those treated with CLP alone. Moreover, the efficacy of the omentum was associated with an impairment in intraperitoneal bacterial clearance together with an increase in the expression of proinflammatory cytokines. Besides, in response to peritoneal infections, the size and quantity of the omental milky spots (MSs) were increased tremendously and they also support innate-like B1 cell responses and local IgM production in the peritoneal cavity. Furthermore, not only the migration but also the functional activities of neutrophils were diminished in the absence of the omentum. These data collectively show that the omentum contributes more to peritoneal immune responses during septic peritonitis than has heretofore been recognized. Thus, harnessing the function of MS-containing omentum to increase its protective effectiveness may exert important biological and therapeutic implications for the control of intra-abdominal infections.

[Fundamental pathological mechanisms underlying gastro-intestinal cancer peritoneal metastasis].

Gastrointestinal cancer peritoneal metastasis(GICPM) is one of the biggest challenges of clinical treatment. The ultimate solution to the problem requires the clinicians to accurately understand cytologic and molecular pathological mechanisms behind GICPM, and apply such knowledge in the clinical decision-making process for diagnosis and treatment of individual patient, so as to realize "prevention" and "treatment" proactively. The core cytopathological mechanisms behind GICPM, which are closely related to clinical treatment decisions, are as follows: (1) free cancer cells or clusters in peritoneal cavity colonize the peritoneum, resulting in irreversible pathological damage to peritoneal mesothelial cells; (2) the colonized cancer cells further invade the specific structure of the peritoneal milky spots and initiate an accelerated invasive growth process; (3) the process of peritoneal interstitial fibrosis aggravates the structural destruction of the peritoneum; (4) the interaction between cancer cells and immune cells in the milk spots forms a permissive immune microenvironment that promotes the growth of peritoneal metastatic cancer. These four core cytopathological mechanisms are mutually causal and promote each other, forming a vicious circle of GICPM development. As long as clinicians accurately understand these four points, it is possible to grasp the opportunity of clinical diagnosis and treatment, change reactive and passive treatment into preventive and proactive treatment, and improve the clinical diagnosis and treatment landscape of GICPM.

Specialized immune responses in the peritoneal cavity and omentum.

The peritoneal cavity is a fluid filled space that holds most of the abdominal organs, including the omentum, a visceral adipose tissue that contains milky spots or clusters of leukocytes that are organized similar to those in conventional lymphoid tissues. A unique assortment of leukocytes patrol the peritoneal cavity and migrate in and out of the milky spots, where they encounter Ags or pathogens from the peritoneal fluid and respond accordingly. The principal role of leukocytes in the peritoneal cavity is to preserve tissue homeostasis and secure tissue repair. However, when peritoneal homeostasis is disturbed by inflammation, infection, obesity, or tumor metastasis, specialized fibroblastic stromal cells and mesothelial cells in the omentum regulate the recruitment of peritoneal leukocytes and steer their activation in unique ways. In this review, the types of cells that reside in the peritoneal cavity, the role of the omentum in their maintenance and activation, and how these processes function in response to pathogens and malignancy will be discussed.

Mechanisms of peritoneal dissemination in gastric cancer.

Peritoneal dissemination is the most frequent metastatic pattern of gastric cancer, but the mechanisms underlying peritoneal dissemination are yet to be elucidated. Paget's 'seed and soil' hypothesis is recognized as the fundamental theory of metastasis. The 'seeding' theory proposes that the formation of peritoneal dissemination is a multistep process, including detachment from the primary tumour, transmigration and attachment to the distant peritoneum, invasion into subperitoneal tissue and proliferation with blood vascular neogenesis. In the present review, the progress of each step is discussed. Milky spots, as a lymphatic apparatus, are indicative of lymphatic orifices on the surface of the peritoneum. These stomata are open gates for peritoneal-free cancer cells to migrate into the submesothelial space. Therefore, milky spots provide suitable 'soil' for cancer cells to implant. Other theories have also been proposed to clarify the peritoneal dissemination process, including the transvessel metastasis theory, which suggests that the peritoneal metastasis of gastric cancer develops via a vascular network mediated by hypoxia inducible factor-1α.

Fundamental pathological mechanisms underlying gastro-intestinal cancer peritoneal metastasis / 中华胃肠外科杂志

Gastrointestinal cancer peritoneal metastasis(GICPM) is one of the biggest challenges of clinical treatment. The ultimate solution to the problem requires the clinicians to accurately understand cytologic and molecular pathological mechanisms behind GICPM, and apply such knowledge in the clinical decision-making process for diagnosis and treatment of individual patient, so as to realize "prevention" and "treatment" proactively. The core cytopathological mechanisms behind GICPM, which are closely related to clinical treatment decisions, are as follows: (1) free cancer cells or clusters in peritoneal cavity colonize the peritoneum, resulting in irreversible pathological damage to peritoneal mesothelial cells; (2) the colonized cancer cells further invade the specific structure of the peritoneal milky spots and initiate an accelerated invasive growth process; (3) the process of peritoneal interstitial fibrosis aggravates the structural destruction of the peritoneum; (4) the interaction between cancer cells and immune cells in the milk spots forms a permissive immune microenvironment that promotes the growth of peritoneal metastatic cancer. These four core cytopathological mechanisms are mutually causal and promote each other, forming a vicious circle of GICPM development. As long as clinicians accurately understand these four points, it is possible to grasp the opportunity of clinical diagnosis and treatment, change reactive and passive treatment into preventive and proactive treatment, and improve the clinical diagnosis and treatment landscape of GICPM.