Autopsy findings of fatal retroperitoneal hemorrhage after traumatic rupture of bilateral renal angiomyolipoma.

The present work reports the autopsy findings of a unique case characterized by fatal retroperitoneal hemorrhage following the traumatic rupture of bilateral renal angiomyolipomas. Renal angiomyolipomas are generally benign tumors with an unpredictable clinical course, ranging from asymptomatic to sudden rupture and hemorrhagic shock. They may be associated with genetic disorders such as tuberous sclerosis complex. The case under investigation is unprecedented in the medical literature due to its bilateral nature and fatal outcome. Autopsy analysis revealed an extensive retroperitoneal hemorrhage originating from bilateral ruptured tumors. Microscopic examination found features consistent with bilateral renal angiomyolipoma. Circumstantial information identified a traffic accident before the death, considering it as the cause of the tumors' traumatic rupture. In this case, due to the severity of the situation, immediate medical measures-such as fluid resuscitation, coagulopathy correction, and surgical treatment, which are usually lifesaving-could not be performed. This led to the patient being declared dead at the scene of the crash.

Can a "broken heart" successfully be transplanted? A brief report.

A 59-year-old woman, with dilated ischemic cardiomyopathy, was urgently admitted to our Intensive Care Unit for cardiogenic shock. ECMO VA was implanted and placed on the national emergency waitlist for transplantation. A potential donation was identified ten days later. The donor was a 58-year-old woman, with no cardiovascular risk factors, had died of a rupture of a cerebral aneurysm with left ventricle dysfunction due to Takotsubo syndrome. Brain injuries such as hemorrhage, trauma and stroke have been extensively documented in literature to cause a surge in stress hormones, such as catecholamines. Such a surge can have a direct effect on the heart, resulting in a transient myocardial dysfunction commonly referred to as "Takotsubo cardiomyopathy" or "broken heart syndrome". Many studies have shown that hearts that are dysfunctional at the start of transplant screening, with normal contractile function at the time of organ retrieval, have similar outcomes to hearts that do not have dysfunction. In our case, the transplanted heart, at the time of sampling, still had moderate dysfunction (EF 40%) which completely disappeared after the transplant.

Autopsy findings of fatal retroperitoneal hemorrhage after traumatic rupture of bilateral renal angiomyolipoma

ABSTRACT The present work reports the autopsy findings of a unique case characterized by fatal retroperitoneal hemorrhage following the traumatic rupture of bilateral renal angiomyolipomas. Renal angiomyolipomas are generally benign tumors with an unpredictable clinical course, ranging from asymptomatic to sudden rupture and hemorrhagic shock. They may be associated with genetic disorders such as tuberous sclerosis complex. The case under investigation is unprecedented in the medical literature due to its bilateral nature and fatal outcome. Autopsy analysis revealed an extensive retroperitoneal hemorrhage originating from bilateral ruptured tumors. Microscopic examination found features consistent with bilateral renal angiomyolipoma. Circumstantial information identified a traffic accident before the death, considering it as the cause of the tumors' traumatic rupture. In this case, due to the severity of the situation, immediate medical measures—such as fluid resuscitation, coagulopathy correction, and surgical treatment, which are usually lifesaving—could not be performed. This led to the patient being declared dead at the scene of the crash.

Colo-colic intussusception in an adult caused by lipoma: Case report of a rare condition.

This report describes the case of a 56-year-old woman who presented at the emergency room with a 3-week history of severe, intermittent abdominal pain. A CT scan revealed colo-colic intussusception caused by a large, substenosing mass with predominant adipose density. Subsequent endoscopic examination with biopsy revealed a necrotic tissue covering the mass, without definitive histological characterization. A second biopsy led to the extremely rare diagnosis of colo-colic lipoma. While intussusception is rare in adults, it's important to consider it as a differential diagnosis, especially when presenting with abdominal pain and signs of bowel obstruction. Timely diagnosis and appropriate treatment are essential to prevent complications.

Untailored vs. Gender- and Body-Mass-Index-Tailored Skeletal Muscle Mass Index (SMI) to Assess Sarcopenia in Advanced Head and Neck Squamous Cell Carcinoma (HNSCC).

(1) Background: Sarcopenia lasting >1 year might be considered a chronic condition in many HNSCC patients. CT-scan-derived Skeletal Muscle Mass Index (SMI) is an established surrogate of sarcopenia; yet, the cut-off reported in the literature (literature-based, lb-SMI < 43.2) is mainly based on the risk of chemoradiotherapy-induced toxicity, and the optimal value to discriminate OS is under-investigated. (2) Methods: The effect on OS of the lb-SMI cutoff was compared with an untailored OS-oriented SMI cutoff obtained in a cohort of consecutive advanced HNSCC patients treated with primary chemoradiotherapy, bio-chemotherapy or chemo-immunotherapy (cohort-specific, cs-SMI cutoff). Gender- and BMI-tailored (gt-SMI and bt-SMI) cut-offs were also evaluated. Cutoff values were identified by using the maximally selected rank statistics for OS. (3) Results: In 115 HNSCC patients, the cs-SMI cutoff was 31.50, which was lower compared to the lb-SMI reported cut-off. The optimal cut-off separately determined in females, males, overweight and non-overweight patients were 46.02, 34.37, 27.32 and 34.73, respectively. gt-SMI categorization had the highest effect on survival (p < 0.0001); its prognostic value was independent of the treatment setting or the primary location and was retained in a multivariate cox-regression analysis for OS including other HNSCC-specific prognostic factors (p = 0.0004). (4) Conclusions: A tailored SMI assessment would improve clinical management of sarcopenia in chemoradiotherapy-, bio-chemotherapy- or chemo-immunotherapy-treated HNSCC patients. Gender-based SMI could be used for prognostication in HNSCC patients.

Mucinous and Signet-Ring Cell Colonic Adenocarcinoma in Inflammatory Bowel Disease: A Case-Control Study.

A higher frequency of mucinous and signet-ring cell colonic adenocarcinoma has been reported in inflammatory bowel disease (IBD). The primary aim was to investigate the frequency of mucinous and signet-ring cell colorectal adenocarcinoma in patients with IBD (Cases) versus age-matched non-IBD Controls. The secondary aims were to compare the characteristics of these two histotypes of colorectal cancer (CRC) in IBD patients vs. Controls and to search for specific risk factors in IBD. In a case-control study, all IBD patients with CRC diagnosed from 2000 to 2022 were enrolled and matched for age (1:2) with non-IBD Controls with CRC. The study population included 120 CRC patients (40 IBD, 80 Controls). In IBD, CRC included standard adenocarcinoma in 23 (57.5%) patients mucinous/signet-ring cell adenocarcinoma in 17 (42.5%) patients. The proportion of mucinous/signet-ring cell adenocarcinoma was higher in IBD than in Controls (17 [42.5%] vs. 18 [22.5%]; p = 0.03). In rectal CRC, the proportion of mucinous/signet-ring cell adenocarcinoma was higher than standard adenocarcinoma in IBD (8 [47.1%] vs. 4 [17.4%]; p = 0.04) but not in Controls (4 [22.2%] vs. 20 [32.2%]; p = 0.59). In rectal CRC, the proportion of these two histotypes was higher in Cases than in Controls (8/12 [66.6%] vs. 4/24 [16.6%]; p = 0.008), with no risk factors identified in IBD. CRC was more frequently represented by mucinous/signet-ring cell adenocarcinoma in IBD than in age-matched non-IBD Controls. In IBD, these two CRC histotypes were more frequent in the rectum.

Ascorbic acid reduces Ropivacaine-induced myotoxicity in cultured human osteoporotic skeletal muscle cells.

BACKGROUND: Osteoporosis is a worldwide health issue. Loss of bone mass is a potential risk factor for fragility fractures, and osteoporotic fractures place a considerable burden on society. Bone and muscle represent a functional unit in which the two tissues are intimately interconnected. Ropivacaine is a potent local anesthetic used in clinical practice for intraoperative anesthesia and postoperative pain management, in particular for hip surgery. When injected, Ropivacaine can diffuse locally through, in particular in surrounding skeletal muscle tissue, causing dose-dependent cytotoxicity, oxidative stress and myogenesis impairment. Based on those evidences, we focused our attention on Ropivacaine-induced cytotoxicity on cultured human myoblasts. METHODS: Primary human myoblasts and myotubes from healthy subjects, osteoarthritic and osteoporotic patients (OP) were cultured in the presence of Ropivacaine. In some experiments, ascorbic acid (AsA) was added as a potent antioxidant agent. Cell viability and ROS levels were evaluated to investigate the myotoxic activity and Real-Time PCR and Western blot analysis carried out to investigate the expression of proliferation and myogenic markers. RESULTS: A dose-dependent decrease of cell viability was observed after Ropivacaine exposure in both OP myoblasts and myotubes cultures, whereas those effects were not observed in the presence of Propofol, a general anesthetic. The adding of AsA reduced Ropivacaine negative effects in OP myoblast cultures. In addition, Ropivacaine exposure also increased ROS levels and upregulated Nox4 expression, an enzyme primarily implicated in skeletal muscle ROS generation. AsA treatment counteracted the oxidant activity of Ropivacaine and partially restored the basal condition in cultures. Positive myogenic markers, such as MyoD and Myf5, were downregulated by Ropivacaine exposure, whereas myostatin, a negative regulator of muscle growth and differentiation, was upregulated. The phenotypic deregulation of myogenic controllers in the presence of Ropivacaine was counteracted by AsA treatment. CONCLUSIONS: Our findings highlight the oxidative stress-mediated myotoxic effect of Ropivacaine on human skeletal muscle tissue cell cultures, and suggest treatment with AsA as valid strategy to mitigate its negative effects and allowing an ameliorated functional skeletal muscle recovery in patients undergoing hip replacement surgery for osteoporotic bone fracture.

A high-performance xylene-free tissue-clearing agent for routine histology: Preliminary histomorphological results.

After the discovery of the hazardous effects of xylene, less toxic substitutes were proposed for routine histology in the last years. However, the introduction of new xylene-free substitutes in histological processes requires a careful evaluation of their performance in terms of morphological and microscopic details to permit a solid diagnosis as well as good quality immunohistochemical and biomolecular analyses. In this study, we analyzed the performance of a new commercially available xylene-free Tissue-Tek® Tissue-Clear® agent in comparison with another routine xylene-free solvent yet available and employed in routine histological process. Serial histological tissue samples (n = 300) were selected and processed with the two clearing agents. Comparison and evaluation were also performed on slides obtained 6 months after paraffin embedding and archive storage. Blinded semiquantitative analysis of technical performance and morphological details, including tissue architecture and nuclear and cytoplasmic details, was performed on Haematoxylin-Eosin stained sections by two technicians and two pathologists, respectively. Evaluation of tissue slides documented a good overall histological performance in slides obtained after processing with the two different clearing agents. Slides obtained with Tissue-Tek® Tissue-Clear® displayed a higher score in some quality parameters, further supporting its use as a valid alternative to the other commercial routine xylene-free solvents.

Overlapping features of hepatic complications after hematopoietic cell transplantation in a rare T-cell lymphoma: A clinical challenge.

We present the case of a young adult, who developed several hepatic post-HCT complications, which made differential diagnosis extremely difficult.

Endoscopic Ultrasound Plus Endoscopic Retrograde Cholangiopancreatography Based Tissue Sampling for Diagnosis of Proximal and Distal Biliary Stenosis Due to Cholangiocarcinoma: Results from a Retrospective Single-Center Study.

Differentiating between benign and malignant biliary stenosis (BS) is challenging, where tissue diagnosis plays a crucial role. Endoscopic retrograde cholangiopancreatography (ERCP)-based tissue sampling and endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) or biopsy (FNB) are used to obtain tissue specimens from BS. The aim of this retrospective study was to evaluate the diagnostic yield of EUS-FNA/B plus ERCP with brushing or forceps biopsy in BS. All endoscopic procedures performed in patients with BS at our gastroenterology unit were reviewed. The gold standard for diagnosis was histopathology of surgical specimens or the progression of the malignancy at radiological or clinical follow-up. A total of 70 endoscopic procedures were performed in 51 patients with BS. Final endoscopic diagnosis was reached in 96% of the patients and was malignant in 61.7% and benign in 38.3% of cases. Sensitivity, specificity, and diagnostic accuracy were 73.9%, 100%, and 80%, respectively, for EUS-FNA/B; 66.7%, 100%, and 82.5% for ERCP; and 83.3%, 100%, and 87.5% for both procedures carried out in the same session. The combination of EUS and ERCP tissue sampling seems to increase diagnostic accuracy in defining the etiology of BS. Performing both procedures in a single session reduces the time required for diagnostic work-up and optimizes resources.

Effects of H2O2 Treatment Combined With PI3K Inhibitor and MEK Inhibitor in AGS Cells: Oxidative Stress Outcomes in a Model of Gastric Cancer.

Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with H2O2 alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with H2O2 combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after H2O2 treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed ErbB2 and OGG1 increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration via a different modulation of PI3K and MAPKs pathways. Moreover, the observed ErbB2 and OGG1 induction is a cellular response to protect the cells from H2O2-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used.

Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology.

Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyperactivation of mitogen-activated protein kinase (MAPK) and PI3K/Akt, which mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationships between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K/Akt and MAPK/ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a human non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the results obtained by gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/PTC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells). Gene expression data also delineated that MUTYH gene could play a physiological role in crosstalk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall, our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements.

Ileal Neuroendocrine Tumor in a Patient with Sclerosing Mesenteritis: Which Came First?

BACKGROUND Jejunoileal neuroendocrine tumors (JI-NETs) are rare tumors that can be associated with mesenteric fibrosis. This case report is of an incidental finding of a JI-NET in a patient who was previously misdiagnosed with sclerosing mesenteritis. CASE REPORT A 42-year-old man was admitted to our institution with diffuse abdominal pain and clinical and radiographic signs of bowel obstruction. He had a previous diagnosis of sclerosing mesenteritis, which had been histologically diagnosed after an exploratory laparoscopy performed in 2009 for recurrent acute abdominal pain. He was also annually monitored through computed tomography scans for an incidentally discovered, gradually enlarging mesenteric mass for which a "wait and watch" management approach was adopted. After a period of fasting and observation, the patient underwent an urgent exploratory laparotomy because of his worsening condition. Intraoperatively, an ileocecal resection was performed, along with excision of the known mesenteric mass. The pathology report revealed an ileal NET with nodal metastases within the mesentery and mesenteric tumor deposits (pT3N1). CONCLUSIONS JI-NETs are rare entities, which are usually encountered as incidental findings or in patients with unspecific abdominal pain. Our case represents a probable delayed diagnosis of JI-NET in the context of sclerosing mesenteritis; therefore, a possible association between these 2 conditions should be investigated.

Management of Low Rectal Cancer Complicating Ulcerative Colitis: Proposal of a Treatment Algorithm.

Low rectal Carcinoma arising at the background of Ulcerative Colitis poses significant management challenges to the clinicians. The complex decision-making requires discussion at the multidisciplinary team meeting. The published literature is scarce, and there are significant variations in the management of such patients. We reviewed treatment protocols and operative strategies; with the aim of providing a practical framework for the management of low rectal cancer complicating UC. A practical treatment algorithm is proposed.

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma.

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Detection and Physicochemical Characterization of Membrane Vesicles (MVs) of Lactobacillus reuteri DSM 17938.

Membrane vesicles (MVs) are bilayer structures which bleb from bacteria, and are important in trafficking biomolecules to other bacteria or host cells. There are few data about MVs produced by the Gram-positive commensal-derived probiotic Lactobacillus reuteri; however, MVs from this species may have potential therapeutic benefit. The aim of this study was to detect and characterize MVs produced from biofilm (bMVs), and planktonic (pMVs) phenotypes of L. reuteri DSM 17938. MVs were analyzed for structure and physicochemical characterization by Scanning Electron Microscope (SEM) and Dynamic Light Scattering (DLS). Their composition was interrogated using various digestive enzyme treatments and subsequent Transmission Electron Microscopy (TEM) analysis. eDNA (extracellular DNA) was detected and quantified using PicoGreen. We found that planktonic and biofilm of L. reuteri cultures generated MVs with a broad size distribution. Our data also showed that eDNA was associated with pMVs and bMVs (eMVsDNA). DNase I treatment demonstrated no modifications of MVs, suggesting that an eDNA-MVs complex protected the eMVsDNA. Proteinase K and Phospholipase C treatments modified the structure of MVs, showing that lipids and proteins are important structural components of L. reuteri MVs. The biological composition and the physicochemical characterization of MVs generated by the probiotic L. reuteri may represent a starting point for future applications in the development of vesicles-based therapeutic systems.

Identification of the zinc finger 216 (ZNF216) in human carcinoma cells: a potential regulator of EGFR activity.

Epidermal Growth Factor Receptor (EGFR), a member of the ErbB family of receptor tyrosine kinase (RTK) proteins, is aberrantly expressed or deregulated in tumors and plays pivotal roles in cancer onset and metastatic progression. ZNF216 gene has been identified as one of Immediate Early Genes (IEGs) induced by RTKs. Overexpression of ZNF216 protein sensitizes 293 cell line to TNF-α induced apoptosis. However, ZNF216 overexpression has been reported in medulloblastomas and metastatic nasopharyngeal carcinomas. Thus, the role of this protein is still not clearly understood. In this study, the inverse correlation between EGFR and ZNF216 expression was confirmed in various human cancer cell lines differently expressing EGFR. EGF treatment of NIH3T3 cells overexpressing both EGFR and ZNF216 (NIH3T3-EGFR/ZNF216), induced a long lasting activation of EGFR in the cytosolic fraction and an accumulation of phosphorylated EGFR (pEGFR) more in the nuclear than in the cytosolic fraction compared to NIH3T3-EGFR cells. Moreover, EGF was able to stimulate an increased expression of ZNF216 in the cytosolic compartment and its nuclear translocation in a time-dependent manner in NIH3T3-EGFR/ZNF216. A similar trend was observed in A431 cells endogenously expressing the EGFR and transfected with Znf216. The increased levels of pEGFR and ZNF216 in the nuclear fraction of NIH3T3-EGFR/ZNF216 cells were paralleled by increased levels of phospho-MAPK and phospho-Akt. Surprisingly, EGF treatment of NIH3T3-EGFR/ZNF216 cells induced a significant increase of apoptosis thus indicating that ZNF216 could sensitize cells to EGF-induced apoptosis and suggesting that it may be involved in the regulation and effects of EGFR signaling.