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The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing. Tissue-resident marcophages have both generic and tissue-specific functions, but how the latter functions are imbued is still unclear. Here the authors show that peritoneal macrophages express a specialised genetic programme to utilise the locally enriched glutamate for a metabolic setting that facilitates protective in situ immunity.

Various types of tumors, particularly those originating from the ovary and gastrointestinal tract, display a strong predilection for the peritoneal cavity as the site of metastasis. The intraperitoneal spread of a malignancy is orchestrated by a reciprocal interplay between invading cancer cells and resident normal peritoneal cells. In this review, we address the current state-of-art regarding colonization of the peritoneal cavity by ovarian, colorectal, pancreatic, and gastric tumors. Particular attention is paid to the pro-tumoral role of various kinds of peritoneal cells, including mesothelial cells, fibroblasts, adipocytes, macrophages, the vascular endothelium, and hospicells. Anatomo-histological considerations on the pro-metastatic environment of the peritoneal cavity are presented in the broader context of organ-specific development of distal metastases in accordance with Paget’s “seed and soil” theory of tumorigenesis. The activity of normal peritoneal cells during pivotal elements of cancer progression, i.e., adhesion, migration, invasion, proliferation, EMT, and angiogenesis, is discussed from the perspective of well-defined general knowledge on a hospitable tumor microenvironment created by the cellular elements of reactive stroma, such as cancer-associated fibroblasts and macrophages. Finally, the paper addresses the unique features of the peritoneal cavity that predispose this body compartment to be a niche for cancer metastases, presents issues that are topics of an ongoing debate, and points to areas that still require further in-depth investigations.

A recent study published inNature Cell Biologyhas shown that tumour spheres that maintain an inverted epithelial architecture originate from primary colorectal cancers and can collectively invade the peritoneum, initiating metastasis.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare disease affecting predominantly children and young adults and for which the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) after complete cytoreductive surgery (CCRS) remains unknown. To identify patients with DSRCT without extraperitoneal metastases (EPM) who underwent CCRS between 1991 and 2015, a retrospective nation-wide survey was conducted by crossing the prospective and retrospective databases of the French Network for Rare Peritoneal Malignancies, French Reference Network in Sarcoma Pathology, French Sarcoma Clinical Network and French Pediatric Cancer Society. Among the 107 patients with DSRCT, 48 had no EPM and underwent CCRS. The median peritoneal cancer index (PCI) was 9 (range: 2-27). Among these 48 patients, 38 (79%) had pre- and/or postoperative chemotherapy and 23 (48%) postoperative whole abdominopelvic radiotherapy (WAP-RT). Intraperitoneal chemotherapy was administered to 11 patients (23%): two received early postoperative intraperitoneal chemotherapy (EPIC) and nine HIPEC. After a median follow-up of 30 months, the median overall survival (OS) of the entire cohort was 42 months. The 2-y and 5-y OS were 72% and 19%. The 2-y and 5-y disease-free survival (DFS) were 30% and 12%. WAP-RT was the only variable associated with longer peritoneal recurrence-free survival and DFS after CCRS. The influence of HIPEC/EPIC on OS and DFS was not statistically conclusive. The benefit of HIPEC is still unknown and should be evaluated in a prospective trial. The value of postoperative WAP-RT seems to be confirmed.

BackgroundFor surgical endometriosis, treatment key is to properly identify the peritoneal lesions. The aim of this clinical study was to investigate if advanced imaging improves the detection rate by comparing narrow-band imaging (NBI), near-infrared imaging with indocyanine green (NIR-ICG), or three-dimensional white-light imaging (3D), to conventional two-dimensional white-light imaging (2D) for the detection of peritoneal endometriotic lesions.MethodsThis study was a prospective, single-center, randomized within-subject, clinical trial. The trial was conducted at Amsterdam UMC—Location VUmc, a tertiary referral hospital for endometriosis. 20 patients with ASRM stage III–IV endometriosis, scheduled for elective laparoscopic treatment of their endometriosis, were included. During laparoscopy, the pelvic region was systematically inspected with conventional 2D white-light imaging followed by inspection with NBI, NIR-ICG, and 3D imaging in a randomized order. Suspected endometriotic lesions and control biopsies of presumably healthy peritoneum were taken for histological examination. The pathologist was blinded for the method of laparoscopic detection. Sensitivity and specificity rates of the enhanced imaging techniques were analyzed. McNemar’s test was used to compare sensitivity to 2D white-light imaging and Method of Tango to assess non-inferiority of specificity.ResultsIn total, 180 biopsies were taken (117 biopsies from lesions suspected for endometriosis; 63 control biopsies). 3D showed a significantly improved sensitivity rate (83.5% vs. 75.8%, p = 0.016) and a non-inferior specificity rate (82.4% vs. 84.7%, p = 0.009) when compared to 2D white-light imaging. The single use of NBI or NIR-ICG showed no improvement in the detection of endometriosis. Combining the results of 3D and NBI resulted in a sensitivity rate of 91.2% (p < 0.001).ConclusionEnhanced laparoscopic imaging with 3D white light, combined with NBI, improves the detection rate of peritoneal endometriosis when compared to conventional 2D white-light imaging. The use of these imaging techniques enables a more complete laparoscopic resection of endometriosis.

Lumboperitoneal shunt surgery has the potential to alleviate symptoms of normal pressure hydrocephalus but the benefits of such surgery have not been tested in a randomised trial. The aim of this trial was to determine the safety and efficacy of the lumboperitoneal shunt surgery for this disorder. For the open-label randomised SINPHONI-2 trial, eligible participants (60–85 years of age) with idiopathic normal pressure hydrocephalus, with ventriculomegaly, and tightness of the high-convexity and medial subarachnoid spaces on MRI, were recruited from 20 neurological and neurosurgical centres in Japan. Enrolled participants were randomly assigned in a 1:1 ratio according to a random code generated by the trial statistician, with a permuted block design (using a block size of 4 or 6) within each centre, to receive lumboperitoneal shunt surgery within 1 month after randomisation, or to surgery postponed for 3 months. Patients and assessors were not masked to treatment assignment. The primary endpoint was favourable outcome, defined as an improvement of one point or more on the modified Rankin scale (mRS) at 3 months after randomisation, analysed by intention to treat, and the main secondary endpoint was the same outcome 12 months after surgery, analysed per protocol. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), number UMIN000002730. Between March 1, 2010, and Oct 19, 2011, 93 patients with idiopathic normal pressure hydrocephalus were enrolled and randomly assigned to the immediate treatment group (n=49) or the postponed treatment group (n=44). More patients in the immediate treatment group than in the postponed treatment group had an improvement of one point or more on the mRS at 3 months: 32 (65%) of 49 in the immediate group vs 2 (5%) of 44 in the postponed group (difference 61% [95% CI 42–68]; p<0·0001). The number of patients who had an improvement of one point or more on the mRS at 12 months after surgery was similar between the two groups: 30 (67%) of 45 patients in the immediate group vs 22 (58%) of 38 in the postponed group (difference 9% [95% CI −14 to 31]; p=0·496). The proportions of patients with serious adverse events did not differ significantly between the groups during the 3 months post-randomisation (7 [15%] of 46 in the immediate group vs 1 [2%] of 42 in the postponed group; p=0·060). During the 12 months after surgery, 19 (22%) of 87 patients had serious adverse events, the most common of which was cerebral infarction (six patients [7%]). Our results suggest that lumboperitoneal shunt surgery might be beneficial for patients with idiopathic normal pressure hydrocephalus and, if these findings are confirmed in larger studies, could be a first-line treatment option for this disease. Johnson & Johnson and Nihon Medi-Physics.

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo , thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs. Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.