Focal Necrosis Research Articles

Histopathological changes of myocytes in restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare primary myocardial disease, and its pathological features are yet to be determined. Restrictive cardiomyopathy with MHY7 mutation was diagnosed in a 65-year-old Japanese woman. Electron microscopy of a myocardial biopsy revealed electron-dense materials resulting from focal myocyte degeneration and necrosis as well as tubular structures and pseudo-inclusion bodies in some nuclei. These features may be associated with the pathogenesis of RCM.

IFN‐alpha receptor deficiency enhances host resistance to oral Salmonella enterica serovar Typhimurium infection during murine pregnancy

Maternal tolerance during pregnancy increases the risk of infection with certain intracellular pathogens. Systemic Salmonella enterica serovar Typhimurium (S.Tm) infection during pregnancy in normally resistant 129X1/SvJ mice leads to severe placental infection, as well as fetal and maternal deaths. However, the effect of oral infection with S.Tm in pregnant mice and the roles of infection-induced inflammation and cell death pathways in contributing to susceptibility to infection are unclear. Non-pregnant and pregnant C57BL/6J wild-type (WT) and cell death pathway-altered mice (IFNAR1-/- , Caspase-1, 11-/- , RIP3-/- ) were infected orally with S.Tm. Host survival and fetal resorption were determined. Bacterial burden in mesenteric lymph nodes (MLNs), spleen, liver, and placentas was enumerated at various time points post-infection. Serum cytokine expression was measured through cytometric bead array. Oral infection of WT mice with S.Tm on days 9-10 of gestation resulted in systemic dissemination of the bacteria, substantial placental colonization, and fetal loss 5days post-infection. Histopathological examination of the placentas indicated that infection-induced widespread focal necrosis and neutrophil infiltration throughout the spongiotrophoblast (SpT) layer. In the non-pregnant state, IFNAR1-/- mice exhibited increased survival following oral S.Tm infection relative to Caspase-1, 11-/- , RIP3-/- , and WT mice. The increased resistance to S.Tm infection in IFNAR1-/- mice was seen during pregnancy as well, with decreased bacterial burden within MLNs, spleen, and placenta, which correlated with the decreased resorptions relative to WT and Caspase-1, 11-/- mice. Oral S.Tm exposure leads to placental infection, inflammation, and resorption, whereas IFNAR1 deficiency enhances host resistance both in the non-pregnant and pregnant states.

Abstract #1001394: A Rare Endocrine Complication of the COVID-19 Vaccine

Pituitary adenomas are a common, asymptomatic finding in the general population. They are usually diagnosed incidentally on imaging studies. Rarely, pituitary adenomas can progress to pituitary apoplexy, defined as hemorrhage and/or infarction and are often associated with a triggering event. A 44 year old man with a history of hypogonadism presented to the hospital for fevers, chills and blurry vision that started after he received his second COVID-19 vaccine three days prior. The day following his vaccine, he initially developed subjective fevers, chills and myalgia which he self-treated with over the counter analgesics at home. Three days after the vaccine, he developed blurry vision along with change in mental status which brought him to the hospital. When he initially presented to an outside hospital, vital signs showed hypotension with MAP of 57 and fever of 103 degrees fahrenheit. MRI of the head showed a 4.7cm sellar and suprasellar mass with optic chiasm compression and left sphenoidal extension. Labs at the time showed FSH 10.5 IU/L, LH 3.3 IU/L, Prolactin 1.2 ng/mL, Cortisol 9.3 ug/dL at 5am, ACTH 7 pg/mL, TSH 2.90 uIU/mL, free T4 1.33 ng/dL and free T3 3.88 ng/dL. Due to the patient's hypotension and findings on imaging studies, there was concern for adrenal insufficiency and the patient was started on stress dose steroids. He was transferred to a tertiary care center and vitals at the time were significant for a temperature 105.9 degrees fahrenheit but otherwise hemodynamically stable. He underwent an endoscopic transsphenoidal resection of the pituitary tumor given compression of the optic chiasm. Pathology report was consistent with pituitary adenoma with focal hemorrhage and necrosis of pituitary adenoma cells. Patient currently remains on maintenance dose steroids and levothyroxine. Pituitary apoplexy can occur either spontaneously or due to a stressful trigger. There have been no case reports showing the novel COVID-19 vaccine leading to pituitary infarction or hemorrhage. Although the pathophysiology is not entirely clear, our patient may have developed a robust immune response that could have potentially been a trigger leading to a pituitary apoplexy.

Cell stiffness predicts cancer cell sensitivity to ultrasound as a selective superficial cancer therapy.

We hypothesize that the biomechanical properties of cells can predict their viability, with Young's modulus representing the former and cell sensitivity to ultrasound representing the latter. Using atomic force microscopy, we show that the Young's modulus stiffness measure is significantly lower for superficial cancer cells (squamous cell carcinomas and melanoma) compared with noncancerous keratinocyte cells. In vitro findings reveal a significant difference between cancerous and noncancerous cell viability at the four ultrasound energy levels evaluated, with different cell lines exhibiting different sensitivities to the same ultrasound intensity. Young's modulus correlates with cell viability (R 2 = 0.93), indicating that this single biomechanical property can predict cell sensitivity to ultrasound treatment. In mice, repeated ultrasound treatment inhibits tumor growth without damaging healthy skin tissue. Histopathological tumor analysis indicates ultrasound‐induced focal necrosis at the treatment site. Our findings provide a strong rationale for developing ultrasound as a noninvasive selective treatment for superficial cancers.

Case report: histopathology and molecular pathology analysis on enteric tissue of a COVID-19 patient

AimsPatients with COVID-19 can also have enteric symptoms. Here we analyzed the histopathology of intestinal detachment tissue from a patient with COVID-19.MethodsThe enteric tissue was examined by hematoxylin & eosin stain, PAS (Periodic acid–Schiff) staining, Gram staining, Ziehl–Neelsen stain and Grocott’s Methenamine Silver (GMS) Stain. The distribution of CD3, CD4, CK20 and CD68, cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) antigen were determined by immunohistochemistry. In situ hybridization (ISH) of SARS-CoV-2 and Epstein-Barr virus-encoded small RNA (EBER) were also performed.ResultsWe observed mucosal epithelium shedding, intestinal mucosal erosion, focal inflammatory necrosis with hemorrhage, massive neutrophil infiltration, macrophage proliferation accompanied by minor lymphocyte infiltration. Fungal spores and gram positive cocci but not mycobacteria tuberculosis were identified. Immunohistochemistry staining showed abundant CD68+ macrophages but few lymphocytes infiltration. HSV, CMV and EBV were negative. ISH of SARS-CoV-2 RNA showed positive signal which mostly overlapped with CD68 positivity.ConclusionsThe in situ detection of SARS-CoV-2 RNA in intestinal macrophages implicates a possible route for gastrointestinal infection. Further study is needed to further characterize the susceptibility of enteric cells to SARS-CoV-2 infection.

69-Year-Old Man With Nasal Congestion and Pre-Syncope

69-Year-Old Man With Nasal Congestion and Pre-Syncope

Effect of electroacupuncture on the hemorheology and hepatic microcirculation in mice with chronic alcoholic liver injury

To observe the effect of electroacupuncture (EA) on the hemorheology and hepatic microcirculation in mice with chronic alcoholic liver injury (cALI), so as to explore the microcirculation mechanism of EA underlying regulating liver function in cALI mice. Forty Kunming mice were randomly assigned to control, model, acupoint EA and non-acupoint EA groups, with 10 mice in each group. The cALI model was established by gavage with 50% ethanol (15 mL/kg，2 times per day with 8 hours' interval) for 28 d. Mice in the acupoint EA group received EA at bilateral "Zusanli" (ST36) and "Ganshu"(GB11) for 20 min, once daily for 14 d. And mice in the non-acupoint EA group received EA the spot about 1 cm lateral to GB11 and 0.5 cm lateral to ST36 respectively for 20 min, once daily for 14 d. The hepatic blood perfusion (HBP) of mice was detected by laser speckle perfusion imaging. The index of hemorheology, serum markers of liver function and hepatic histology in mice were observed by automatic blood rheometer, automatic bio-analysis machine and H.E. staining, respectively. Compared with the control group, the HBP of the model group was significantly decreased (P<0.05); the low-cut whole blood viscosity, plasma viscosity, and erythrocyte sedimentation level were significantly increased （P<0.05）, and the red blood cell deformation index was significantly decreased (P<0.05); serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) increased significantly (P<0.05) in the model group. Hepatocyte steatosis accompanied by inflammatory cell infiltration and focal necrosis was observed in the model group. After EA at ST36 and GB11, and in comparison with the model group showed that the HBP was significantly increased (P<0.05); the low-cut whole blood viscosity, plasma viscosity, erythrocyte sedimentation rate and serum GGT were significantly decreased (P<0.05), and the red blood cell deformation index was significantly increased (P<0.05）; the degree of fatty degeneration in the liver tissue was reduced, and the focal necrosis was reduced. The plasma viscosity, erythrocyte sedimentation rate were significantly decreased (P<0.05), and the red blood cell deformation index was significantly increased in the non-acupoint EA group relevant to the model group (P<0.05). The erythrocyte sedimentation rate and the red blood cell deformation index of the acupoint EA group was significantly lower than that of the non-acupoint EA group (P<0.05). EA at ST36 and GB11 could improve the hemorheological disorder and the hepatic microcirculation, and inhibit the deve-lopment of liver injury in cALI mice.

Extraventricular Neurocytoma in Parietal Lobe

AbstractExtraventricular neurocytoma (EVN) was classified as a World Health Organization (WHO) grade II tumor; however, EVN is not fully understood; it presents a variable histological feature that included oligodendroglioma-like, neuropil-like matrix, ganglion or gangloid cells, perivascular pseudorosettes, vessel hyalinization, calcifications, and myxoid degeneration. In some very rare cases, atypical histological features such as increased mitotic figures, focal necrosis, endothelial cell proliferation, and Ki-67 index of &gt;2% made this tumor more aggressive and more susceptible to recur. We present the case of a young patient who presents with a 2-year history of seizure without other symptoms. Magnetic resonance imaging reveals a parietal lobe and well-circumscribed lesion treated by gross total resection and adjuvant radiotherapy. Clear guidelines to treat this kind of lesions are not well established and there is not a consensus of correct treatment in these tumors.

The Clinical and Pathological Features of Children With Microscopic Polyangiitis.

Objective: The aim of this study was to explore the clinical features, pathological characteristics, and the prognosis of children with microscopic polyangiitis (MPA).Methods: Ten children with MPA that were hospitalized in our hospital were included in this study. The children's pre-diagnosis status, clinical manifestations, renal pathology, treatment, and prognosis data were analyzed retrospectively.Results: All 10 cases included female patients with a median age of 8.9 years old at the time of diagnosis. MPO-ANCA antibody was positive in all cases, combined with a positive anti-GBM antibody in two cases. Nine cases had primary AAV and one had antithyroid drug (ATD)-associated MPA (secondary to methimazole). Renal involvement was found in all 10 patients, lung impairment was present in eight cases, and anemia was present in nine patients. Renal biopsies were performed in all 10 patients. Segmental focal or global glomerular necrosis was observed in 70% of the patients (7/10). The treatment mainly included steroid use combined with Cyclophosphamide and Mycophenolate. The follow-up s of the patients revealed normal renal function in eight patients and progression to end-stage renal disease (ESRD) in two patients.Conclusions: Female predisposition and positive MPO-ANCA antibody were prominent in children with MPA. The patients' kidneys and lungs were the most frequently involved organs. Corticosteroid combined with immunosuppressive therapy was recommended for the treatment of MPA. Early diagnosis, prompt aggressive treatment, and regular follow-ups are also very important factors associated with a good prognosis.

Yttrium-90 Radioembolization to the Prostate Gland: Proof of Concept in a Canine Model and Clinical Translation

PurposeTo investigate the feasibility, safety, and absorbed-dose distribution of prostatic artery radioembolization (RE) in a canine model. Materials and MethodsFourteen male castrated beagles received dihydroandrosterone/estradiol to induce prostatic hyperplasia for the duration of the study. Each dog underwent fluoroscopic prostatic artery catheterization. Yttrium-90 (90Y) microspheres (TheraSphere; Boston Scientific, Marlborough, Massachusetts) were delivered to 1 prostatic hemigland (dose escalation from 60 to 200 Gy), with the contralateral side serving as a control. Assessments for adverse events were performed throughout the follow-up (Common Terminology Criteria for Adverse Events v5.0). Positron emission tomography/magnetic resonance (MR) imaging provided a confirmation after the delivery of absorbed-dose distribution. MR imaging was performed before and 3, 20, and 40 days after RE. Tissue harvest of the prostate, rectum, bladder, urethra, penis, and neurovascular bundles was performed 60 days after RE. ResultsAll the animals successfully underwent RE. Positron emission tomography/MR imaging demonstrated localization to and good coverage of only the treated hemigland. No adverse events occurred. The MR imaging showed a significant dose-dependent decrease in the treated hemigland size at 40 days (25%–60%, P < .001). No extraprostatic radiographic changes were observed. Necropsy demonstrated no gross rectal, urethral, penile, or bladder changes. Histology revealed RE-induced changes in the treated prostatic tissues of the highest dose group, with gland atrophy and focal necrosis. No extraprostatic RE-related histologic findings were observed. ConclusionsProstate 90Y RE is safe and feasible in a canine model and leads to focal dose-dependent changes in the gland without inducing unwanted extraprostatic effects. These results suggest that an investigation of nonoperative prostate cancer is warranted.

POS-103 ACTIVE TUBERCULOSIS INFECTION COMPLICATED BY RENAL VEIN THROMBOSIS IN A RENAL TRANSPLANT RECIPIENT: A CASE REPORT

Allograft renal vein thrombosis is a rare complication of kidney transplantation. Most cases occur in the first weeks after transplantation and they are most related to donor, recipient, surgery, and immunosuppression, with mechanical factors. Allograft loss is the usual outcome. Data regarding late renal vein thrombosis are scarce and different mechanisms are incriminated. We report an unusual case of late renal vein thrombosis complicating Tuberculosis in renal transplant patient. A 34-year-old man had undergone living related kidney transplantation in 2012. His native kidney disease was of undetermined cause. His maintenance immunosuppression included prednisone,Tacrolimus with dose adjusted to obtain trough levels between 5 and 7 ng/mL, and mycophenolate mofetil. At last follow-up in June 2020, his serum creatinine was at 14 mg/L. In June 2020 he was diagnosed with Tuberculous lymphadenitis. Mycobacterium tuberculosis infection was confirmed by the histopathology examination of the axillary lymph node puncture specimen which revealed caseating granuloma. First-line Anti Tubercular Therapy (ATT) consisting in the association of isoniazid, rifampicin, pyrazinamide, and ethambutol was started and the patient was discharged. Three weeks later, he presented with right-sided abdominal pain over the kidney transplant. There was no fever or urinary symptoms. Routine investigations revealed acute renal failure with a serum creatinine level of 30mg/L. Progressive deterioration of allograft function was documented, and the patient became anuric within a few days. Hemodialysis was started. Doppler ultrasound examination of the abdomen revealed deep allograft venous thrombosis( the superior branch of the vein). Renal graft biopsy was performed revealing acute renal tubular necrosis with vascular congestion and no histological feature of acute rejection was noted. Pro-thrombotic and auto-immune studies were normal and the Polymerase Chain Reaction of cytomegalovirus was negative. The patient was put on low-molecular-weight heparin and 15 days later, acenocoumarol was started. He recovered diuresis, hemodialysis treatment was discontinued and his serum creatinine decreased from a peak of 100 mg/L to discharge creatinine of 17 mg/L. First-line Anti Tubercular Therapy (ATT) was sustained with a good clinical response. Follow-up angio-magnetic resonance imaging revealed the persistence of thrombus with non-filling of the superior branch of allograft renal vein and focal cortical necrosis was noted. Our case shows that venous thrombosis may complicate active tuberculosis and that this event can occur early at presentation or later in the course of the disease. The particularity of our case is the unusual site of thrombosis and it’s presentation in a transplant patient.

Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma.

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.

Histological growth patterns and molecular analysis of resected colorectal lung metastases

Lung is the site of metastasis in about 15–25 % of colorectal cancer (CRC) patients. Lung metastasectomy of CRC represents a standard therapy in patients with resectable metastases. In this study we investigated both histological patterns of metastases and mutations in MAPkinase pathway genes and their relationship to prognosis. The study included 74 patients that underwent metastasectomy of colorectal lung metastasis (CLM). In patients that underwent surgical resection of more than one metastasis in the same operation the largest was chosen. In patients that had undergone multiple lung metastasectomy only the sample from the first metastasectomy was included. Histologically metastases were scored according to amount and distribution of necrosis and fibrosis and three patterns were identified: “pattern A”, metastasis with extensive, confluent central necrosis surrounded by a rim of neoplastic glands; “pattern B”, metastasis characterized by a proliferation of neoplastic glands in a dense stroma with focal necrosis mainly intraglandular; “pattern C”, metastasis with a mixed A and B morphology. In all samples direct sequencing of exon 2 of KRAS and NRAS genes and exon 15 of BRAF genes was carried out.Histological patterns weren’t related to metastasis size or other clinical features however pattern C metastases showed a significant worst disease free survival (DFS). KRAS mutations were observed in 39 % of patients. Mutations in KRAS codon 13 resulted significantly associated with synchronous metastasis and poor prognosis. No mutations were identified in exon 2 NRAS gene whilst 1.4 % harboured a mutation in BRAF. To our knowledge this is the first study that investigates in a large series of CLM histological growth patterns, molecular alterations and their relationship to prognosis. Our data suggest a prognostic role in CLM of KRAS specific mutations and histopathological patterns.

Elevated Liver Function in a Bilateral Lung Transplant Recipient with Scleroderma: Is the Medication to Blame?

<h3>Introduction</h3> Scleroderma (SSc) is an autoimmune disease that can result in end-stage interstitial lung disease (ILD). Rarely, SSc has been associated with primary sclerosing cholangitis (PSC). Lung transplant may be considered for the advanced treatment of SSc-related ILD. Herein, we describe the case of a lung transplant recipient with SSc who also presented a challenging diagnosis of PSC. <h3>Case Report</h3> The patient is a 47-year-old female bilateral lung transplant recipient with history of SSc-related ILD and pulmonary hypertension. Maintenance immunosuppression consisted of tacrolimus, prednisone, and mycophenolate mofetil, and itraconazole was administered for anti-fungal prophylaxis. Early post-transplant, the patient experienced a tonic-clonic seizure related to tacrolimus toxicity. Decision was made to substitute cyclosporine, and levetiracetam was initiated for seizure prophylaxis. We then observed subtle elevations in her liver function tests. All medications were discontinued, without change in liver function, prompting MRI of the abdomen (Figure 1) which revealed multifocal areas of beaded appearance of the central intrahepatic ducts, suggesting PSC. Liver biopsy revealed focal portal tract fibrosis with bile duct lymphocytic exocytosis and vacuolar change, bile ductular proliferation, focal central venous minimal endothelialitis, and focal lobular necrosis with scattered lobular microgranulomata, with a differential of graft versus host disease. Ursodiol was started, and the patient underwent endoscopic retrograde cholangiopancreatography, which confirmed PSC. With no other interventions, liver function normalized. <h3>Summary</h3> Extrapulmonary sclerosis is a concern in lung transplant recipients with SSc. Esophageal involvement tends to garner the most attention from clinicians, yet this case raises awareness for PSC as a rare condition coincident with SSc. Medication use may be misleading when diagnosing the cause of elevated liver function.

Nephroprotective effect of Emblica officinalis fruit extract against malachite green toxicity in piscine model: Ultrastructure and oxidative stress study.

Malachite green (MG) is a multi-application dye with raised concern as aquatic toxicant. Cyprinus carpio fingerlings were exposed to MG and simultaneously fed with Emblica officinalis (EO) fruit extract to mitigate the MG induced nephrotoxicity. MG exposure developed depressed activity of antioxidant enzymes such as catalase, superoxide dismutase, glutathione-s-transferase, and reduced glutathione, while levels of malondialdehyde got significantly (p < .05) elevated after 60 days MG exposure. H&E staining revealed increased intracellular space, vacuolation, fluid-filled spaces, damaged brush border lining of proximal convoluted tubule (PCT), focal necrosis, nuclear transformations and shrunken glomerulus. Further, Transmission electron microscope study detailed structural cytotoxicity with the appearance of the heterochromatic nucleus, electron-dense lysosomal bodies, damaged brush border lining of PCT, and necrosis; glomerulus exhibited erythrocyte infiltration and fused pedicels of podocyte. While, EO extract supplemented diet culminated in the restoration of the renal cytoarchitecture and significantly (p < .05) enhanced activity of antioxidant enzymes.

Evaluation of a New Histoplasma spp. Quantitative RT-PCR Assay

Laboratory diagnosis of histoplasmosis is based on various methods, including microscopy, culture, antigen, and DNA detection of Histoplasma capsulatum var. capsulatum or Histoplasma capsulatum var. duboisii. To improve sensitivity of existing real-time quantitative PCR (qPCR) assays, we developed a new RT-qPCR assay that allows amplification of whole nucleic acids of Histoplasma spp. validated on suspected cases. The limit of detection was 20 copies, and the specificity against 114 fungal isolates/species was restricted to Histoplasma spp. Whole nucleic acids of 1319 prospectively collected consecutive samples from 907 patients suspected of having histoplasmosis were tested routinely between May 2015 and May 2019 in parallel with standard diagnostic procedures performed in parallel. Forty-four had proven histoplasmosis attributable to H. capsulatum var. capsulatum (n = 40) or H.capsulatum var. duboisii (n = 4) infections. The results of RT-qPCR were positive in 43 of 44 patients (97.7% sensitivity) in at least one specimen. Nine of 863 cases (99% specificity) were RT-qPCR positive and therefore classified as possible cases. RT-qPCR was positive in 13 of 30 (43.3%) blood samples tested in proven cases. A positive RT-qPCR result in blood was significantly associated with H. capsulatum var. capsulatum progressively disseminated histoplasmosis with a positive RT-qPCR result in 92.3% of the immunocompromised patients with disseminated disease. This new Histoplasma RT-qPCR assay enabling amplification of H. capsulatum var. capsulatum and H. capsulatum var. duboisii is highly sensitive and allows the diagnosis of histoplasmosis advantageously from blood and bronchoalveolar lavage fluid.

Spindle cell oncocytoma of the sella turcica with anaplastic features and rapid progression in short-term follow-up: a case report with proposal of distinctive radiologic features.

We present a rare case of spindle cell oncocytoma (SCO) of the sella turcica with malignant histologic features and rapid progression. A 42-year-old woman experienced bilateral blurred vision and was preoperatively misdiagnosed as having a pituitary macroadenoma on magnetic resonance imaging. After surgery, SCO was diagnosed by the histopathologic features of interlacing fascicles of spindle tumor cells with finely granular, eosinophilic cytoplasm. Focal anaplastic changes and necrosis were present. Immunohistochemically, the tumor cells were positive for vimentin, epithelial membrane antigen, S-100, galectin-3, and thyroid transcription factor 1. Four months later, the tumor had progressed, and second surgery with adjuvant radiotherapy was performed; the patients remains under observation. In this report, we proposed distinctive radiologic features for differential diagnosis between SCO and other pituitary tumors.

A205 PEMBROLIZUMAB ASSOCIATED SCLEROSING CHOLANGITIS RESPONDS TO COMBINATION OF STEROIDS AND MYCOPHENOLIC ACID: A CASE REPORT

Abstract Background Pembrolizumab is a check point inhibitor that targets programmed cell death receptor ligand 1 (PD-L1). However, check-point inhibitors are associated with its characteristic adverse event know as immune related adverse events that can affect a myriad of organ systems. In the hepatobiliary system, the most commonly described iRAE is hepatitis/hepatotoxicity and latest oncology guidelines offer recommendations on treatment and followup of immunotherapy related hepatitis (1). However, a more rare presentation of iRAE, that have only been described as case reports or case series, is secondary cholangitis. We report one of such a case. Aims Case report Methods Case report Results The patient is a 55 year-old Caucasian female know for lung adenocarcinoma presented to the emergency room on May 5th, 2020, having received her 8th cycle of pembrolizumab. Her blood works mildly elevated transaminitis; ALT 78 U/L, AST 11 U/L, alkaline phosphate of 130 U/L, and total bilirubin of 3.5 umol/L. MRI of the abdomen showed a normal appearing liver without focal parenchymal lesion, no biliary stones or obstructing masses, dilated common bile duct at 11 mm with small pericholecystic free fluid, and normal gall badder thickness of 2 mm. There was also notion of minimally prominent intrahepatic biliary radicles seen within the CBD. Etiology workup of cholestatic transaminitis was negative. A diagnosis of immunotherapy related sclerosing cholangitis was posed and the patient was treated with MMF and prednisone with good response. Conclusions Discussion This patient seems to have developed immunotherapy mediated cholangitis. Liver biopsy when performed in liver injury tend to show lobular hepatitis, with liver parenchyma infiltrated with lymphocytes and focal necrosis with acidophilic bodies. However, there seems to be another, less frequent pattern of injury described with pembrolizumab and associated with cholangiopathy, resembling primary biliary cholangitis. It is characterized with portal tracts enlarged with fibrosis and inflammatory cells infiltration; infiltrating cells are lymphocytes (2). Biliary epithelium with fibrosis with CD8+ T cells infiltration seem to be recurrently reported in case reports. (3, 4). Other cases have been describe in the literature. In many cases, steroid therapy was attempted, but response rates seem to be inconsistent. Nivolumab related cholangitis have been also been described and characterized by extra hepatic bile duct dilatation along with negative immunological markers such as ANA and IgG4 in patients with non-small cell lung cancer, and seems to respond only moderately to steroid therapy (6). Retrospective data of nivolumab related cholangiopathy seems to suggest that there is favourable response to the combination of MMF and steroid therapy (7). Funding Agencies None

The Effect of Stress Using Long-Term Continuous LightExposure on Liver Cells in Male and Female Wistar Rats

AbstractBackground: Many modern lifestyles are unhealthy andcan negatively affect our health. Many studies showed thatthe stress caused pronounced action on the structure of variousbody systems. The liver is one of the body organs that can beheavily affected by stress. The liver can withstand stress forlonger periods and shows signs of damage very late althoughthe structural changes can be detected very early.Aim of Study: Is to examine the acute and chronic effect of acute and chronic stress of long-term continuous light exposure on the structure of the liver tissues.Material and Methods: 48 male and female Wistar rats (250-300g) were enrolled in 6 groups (n=8/group). Group (a);Normal male control group with normal light/dark exposure.Group (b); Normal female control group with normal light/darkexposure. Group (c); Continuous room light for 3 weeks malegroup as an acute stress model in which normally fed malerats exposed to continuous room light exposure for 3 weeks.Group (d); Continuous room light for 3 weeks female groupas an acute stress model in which normally fed female ratsexposed to continuous room light exposure for 3 weeks.Group (e); Continuous room light for 3 months male groupas a chronic stress model in which normally fed male ratsexposed to continuous light exposure for 3 months. Group (f); Continuous room light for 3 months female group as achronic stress model in which normally fed female rats exposed to continuous light exposure for 3 months.Results: Sections of liver tissues of the groups who livedunder acute stress showed generally, preserved hepatic archi-tecture. The hepatocytes showed marked ballooning (vacuolardegeneration). The sinusoids and central veins showed con-gestion. Sections of liver tissues of the groups who livedunder chronic stress conditions showed in general, preservedhepatic architecture. The hepatocytes showed ballooning (vacuolar degeneration), focal spotty necrosis, together withsome binucleated cells. The sinusoids & central vein showedcongestion.Conclusion: This study used 48 Wistar mice as a modelto assess the effect of stress on liver tissues. Continuous roomlight exposure was used as acute stress for 3 weeks and aschronic stress for 3 months. This stressful stimulus and its deleterious effect on the liver may be supported by the theoryof sympathetic nervous system overactivity. The examinedliver tissues in this study showed congestive and degenerativechanges both in acute and chronic stressed animals. Changingmodern lifestyles to one that respects the natural chronobiologyis important for our wellbeing.

Відтворення експериментальної моделі впливу на печінку гострого стресу шляхом фіксації щурів за шийну складку

Stress-related studies remain relevant notwithstanding its long-lasting history of research. Experimental studies are crucial in the study the impact of stress on a living organism. Currently, there is a great variety of simulation animal acute stress reaction models, in particular, cervical fold suspension of mice, which is cost effective and easy-to-use. However, there are insufficient data on using this technique to reproduce the acute stress response in rats, particularly, in studying the impact of immobilization stress on the liver. The purpose of the work was to study the impact of 6-hour-long cervical fold suspension simulation model of acute immobilization stress on the albino rats’ liver. Material and methods. Based on the international bioethical regulations, 20 male albino rats were involved into the study. The intact animals were assigned into group I (n=10) (control); the animals, exposed to 6-hour-long cervical fold suspension simulation model of acute immobilization stress were assigned to experimental group (n=10) (group II). After euthanasia, macro- and microscopic examination of the liver was performed. Micro-specimens were stained with hematoxylin and eosin. Results and discussion. The macroscopic examination of the liver did not reveal any visual differences in the rats of the experimental group compared to the control ones. Histological study of the liver specimens of group II rats showed that the experimental model of simulated acute immobilization stress in rats by atraumatic cervical fold suspension for 6 hours caused significant changes. They were especially pronounced in the bloodstream of the liver, manifested by the plethora and the phenomena of interlobular vein thrombosis. The central veins were also plethoric and a significant dilatation of the perisinusoidal spaces was noted. Changes in the hemomicrocirculation were characterized by manifestations of blood stasis and sludge in most sinusoidal capillaries. We detected the phenomena of tissue infiltration by the segmented neutrophils, as well as macrophages and lymphocytes perivascularly and in the portal tracts. Changes were also found in the liver cells, namely, the phenomena of karyopyknosis; subcapsular focal colliquational necrosis in the individual hepatocytes; hydropic dystrophy in hepatocytes located on the periphery of the liver lobuli. Conclusion. The implementation of experimental model of acute immobilization stress in rats by atraumatic cervical fold suspension caused significant histological changes in rat liver