Reproducibility of Morphologic Parameters of the International Endocervical Adenocarcinoma Criteria and Classification System and Correlation With Clinicopathologic Parameters: A Multi-Institutional Study.

Endocervical adenocarcinomas (ECAs) have been recently reclassified according to their morphologic features linked to etiology by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and this system is adopted by WHO 2020. This classification separates the ECAs as human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) subtypes. According to WHO 2020, high risk (HR)-HPV association can be histologically recognized by the presence of luminal mitoses and apoptosis. Therefore, investigating the reproducibility of the morphologic criteria of this new classification will be important in observing the recognizability of tumor types. Full slide sets of 94 ECAs were collected from 4 institutions in Turkey and reclassified on the basis of IECC/WHO 2020 criteria and the presence or absence of HR-HPV. HR-HPV presence was confirmed by HPV DNA in situ hybridization, p16 immunohistochemistry and in conflicted cases with real time-polymerase chain reaction. The final diagnoses were given based on the combination of the histologic evaluation and ancillary test results. Our cohort consisted of 73.4% HPVA and 26.6% HPVI cases. According to the WHO 2020 criteria 92.7% of HPVAs and 88% of HPVIs were easily classified. HPV DNA in situ hybridization was positive in 91.3% of the HPVAs and p16 was positive in all HPVAs, and also positive in 8% of the HPVIs. In conclusion, most of the ECAs can be diagnosed by their characteristic morphologic features by the WHO 2020 criteria. However, we want to emphasize that mitosis/apoptosis criteria may not be helpful especially in mucinous ECAs and ancillary tests for HR-HPV should be used in challenging cases.

The prognostic significance of stage I ovarian clear cell and endometrioid carcinomas arising from endometriotic cysts: is it a myth?

PURPOSE: The aim of this study was to determine the clinicopathologic features and the prognostic significance of Stage I ovarian clear cell and endometrioid carcinomas arising from endometriotic cysts. MATERIALS AND METHODS: Patients with either Stage I ovarian clear cell or endometrioid carcinoma were divided into three groups. *Group 1: Patients with cancers arising from endometriotic cysts *Group 2: Patients with ovarian and pelvic endometriosis *Group 3: Patients without endometriosis Patient characteristics (overall survival and disease-free survival) were compared between groups. RESULTS: Of the 78 patients who participated in this study, 39 were in group 1, 13 were in group 2, and 26 were in group 3. The mean age in groups 1, 2, and 3 were 46 years, 54 years, and 48 years, respectively (p = 0.39). Tumoral characteristics, including capsule rupture, positive cytology, grade, and the presence of synchronous endometrial cancer were similar in both groups. The 5-year overall survival rate in groups 1, 2, and 3 were 100, 90, and 93%, respectively (p = 0.4). Moreover, the recurrence rates did not differ significantly between groups. Furthermore, subgroup analysis of clear cell carcinoma and endometrioid adenocarcinoma separately showed no effect of endometriosis on disease-free survival (DFS) or overall survival (OS). CONCLUSION: Clear cell or endometrioid ovarian carcinoma arising from ovarian and/or pelvic endometriosis shares the same clinicopathologic characteristics with their counterparts that do not arise from endometriosis and patients have similar overall and disease-free survival.

The preoperative albumin level is an independent prognostic factor for optimally debulked epithelial ovarian cancer.

PURPOSE: A low albumin level has been reported to be a prognostic factor for various cancers. The aim of this study was to determine the association between preoperative serum albumin level and survival in patients with epithelial ovarian cancer (EOC). METHODS: Records of 337 patients with EOC that underwent optimal cytoreductive surgery were retrospectively reviewed. Threshold albumin level was planned as 32.5 g L-1 due to the statistical analyses. RESULTS: Mean overall survival was 51.5 months. Area under the ROC curve was found statistically significant for the discriminative role of albumin for survival outcome (AUC = 0.857, 95% CI 0.813-0.90, P < 0.001). The best cut-off point for albumin was determined as 32.5 g L-1. The sensitivity rate, specificity rate, positive and negative predictive values, and accuracy rate for this cut-off level were found 67.2, 91.2, 81.2, 83.1, and 82.5%, respectively. Preoperative hypoalbuminemia was noted in 101 (30.0%) of the patients, of which 6.2% had an albumin level <25 g L-1. The albumin level was independently and significantly associated with overall survival (HR 2.6; 95% CI 2.1-3.1; P < 0.001). Subgroup analysis showed that patients with an albumin level <32.5 and ≥32.5 g L-1 had mean estimated overall survival of 40.6 and 96.0 months, respectively. Age, stage, and presence of ascites were the other independent significant factors. CONCLUSIONS: The preoperative albumin level is an independent prognostic factor for overall survival in optimally debulked EOC patients. Further investigations about preoperative albumin level in prognostic models will contribute to the literature.

Serous versus high-grade endometrioid endometrial carcinoma: immunohistochemistry of RFP is not useful for differentiation.

We evaluated the immunohistochemical expression of ret finger protein (RFP) along with conventional immunohistochemical markers in endometrioid and serous carcinomas of the endometrium. A total of 124 endometrial carcinoma cases (24 grade 1 endometrioid, 60 grade 3 endometrioid, 40 serous) were retrieved from pathology archives. Tissue microarrays were constructed. The expression of RFP, WT1, ER, PR, p53 and p16 was examined immunohistochemically. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve,  statistic for interobserver reproducibility, Kruskal-Wallis test, Mann-Whitney U test and Fisher's exact tests were performed for statistical analyses. The mean RFP score was 1.54 in grade 1 endometrioid, 4.31 in grade 3 endometrioid, and 6.31 in serous carcinomas (p < 0.001). Overall, RFP scores were higher both in serous and grade 3 endometrioid carcinoma (p > 0.05), and significantly lower in grade 1 endometrioid carcinoma (p < 0.05). p16 and p53 staining patterns were able to differentiate between high-grade endometrioid and serous carcinoma (p < 0.001). ER, PR and WT-1 did not reach statistical significance for subtyping. The  values of the general agreement between the observers were 0.737 and 0.727 for endometrioid and serous carcinomas respectively (p < 0.001). Diffuse p53 and p16 staining provides the most sensitive and specific immunomarkers for differentiating high-grade endometrioid and serous carcinomas.

Fertility-sparing approach to malignant ovarian germ cell tumors - Oncologic and obstetric outocome: A retrospective study.

OBJECTIVE: To evaluate oncologic (such as disease-free and overall survival) and obstetric outcomes in patients diagnosed with malignant ovarian germ cell tumors (MOGCTs). METHODS: Patients diagnosed with MOGCTs between March 2007 and February 2022 were evaluated and patients who underwent fertility sparing surgery were included in this retrospective study. The obstetric and oncologic outcomes were evaluated by collecting data up until the patient's last follow-up visit from the hospital records and patient files. The study was approved by Baskent University Institutional Review Board (KA23/124). RESULTS: Seventy FSS patients were included in this study. The median age of the patients was 22.5 years (range: 11-37). The median follow-up time was 92.0 months (10-189). Immature teratoma was the most common histological subtype (32.9%). Bilateral involvement was detected in only one patient with immature teratoma (1.4%). The 5-year DFS rates of immature teratoma, dysgerminoma, yolk sac, and mixed germ cell histologic types were 91.1%, 94.1%, 82.4%, and 88.9%, respectively (P: 0.716). The 5-year OS rates of the same histologic types were 95.7%, 100%, 88.2%, and 88.9%, respectively (P = 0.487). All patients (100%) had a regular menstrual cycle after the completion of adjuvant treatment. The mean time between the last chemotherapy and menstruation was 4.38 months. To date, a total of 34 patients tried to conceive after the completion of disease treatment. A total of 23 (67.6%) patients conceived, resulting in 27 live births in 22 (100%) patients. CONCLUSION: Fertility preservation should be the first treatment option in MOGCTs in young patients due to the unilateral involvement of the disease and its chemosensitive nature.

Efficacy of the Sonoelastography Method for Diagnosis of Fibrosis in Renal Transplant Patients.

OBJECTIVES: Although biopsy is the most important method for diagnosing the cause of renal allograft dysfunction, sonoelastography, a new ultrasonography method, can be used to distinguish between the soft or hard nature of lesions. In this study, our aim was to investigate whether sonoelastography could diagnose fibrosis in renal transplant patients. MATERIALS AND METHODS: In this prospective study, we included patients over 18 years old who were recommended for clinical biopsy. Sonoelastographic evaluation was made by conducting acoustic radiation force impulse measurements for each patient after they were admitted to the clinic for biopsy. Measurements were performed just before the biopsy procedure. All results were examined by 2 experienced radiologists using the Siemens S3000 Ultrasound Machine (Erlangen, Germany). Comparisons of ultrasonographic values with biopsy results were made with SPSS software (SPSS: An IBM Company, version 20, IBM Corporation, Armonk, NY, USA). RESULTS: Of the 65 patients included in this study, pathology showed acute T-cell-mediated rejection in 37 patients. There was a significant correlation between the pathologic Banff scores and the sonographic acoustic radiation force impulse values (P = .002), where the degree of Banff increased as the mean acoustic radiation force impulse values elevated. A rise in mean impulse values correlated with increased degree of interstitial fibrosis in renal allografts. Renal parenchymal echogenicity of patients significantly differed by sex (P = .009), with an average renal echogenicity of grade 1 in women and grade 0 in men. Also, a statistically significant difference was found between age of the renal transplant recipient and resistive index values. CONCLUSIONS: Our study showed a significant correlation between Banff degree and the acoustic radiation force impulse values of renal transplant patients. In addition to biopsy, sonoelastography can be beneficial for the diagnosis of fibrosis in renal transplant patients.

Antiproliferative and Mitochondrial Protective Effects of Apigenin in an Oxygen-Induced Retinopathy In Vivo Mouse Model.

Purpose: To investigate the effects of a common dietary flavonoid apigenin on retinal endothelial cell proliferation, retinal morphological structure, and apoptotic cell death in an oxygen-induced retinopathy (OIR) mouse model to evaluate the possibility of the use of apigenin in the treatment of ocular neovascular diseases (ONDs). Methods: Ninety-six newborn C57BL/6J mice were included. Eight groups were randomized, each including 12 mice. Two negative control groups were kept in room air: the first without any injection and the second received intravitreal (IV) dimethyl sulfoxide (DMSO), which is the solvent we used. The OIR groups were exposed to 75% ± 2% oxygen from postnatal days (PD) 7 to 12. On PD 12, the mice were randomly assigned to 6 groups: 2 OIR control groups (1 received no injection, 1 received IV-DMSO), 2 IV-apigenin groups (10 and 20 µg/mL), and 2 intraperitoneal (IP)-apigenin groups (10 and 20 mg/kg). We quantified retinal endothelial cell proliferation by counting neovascular tufts in cross-sections and examined histological and ultrastructural changes through light and electron microscopy. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL). Results: We detected a significant increase in endothelial cell proliferation in the OIR groups. Groups receiving apigenin, both IP and IV, had significant decreases in endothelial cells, atypical mitochondrion count, and apoptotic cells compared with the groups receiving no injections. None of the apigenin-injected groups revealed cystic degeneration or cell loss. Conclusions: Apigenin suppresses neovascularization, has antiapoptotic and antioxidative effects in an OIR mouse model, and can be considered a promising agent for treating OND. Clinical trial (Project number: DA15/19).

Doxycycline causes regression of endometriotic implants: a rat model.

BACKGROUND: Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase (MMP) activity. The aim of this study was to assess the effects of Dox in a rat endometriosis model. METHODS: Endometriosis was surgically induced in 40 rats by transplanting of endometrial tissue. After 3 weeks, repeat laparotomies were performed to check the implants and the animals were randomized into four groups: Group I, low-dose Dox (5 mg/kg/day); Group II, high-dose Dox (40 mg/kg/day); Group III, leuprolide acetate 1 mg/kg single dose, s.c.; and Group VI (controls), no medication. The treatment, initiated on the day of surgery and continuing for 3 weeks, was administered to the study groups. Three weeks later, the rats were euthanized and the implants were evaluated morphologically and histologically for immunoreactivity of MMP-2 and -9, and interleukin-6 (IL-6) concentration in the peritoneal fluid was assayed. RESULTS: Treatment with leuprolide acetate, or high-dose or low-dose Dox caused significant decreases in the implant areas compared with the controls (P = 0.03, P = 0.006, and P = 0.001, respectively). IL-6 levels in peritoneal fluid decreased in Group I (P = 0.02) and Group III (P < 0.05). MMP H scores were significantly lower in the group that received low-dose Dox in both epithelial and stromal MMP-2 and -9 immunostaining when compared with the control group [P = 0.048, P = 0.002, P = 0.007 and P = 0.002, respectively, MMP-2 (epithelia), MMP-2 (stroma), MMP-9 (epithelia) and MMP-9 (stroma)]. CONCLUSIONS: Low-dose Dox caused regression of endometriosis in this experimental rat model.

Antiproliferative and anti-apoptotic effect of astaxanthin in an oxygen-induced retinopathy mouse model.

OBJECTIVE: To evaluate the impact of intravitreal (IV) and intraperitoneal (IP) astaxanthin (AST) injections on neovascular development (ND), retinal morphology, and apoptotic activity in a C57BL/6J mouse model with hyperoxia-induced retinopathy (HIR). DESIGN: C57BL/6J mouse model. METHODS: Two negative control groups (n = 6 each; one of which received IV sterile dimethyl sulfoxide [DMSO]) of C57BL/6J-type mice were exposed to room air. The HIR groups included 36 C57BL/6J-type mice exposed to 75% ± 2% oxygen from postnatal day (PD) 7 to PD 12. On PD 12, these mice were randomized into 6 groups (n = 6 each): 2 HIR control groups (one of which received IV-DMSO), 2 IV-AST groups (10 and 100 µg/mL), and 2 IP-AST groups (0.5 and 5 mg/kg). We measured ND by counting neovascular tufts in cross sections and examined histological, ultrastructural changes via light and electron microscopy. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated nick end-labeling. RESULTS: No ND was detected in the negative control groups. ND levels were not significantly different between high- and low-dose AST for either means of administration. However, ND levels were significantly lower in the AST groups, regardless of delivery, compared to the control groups. The means of delivery (IP versus IV) also yielded significant differences in ND. The incidence of mitochondrial dysmorphology and apoptosis were lower in groups receiving AST. CONCLUSIONS: AST seems to suppress ND and has anti-apoptotic activity in the HIR mouse model.

Effect of intravitreal and intraperitoneal cyanidin-3-glucoside injection in oxygen-induced retinopathy mouse model.

Purpose: To evaluate the effect of cyanidin-3-glucoside (C3G) in oxygen-induced retinopathy (OIR) mouse model. Methods: In this experimental study, 10 C57BL / 6J type mice exposed to room air comprised two control groups (n = 5 each; a negative control and a group receiving intravitreal sterile dimethyl sulfoxide [IVS DMSO]). Thirty C57BL / 6J type mice exposed to 75% ± 2% oxygen from postnatal day 7 to postnatal day 12 comprised the OIR groups. On postnatal day 12, these mice were randomized into six groups (n = 5 each): two OIR control groups (negative control and IVS DMSO), two intravitreal C3G groups (300 and 600 ng/µL), and two intraperitoneal C3G groups (0.05 and 0.1 mg/kg). We quantified neovascularization by counting endothelial cell proliferation on the vitreal side of the inner limiting membrane of the retina and examined histological and ultrastructural changes via light and electron microscopy and apoptosis by terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling. Results: The intravitreal C3G groups yielded lower endothelial cell counts compared with the intravitreal DMSO group. The intraperitoneal high-dose group had lower cell counts compared with the OIR control groups. Electron microscopy revealed significantly less mitochondrial dysmorphology in intravitreal groups and the high-dose intraperitoneal mice. We noted no difference in apoptotic cell count between the controls, low-dose intravitreal, and both intraperitoneal groups. However, apoptotic cell count was significantly higher in the high-dose intravitreal group. Conclusion: C3G suppresses endothelial cell proliferation in an OIR mouse model, leads to a reduced hyperoxia-induced mitochondrial dysmorphology, but increases apoptotic cell death in high concentrations.

A single-center experience of post-transplant lymphoproliferative disorder (PTLD) cases after pediatric liver transplantation: Incidence, outcomes, and association with food allergy.

BACKGROUND/AIMS: We evaluated our 16-year single-center experience of pediatric post-transplant lymphoproliferative disorder (PTLD) cases who underwent liver transplantation between 2001 and 2017. MATERIALS AND METHODS: Of the 236 pediatric patients who underwent liver transplantation between 2001 and 2017, the clinical and laboratory data of eight patients diagnosed with PTLD were reviewed. The pre-transplant Epstein-Barr virus (EBV) status of 172 patients was also recorded. RESULTS: The total incidence of PTLD was 3.4%. The incidence of PTLD was 10% in pre-transplant EBV immunoglobulin G (IgG)-seronegative patients and 0.8% in pre-transplant EBV IgG-seropositive patients. The mean age of the patients at liver transplantation was 2.71±3.21 years, and four patients were aged below 1 year at the time of transplantation. PTLD was diagnosed at 21.81±18.1 months after transplantation. The primary site of involvement was variable among patients: peripheral and mediastinal lymph nodes, stomach and intestine, transplanted graft, bone marrow, and nasopharynx. The eosinophil count varied greatly among patients, with a mean value of 524.62±679/mm3. Three patients had a food allergy and were administered an elimination diet at the time of PTLD diagnosis. Six patients had PTLD of B-cell origin. One patient died due to neutropenic sepsis during chemotherapy, whereas seven patients were followed up in full remission for 7.75±4 years. CONCLUSION: PTLD is a life-threatening complication of solid-organ transplantation with a heterogeneous clinical spectrum. Food allergy had a close association with PTLD. A close follow-up of patients with risk factors and an early diagnosis with appropriate treatment may lead to a better outcome.

Liver Biopsy Results in Potential Donor Evaluation in Living Related Liver Transplant.

OBJECTIVES: The number of living-donor liver transplants has been increasing due to the growing discrepancy between the number of patients on wait lists for liver transplant and the availability of deceased donations. Evaluations of potential liver donors should ensure the safety of the surgical procedure for both the donor and recipient. Liver biopsy is the criterion standard for selecting optimal donors. In this study, we evaluated the importance of preoperative liver biopsy in selecting donor candidates. MATERIALS AND METHODS: We evaluated the data of 612 living-related liver donor candidates who received liver biopsies between January 2001 and June 2017 at our center. RESULTS: In the 612 liver donor candidates (328 male, 284 female; age range, 18-69 years), 416 liver biopsies (68%) were reported as normal and 196 liver biopsies (32%) had pathologic findings. Of 196 donors with pathologic findings, 86 (44%) had fatty changes and 24 (12%) had portal inflammation. CONCLUSIONS: The high rate of pathologic findings in liver biopsy of healthy-appearing donor candidates indicated the importance of liver biopsy in the preoperative evaluation of donors.

Evaluation of neointimal hyperplasia on tranilast-coated synthetic vascular grafts: an experimental study.

Tranilast is an antiallergic drug that interferes with proliferation and migration of vascular smooth muscle cell induced by platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1). We investigated the local effect of tranilast on neointimal hyperplasia using tranilast-coated prosthetic grafts. The inner sides of the thin-walled polytetrafluoroethylene (PTFE) grafts were coated with chitosan and tranilast containing chitosan solution. Wistar albino rats (32) were used in the study. Patches (1 x 2 mm) for vascular grafts were prepared. Three groups were tested: group 1 (n = 12; tranilast coated), group 2 (n = 10; adhesive-only film-layer-coated), and group 3 (n = 10; normal ePTFE patch grafts sutured to the carotid arteries of the rats). Recipient sites of the carotid arteries were excised 4 weeks after surgery. All sections were examined histologically for graft patency, thrombus formation, and neointimal thickness. Expression of PDGF, fibroblast growth factor, and TGF-beta1 on cross-sections of the neointima were evaluated by immunohistochemistry. No significant differences were found regarding mean neointimal thicknesses. PDGF and TGF-beta-1 expressions were significantly lower in group 1. Although a decrease in local effect of tranilast was observed for growth factor expressions at a drug concentration of 0.05 mg/cm(2), a significant reduction in neointimal hyperplasia was not achieved. The coating concentration of 0.05 mg/cm(2) may have been too low to produce an antiproliferative effect. Given our promising results, further studies are recommended and planned using different drug concentrations and time intervals.

Diagnostic and Treatment Reproducibility of Cervical Intraepithelial Neoplasia / Squamous Intraepithelial Lesion and Factors Affecting the Diagnosis.

OBJECTIVE: Inter-observer differences in the diagnosis of HPV related cervical lesions are problematic and response of gynecologists to these diagnostic entities is non-standardized. This study evaluated the diagnostic reproducibility of "cervical intraepithelial neoplasia" (CIN) and "squamous intraepithelial lesion" (SIL) diagnoses. MATERIAL AND METHOD: 19 pathologists evaluated 66 cases once using H&E slides and once with immunohistochemical studies (p16, Ki-67 and Pro-ExC). Management response to diagnoses was evaluated amongst 12 gynecologists. Pathologists and gynecologists were also given a questionnaire about how additional information like smear results and age modify diagnosis and management. RESULTS: We show moderate interobserver diagnostic reproducibility amongst pathologists. The overall kappa value was 0.50 and 0.59 using the CIN and SIL classifications respectively. Impact of immunohistochemical evaluation on interpretation of cases differed and there was lack of statistically significant improvement of interobserver diagnostic reproducibility with the addition of immunohistochemistry. We saw that choice of treatment methods amongst gynecologists varied and overall concordance was only fair to moderate. The CIN2 diagnostic category was seen to have the lowest percentage agreement amongst both pathologists and gynecologists. We showed that pathologists had diagnostic "styles" and gynecologists had management "styles". CONCLUSION: In summary each pathologist had different diagnostic tendencies which were affected not only by histopathology and marker studies, but also by the patient management tendencies of the gynecologist that the pathologist worked with. The two-tiered modified Bethesda system improved diagnostic agreement. We concluded that immunohistochemistry should be used only to resolve problems in select cases and not for every case.

What does the Data of 354,725 Patients from Turkey Tell Us About Cervical Smear Epithelial Cell Abnormalities? - The Epithelial Cell Abnormality Rate is Increasing - Quality Control Studies and Corrective Activity are Musts.

OBJECTIVE: There is no other screening program close to the success rate of PAP test. Cervical cytology constitutes a large workload so that quality control in cervical cytology is important for the quality assurance of pathology laboratories. MATERIAL AND METHOD: In this study, we collected the cervical cytology results from all over Turkey and discussed the parameters influencing the quality of the PAP test. The study was conducted with Turkish gynaecopathology working group and 38 centers (totally 45 hospitals) agreed to contribute from 24 different cities. The study was designed to cover the cervical cytology results during 2013. The results were evaluated from the data based on an online questionnaire. RESULTS: The total number of Epithelial Cell Abnormality was 18,020 and the global Epithelial Cell Abnormality rate was 5.08% in the total 354,725 smears and ranging between 0.3% to 16.64% among centers. The Atypical squamous cells /Squamous intraepithelial lesion ratios changed within the range of 0.21-13.94 with an average of 2.61. When the centers were asked whether they performed quality assurance studies, only 14 out of 28 centers, which shared the information, had such a control study and some quality parameters were better in these centers. CONCLUSION: There is an increase in the global Epithelial Cell Abnormality rate and there are great differences among centers. Quality control studies including the Atypical squamous cells/Squamous intraepithelial lesion ratio are important. Corrective and preventive action according to quality control parameters is a must. A cervical cytology subspecialist in every center can be utopic but a dedicated pathologist in the center is certainly needed.

[Multiple myeloma of the sphenoid sinus: a case report]. / Sfenoid sinüs multipl miyelomu: Olgu sunumu.

Plasma cell neoplasms of the head and neck region can be extramedullary plasmacytoma of the bone, solitary plasmacytoma of the bone, and local manifestations of multiple myeloma. A 70-year-old male patient was admitted to our hospital with diplopia of four-day history. Magnetic resonance imaging showed soft tissue in the sphenoid sinus. Endoscopic biopsy was taken from the sphenoid sinus, which revealed multiple myeloma. Despite medical therapy for multiple myeloma, the patient died after a year.

The effects of tacrolimus and mycophenolate mofetil on regression of encapsulating peritoneal sclerosis in a rat model / Efectos del tacrolimus y el micofenolato mofetil en la regresión de la esclerosis peritoneal encapsulante en ratas

ABSTRACT Objective: Encapsulating peritoneal sclerosis (EPS) is a rare, but potentially fatal complication of peritoneal dialysis. Currently, treatment of peritoneal fibrosis is not fully possible yet. In this study, we aimed to demonstrate the effects of tacrolimus therapy on peritoneal fibrosis and inflammation when administered alone or with mycophenolate mofetil (MMF) in the EPS model induced in rats. Methods: Thirty six Wistar albino rats were separated into six equal groups. Group I was the control group. Group II-VI were administered intraperitoneal chlorhexidine (CH) for induced EPS model in rats. Group II, IV, V, VI were administered isotonic liquid, tacrolimus, tacrolimus and concurrently with CH, tacrolimus and MMF together, respectively. Group III was not administered any drug. All peritoneal samples were stained immunohistochemically with matrix metalloproteinase-2 (MMP-2) antibody. Thickness of peritoneal fibrosis, subserosal large collagen fibers, subserosal fibroblast proliferation and subserosal fibrotic matrix deposition were evaluated. Results: Comparing the experimentally induced EPS groups, the best histopathological results and the largest staining with MMP-2 were achieved in Group VI. Furthermore, in all treatment groups (IV, V, VI) more staining with MMP-2 was detected compared to non-treatment groups (I, II, III) but no statistically significant differences were found among all groups. A statistically significant remission was observed in all histopathological parameters, primarily peritoneal thickness in rats that were administered MMF with tacrolimus, compared to rats which were administered tacrolimus only. Conclusion: Concurrent use of tacrolimus and MMF in the treatment of EPS may be a promising approach.

RESUMEN Objetivos: La esclerosis peritoneal encapsulante (EPE) es una complicación rara, peropotencialmente fatal de la diálisis peritoneal. Actualmente, el tratamiento de la fibrosis peritoneal aún no es posible. En este estudio, apuntamos a demostrar los efectos de la terapia con tacrolimus en la fibrosis peritoneal y la inflamación cuando se administran solos o con micofenolato de mofetilo (MMF) en el modelo EPE inducido en ratas. Métodos: Treinta y seis ratas Wistar albinas se separaron en seis grupos iguales. El Grupo I era el grupo de control. En los grupos II-VI se administró clorhexidina intraperitoneal (CH) para el modelo EPE inducido en ratas. En los Grupos II, IV, V, VI se administró respectivamente líquido isotónico, tacrolimus, tacrolimus y CH y finalmente tacrolimus y MMF juntos. El grupo III no recibió ningún medicamento. Todas las muestras peritoneales se tiñeron inmunohistoquímicamente con el anticuerpo Matrix Metaloproteinasa-2 (MMP- 2). Se evaluó el grosor de la fibrosis peritoneal, se evaluaron las fibras de colágeno grandes subserosas, la proliferación de fibroblastos subserosa y la deposición de la matriz fibrótica subserosa. Resultados: Comparando los grupos de EPE inducidos experimentalmente, los mejores resultados histopatológicos y la tinción con MMP- 2 más extensa se lograron en el Grupo VI. Además, en todos los grupos de tratamiento (IV, V, VI) se detectó más tinción con MMP-2 en comparación con los grupos de no tratamiento (I, II, III), pero no se encontraron diferencias estadísticamente significativas entre todos los grupos. Se observó una remisión estadísticamente significativa en todos los parámetros histopatológicos, principalmente el espesor peritoneal en ratas que recibieron MMF con tacrolimus, en comparación con las ratas que recibieron solo tacrolimus. Conclusión: El uso concurrente de tacrolimus y MMF en el tratamiento de EPS puede ser una aplicación prometedora.

Effects of heparin on bacterial translocation and gut epithelial apoptosis after burn injury in the rat: dose-dependent inhibition of the complement cascade.

This study investigated levels of complement inhibition, apoptosis of gut epithelium, and bacterial translocation (BT) associated with different doses of heparin in rats with severe burns. After burn injury, the animals in Groups 1, 2, 3, and 4 received intravenous tail-vein bolus heparin doses of 150, 300, 600, and 1200 U/kg, respectively. Group 5 received no heparin after burn injury. Group 6 served as control group. According to the results, Group 2 had the highest rate of positive staining for C3, and Group 4 had the lowest rate. There were significant differences between these two groups with respect to distribution of immunoflouresein scores for C3 (p=0.01). Group 5 had the highest mean TUNEL index of all the groups (258/10) (p=0.01). On electron microscopy, the connective tissue cells in the ileal submucosa from Groups 4 and 5 showed more significant apoptotic changes than the corresponding cells in the other groups. The total BT values in Group 4 (129 x 10(4) CFU) and Group 5 (100 x 10(4) CFU) were both significantly higher than those in the other groups (p=0.01). Group 1 had the lowest total BT value (6.1 x 10(2) CFU) (p=0.001). In summary, our results confirm that heparin administration after significant burn injury in rats can reduce BT, and that the effect is related to dose. The findings also indicate that levels of BT after burn injury increase in parallel with the extent of gut epithelial cell apoptosis.

Report of 3 Patients With Urea Cycle Defects Treated With Related Living-Donor Liver Transplant.

Urea cycle defects are a group of metabolic disorders caused by enzymatic disruption of the urea cycle pathway, transforming nitrogen to urea for excretion from the body. Severe cases present in early infancy with life-threatening metabolic decompensation, and these episodes of hyperammonemia can be fatal or result in permanent neurologic damage. Despite the progress in pharmacologic treatment, long-term survival is poor especially for severe cases. Liver transplant is an alternative treatment option, providing sufficient enzymatic activity and decreasing the risk of metabolic decompensation. Three patients with urea cycle defects received related living-donor liver transplants at our hospital. Patients presented with late-onset ornithine transcarbamylase deficiency, argininosuccinate lyase deficiency, and citrullinemia. Maximum pretransplant ammonia levels were between 232 and 400 µmol/L (normal range is 18-72 µmol/L), and maximum posttransplant values were 52 to 94 µmol/L. All patients stopped medical treatment and dietary protein restriction for urea cycle defects after transplant. The patient with late-onset ornithine transcarbamylase deficiency already had motor deficits related to recurrent hyperammonemia attacks pretransplant. A major improvement could not be achieved, and he is wheelchair dependent at the age of 6 years. The other 2 patients had normal motor and mental skills before transplant, which have continued 12 and 14 months after transplant. Hepatic artery thrombosis in the patient with the ornithine transcarbamylase deficiency, intraabdominal infection in the patient with argininosuccinate lyase deficiency, and posterior reversible encephalopathy syndrome in the patient with citrullinemia were early postoperative complications. Histopathologic changes in livers explanted from patients with ornithine transcarbamylase deficiency and citrullinemia were nonspecific. The argininosuccinate lyase-deficient patient had portoportal fibrosis and cirrhotic nodule formation. In conclusion, liver transplant was a lifesaving procedure for our patients. Proper timing for transplant is important because high ammonia levels may result in permanent neurologic damage; however, transplant at younger ages also may increase morbidity.

A giant villous adenoma case mimicking right colon carcinoma.

An 85-year-old woman was admitted to our hospital due to pain and swelling in her right inguinal region. She had a right inguinal hernia. Abdominal computerized tomography revealed an 8 x 8 cm cecal mass and also a 13.5 cm segmental asymmetric nodular thickening of the cecum. Colonoscopic examination revealed a sessile polypoid mucus-secreting mass mimicking carcinoma that narrowed the cecal lumen. Histopathological examinations of sections from colonoscopic biopsy materials on light microscopy revealed villous adenoma morphology. The patient underwent operation, and an 18 x 6 x 4 cm mass, which partially obstructed the cecum, was seen. A right hemicolectomy was performed for complete excision. Histopathological examination revealed a pure villous adenoma, and there was no sign of malignant degeneration. On the 6th postoperative day, the patient was discharged from the hospital. During follow-ups at three-month intervals throughout one year, no abnormal colonoscopic or laboratory findings were assessed. We believe that, in older patients with inguinal hernia, presence of intraabdominal mass should be considered. Furthermore, we showed in this report that villous adenomas can reach significant dimensions without causing any obstructing signs or electrolyte imbalance and can mimic colon carcinoma.