Histopathological Markers Research Articles

ODP055 The methylation pattern of a unique Bilateral para-overian Adrenal Rest Tumor in a girl with Nicotinamide Nucleotide Transhydrogenase mutation

Abstract Background Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females, reported so far only in noncompliant patients with congenital adrenal hyperplasia and elevated ACTH levels, is very rare (<20 cases world-wide). This study characterizes the pathophysiology, the molecular ontogeny and methylation analysis of a unique ART in a female with adrenal failure due to the G200S mutation in NNT Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation followed for adrenal insufficiency reappeared to follow-up with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (> 1500 pmol/l). Pelvic MRI and Ultrasound demonstrated one sided paraovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para ovarian mesosalpinx masses involving the serosa of the Fallopian tube, (3 and 1 cm in diameter). The testosterone level normalized within one day after surgical removal of those masses (0.2 nmol/l). Results Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary marker ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the positive Gene expression of Cyp17a1, Cyp21a2 and Mc2r cDNA but not Pomc suggesting adrenal but not pituitary origin of the tissue. We further profiled the epigenomic profile of several adrenal rest tumors from both ovarian and testes origins using the Infinium Methylation EPIC array. We characterized the adrenal-specific features by comparing the tumors from the two different originating sites to published methylation array data on healthy adrenal tissue. We further investigated cancer-specific methylation changes to identify activated cancer pathways, and used the methylation arrays to identify somatic copy number alterations. Finally, we analyzed the likely developmental origin of these tumors by comparing to published methylation array data of developmental and adult reproductive tissues. Conclusion This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. The laparoscopic surgical findings indicate that imaging techniques may be insufficient in identification of such rest tumors and call for laparoscopy when clinical findings are suggestive. An early detection of this tumor could preserve fertility. Using histopathology markers cDNA studies and epigenomic profiling by methylation studies, our study shows for the first time that female ART originates from adrenal cells. The growth of a functional androgen producing "tumor" indicates that functional NNT protein is NOT required for androgen synthesis in contrast to glucocorticoids and that a zona reticularis similar tissue in ART is responsive to ACTH stimulation. Presentation: No date and time listed

Predicting histopathology markers of endometrial carcinoma with a quantitative image analysis approach based on spherical harmonics in multiparametric MRI

PurposeIdentifying optimal machine learning pipelines for computer-aided diagnosis is key for the development of robust, reproducible, and clinically relevant imaging biomarkers for endometrial carcinoma. The purpose of this study was to introduce the mathematical development of image descriptors computed from spherical harmonics (SPHARM) decompositions as well as the associated machine learning pipeline, and to evaluate their performance in predicting deep myometrial invasion (MI) and histopathological high-grade in preoperative multiparametric magnetic resonance imaging (MRI). Patients and methodsThis retrospective study included 128 women with histopathology-confirmed endometrial carcinomas who underwent 1.5-T MRI before hysterectomy between January 2011 and July 2015. SPHARM descriptors of each tumor were computed on multiparametric MRI images (T2-weighted, diffusion-weighted, dynamic contrast-enhanced-MRI and apparent diffusion coefficient maps). Tensor-based logistic regression was used to classify two-dimensional SPHARM rotationally-invariant descriptors. Head-to-head comparisons with radiomics analyses were performed with DeLong tests with Bonferroni-Holm correction to compare diagnostic performances. ResultsWith all MRI contrasts, SPHARM analysis resulted in area under the curve, sensitivity, specificity, and balanced accuracy values of 0.94 (95% confidence interval [CI]: 0.85, 1.00), 100% (95% CI: 100, 100), 74% (95% CI: 51, 92), 87% (95% CI: 78, 98), respectively, for predicting deep MI. For predicting high-grade tumor histology, the corresponding values for the same diagnostic metrics were 0.81 (95% CI: 0.64, 0.90), 93% (95% CI: 67, 100), 63% (95% CI: 45, 79) and 78% (95% CI: 64, 86). The corresponding values achieved via radiomics were 0.92 (95% CI: 0.82, 0.95), 82% (95% CI: 65, 93), 80% (95% CI: 51, 94), 81% (95% CI: 70, 91) for deep MI and 0.72 (95% CI: 0.58, 0.83), 93% (95% CI: 65, 100), 55% (95% CI: 41, 69), 74% (95% CI: 52, 88) for high-grade histology. The diagnostic performance of the SPHARM analysis was not significantly different (P = 0.62) from that of radiomics for predicting deep MI but was significantly higher (P = 0.044) for predicting high-grade histology. ConclusionThe proposed SPHARM analysis yields similar or higher diagnostic performance than radiomics in identifying deep MI and high-grade status in histology-proven endometrial carcinoma.

Predicting Recurrence of Non-Muscle-Invasive Bladder Cancer: Current Techniques and Future Trends.

Simple SummaryNon-muscle-invasive bladder cancer is associated with its high rates of progression and recurrence, the proper diagnosis and management can save lives. Bladder cancer is the tenth most common type of cancer in the world. This review discusses the current markers used in the recurrence prediction of non-muscle-invasive bladder cancer and future trends, published in the last decade, in addition to the limitations and future prospects in the field of AI-based prediction systems.Bladder cancer (BC) is the 10th most common cancer globally and has a high mortality rate if not detected early and treated promptly. Non-muscle-invasive BC (NMIBC) is a subclassification of BC associated with high rates of recurrence and progression. Current tools for predicting recurrence and progression on NMIBC use scoring systems based on clinical and histopathological markers. These exclude other potentially useful biomarkers which could provide a more accurate personalized risk assessment. Future trends are likely to use artificial intelligence (AI) to enhance the prediction of recurrence in patients with NMIBC and decrease the use of standard clinical protocols such as cystoscopy and cytology. Here, we provide a comprehensive survey of the most recent studies from the last decade (N = 70 studies), focused on the prediction of patient outcomes in NMIBC, particularly recurrence, using biomarkers such as radiomics, histopathology, clinical, and genomics. The value of individual and combined biomarkers is discussed in detail with the goal of identifying future trends that will lead to the personalized management of NMIBC.

An update on oral peripheral nerve sheath tumors.

Peripheral nerve sheath tumors (PNSTs) are defined as type of sarcomas that develops in cells which forms a protective sheath (covering) around the peripheral nerve, i.e., the cells of myelin sheath. Nerve tumors are of neuroectodermal in origin as it was composed of small rounded ectodermal cells that affect exclusively soft tissues. PNSTs are most common neoplasm with classic clinicopathological features, but they are diagnostically challenging. They consist of wide spectrum of tumors ranging from benign tumors to malignant nerve sheath tumors and its prevalent in oral tissues. Diagnosis of PNSTs are quite hectic but made possible by histopathology and immunohistological markers.

PSMA-Directed Imaging and Therapy of Salivary Gland Tumors: A Single-Center Retrospective Study.

We analyzed the diagnostic performance of prostate-specific membrane antigen (PSMA) PET/CT and the dosimetry, efficacy, and safety of 177Lu-PSMA-617 radioligand therapy (RLT) in salivary gland malignancies (SGMs). Methods: We identified 28 SGM patients with PSMA PET/CT from our database. CT and PSMA PET/CT images were evaluated separately by 3 masked readers in joint reading sessions. Pathologic findings were grouped into 6 TNM regions, and lesion-based disease extent was classified as no disease (n = 1, 4%), unifocal (n = 2, 7%), oligometastatic (n = 9, 32%), multifocal (n = 3, 11%), or disseminated (n = 13, 47%). For each region, the SUVmax of the lesion with the highest uptake was measured and the visual PSMA expression score was evaluated on a per-patient basis using PROMISE criteria. The association between PSMA expression and clinical and histopathologic markers was tested using the Student t test. Five patients underwent PSMA RLT with intratherapeutic dosimetry. Response was assessed using RECIST 1.1, and adverse events were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events. Results: Compared with CT, PSMA PET/CT demonstrated additional metastatic lesions in 11 of 28 (39%) patients, leading to upstaging of TNM and lesion-based disease extent in 3 (11%) and 6 (21%) patients, respectively. PSMA PET/CT detected CT-occult local tumor, regional lymph nodes, nonregional lymph nodes, and bone metastases in 1 (4%), 4 (14%), 2 (7%), and 4 (14%) patients, respectively; no additional lesions were detected in the other predefined regions. PSMA expression level was higher than liver in 6 patients (25%). A significantly higher SUVmax was observed in male than female patients (15.8 vs. 8.5, P = 0.007) and in bone than lung lesions (14.2 vs. 6.4, P = 0.006). PSMA RLT was discontinued after 1 cycle in 3 of 5 patients because of insufficient tumor doses. No adverse events of grade 4 or higher occurred. Conclusion: In SGMs, PSMA PET/CT demonstrated a superior detection rate and led to upstaging in about one third of patients when compared with CT. The male sex and the presence of bone metastases were associated with significantly higher PSMA expression. PSMA RLT was well tolerated, but most patients did not have more than 1 cycle because of insufficient tumor doses.

Worst pattern of invasion in oral squamous cell carcinoma is an independent prognostic factor.

IntroductionBiologic aggressiveness of OSCC (Oral Cavity Squamous Cell Carcinoma), has intrigued research in various prognosticating histopathological markers over past few decades. DOI (Depth of Invasion) is one such histopathological factor which affects outcomes and was included in the AJCC 8th edition TNM staging. Pattern of Invasion (POI) has been widely reported as an adverse prognostic factor associated with higher locoregional failure and poor prognosis. However, these factors are not utilized for treatment decision making and for outcome assessment.Materials and methodsThis is a retrospective analysis of 320 patients with OSCC who underwent treatment, from October 2018–February 2020. Clinic demographic details were extracted from electronic medical records. Univariate and multivariate analysis was done for the parameters. WPOI (Worst Pattern of Invasion) was correlated with all histopathological prognostic factors. Survival analysis was done using Kaplan Meier for WPOI type's I–V. DFS (Disease free Survival) was evaluated for different grades of WPOI.ResultsWe analyzed the results comparing, early and advanced T (Tumor) stages, cohesive WPOI I-III, non-cohesive WPOI IV-V. Univariate analysis showed a significant association of T-stage (p = 0.001), N (Nodal) -stage (p = 0.002), DOI (p = 0.008), PNI (Peri-neural invasion) (0.001) and Tumor differentiation Grade (p = 0.001). On multivariate analysis, non-cohesive WPOI (IV & V) showed significant association with grade, PNI, DOI (0.002, 0.033 & 0.033 respectively). Non-cohesive WPOI had significantly higher locoregional failures and short DFS.ConclusionPresence of invasive WPOI is associated with advanced T stage, poor differentiation, PNI, greater depth of invasion, and higher chances of nodal metastasis. WPOI is associated with poor DFS, treatment intensification in early stage disease with WPOI type IV & V may improve survival.

Tanshinone IIA reduces pyroptosis in rats with coronary microembolization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway.

Pyroptosis is an inflammatory form of programmed cell death that is linked with invading intracellular pathogens. Cardiac pyroptosis has a significant role in coronary microembolization (CME), thus causing myocardial injury. Tanshinone IIA (Tan IIA) has powerful cardioprotective effects. Hence, this study aimed to identify the effect of Tan IIA on CME and its underlying mechanism. Forty Sprague–Dawley (SD) rats were randomly grouped into sham, CME, CME + low-dose Tan IIA, and CME + high-dose Tan IIA groups. Except for the sham group, polyethylene microspheres (42 µm) were injected to establish the CME model. The Tan-L and Tan-H groups received intraperitoneal Tan IIA for 7 days before CME. After CME, cardiac function, myocardial histopathology, and serum myocardial injury markers were assessed. The expression of pyroptosis-associated molecules and TLR4/MyD88/NF-κB/NLRP3 cascade was evaluated by qRT-PCR, Western blotting, ELISA, and IHC. Relative to the sham group, CME group's cardiac functions were significantly reduced, with a high level of serum myocardial injury markers, and microinfarct area. Also, the levels of caspase-1 p20, GSDMD-N, IL-18, IL-1β, TLR4, MyD88, p-NF-κB p65, NLRP3, and ASC expression were increased. Relative to the CME group, the Tan-H and Tan-L groups had considerably improved cardiac functions, with a considerably low level of serum myocardial injury markers and microinfarct area. Tan IIA can reduce the levels of pyroptosis-associated mRNA and protein, which may be caused by inhibiting TLR4/MyD88/NF-κB/NLRP3 cascade. In conclusion, Tanshinone IIA can suppress cardiomyocyte pyroptosis probably through modulating the TLR4/MyD88/NF-κB/NLRP3 cascade, lowering cardiac dysfunction, and myocardial damage.

Mechanical properties of breast, kidney, and thyroid tumours measured by AFM: Relationship with tissue structure

The mechanical properties of the extracellular matrix are essential for regulating cancer cell behavior, but how they change depending on tumour type remains unclear. The aim of the current study was to determine how the mechanical properties of tumours that frequently metastasize to bones were affected depending on histological type. Human breast, kidney, and thyroid specimens containing tumour and normal tissue were collected during surgery. The elastic modulus and elastic fraction of each sample were characterized using atomic force microscopy and compared with histopathological markers. We observed that tumour mechanical properties were differentially affected depending on organ and histological type. Indeed, clear cell renal carcinoma and poorly differentiated thyroid carcinoma displayed a decrease in the elastic modulus compared to their normal counterpart, while breast tumours, papillary renal carcinoma and fibrotic thyroid tumours displayed an increase in the elastic modulus. Elastic fraction decreased only for thyroid tumour tissue, indicating an increase in viscosity. These findings suggest a unique mechanical profile associated with each subtype of cancer. Therefore, viscosity could be a discriminator between tumour and normal thyroid tissue, while elasticity could be a discriminator between the subtypes of breast, kidney and thyroid cancers.

The relationship between primary colorectal cancer histology and the histopathological growth patterns of corresponding liver metastases

BackgroundThe histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in colorectal cancer liver metastasis (CRLM). This study evaluates the relationship between the HGP and primary colorectal cancer (CRC) histopathology.MethodsA total of 183 treatment-naive patients with resected CRC and CRLM were included. Thirteen CRC histopathology markers were determined and compared between the desmoplastic and non-desmoplastic HGP; tumour sidedness, pT&pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. Logistic regression analysis was performed using both CRC and CRLM characteristics.ResultsUnfavourable CRC histopathology was more frequent in non-desmoplastic CRLM for all markers evaluated, and significantly so for a lower TIL density, absent Crohn’s-like lymphoid reaction, and a “non-mature” stroma (all p < 0.03). The cumulative prevalence of unfavourable CRC histopathology was significantly higher in patients with non-desmoplastic compared to desmoplastic CRLM, with a median (IQR) of 4 (3–6) vs 2 (1–3.5) unfavourable characteristics observed, respectively (p < 0.001). Multivariable regression with 9 CRC histopathology markers and 2 CRLM characteristics achieved good discriminatory performance (AUC = 0.83).ConclusionsThe results of this study associates primary CRC histopathology with the HGP of corresponding liver metastases.

Post-stroke low-frequency whole-body vibration improves cognition in middle-aged rats of both sexes.

Low-frequency whole-body vibration (WBV; 40 Hz), a low impact form of exercise, intervention for a month following moderate transient middle-cerebral artery occlusion (tMCAO) reduces infarct volume and improves motor function in reproductively senescent, middle-aged female rats. Since post-stroke cognitive decline remains a significant problem, the current study aims to investigate the efficacy of WBV in ameliorating post-tMCAO cognitive deficits and to determine the underlying putative mechanism(s) conferring benefits of WBV in middle-aged rats. Middle-aged rats of both sexes were randomly assigned to tMCAO (90 min) or sham surgery followed by exposure to either WBV (twice a day for 15 min each for 5 days a week over a month) or no WBV treatment groups. Following the last WBV treatment, rats were tested for hippocampus-dependent learning and memory using a water maze followed by harvesting brain and blood samples for histopathological and inflammatory marker analyses, respectively. Results show that post-tMCAO WBV significantly lessens cognitive deficits in rats of both sexes. Post-tMCAO WBV significantly decreased circulating pro-inflammatory cytokines and increased serum levels of irisin, a muscle-derived hormone that may play a role in brain metabolism and inflammation regulation, which suggests putative beneficial mechanisms of WBV.

Clinicopathologic Significance of Predominant Lambda Light Chain Deposition in IgA Nephropathy

IgA nephropathy (IgAN) differs from other glomerular diseases by the frequently predominant lambda over kappa light chain deposition. Using the Cure Glomerulonephropathy (CureGN) IgAN cohort, we aimed to determine whether predominant lambda chain deposition is associated with worse clinical outcomes or histopathologic markers of more active disease. Patients were categorized based on the intensity of light chain staining. The lambda dominant (LD) group was defined by a difference in intensity score of lambda minus kappa≥ 1+ and the kappa-lambda codominant (KL) group by a difference< 1+. We compared the clinical course of patients in each category from the time of kidney biopsy and time of enrollment into CureGN to the time of remission (proteinuria< 0.3 g/g), 50% reduction in estimated glomerular filtration rate (eGFR), or progression to end-stage kidney disease (ESKD). We also analyzed differences in histopathologic characteristics between the 2 groups. Among 440 patients, we found no significant differences between groups in baseline clinical characteristics nor in rates of remission, 50% reduction in eGFR, or progression to ESKD. Patients in the LD group had a modestly greater frequency of IgG staining≥ 1+. The biopsy results of 234 patients reviewed by CureGN pathologists revealed a greater frequency of endocapillary hypercellularity (51.1% vs. 36.3%, P= 0.04) in the LD group, but no other significant difference in histopathologic features. In IgAN, we found an association between lambda predominance and increased endocapillary hypercellularity, but no association with clinical outcomes.

Pheochromocytoma and paraganglioma during childhood and adolescence

Pheochromocytoma and paraganglioma belong to the group of rare catecholamine-producing tumours during childhood and adolescence. They occur most frequently in patients with tumour predisposition syndromes. Imaging is essential to assess tumour stage and to plan therapy initiation. The aim of this review is asummary of the most important characteristics of the aforementioned tumour entities with aspecial focus on imaging. In particular, magnetic resonance imaging (MRI) as well as nuclear medicine techniques are presented. Diagnostic methods in patients with pheochromocytoma and paraganglioma are presented based on the literature and own case reports. The radiologic modality of choice for the staging of catecholamine-producing tumours during childhood and adolescence is MRI, due to the lack of ionizing radiation and high soft tissue contrast. In addition, 123-I-meta-iodo-benzyl-guanidine (MIBG) scintigraphy and positron emission tomography/computer tomography (PET/CT) are performed. Whole-body MRI is particularly important as ascreening tool in patients with atumour predisposition syndrome. Radiologic imaging and nuclear medicine techniques are important for the assessment of disease stage and therapy planning in patients with catecholamine-producing tumours. Detection of metastatic disease is essential, as there are no known histopathologic markers, which can predict the metastatic potential of the tumours.

Femtosecond laser attenuates oxidative stress, inflammation, and liver fibrosis in rats: Possible role of PPARγ and Nrf2/HO-1 signaling

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins that occurs in chronic liver injury. Inflammation and oxidative stress play a key role in fibrogenesis which can develop into cirrhosis and carcinoma. Low-level laser therapy (LLLT) has promising therapeutic effects against fibrogenesis; however, the specific underlying mechanism is not fully elucidated. We investigated the potential of LLLT to attenuate carbon tetrachloride (CCl4)-induced liver fibrosis in rats, focusing on oxidative injury, inflammatory response, and the possible role of PPARγ and Nrf2/HO-1 signaling. Rats were given CCl4 and exposed to LLLT twice/week for 6 weeks and blood and liver samples were collected for analysis. CCl4 caused liver injury and fibrosis manifested by hepatocyte injury, steatosis, inflammatory cell infiltration, and accumulation of collagen, elevated serum transaminases and bilirubin, and decreased albumin. ROS, MDA, NO, NF-κB p65, TNF-α, iNOS, TGF-β1, and IL-6 were increased in the liver of CCl4-administered rats. Exposure to LLLT ameliorated histopathological alterations, collagen deposition, and liver function markers, and downregulated hepatic α-SMA, collagen 1A1, and collagen 3A1. In Addition, LLLT decreased ROS, MDA, NO, NF-κB p65, TGF-β1, and pro-inflammatory mediators, and enhanced antioxidant defenses. These effects were associated with upregulated PPARγ, Nrf2, and HO-1, both gene and protein expression. In conclusion, LLLT attenuated liver fibrosis by suppressing ECM production and deposition, oxidative injury and inflammation, and upregulating PPARγ and Nrf2/HO-1 signaling.

Apoptotic changes in the intestinal epithelium of Cryptosporidium-infected mice after silver nanoparticles treatment versus nitazoxanide.

Cryptosporidium has been identified as one of the prevalent opportunistic parasites that cause diarrhea, which may be persistent and fatal. Current chemotherapeutic agents, including nitazoxanide (NTZ), are frequently associated with therapeutic failure, and their roles in the induction of apoptosis in cryptosporidiosis remain to be a topic of debate. Thus, this study aimed to assess the apoptotic changes in cryptosporidiosis in immunocompetent (IC) and immunosuppressed (IS) mice after treatment with silver nanoparticles (AgNPs) and NTZ either alone or after loading. In total, 120 laboratory-bred Swiss albino mice were divided into two groups. Group A included IC mice, while Group B included IS mice. Both groups were divided into six subgroups: noninfected nontreated, infected nontreated, infected AgNP-treated, infected NTZ-treated, infected AgNP-loaded NTZ (full-dose)-treated, and infected AgNP-loaded NTZ (half-dose)-treated. The assessment was achieved through parasitological, histopathological, and apoptotic marker expression evaluation. AgNP-loaded NTZ (different doses) treatment showed the highest oocyst shedding reduction and remarkable improvement in histopathological changes, followed by individual treatment with NTZ and then AgNPs in IC and IS mice. Results of apoptotic marker expression revealed that AgNP-loaded NTZ treatment exhibited a promising role in regulating apoptotic changes in cryptosporidiosis through the expression of the lowest levels of cytochrome C and caspase-3 in IC and IS mice at the end of the experiment. Therefore, AgNP-loaded NTZ can be a potential therapeutic agent against cryptosporidiosis for IC and IS mice.

Lunasin protease inhibitor concentrate decreases pro-inflammatory cytokines and improves histopathological markers in dextran sodium sulfate-induced ulcerative colitis

Lunasin protease inhibitor concentrate (LPIC) is a novel combination of soy bioactive peptide lunasin, Kunitz and Bowman-Birk protease inhibitors. The reported anti-inflammatory and anticancer properties of each one of them suggest LPIC as a promising candidate for the treatment of inflammatory-related diseases. Our objective was to assess the in vivo anti-inflammatory properties of LPIC. First, an in vitro test was performed in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophages by measuring the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) as inflammatory markers. For the in vivo model, ulcerative colitis (UC) was induced in mice via oral administration of dextran sodium sulfate (DSS). LPIC treatment was performed via daily intraperitoneal injection of 50 mg/kg body weight. Body weight, visible blood in stool and stool consistency were scored daily as macroscopic indicators of disease progression. Occult blood was evaluated by the presence of hemoglobin in stool every third day. Colon length, caecum weight, colonic myeloperoxidase activity (MPO), presence of pro-inflammatory cytokines in blood and colon, changes in the architecture, and expression of inducible nitric oxide synthase (iNOS) in colonic tissue were evaluated. In vitro, LPIC induced production of NO and maintained cytokine levels in comparison to activated untreated macrophages. In vivo, LPIC increased colonic bleeding and did not improve macroscopic markers of the disease, but reduced colonic IL-1β and IL-6, decreased systemic circulation of TNF-α, attenuated neutrophils infiltration and iNOS expression in colonic tissue, and diminished the damage in colonic architecture. Our results suggest that combinations of peptides in LPIC may counteract the anti-inflammatory properties in vitro; while in vivo, LPIC can significantly reduce the histopathological damage, hence is a possible therapeutic strategy to attenuate UC.

Development and Validation of Multiparametric MRI-based Radiomics Models for Preoperative Risk Stratification of Endometrial Cancer.

Background Stratifying high-risk histopathologic features in endometrial carcinoma is important for treatment planning. Radiomics analysis at preoperative MRI holds potential to identify high-risk phenotypes. Purpose To evaluate the performance of multiparametric MRI three-dimensional radiomics-based machine learning models for differentiating low- from high-risk histopathologic markers-deep myometrial invasion (MI), lymphovascular space invasion (LVSI), and high-grade status-and advanced-stage endometrial carcinoma. Materials and Methods This dual-center retrospective study included women with histologically proven endometrial carcinoma who underwent 1.5-T MRI before hysterectomy between January 2011 and July 2015. Exclusion criteria were tumor diameter less than 1 cm, missing MRI sequences or histopathology reports, neoadjuvant therapy, and malignant neoplasms other than endometrial carcinoma. Three-dimensional radiomics features were extracted after tumor segmentation at MRI (T2-weighted, diffusion-weighted, and dynamic contrast-enhanced MRI). Predictive features were selected in the training set with use of random forest (RF) models for each end point, and trained RF models were applied to the external test set. Five board-certified radiologists conducted MRI-based staging and deep MI assessment in the training set. Areas under the receiver operating characteristic curve (AUCs) were reported with balanced accuracies, and radiologists' readings were compared with radiomics with use of McNemar tests. Results In total, 157 women were included: 94 at the first institution (training set; mean age, 66 years ± 11 [SD]) and 63 at the second institution (test set; 67 years ± 12). RF models dichotomizing deep MI, LVSI, high grade, and International Federation of Gynecology and Obstetrics (FIGO) stage led to AUCs of 0.81 (95% CI: 0.68, 0.88), 0.80 (95% CI: 0.67, 0.93), 0.74 (95% CI: 0.61, 0.86), and 0.84 (95% CI: 0.72, 0.92), respectively, in the test set. In the training set, radiomics provided increased performance compared with radiologists' readings for identifying deep MI (balanced accuracy, 86% vs 79%; P = .03), while no evidence of a difference was observed in performance for advanced FIGO stage (80% vs 78%; P = .27). Conclusion Three-dimensional radiomics can stratify patients by using preoperative MRI according to high-risk histopathologic end points in endometrial carcinoma and provide nonsignificantly different or higher performance than radiologists in identifying advanced stage and deep myometrial invasion, respectively. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kido and Nishio in this issue.

Sulindac acetohydrazide derivative attenuates against cisplatin induced organ damage by modulation of antioxidant and inflammatory signaling pathways

This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM. Biochemical enzyme activity, histopathology, tissue antioxidant, and oxidative stress markers were examined. RT-PCR and western blot analyses were conducted for the expression of inducible cyclooxygenase enzyme (COX-2), nuclear factor kappa beta (NF-κB), p65, IL-1, TNF-α, and inducible nitric oxide synthase (iNOS). Flow cytometry analysis of CD4 + TNF-α, CD4 + COX-2, and CD4 + STAT-3 cells in whole blood was performed. Structural and dynamic behavior of DMFM upon binding with receptor molecule molecular docking and dynamic simulations were performed using bioinformatics tools and software. Treatment with DMFM reversed cisplatin-induced malondialdehyde (MDA) and nitric oxide (NO) induction, whereas the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) in the kidney, heart, liver, and brain tissues were increased. DMFM administration normalized plasma levels of biochemical enzymes. We observed a marked decline in CD4 + STAT3, TNF-α, and COX2 cell populations in whole blood after treatment with DMFM. DMFM downregulated the expression factors related to inflammation at the mRNA and protein levels, i.e., IL-1, TNF-α, iNOS, NF-κB, STAT-3, and COX-2. Dynamic simulations and in silico docking data supports the experimental findings. Our experimental and in silico results illustrated that DMFM may affect protective action against cisplatin-induced brain, heart, liver, and kidney damage via reduction of inflammation and ROS.

Pituicytoma: A Report of Two Cases and Literature Review

Abstract Introduction Pituicytoma is a rare form of primary benign tumor of the neurohypophysis and infundibulum. There have been 140 reported cases in world literature that could be found in our search. Here we discuss about the presentation, radiological features, treatment, histopathology, and immunohistochemical markers of two cases, along with a brief review of literature. Materials and Methods A 48-year-old female presented with headache and painless visual loss for 4 years. Examination revealed bitemporal hemianopia and normal fundus. Hormonal profile was normal. Magnetic resonance imaging (MRI) showed 2.6 × 2.8 × 3.3 cm, thin-walled, cystic sellar and suprasellar lesions stretching the optic chiasm superiorly. Endoscopic transnasal, transsphenoidal gross total excision was done. Histopathological examination (HPE) and immunohistochemistry (IHC) were suggestive of pituicytoma.A 55-year-old male presented with intermittent headache and vomiting for 3 months. Examination was unremarkable. Hormonal profile was normal. MRI showed lobulated mass of size 1.4 × 1.9 × 2.0 cm, arising from anterior pituitary and extending to the suprasellar cistern. Lesion was hyperintense in T1-weighted and heterointense in T2-weighted images, and Fluid attenuated inversion recovery images (FLAIR) with homogenous contrast enhancement pushed the optic chiasm superiorly. Endoscopic transnasal partial excision of the lesion was done. HPE and IHC were suggestive of pituicytoma. Results Total number of cases was 142, of which 71 were males (50%) and 71 were females (50%). Age ranged between 7 and 83 years (mean 49.2, median 48). Brain imaging was available in 110 cases. Size of the lesion varied from 4 to 72 mm (mean 27 mm). Location was either pure sellar (24.3%) or with extension into the suprasellar cistern (34.3%) and/or the cavernous sinuses (7.1%). Lesions in MRI were solid (84%) with few areas of cystic changes, while contrast enhancement of solid portion was in 92% (homogenous in 80% and heterogeneous in 20%) of the cases. One case showed features of hemorrhage while no case showed calcification. Treatment was primarily surgical (120 out of 130 cases): transsphenoidal excision in 70% of the cases and craniotomy and excision in 30%. Preoperative embolization of arterial feeders was done in two cases and postoperative radiation was given in one case. Gross total resection was done in 46.3%, subtotal resection in 40%, partial resection in 12.6%, and biopsy was done in 1.1% of the cases in the study. Follow-up ranged from 2 to 134 months (average 31.2, median 19). Recurrence or regrowth was documented in 23 patients, treatment in 18 patients, and resurgery was done in 12 cases, followed by radiotherapy in 5. In six cases, radiotherapy was used in isolation. Improvement in the visual deficit was seen in 26 patients, and remained unchanged in 3. Among the patients with preoperative endocrine dysfunction, 10 improved while 11 suffered a worsening. Ten patients had new postoperative endocrine alteration. Only one fatal case was registered. Conclusion Pituicytoma is a rare World Health Organization grade I tumor of the sellar and suprasellar region, presenting with varied clinical, radiological, and hormonal features. Histopathology and immunohistochemistry form the mainstay in diagnosis. Surgical excision with transsphenoidal approach is ideal. Prognosis in general is good after surgical resection alone or in conjunction with radiotherapy.

Jian-Pi-Yi-Shen Formula Improves Adenine-Induced Chronic Kidney Disease via Regulating Tryptophan Metabolism and Aryl Hydrocarbon Receptor Signaling.

Traditional Chinese medicine (TCM) is an important complementary and alternative branch of chronic kidney disease (CKD) therapy. Jian-Pi-Yi-Shen formula (JPYSF) is a TCM formula used for treating CKD with good efficacy. However, the underlying mechanisms of JPYSF in treating CKD remain to be elucidated. The purpose of the present study was to investigate the renoprotective effect and potential mechanism of JPYSF in treating CKD. CKD rat model was induced by feeding a diet containing 0.75% w/w adenine for 4 weeks. JPYSF was given by gavage every day, starting from the 3rd week of the adenine-containing diet and continuing for 4 weeks at the dose of 10.89 g/kg. Renal injury was evaluated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathology, and fibrotic markers expression. Serum levels of tryptophan metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Aryl hydrocarbon receptor (AHR) signaling was tested by Western blot analysis. The results found that JPYSF treatment significantly lowered Scr and BUN levels, improved renal pathological injury, and down-regulated fibrotic markers expression in CKD rats. Furthermore, JPYSF significantly reduced the levels of 10 tryptophan metabolites in the serum of CKD rats and restored the level of tryptophan. Additionally, the kidney expression of AHR signaling was enhanced in CKD rats and was further suppressed in JPYSF treated rats. These results suggested that JPYSF protected against adenine-induced CKD via modulating tryptophan metabolism and AHR activation.

Accumulation of molybdenum in major organs following repeated oral administration of bis-choline tetrathiomolybdate in the Sprague Dawley rat.

Molybdenum is an essential dietary trace element required for several critical enzyme systems. High intake is associated with toxicity in ruminants and animal studies. The proposed therapeutic use of molybdenum-based drugs poses a potential risk for accumulation through chronic administration of therapeutic doses of this element. The current experiment was designed to study the effect of daily dosing of a molybdenum compound, bis-choline tetrathiomolybdate (TTM), in Sprague Dawley rats using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-ToF-MS) and two dosing levels of TTM for up to 3months. To investigate if molybdenum accumulation was associated with tissue toxicity, histopathology, haematology and clinical biochemistry markers of toxicity were incorporated into the study design. There were no behavioural signs of toxicity to the rats, and no clinical or anatomic pathology was associated with treatment. The current data did show a progressive accumulation of molybdenum within the adrenal gland, kidneys, liver, spleen, brain and testes. Although this was not associated with tissue toxicity within the 3-month study design, greater exposure over a longer period of time has the potential for producing adverse pathophysiological cellular function. Tissue toxicity, as a result of local excessive accumulation of molybdenum over time, has clear implications for the therapeutic use of molybdenum in humans and demands sensitive monitoring of tissue molybdenum levels to avoid toxicity. The current study highlights the shortcomings of conventional biomonitoring approaches to detect molybdenum accumulation with the goal of avoiding molybdenum-associated toxicity.