Antitumor efficacy of synthesized Ag-Au nanocomposite loaded with PEG and ascorbic acid in human lung cancer stem cells.

Lung cancer is the leading cause of mortality worldwide of which non-small cell lung carcinoma constitutes majority of the cases. High mortality is attributed to early metastasis, late diagnosis, ineffective treatment and tumor relapse. Chemotherapy and radiotherapy form the mainstay of its treatment. However, their associated side effects involving kidneys, nervous system, gastrointestinal tract, and liver further adds to dismal outcome. These disadvantages of conventional treatment can be circumvented by use of engineered nanoparticles for improved effectiveness with minimal side effects. In this study we have synthesized silver gold nanocomposite (Ag-Au NC) using polyethylene glycol and l-ascorbic acid as surfactant and reducing agent respectively. Synthesized nanocomposite was characterized by ultraviolet-visible absorption, dynamic light scattering, scanning and transmission electron microscopy. Compositional analysis was carried out by energy dispersive X-ray analysis and average pore diameter was estimated using Barrett-Joyner-Halenda method. In-silico molecular docking analysis of the synthesized NC against active regions of epidermal growth factor receptor revealed good binding energy. Subsequently, we investigated the effect of NC on growth and stem cell attributes of A549 lung cancer cells. Results showed that NC was effective in inhibiting A549 cell proliferation, induced DNA damage, G2/M phase arrest and apoptosis. Further, tumor cell migration and spheroid formation were also negatively affected. NC also enhanced reactive oxygen species generation and mitochondrial depolarization. In addition, the effect of NC on putative cancer stem cells in A549 cells was evaluated. We found that Ag-Au NC at IC50 targeted CD44, CD24, CD166, CD133 and CD326 positive cancer stem cells and induced apoptosis. CD166 positive cells were relatively resistance to apoptosis. Together our results demonstrate the anticancer efficacy of Ag-Au NC mediated by a mechanism involving cell cycle arrest and mitochondrial derangement.

Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.

Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses.

Defatting of Human Livers During Long-Term e x situ Normothermic Perfusion: Novel Strategy to Rescue Discarded Organs for Transplantation.

OBJECTIVE: To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. BACKGROUND: Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary nonfunction. Effective strategies preventing such outcomes are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to 2 weeks and providing a unique window of opportunity for defatting before transplantation. METHODS: Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ normothermic machine perfusion. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents were measured simultaneously. RESULTS: Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. Ten livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic functions remained preserved for most grafts until perfusion ended. CONCLUSION: Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

Osseous-Tissue Tumor Reporting and Data System With Diffusion-Weighted Imaging of Bone Tumors-An Interreader Analysis and Whether It Adds Incremental Value on Tumor Grading Over Conventional Magnetic Resonance Imaging.

OBJECTIVE: The aim of the study is to determine whether the use of diffusion-weighted imaging (DWI) provides incremental increase in performance in the osseous-tissue tumor reporting and data system (OT-RADS) with the hypothesis that use of DWI improves interreader agreement and diagnostic accuracy. METHODS: In this multireader cross-sectional validation study, multiple musculoskeletal radiologists reviewed osseous tumors with DW images and apparent diffusion coefficient maps. Four blinded readers categorized each lesion using the OT-RADS categorizations. Intraclass correlation (ICC) and Conger κ were used. Diagnostic performance measures including area under the receiver operating curve were reported. These measures were then compared with the previously published work that validated OT-RADS but did not include incremental value assessment of DWI. RESULTS: One hundred thirty-three osseous tumors of the upper and lower extremities (76 benign, 57 malignant) were tested. Interreader agreement for OT-RADS with DWI (ICC = 0.69) was slightly lower (not statistically different) from the previously published work that did not incorporate DWI (ICC = 0.78, P > 0.05). The mean sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating curve including DWI of the 4 readers were 0.80, 0.95, 0.96, 0.79, and 0.91, respectively. In the previously published work without DWI, the mean values of the readers were 0.96, 0.79, 0.78, 0.96, and 0.94, respectively. CONCLUSIONS: The addition of DWI to the OT-RADS system does not allow significantly improved area under the curve diagnostic performance measure. Conventional magnetic resonance imaging can be prudently used for OT-RADS for reliable and accurate characterization of bone tumors.

Prevalence, risk, and outcomes of venous thromboembolic events in kidney transplant recipients: a nested case-control study.

INTRODUCTION: Thromboembolism is more common in kidney transplant recipients (KTRs) than in the general population. Studies evaluating arterial and venous thromboembolism (VTE) in KTRs are scarce and the magnitude and risk factors are mostly undefined. METHODS: A nested control study was conducted from January 1, 2007, to December 31, 2019. Adult KTRs who were detected to have VTE events during this period were included. The primary outcome was to assess the prevalence of VTE in this population. Secondary outcomes were the assessment of the time to occurrence of the thromboembolic events after transplantation and assessing the risk factors and patient survival. For each subject studied, 4 controls were matched from the data set. RESULTS: Amongst 2158 patients, 97 (4.5%) were found to have VTE. The median follow-up time was 3.9 years (6-156 months). A total of 101 VTE events were recorded. The most common site of VTE was the lower limb deep vein thrombosis in 79 patients (0.03%)).In multivariate Cox regression analysis, serum creatinine of more than 3 mg/dl [HR 1.30, 95% CI (1.03-1.38)] was independently associated with increased VTE risk. Patients who developed a VTE had higher mortality as compared to patients who did not develop VTE. No increased risk of graft failure was found in VTE patients. CONCLUSION: This study suggests that kidney transplantation surgery is a moderate risk factor for VTE, and VTE is associated with higher morbidity and mortality. However, prospective studies are needed to establish a definite role of VTE in outcomes in KTRs.

Assessment of iron nanoparticle distribution in mouse models using ultrashort-echo-time MRI.

Microscopic magnetic field inhomogeneities caused by iron deposition or tissue-air interfaces may result in rapid decay of transverse magnetization in MRI. The aim of this study is to detect and quantify the distribution of iron-based nanoparticles in mouse models by applying ultrashort-echo-time (UTE) sequences in tissues exhibiting extremely fast transverse relaxation. In 24 C57BL/6 mice (two controls), suspensions containing either non-oxidic Fe or AuFeOx nanoparticles were injected into the tail vein at two doses (200 µg and 600 µg per mouse). Mice underwent MRI using a UTE sequence at 4.7 T field strength with five different echo times between 100 µs and 5000 µs. Transverse relaxation times T2 * were computed for the lung, liver, and spleen by mono-exponential fitting. In UTE imaging, the MRI signal could reliably be detected even in liver parenchyma exhibiting the highest deposition of nanoparticles. In animals treated with Fe nanoparticles (600 µg per mouse), the relaxation time substantially decreased in the liver (3418 ± 1534 µs (control) versus 228 ± 67 µs), the spleen (2170 ± 728 µs versus 299 ± 97 µs), and the lungs (663 ± 101 µs versus 413 ± 99 µs). The change in transverse relaxation was dependent on the number and composition of the nanoparticles. By pixel-wise curve fitting, T2 * maps were calculated showing nanoparticle distribution. In conclusion, UTE sequences may be used to assess and quantify nanoparticle distribution in tissues exhibiting ultrafast signal decay in MRI.

Interaction of a defect with the reference curvature of an elastic surface.

The morphological response of two-dimensional curved elastic sheets to an isolated defect (dislocation/disclination) is investigated within the framework of Föppl-von Kármán shallow shell theory. The reference surface, obtained as a shell configuration in the absence of defect and external forces, accordingly has a finite non-zero curvature. The interaction of the defect with the curvature of the reference surface is emphasized through the problem of defect driven buckling of an elastic sheet. Detailed bifurcation diagrams, including the post-buckling deformation behaviour, are plotted for several combinations of defect types, reference curvatures, and boundary conditions. A pitchfork bifurcation is obtained when the reference surface is flat irrespective of the defect type and boundary condition. For curved reference surfaces there are some cases where the pitchfork bifurcation persists and others where it does not. The varied response demonstrates the rich interaction of the defects with the curvature of the reference surface.

Short- and long-term outcomes of early initiation of peritoneal dialysis following catheter insertion.

INTRODUCTION: Early-start peritoneal dialysis (PD) (use of PD catheter within 48 hours of insertion) is an innovative approach for prompt initiation of PD. AIM: This study was conducted to analyze the outcomes of early-start PD. MATERIALS AND METHODS: A total of 100 patients on PD were retrospectively analyzed. Patients were grouped according to the "break-in period": < 48 hours (PD1) and ≥ 14 days (PD2). PD was initiated with low dwell volumes (500 mL) in a recumbent position within 48 hours of surgery. PD prescription was gradually incremented over 10 days to minimize any complications. RESULTS: In our study, there were 48 patients in the PD1 group and 52 in the PD2 group. The most common cause of end-stage kidney disease (ESKD) was diabetes mellitus in both groups. Incidence of early mechanical complications (within 30 days of catheter insertion), such as catheter obstruction, early catheter leakage, catheter malposition, tip migration, and infectious complications, were not found to be higher in the PD1 group. 1- and 4-year catheter patency rates were 97.0% and 96.2% in the PD1 group, respectively. These rates were comparable with those in the PD2 group. Early-start PD was not associated with an increased incidence of catheter failure (HR = 1.0, 95% CI 0.28 - 3.47). CONCLUSION: An early break-in period of < 48 hours is a feasible option for ESKD patients without any significantly increased risk of mechanical or infectious complications. It offers a safe and efficacious option for renal replacement therapy.

Three-Dimensional Isotropic Versus Conventional Multisequence 2-Dimensional Magnetic Resonance Imaging of Sacroiliac Joints in Suspected Axial Spondyloarthritis.

OBJECTIVES: The aims of the study were to systematically evaluate the sacroiliac joints of a consecutive series of patients with clinically suspected axial spondyloarthritis and to compare the diagnostic efficacy of 3-dimensional (3D) imaging versus conventional multisequence 2D techniques for sacroiliitis. METHODS: In this cross-sectional multireader validation study, imaging studies of 104 consecutive patients with clinically suspected axial spondyloarthritis obtained with a rheumatology lumbosacral magnetic resonance imaging protocol were evaluated. Three-dimensional coronal oblique reconstructions parallel to the long axis of the sacrum were created. Two blinded readers evaluated 2D and 3D images separately for each study, and findings were compared with the reference standard for the final diagnosis and disease activity. Cohen κ and diagnostic performance measures on 2D and 3D imaging were evaluated and compared. RESULTS: With 2D versus 3D imaging, respectively, the sensitivity for detecting inflammatory cases was 57% versus 62% ( P = 0.1007), the sensitivity for detecting mechanical cases was 89% versus 76% ( P = 0.0312), the sensitivity for detecting active sacroiliitis was 49% versus 64% ( P = 0.0014), and the specificity for detecting active sacroiliitis was 87% versus 76% ( P = 0.0016). Interreader agreement of 2D imaging showed an overall range of κ = 0.27-0.85, and it was best for evaluation of bony ankylosis (κ = 0.85). Interreader agreement of 3D imaging was in an overall range of κ = 0.15-0.64. CONCLUSIONS: Single 3D isotropic magnetic resonance imaging provided adequate assessment of sacroiliac joints in this study and demonstrated significantly higher sensitivity and lower specificity for detecting active sacroiliitis. The initial results indicate that 3D imaging could be used for future works for screening sacroiliitis and abdominopelvic enthesopathy.

CMV presenting as a skin growth in renal transplant patient.

CMV infection is one of the most common opportunistic infection in kidney transplant patients. If not treated, it is associated with increased mortality and graft loss. It can present as viremia or CMV disease in the form of CMV syndrome or tissue invasive CMV disease. The cutaneous presentation of CMV disease is a rare finding. Its identification is vital as cutaneous CMV infection can signal systemic infection and poor prognosis. In our case, 46-year-old male who was a post renal allograft recipient (RAR) presented as a protuberant growth over the medial side of the left ankle. On skin biopsy, nucleomegaly and inclusion bodies were seen in the epithelial cells. Immunohistochemistry was positive for CMV infection. Patient was treated with Ganciclovir, however, he succumbed to death because of severe sepsis due to secondary bacterial infection. Thus, CMV disease should always be kept in mind in immunocompromised patients like post RAR patients who present with cutaneous features like ulcerative lesions or fungating growth.

Outcomes of symptomatic coronavirus disease 19 in maintenance hemodialysis patient in India.

BACKGROUND: Maintenance hemodialysis (MHD) patients face disadvantages with higher risk of acquiring SARS-CoV-2 infection, atypical manifestations, and associated multiple comorbidities. We describe patients' outcomes with symptomatic COVID-19 on MHD in a large cohort of patients from India. METHODS: Data were collected prospectively from hemodialysis units in 11 public and private hospitals between March 15, 2020, and July 31, 2020. The survival determinants were analyzed using stepwise backward elimination cox-regression analysis. RESULTS: Of the 263 total patients (mean age 51.76 ± 13.63 years and males 173) on MHD with symptomatic COVID-19, 35 (13.3%) died. Those who died were older (p = 0.01), had higher frequency of diabetic kidney disease (p = 0.001), comorbidities (p = 0.04), and severe COVID-19 (p = 0.001). Mortality was higher among patients on twice-weekly MHD than thrice-weekly (p = 0.001) and dialysis through central venous catheter (CVC) as compared to arteriovenous fistula (p = 0.001). On multivariate analysis, CVC use (HR 2.53, 95% CI 1.26-5.07, p = 0.009), disease severity (HR = 3.54, 95% CI 1.52-8.26, p = 0.003), and noninvasive ventilatory support (HR 0.59, 95% CI 0.25-0.99, p = 0.049) had significant effect on mortality. CONCLUSION: The adjusted mortality risk of COVID-19 in MHD patients is high in patients associated with severe COVID-19 and patients having CVC as vascular access.

Osseous Tumor Reporting and Data System-Multireader Validation Study.

OBJECTIVE: To develop and validate an Osseous Tumor Reporting and Data System (OT-RADS) with the hypothesis that the proposed guideline is reliable and assists in separating benign from malignant osseous tumors with a good area under the curve, and that could assist further patient management. METHODS: In this multireader cross-sectional validation study, an agreement was reached for OT-RADS categories based on previously described magnetic resonance imaging features and consensus of expert musculoskeletal radiologists. World Health Organization classification was used, and a wide spectrum of benign and malignant osseous tumors was evaluated. Magnetic resonance imaging categories were as follows: OT-RADS 0-incomplete imaging; OT-RADS I-negative; OT-RADS II-definitely benign; OT-RADS III-probably benign; OT-RADS IV-suspicious for malignancy or indeterminate; OT-RADS V-highly suggestive of malignancy; and OT-RADS VI-known biopsy-proven malignancy or recurrent malignancy in the tumor bed. Four blinded readers categorized each tumor according to OT-RADS classification. Intraclass correlation (ICC) and Conger κ were used. Diagnostic performance measures including area under the receiver operating curve were reported. Osseous Tumor Reporting and Data System was dichotomized as benign (I-III) and malignant (IV and V) for calculating sensitivity and specificity. RESULTS: Interreader agreement for OT-RADS (ICC = 0.78) and binary distinction of benign versus malignant (κ = 0.67) were good to excellent, while agreement for individual tumor feature characteristics were poor to fair (ICC = 0.25-0.36; κ = 0.16-0.39). The sensitivities, specificities, and area under the receiver operating curve of the readers ranged from 0.93-1.0, 0.71-0.86, and 0.92-0.97, respectively. CONCLUSIONS: Osseous Tumor Reporting and Data System lexicon is reliable and helps stratify tumors into benign and malignant categories. It can be practically used by radiologists to guide patient management, improve multidisciplinary communications, and potentially impact outcomes.

Deep neural network improves fracture detection by clinicians.

Suspected fractures are among the most common reasons for patients to visit emergency departments (EDs), and X-ray imaging is the primary diagnostic tool used by clinicians to assess patients for fractures. Missing a fracture in a radiograph often has severe consequences for patients, resulting in delayed treatment and poor recovery of function. Nevertheless, radiographs in emergency settings are often read out of necessity by emergency medicine clinicians who lack subspecialized expertise in orthopedics, and misdiagnosed fractures account for upward of four of every five reported diagnostic errors in certain EDs. In this work, we developed a deep neural network to detect and localize fractures in radiographs. We trained it to accurately emulate the expertise of 18 senior subspecialized orthopedic surgeons by having them annotate 135,409 radiographs. We then ran a controlled experiment with emergency medicine clinicians to evaluate their ability to detect fractures in wrist radiographs with and without the assistance of the deep learning model. The average clinician's sensitivity was 80.8% (95% CI, 76.7-84.1%) unaided and 91.5% (95% CI, 89.3-92.9%) aided, and specificity was 87.5% (95 CI, 85.3-89.5%) unaided and 93.9% (95% CI, 92.9-94.9%) aided. The average clinician experienced a relative reduction in misinterpretation rate of 47.0% (95% CI, 37.4-53.9%). The significant improvements in diagnostic accuracy that we observed in this study show that deep learning methods are a mechanism by which senior medical specialists can deliver their expertise to generalists on the front lines of medicine, thereby providing substantial improvements to patient care.

Interventional Radiology in Obstetric Emergencies.

Postpartum hemorrhage (PPH) is one of the common causes of morbidity as well as mortality among pregnant women. Obstetric hemorrhage embolization (OHE)/uterine artery embolization (UAE) is the preferred treatment for PPH which has failed medical therapy. In cases of placental accreta spectrum (PAS), balloon catheter can be prophylactically placed in internal iliac arteries (IIAs) bilaterally before delivery to enable postpartum control of bleeding. An inferior vena cava (IVC) filter can be placed under fluoroscopy for a pregnant woman with deep vein thrombosis (DVT) for whom anticoagulation is contraindicated or needs to be stopped at the time of labor. Injection of chemical into the gestational sac can be performed under ultrasonography (USG) guidance to treat ectopic pregnancy. Percutaneous or transvaginal drainage of a collection can be done by ultrasound or computed tomography (CT) guidance for puerperal sepsis. Percutaneous nephrostomy (PCN) is performed for obstructive ureterolithiasis in case of urosepsis or significant stone burden. Sonography should be used for the guidance of interventional radiology (IR) procedures whenever possible. Fluoroscopy must be used only if necessary, giving special attention to radiation-sparing maneuvers. How to cite this article: Kulkarni S, Shetty NS, Gupta A, Rao S, Bansal H. Interventional Radiology in Obstetric Emergencies. Indian J Crit Care Med 2021;25(Suppl 3):S273-S278.

Superconducting properties of tungsten nanowires fabricated using focussed ion beam technique.

We report superconducting properties of tungsten meander structures fabricated using the focussed ion beam (FIB) induced technique. Three meander structures with individual line widths of ∼70, ∼300 and ∼450 nm were fabricated for evaluation and comparison of the superconducting properties. The resistance-temperature characteristics of the meanders were measured and analysed down to a temperature of 100 mK. The superconducting properties such as critical temperature (T C) and upper-critical field (H C2) of these wires are in comparison to the reported values of FIB deposited tungsten available in literature. While the normal state resistance increases sharply as the width of the wire decreases, the superconducting transition temperature registered a slight decrease. Significant amount of residual resistance (3.8% of normal state value at 100 mK) was observed for the sample with the lowest width (70 nm). The residual resistance trails as function of temperature was analysed invoking theoretical models governing the phase slip induced dissipations in superconducting nanowires. The results indicated signature of phase slips as the width of the wire decreases: thermally activated phase slips dominant near to the T C and quantum phase slip (QPS) near to T C as well as much below to the T C. The magneto-resistance isotherms indicated quantum phase transitions (QPT); typical of a superconductor-to-insulator transition (SIT) driven by magnetic field. The SIT transition which originates from the intrinsic disorder present in the sample can be tuned by an external parameter such as magnetic field, and can be modelled by standard theories of QPT for quasi 2D or (2 + 1) D XY models. The successful fabrication of meander structures of W using FIB and the demonstration of superconductivity suggest that FIB deposited W can be exploited for many of the technological applications of superconducting nanowires such as superconducting nanowire single photon detectors, bolometers, transition edge sensors and even for quantum current standard employing the QPS phenomenon.

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation.

OBJECTIVE: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP. DESIGN: We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))-a model to study AIP development-with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. RESULTS: p21 deficiency in LT mice (LTp21-/-) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T-B cell infiltration. Interestingly, LT and LTp21-/- mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21-/- pancreata. CONCLUSIONS: Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.

Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin.

BACKGROUND: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. METHODS: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. RESULTS: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. CONCLUSION: RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.

Exogenous melatonin protects small-for-size liver grafts by promoting monocyte infiltration and releases interleukin-6.

Defective regeneration of small-for-size (SFS) liver remnants and partial grafts remains a key limiting factor in the application of liver surgery and transplantation. Exogenous melatonin (MLT) has protective effects on hepatic ischemia-reperfusion injury (IRI), but its influence on graft regeneration is unknown. The aim of the study is to investigate the role of MLT in IRI and graft regeneration in settings of partial liver transplantation. We established three mouse models to study hepatic IRI and regeneration associated with partial liver transplantation: (I) IR+PH group: 60 minutes liver ischemia (IR) plus 2/3 hepatectomy (PH); (II) IR+exPH group: 60 minutes liver IR plus extended hepatectomy (exPH) associated with the SFS syndrome; (III) SFS-LT group: Arterialized 30% SFS liver transplant. Each group was divided into MLT or vehicle-treated subgroups. Hepatic injury, inflammatory signatures, liver regeneration, and animal survival rates were assessed. MLT reduced liver injury, enhanced liver regeneration, and promoted interleukin (IL) 6, IL10, and tumor necrosis factor-α release by infiltrating, inflammatory Ly6C+ F4/80+ monocytes in the IR+PH group. MLT-induced IL6 significantly improved hepatic microcirculation and survival in the IR+exPH model. In the SFS-LT group, MLT promoted graft regeneration and increased recipient survival along with increased IL6/GP130-STAT3 signaling. In IL6-/- mice, MLT failed to promote liver recovery, which could be restored through recombinant IL6. In the IR+exPH and SFS-LT groups, inhibition of the IL6 co-receptor GP130 through SC144 abolished the beneficial effects of MLT. MLT ameliorates SFS liver graft IRI and restores regeneration through monocyte-released IL6 and downstream IL6/GP130-STAT3 signaling.