Purpose
High-intensity focused ultrasound (HIFU) is challenging in the liver due to the respiratory motion and risks of near-/far-field burns, particularly on the ribs. We implemented a novel design ...of a HIFU phased-array transducer, dedicated to transcostal hepatic thermo-ablation. Due to its large acoustic window and strong focusing, the transducer should perform safely for this application.
Material and Methods
The new HIFU transducer is composed of 256 elements distributed on 5 concentric segments of a specific radius (either 100, 111, or 125 mm). It has been optimally shaped to fit the abdominal wall. The shape and size of the acoustic elements were optimized for the largest emitting surface and the lowest symmetry. Calibration tests have been conducted on tissue-mimicking gels under 3-T magnetic resonance (MR) guidance.
In-vivo
MR-guided HIFU treatment was conducted in two pigs, aiming to create thermal ablation deep in the liver without significant side effects. Imaging follow-up was performed at D0 and D7. Sacrifice and post-mortem macroscopic examination occurred at D7, with the ablated tissue being fixed for pathology.
Results
The device showed −3-dB focusing capacities in a volume of 27 × 46 × 50 mm
3
as compared with the numerical simulation volume of 18 × 48 × 60 mm
3
. The shape of the focal area was in millimeter-range agreement with the numerical simulations. No interference was detected between the HIFU sonication and the MR acquisition.
In vivo
, the temperature elevation in perivascular liver parenchyma reached 28°C above physiological temperature, within one breath-hold. The lesion was visible on Gd contrast-enhanced MRI sequences and post-mortem examination. The non-perfused volume was found in pig #1 and pig #2 of 8/11, 6/8, and 7/7 mm along the LR, AP, and HF directions, respectively. No rib burns or other near-field side effects were visually observed on post-mortem gross examination. High-resolution contrast-enhanced 3D MRI indicated a minor lesion on the sternum.
Conclusion
The performance of this new HIFU transducer has been demonstrated
in vitro
and
in vivo
. The transducer meets the requirement to perform thermal lesions in deep tissues, without the need for rib-sparing means.
Gastritis cystica profunda (GCP) has been defined as a rare submucosal benign gastric lesion with cystic gland growth. Due to its unclear etiopathogenesis, this lesion is often misdiagnosed and ...mistaken for other gastric masses. Currently, a standardized treatment for GCP lesions is still missing. Here, we illustrate a case of a patient admitted to our general surgery department for melena and general discomfort. No history of peptic ulcer or gastric surgery was present. Upper GI endoscopy was performed, showing a distal gastric lesion with a small ulceration on the top. CT-scan and endoscopic ultrasound confirmed the presence of the lesion, compatible with a gastric stromal tumor, without showing any eventual metastasis. Surgical gastric resection was performed. Histological findings were diagnostic for GCP, with cistically ectasic submucosal glands, chronic inflammation, eosinophilic infiltration and foveal hyperplasia. GCP is a very exceptional cause of upper-GI bleeding with specific histological features. Its diagnosis as well as its therapy are challenging, resulting in several pitfalls. Even though it is a rare entity, GCP should always be considered in the differential diagnosis of gastric submucosal lesions.
Sacral chordoma (SC) is a neoplasm arising from residual notochordal cells degeneration. SC is difficult to manage mainly because of anatomic location and tendency to extensive spread. Carbon ion ...radiotherapy (CIRT) is highly precise to selectively deliver high biological effective dose to the tumor target sparing the anatomical structure on its path even if when SC is contiguous to the intestine, and a surgical spacer might be an advantageous tool to create a distance around the target volume allowing radical curative dose delivery with a safe dose gradient to the surrounding organs. This paper describes a double approach-open and hand-assisted laparoscopic-for a silicon spacer placement in patients affected by sacral chordoma undergoing carbon ion radiotherapy.
Six consecutive patients have been enrolled for surgical spacer placement-open (three) or hand-assisted (three)-prior carbon ion radiotherapy treatment in order to increase efficacy of carbon ion radiotherapy minimizing its side effects.
Results showed that silicon spacer placement for SC treatment is feasible both via laparoscopic and laparotomic approach.
Its use might improve CIRT safety and thus efficacy for SC treatment.
Pancreas transplantation for patients with type 1 diabetes is a therapeutic option when other treatments are not effective and physical complications occur. Psychological burden is prominent in ...patients, and non-adherence to treatment is often one manifestation of such difficulties. Time projection is an important factor affected by chronic disease. The prospect of transplantation has the potential to repair this disruption. It could re-establish a continuity in the patient's self and history, by connecting the future to a life that was only about past and present. Taking care of oneself, adhering to treatment, being part of a long-term therapeutic project and going through transplantation are all processes that need a good ability to self-project in time. This is specifically a domain of psychotherapeutic interventions. In this article, the psychological implications of pancreas transplantation for patients and caregivers alike will be discussed, as well as the role of the psychiatrist in the transplantation process.
Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate ...the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms.
Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model.
Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 μm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load.
Maternal obesity increases female offspring’s susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition.
The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.
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•Obese mothers transmit an altered microbiome to their offspring which persists until adulthood.•Maternal obesity increased steatosis, fibrosis and liver inflammation in offspring.•Offspring of obese mothers are at a higher risk of developing liver cancer.•Co-housing offspring of obese and lean mothers restores the gut microbiome and normalizes the liver cancer risk.•Abundance of Erysipelotrichaceae and Lachnospiraceae bacteria correlate with tumor load, Akkermansiaceae with liver inflammation.
According to the Juvenile Diabetes Research Foundation (JDRF), almost 1. 25 million people in the United States (US) have type 1 diabetes, which makes them dependent on insulin injections. ...Nationwide, type 2 diabetes rates have nearly doubled in the past 20 years resulting in more than 29 million American adults with diabetes and another 86 million in a pre-diabetic state. The International Diabetes Ferderation (IDF) has estimated that there will be almost 650 million adult diabetic patients worldwide at the end of the next 20 years (excluding patients over the age of 80). At this time, pancreas transplantation is the only available cure for selected patients, but it is offered only to a small percentage of them due to organ shortage and the risks linked to immunosuppressive regimes. Currently, exogenous insulin therapy is still considered to be the gold standard when managing diabetes, though stem cell biology is recognized as one of the most promising strategies for restoring endocrine pancreatic function. However, many issues remain to be solved, and there are currently no recognized treatments for diabetes based on stem cells. In addition to stem cell resesarch, several β-cell substitutive therapies have been explored in the recent era, including the use of acellular extracellular matrix scaffolding as a template for cellular seeding, thus providing an empty template to be repopulated with β-cells. Although this bioengineering approach still has to overcome important hurdles in regards to clinical application (including the origin of insulin producing cells as well as immune-related limitations), it could theoretically provide an inexhaustible source of bio-engineered pancreases.
Obesity and associated liver disease are a growing public health concern. Pharmacological agents to treat non-alcoholic fatty liver disease are limited. FGF21, a hormone secreted by the liver and ...potent metabolic modulator, is a promising therapeutic target for this indication with several analogs currently in clinical development. However, concerns about a negative effect of FGF21 on female fertility have not been fully addressed.
After induction of obesity, female C57BL/6N mice received a 7-day course of subcutaneously administered FGF21. Control groups received either high-fat diet (HFD) or a normal diet (ND). The mothers were then mated with lean males for 12 weeks. The estrous cycle was recorded for two weeks after breeding. The metabolic phenotype, liver steatosis and reproductive organs were assessed at sacrifice 14 weeks after treatment.
A short-course treatment of FGF21 leads to weight reduction during treatment but has no long-term impact on liver steatosis. A treatment with FGF21 leads to a reduction in the number of pregnancies (0 vs 1, p = 0.019) and no viable pup was born to a mother previously treated with FGF21. The FGF21 treatment affected the number of cycles (1 vs 3, p = 0.048) and amount in diestrus (54 vs 75%, p = 0.008) 12 weeks after the treatment. Additionally, the number of corpora lutea (0.8 vs 3.0, p = 0.016), and mature follicles (0 vs 1, p = 0.037) was reduced compared to the ND group while uterine histology remained unaffected.
A short-term treatment with FGF21 has a long-term effect on female fertility in mice. This represents a potential safety concern for FGF21 analogs currently in clinical development. Reproductive health outcomes should be included in upcoming clinical trials.
FGF21; Fertility; Non-alcoholic fatty liver disease; High-fat diet.
Background: In end-stage chronic liver disease, transplantation represents the only curative option. However, the shortage of donors results in the death of many patients. To overcome this gap, it is ...mandatory to develop new therapeutic options. In the present study, we decellularised pig livers and reseeded them with allogeneic porcine mesenchymal stromal cells (pMSCs) to understand whether extracellular matrix (ECM) can influence and/or promote differentiation into hepatocyte-like cells (HLCs). Methods: After decellularisation with SDS, the integrity of ECM-scaffolds was examined by histological staining, immunofluorescence and scanning electron microscope. DNA quantification was used to assess decellularisation. pMSCs were plated on scaffolds by static seeding and maintained in in vitro culture for 21 days. At 3, 7, 14 and 21 days, seeded ECM scaffolds were evaluated for cellular adhesion and growth. Moreover, the expression of specific hepatic genes was performed by RT-PCR. Results: The applied decellularisation/recellularisation protocol was effective. The number of seeded pMSCs increased over the culture time points. Gene expression analysis of seeded pMSCs displayed a weak induction due to ECM towards HLCs. Conclusions: These results suggest that ECM may address pMSCs to differentiate in hepatocyte-like cells. However, only contact with liver-ECM is not enough to induce complete differentiation.
The global obesity epidemic particularly affects women of reproductive age. Offspring of obese mothers suffer from an increased risk of liver disease but the molecular mechanisms involved remain ...unknown. We performed an integrative genomic analysis of datasets that investigated the impact of maternal obesity on the hepatic gene expression profile of the offspring in mice. Furthermore, we developed a murine model of maternal obesity and studied the development of liver disease and the gene expression profile of the top dysregulated genes by quantitative real-time polymerase chain reaction (qPCR). Our data are available for interactive exploration on our companion webpage. We identified five publicly available datasets relevant to our research question. Pathways involved in metabolism, the innate immune system, the clotting cascade, and the cell cycle were consistently dysregulated in the offspring of obese mothers. Concerning genes involved in the development of liver disease,
,
and six other genes were dysregulated in multiple independent datasets. In our own model, we observed a higher tendency towards the development of non-alcoholic liver disease (60 vs. 20%) and higher levels of alanine aminotransferase (41.0 vs. 12.5 IU/l,
= 0.008) in female offspring of obese mothers. Male offspring presented higher levels of liver fibrosis (2.4 vs. 0.6% relative surface area,
= 0.045). In a qPCR gene expression analysis of our own samples, we found
, and
to be dysregulated by maternal obesity. Maternal obesity represents a looming threat to the liver health of future generations. Our comprehensive transcriptomic analysis will help to better understand the mechanisms of the development of liver disease in the offspring of obese mothers and can give rise to further explorations.
Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace ...damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of
de novo
engineered whole organs for transplantations.
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