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JAMA Surgery Feb 2021Perforated colonic diverticulitis usually requires surgical resection, with significant morbidity. Short-term results from randomized clinical trials have indicated that... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Perforated colonic diverticulitis usually requires surgical resection, with significant morbidity. Short-term results from randomized clinical trials have indicated that laparoscopic lavage is a feasible alternative to resection. However, it appears that no long-term results are available.
OBJECTIVE
To compare long-term (5-year) outcomes of laparoscopic peritoneal lavage and primary resection as treatments of perforated purulent diverticulitis.
DESIGN, SETTING, AND PARTICIPANTS
This international multicenter randomized clinical trial was conducted in 21 hospitals in Sweden and Norway, which enrolled patients between February 2010 and June 2014. Long-term follow-up was conducted between March 2018 and November 2019. Patients with symptoms of left-sided acute perforated diverticulitis, indicating urgent surgical need and computed tomography-verified free air, were eligible. Those available for trial intervention (Hinchey stages
INTERVENTIONS
Patients were assigned to undergo laparoscopic peritoneal lavage or colon resection based on computer-generated, center-stratified block randomization.
MAIN OUTCOMES AND MEASURES
The primary outcome was severe complications within 5 years. Secondary outcomes included mortality, secondary operations, recurrences, stomas, functional outcomes, and quality of life.
RESULTS
Of 199 randomized patients, 101 were assigned to undergo laparoscopic peritoneal lavage and 98 were assigned to colon resection. At the time of surgery, perforated purulent diverticulitis was confirmed in 145 patients randomized to lavage (n = 74) and resection (n = 71). The median follow-up was 59 (interquartile range, 51-78; full range, 0-110) months, and 3 patients were lost to follow-up, leaving a final analysis of 73 patients who had had laparoscopic lavage (mean [SD] age, 66.4 [13] years; 39 men [53%]) and 69 who had received a resection (mean [SD] age, 63.5 [14] years; 36 men [52%]). Severe complications occurred in 36% (n = 26) in the laparoscopic lavage group and 35% (n = 24) in the resection group (P = .92). Overall mortality was 32% (n = 23) in the laparoscopic lavage group and 25% (n = 17) in the resection group (P = .36). The stoma prevalence was 8% (n = 4) in the laparoscopic lavage group vs 33% (n = 17; P = .002) in the resection group among patients who remained alive, and secondary operations, including stoma reversal, were performed in 36% (n = 26) vs 35% (n = 24; P = .92), respectively. Recurrence of diverticulitis was higher following laparoscopic lavage (21% [n = 15] vs 4% [n = 3]; P = .004). In the laparoscopic lavage group, 30% (n = 21) underwent a sigmoid resection. There were no significant differences in the EuroQoL-5D questionnaire or Cleveland Global Quality of Life scores between the groups.
CONCLUSIONS AND RELEVANCE
Long-term follow-up showed no differences in severe complications. Recurrence of diverticulitis after laparoscopic lavage was more common, often leading to sigmoid resection. This must be weighed against the lower stoma prevalence in this group. Shared decision-making considering both short-term and long-term consequences is encouraged.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01047462.
Topics: Aged; Colectomy; Diverticulitis, Colonic; Female; Humans; Intestinal Perforation; Laparoscopy; Male; Norway; Peritoneal Lavage; Sweden
PubMed: 33355658
DOI: 10.1001/jamasurg.2020.5618 -
Frontiers in Immunology 2021Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or...
Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4/80CD11bCD206 M2-like macrophages with no any significant effect on F4/80CD11bCD86 M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4/80Arg1 subset while decreasing the percentage of F4/80iNOS subset. Importantly, TGP treatment increased the percentage of both F4/80CD11bPD-L1 and F4/80CD11bPD-L2 subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS/IFN-γ , indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages . Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4/80CD11bCD206 and F4/80CD11bPD-L2 macrophages through IL-4/STAT6/PD-L2 signaling pathway.
Topics: Animals; B7-H1 Antigen; Biomarkers; Cell Line; Disease Susceptibility; Female; Glucosides; Humans; Interleukin-4; Lupus Nephritis; Macrophage Activation; Macrophages; Mice; Paeonia; Programmed Cell Death 1 Ligand 2 Protein; STAT6 Transcription Factor; Signal Transduction; Terpenes
PubMed: 34290705
DOI: 10.3389/fimmu.2021.683249 -
Bio-protocol Oct 2016In response to pathogen infection and tissue damage, inflammasome sensors such as NLRP3 and AIM2 are activated, which triggers PYRIN domain (PYD)-mediated ASC...
In response to pathogen infection and tissue damage, inflammasome sensors such as NLRP3 and AIM2 are activated, which triggers PYRIN domain (PYD)-mediated ASC nucleation, followed by self-perpetuating ASC polymerization, which ultimately culminates in caspase-1 activation, interleukin (IL)-1β and IL-18 processing and release and pyroptosis (Ratsimandresy ., 2013; Cai ., 2014). Inflammasomes release not only cytokines, but also the polymeric ASC danger particles (pASC) by pyroptosis, which perpetuate and propagate inflammasome responses to bystander cells to engage cell intrinsic ASC and caspase-1 (Baroja-Mazo ., 2014; Franklin ., 2014). In this protocol we describe intraperitoneal injection of polymeric ASC particles as a danger signal and measure neutrophil infiltration and levels of the pro-inflammatory cytokine IL-1β by ELISA in the peritoneal lavage (de Almeida ., 2015).
PubMed: 28516116
DOI: 10.21769/BioProtoc.1944 -
Advanced Science (Weinheim,... Jul 2023Peritoneal metastasis (PM) is the mostcommon form of distant metastasis and one of the leading causes of death in gastriccancer (GC). For locally advanced GC, clinical...
Peritoneal metastasis (PM) is the mostcommon form of distant metastasis and one of the leading causes of death in gastriccancer (GC). For locally advanced GC, clinical guidelines recommend peritoneal lavage cytology for intraoperative PM detection. Unfortunately, current peritoneal lavage cytology is limited by low sensitivity (<60%). Here the authors established the stimulated Raman molecular cytology (SRMC), a chemical microscopy-based intelligent cytology. The authors firstly imaged 53 951 exfoliated cells in ascites obtained from 80 GC patients (27 PM positive, 53 PM negative). Then, the authors revealed 12 single cell features of morphology and composition that are significantly different between PM positive and negative specimens, including cellular area, lipid protein ratio, etc. Importantly, the authors developed a single cell phenotyping algorithm to further transform the above raw features to feature matrix. Such matrix is crucial to identify the significant marker cell cluster, the divergence of which is finally used to differentiate the PM positive and negative. Compared with histopathology, the gold standard of PM detection, their SRMC method could reach 81.5% sensitivity, 84.9% specificity, and the AUC of 0.85, within 20 minutes for each patient. Together, their SRMC method shows great potential for accurate and rapid detection of PM from GC.
Topics: Humans; Peritoneal Neoplasms; Stomach Neoplasms; Peritoneal Lavage; Microscopy; Artificial Intelligence
PubMed: 37114845
DOI: 10.1002/advs.202300961 -
Frontiers in Immunology 2022The peritoneal cavity contains many site-specific immune cells which constitute a unique immune microenvironment. However, it is unclear how the local immune signature...
BACKGROUND
The peritoneal cavity contains many site-specific immune cells which constitute a unique immune microenvironment. However, it is unclear how the local immune signature is altered in patients with peritoneal metastases (PM).
METHODS
Peritoneal lavage fluid or ascites were obtained from 122 patients with various stages of gastric cancer (GC). Cells recovered from peritoneal fluids were immunostained with mAbs for lymphocyte-, macrophage- and tumor cell-specific antigens and the frequencies of leukocyte subsets and antigen expression levels were evaluated with multi-color flowcytometry.
RESULTS
The proportions of CD8(+) T cells, CD3(+)CD56(+) NKT-like cells, and CD3(-)CD56(+) NK cells to CD45(+) leukocytes were significantly reduced in patients with PM compared to those without PM. In patients with PM, the rates of CD8 (+) T cells and NKT-like cells correlated inversely with the tumor leukocyte ratio (TLR), the relative frequency of CD326(+) tumor cells to CD45(+) leukocytes. In contrast, the proportion of CD19(+) B cells was significantly increased in patients with PM, and their proportion correlated positively with the TLR and peritoneal carcinomatosis index (PCI) score. In patients with PM, CD14(+) macrophages tended to be increased with enhanced expression of CD14, CD16 and a M2-macrophage marker, CD163. In particular, macrophages in patients with high TLR contained many granules with high side scatter and CD14 expression in their flow profile compared to those without PM.
CONCLUSION
PM are accompanied by a drastic change in phenotypes of lymphocyte and macrophage in the peritoneal cavity, which might be involved in the development and progression of intraperitoneal tumor growth.
Topics: CD8-Positive T-Lymphocytes; Humans; Killer Cells, Natural; Peritoneal Cavity; Peritoneal Neoplasms; Stomach Neoplasms; Tumor Microenvironment
PubMed: 36119051
DOI: 10.3389/fimmu.2022.969468 -
The Journal of Physiological Sciences :... May 2017Disseminated metastasis is associated with a poor prognosis, and its management in the peritoneal or pleural cavity is crucial in the treatment of cancer. Recent studies... (Review)
Review
Disseminated metastasis is associated with a poor prognosis, and its management in the peritoneal or pleural cavity is crucial in the treatment of cancer. Recent studies show that ion and water transporters play important roles in fundamental cellular functions, including the regulation of cell volume that would be involved in the cancer process. Here, we review the evidence for hypotonic treatments of cancer and evaluate the potential of the cellular physiological approach in clinical management. The regulation of extracellular osmolality is a promising method, with several studies demonstrating the cytocidal effects of hypotonic solution on cancer cells. Peritoneal lavage with distilled water (DW) during surgery is reported to improve the survival rate of patients with spontaneously ruptured hepatocellular carcinoma. The in vitro studies included in this review also indicate the cytocidal effects of hypotonic shock on esophageal, gastric, colonic, pancreatic, and liver cancer cells with several unique methods and apparatuses, such as a differential interference contrast microscope connected to a digital video camera, a high-resolution flow cytometer and re-incubation analysis. The in vivo studies demonstrate the safeness of a peritoneal injection of DW into mice and indicate that the development of dissemination nodules can be prevented by the pre-incubation of cancer cells with DW or the peritoneal injection of DW. We also demonstrate that the blockade of Cl channels/transporters enhances the cytocidal effects of hypotonic shock by inhibiting regulatory volume decrease in various cancer cells. A deeper understanding of molecular mechanisms may lead to the discovery of these cellular physiological approaches as a novel therapeutic strategy for disseminated metastasis.
Topics: Animals; Humans; Hypotonic Solutions; Neoplasm Metastasis; Neoplasms; Osmolar Concentration; Osmotic Pressure; Peritoneal Lavage
PubMed: 28185236
DOI: 10.1007/s12576-017-0528-x -
Surgical Endoscopy Oct 2022This study aimed to compare laparoscopic lavage and sigmoidectomy as treatment for perforated diverticulitis with purulent peritonitis during a 36 month follow-up of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study aimed to compare laparoscopic lavage and sigmoidectomy as treatment for perforated diverticulitis with purulent peritonitis during a 36 month follow-up of the LOLA trial.
METHODS
Within the LOLA arm of the international, multicentre LADIES trial, patients with perforated diverticulitis with purulent peritonitis were randomised between laparoscopic lavage and sigmoidectomy. Outcomes were collected up to 36 months. The primary outcome of the present study was cumulative morbidity and mortality. Secondary outcomes included reoperations (including stoma reversals), stoma rates, and sigmoidectomy rates in the lavage group.
RESULTS
Long-term follow-up was recorded in 77 of the 88 originally included patients, 39 were randomised to sigmoidectomy (51%) and 38 to laparoscopic lavage (49%). After 36 months, overall cumulative morbidity (sigmoidectomy 28/39 (72%) versus lavage 32/38 (84%), p = 0·272) and mortality (sigmoidectomy 7/39 (18%) versus lavage 6/38 (16%), p = 1·000) did not differ. The number of patients who underwent a reoperation was significantly lower for lavage compared to sigmoidectomy (sigmoidectomy 27/39 (69%) versus lavage 17/38 (45%), p = 0·039). After 36 months, patients alive with stoma in situ was lower in the lavage group (proportion calculated from the Kaplan-Meier life table, sigmoidectomy 17% vs lavage 11%, log-rank p = 0·0268). Eventually, 17 of 38 (45%) patients allocated to lavage underwent sigmoidectomy.
CONCLUSION
Long-term outcomes showed that laparoscopic lavage was associated with less patients who underwent reoperations and lower stoma rates in patients alive after 36 months compared to sigmoidectomy. No differences were found in terms of cumulative morbidity or mortality. Patient selection should be improved to reduce risk for short-term complications after which lavage could still be a valuable treatment option.
Topics: Diverticulitis; Diverticulitis, Colonic; Follow-Up Studies; Humans; Intestinal Perforation; Laparoscopy; Peritoneal Lavage; Peritonitis; Treatment Outcome
PubMed: 35606544
DOI: 10.1007/s00464-022-09326-3 -
Frontiers in Immunology 2023Exposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1...
INTRODUCTION
Exposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been demonstrated to critically amplify and dysregulate immune responses. However, the role of TREM-1 in radiation injury remains unknown. Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern, is released from activated or stressed cells during inflammation. We hypothesized that ionizing radiation upregulates TREM-1 expression via eCIRP release to worsen survival.
METHODS
RAW264.7 cells and peritoneal macrophages collected from C57BL/6 wild-type (WT) mice were exposed to 5- and 10-Gray (Gy) radiation. C57BL/6 WT and CIRP-/- mice underwent 10-Gy total body irradiation (TBI). TREM-1 expression on RAW264.7 cells and peritoneal macrophages in vitro and in vivo were evaluated by flow cytometry. eCIRP levels in cell culture supernatants and in peritoneal lavage isolated from irradiated mice were evaluated by Western blotting. We also evaluated 30-day survival in C57BL/6 WT, CIRP-/- and TREM-1-/- mice after 6.5-Gy TBI.
RESULTS
The surface protein and mRNA levels of TREM-1 in RAW264.7 cells were significantly increased at 24 h after 5- and 10-Gy radiation exposure. TREM-1 expression on peritoneal macrophages was significantly increased after radiation exposure in vitro and in vivo. eCIRP levels were significantly increased after radiation exposure in cell culture supernatants of peritoneal macrophages in vitro and in peritoneal lavage in vivo. Moreover, CIRP-/- mice exhibited increased survival after 6.5-Gy TBI compared to WT mice. Interestingly, TREM-1 expression on peritoneal macrophages in CIRP-/- mice was significantly decreased compared to that in WT mice at 24 h after 10-Gy TBI. Furthermore, 30-day survival in TREM-1-/- mice was significantly increased to 64% compared to 20% in WT mice after 6.5-Gy TBI.
CONCLUSION
Our data indicate that ionizing radiation increases TREM-1 expression in macrophages via the release of eCIRP, and TREM-1 contributes to worse survival after total body irradiation. Thus, targeting TREM-1 could have the potential to be developed as a novel medical countermeasure for radiation injury.
Topics: Animals; Mice; Inflammation; Macrophages; Mice, Inbred C57BL; Radiation Injuries; Triggering Receptor Expressed on Myeloid Cells-1
PubMed: 37168858
DOI: 10.3389/fimmu.2023.1151250 -
Clinical Epigenetics Apr 2023The detection of peritoneal metastasis (PM) is limited by current imaging tools. In this prospective study, we aimed to evaluate the sensitivity and specificity of...
Peritoneal cell-free DNA as a sensitive biomarker for detection of peritoneal metastasis in colorectal cancer: a prospective diagnostic study: A prospective diagnostic study.
BACKGROUND
The detection of peritoneal metastasis (PM) is limited by current imaging tools. In this prospective study, we aimed to evaluate the sensitivity and specificity of peritoneal cell-free DNA (cfDNA) for diagnosis of PM.
METHODS
Colorectal cancer (CRC) patients with/without PM were enrolled. The cfDNA experimental personnel and statists were blinded to the diagnosis of PM. Ultradeep sequencing covering large genomic regions (35000X, Next-generation sequencing) of cfDNA in peritoneal lavage fluid (FLD) and matched tumor tissues was performed.
RESULTS
A total of 64 cases were recruited prospectively and 51 were enrolled into final analysis. In training cohort, 100% (17/17) PM patients obtained positive FLD cfDNA, comparing to 5/23 (21.7%) in patients without PM. Peritoneal cfDNA had a high sensitivity of 100% and specificity of 77.3% for diagnosis of PM (AUC: 0.95). In validation group of 11, 5/6 (83%) patients with PM obtained positive FLD cfDNA, comparing to 0/5 in non-PM (P = 0.031) with a sensitivity of 83.3% and specificity of 100%. Positive FLD cfDNA was associated with poor recurrence-free survival (P = 0.013) and was preceding radiographic evidence of recurrence.
CONCLUSIONS
Peritoneal cfDNA is a promising sensitive biomarker for earlier detection of PM in CRC than current radiological tools. It can potentially guide selection for targeted therapies and serve as a surrogate instead of laparoscopic explore in the future. Trial Registration Chinese Clinical Trial Registry at chictr.org.cn (ChiCTR2000035400). URL: http://www.chictr.org.cn/showproj.aspx?proj=57626.
Topics: Humans; Biomarkers, Tumor; Cell-Free Nucleic Acids; Colorectal Neoplasms; DNA Methylation; Mutation; Peritoneal Neoplasms; Prospective Studies
PubMed: 37072801
DOI: 10.1186/s13148-023-01479-9