Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest.

Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868-75. ©2016 AACR.

A Temperature of 40 °C Appears to be a Critical Threshold for Potentiating Cytotoxic Chemotherapy In Vitro and in Peritoneal Carcinomatosis Patients Undergoing HIPEC.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery is a radical but effective treatment option for patients with peritoneal carcinomatosis (PC). Unfortunately, a standardized HIPEC protocol is missing impeding systematic comparisons with regard to minimal effective temperatures. OBJECTIVE: The purpose of the present study was to systematically analyse the precise minimal temperature needed for potentiation of chemotherapy effects in vitro and for patient survival. METHODS: We established a cell line-based model to mimic HIPEC conditions used in clinical practice, and evaluated intracellular drug concentrations and long-term survival using different temperatures ranging from 38 to 42 °C combined with cisplatin or doxorubicin. In parallel, we evaluated the temperature reached in the clinical setting by measuring inflow and outflow, as well as in two locations in the peritoneal cavity in 34 patients. Finally, we determined the influence of different HIPEC temperatures on survival. RESULTS: Long-term survival of cells treated with either cisplatin or doxorubicin was further improved only at temperatures above 40 °C. In patients, during HIPEC, constant temperatures were reached after 10 min in the peritoneal cavity. A temperature above 40 °C for at least 40 min was achieved in 68 % of patients over the 60 min duration of HIPEC. Importantly, we observed a significantly enhanced overall survival (OS) and progression-free survival (PFS) in those patients reaching temperatures above 40 °C. CONCLUSIONS: Hyperthermia significantly potentiated the chemotherapy effects only at temperatures above 40 °C in vitro. Importantly, this temperature threshold was also critical for OS and PFS of PC patients.

C-reactive protein levels in combination with abdominal CT scans is a useful tool to predict the macroscopic appearance in late-stage EPS patients prior to surgery.

BACKGROUND: Diagnosis of encapsulating peritoneal sclerosis (EPS) is based on clinical symptoms, radiologic findings, and macroscopic or histological criteria. Two diagnostic scores for radiologic findings in computed tomography (CT) scans of patients with EPS have been established in the past (by Tarzi et al and Vlijm et al). The macroscopic appearance of EPS has previously been separated into three types. The use of CT scan as a tool to predict different macroscopic phenotypes, leading to specific surgical techniques and different medical treatment, has not yet been investigated. METHODS: We retrospectively analyzed 30 patients with late-stage EPS who underwent major surgery with peritonectomy and enterolysis. The preoperative CT scans were scored according to the two aforementioned established diagnostic CT scores. The macroscopic phenotype, surgical procedure, and laboratory values at the time of surgery were evaluated. CT findings in the different macroscopic phenotypes were analyzed. RESULTS: All patients had highly predictive CT scores for EPS. The macroscopic Type III had significantly higher CT scores compared with the other macroscopic phenotypes. Patients with macroscopic Type I had significantly higher C-reactive protein values compared to EPS Type III. Operation time was significantly longer, and repeated surgery and intraoperative complications were more frequent in EPS Type I compared with EPS Type III (P<0.05). Using the CT score and CRP level, the sensitivities for prediction of EPS I and III were 78% and 87% with corresponding specificities of 67% and 93%. CONCLUSION: Abdominal CT scans might help to identify patients with a higher risk of complications and provide important information for the surgical intervention prior to surgery.

Activation of nuclear factor of activated T cells 5 in the peritoneal membrane of uremic patients.

Peritoneal inflammation and fibrosis are responses to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to high osmolarity via the transcription factor nuclear factor of activated T cells (NFAT5). In the present study, the response of human peritoneal fibroblasts to glucose was analyzed in vitro. Expression levels of NFAT5 and chemokine (C-C motif) ligand (CCL2) mRNA were quantified in peritoneal biopsies of five nonuremic control patients, five uremic patients before PD (pPD), and eight patients on PD (oPD) using real-time PCR. Biopsies from 5 control patients, 25 pPD patients, and 25 oPD patients were investigated using immunohistochemistry to detect the expression of NFAT5, CCL2, NF-κB p50, NF-κB p65, and CD68. High glucose concentrations led to an early, dose-dependent induction of NFAT5 mRNA in human peritoneal fibroblasts. CCL2 mRNA expression was upregulated by high concentrations of glucose after 6 h, but, most notably, a concentration-dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies, NFAT5 mRNA levels were increased in uremic patients compared with nonuremic control patients. No significant difference was found between the pPD group and oPD group. CCL2 mRNA expression was higher in the oPD group. Immunohistochemistry analysis was consistent with the results of mRNA analysis. CD68-positive cells were significantly increased in the oPD group. In conclusion, uremia results in NFAT5 induction, which might promote early changes of the peritoneum. Upregulation of NFAT5 in PD patients is associated with NFκB induction, potentially resulting in the recruitment of macrophages.

Histological and clinical findings in patients with post-transplantation and classical encapsulating peritoneal sclerosis: a European multicenter study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) commonly presents after peritoneal dialysis has been stopped, either post-transplantation (PT-EPS) or after switching to hemodialysis (classical EPS, cEPS). The aim of the present study was to investigate whether PT-EPS and cEPS differ in morphology and clinical course. METHODS: In this European multicenter study we included fifty-six EPS patients, retrospectively paired-matched for peritoneal dialysis (PD) duration. Twenty-eight patients developed EPS after renal transplantation, whereas the other twenty-eight patients were classical EPS patients. Demographic data, PD details, and course of disease were documented. Peritoneal biopsies of all patients were investigated using histological criteria. RESULTS: Eighteen patients from the Netherlands and thirty-eight patients from Germany were included. Time on PD was 78(64-95) in the PT-EPS and 72(50-89) months in the cEPS group (p>0.05). There were no significant differences between the morphological findings of cEPS and PT-EPS. Podoplanin positive cells were a prominent feature in both groups, but with a similar distribution of the podoplanin patterns. Time between cessation of PD to the clinical diagnosis of EPS was significantly shorter in the PT-EPS group as compared to cEPS (4(2-9) months versus 23(7-24) months, p<0.001). Peritonitis rate was significantly higher in cEPS. CONCLUSIONS: In peritoneal biopsies PT-EPS and cEPS are not distinguishable by histomorphology and immunohistochemistry, which argues against different entities. The critical phase for PT-EPS is during the first year after transplantation and therefore earlier after PD cessation then in cEPS.

Incidence of and risk factors for hungry bone syndrome in 84 patients with secondary hyperparathyroidism.

INTRODUCTION: Secondary hyperparathyroidism develops in nearly all patients with end-stage renal disease. Parathyroidectomy is often performed when medical therapy fails. The most common postoperative complication, hungry bone syndrome (HBS), requires early recognition and treatment. MATERIALS AND METHODS: A total of 84 patients who underwent parathyroidectomy because of secondary hyperparathyroidism were investigated. Detailed analysis of laboratory parameters (calcium, phosphate, parathyroid hormone, hemoglobin, and urea levels) and baseline characteristics (age at time of surgery, duration of renal replacement therapy, and medication) was performed to detect preoperative predictors for the development of HBS. RESULTS: Average overall follow-up of the cohort was 4.7 years. Within this time frame, 13 of 84 patients had to undergo a second surgery because of recurrent disease, and HBS occurred in 51.2%. Only decreased preoperative calcium levels and younger age at time of surgery were significant predictors of HBS. Minimal levels of calcium were detected 3 weeks after surgery. Preoperative vitamin D therapy could not prevent HBS and could not shorten the duration of intravenous calcium supplementation. CONCLUSION: HBS is a very common complication after parathyroidectomy. Younger patients and patients with low preoperative calcium levels were at higher risk for the development of HBS. Remarkably, preoperative vitamin D therapy could not prevent HBS and had no impact on the length of intravenous calcium supplementation. Intensive monitoring of calcium levels must be performed for at least 3 weeks after surgery.

Analysis of α-klotho, fibroblast growth factor-, vitamin-D and calcium-sensing receptor in 70 patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Secondary hyperparathyroidism (sHPT) is known as a very common complication in patients with chronic kidney disease, and G-protein-coupled calcium-sensing receptor (CaSR), Vitamin D receptor (VDR) and Fibroblast growth factor receptor (FGFR)/Klotho complexes seem to be involved in its development. METHODS: Hyperplastic parathyroid glands from 70 sHPT patients and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional morphological and immunohistochemical analysis of parathyroid glands was performed after dividing each slide in a 3x3 array. RESULTS: The presence of lipocytes in the normal parathyroid gland and tissue architecture (nodal in patients with sHPT) allows for discrimination between normal parathyroid glands and parathyroid glands of patients with sHPT. Protein expression of Klotho, FGFR, CaSR and VDR was higher in the normal parathyroid glands compared to the sHPT group (p<0.001, p=0.07, p =0.01 and p=0.001). The variability of each protein expression within each tissue slide was high. Therefore correlations between the different immunohistochemical variables were analyzed for each of the nine fields and than analyzed for all patients. Using this analysis, a highly significant positive correlation could be found between the expression of FGFR and VDR (p=0.0004). Interestingly, in terms of VDR we found a shift to a more mixed nuclear/cytoplasmic staining in the HPT group compared to normal parathyroid gland cells, which showed solitary nuclear staining for VDR (p>0.05). CONCLUSIONS: CaSR, VDR and an impaired Klotho-FGFR-axis seem to be the major players in the development of sHPT. Whether the detected correlation between FGFR and VDR and the shift to a more mixed nuclear/cytoplasmic staining of VDR will yield new insights into the pathogenesis of the disease has to be evaluated in further studies.

Phenotypes of encapsulating peritoneal sclerosis--macroscopic appearance, histologic findings, and outcome.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis (PD), with clinical signs of abdominal pain, bowel obstruction, and weight loss in late stages. METHODS: We retrospectively analyzed all patients who were diagnosed with EPS between March 1998 and October 2011 in our department of nephrology. We focused on the 24 EPS patients who underwent surgery because of symptomatic late-stage EPS. We identified 3 different macroscopic phenotypes of EPS that we categorized as types I - III. We correlated histologic findings with those macroscopic phenotypes of EPS. The postoperative and long-term outcomes were evaluated by macroscopic phenotype. RESULTS: Duration of PD was longer in type III than in types I and II EPS (p = 0.05). We observed no other statistically significant differences between the groups in baseline characteristics, except for operation time, which was longer in the type I than in the type III group (p = 0.02). Furthermore, we observed no statistically significant difference between the groups with respect to the onset of complaints before surgery (7.8 ± 5.9 months vs 7.0 ± 7.0 months vs 6.5 ± 5.3 months). Concerning patient outcomes, there was no evidence that any of the macroscopic EPS types was associated with more major or minor complications after surgery. For all study patients, follow-up was at least 3 years, with 19 patients still being alive, and 16 having no or very mild complaints. The typical histologic findings of EPS were present in all macroscopic types; only fibrin deposits were more prominent in type II than in type III. CONCLUSIONS: We describe 3 subtypes of EPS based on macroscopic findings. Postoperative treatment should probably not be influenced by the macroscopic EPS phenotype. Whether the different phenotypes represent different pathophysiologic processes remains unclear and has to be further evaluated.

Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism.

The presentation of patients with primary hyperparathyroidism is often atypical and ranges from normocalcemic, primary hyperparathyroidism to severe, symptomatic hypercalcemia. G-protein-coupled, calcium-sensing receptor (CaSR), vitamin D receptor (VDR), and fibroblast growth factor receptor (FGFR)/klotho complexes seem to be involved in the development of pHPT. Parathyroid glands from 53 patients with pHPT and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional detailed morphological and immunohistochemical analyses of parathyroid glands were performed after dividing each slide in a 3 × 3 array. From morphology, the number of lipocytes was significantly lower in parathyroid tissue glands in the pHPT group (p < 0.001). Protein expressions of klotho, CaSR, and VDR were significantly reduced in the pHPT compared with the control group (p = 0.004, p = 0.007, p < 0.001). No differences were seen between the two groups (p = 0.35) regarding expression of FGFR. Correlations between expression showed significant positively correlations between klotho and CaSR and FGFR and VDR. No correlations between klotho expression and serum calcium levels could be detected (R = -0.13, p = 0.66), but there were positive correlations between expressions of CaSR/serum phosphate and klotho/serum phosphate. Impaired protein expression of CaSR and VDR seem to be involved in the development of pHPT. The role of the FGFR/klotho-axis remains still unclear. Correlations between protein expression of CaSR and serum phosphate and klotho and serum phosphate levels could be detected. Whether these findings give new insights into the pathogenesis of the disease is yet unknown and has to be elucidated.

Efficacy and morbidity of surgical therapy in late-stage encapsulating peritoneal sclerosis.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis composed of chronic abdominal pain, chronic ileus, and severe malnutrition. Operative therapy for EPS is a complex procedure, including perionectomy and enterolysis (PEEL). In contrast to simple adhesiolysis, PEEL comprises a restitution of intestinal passage and prevention of recurrent disease by decapsulation and partial deserosation. METHODS: We reviewed the treatment of patients with EPS at our referral center regarding perioperative morbidity, mortality, and long-term outcome. Only patients who underwent PEEL were included. Preoperative general status was ascertained by APACHE-II score and body mass index. Postoperative morbidity was stratified into minor and major complications. RESULTS: Between the years 2003 and 2010, 26 of 45 patients with late-stage EPS underwent PEEL. Median age was 54 years, APACHE-II score was 15, and body mass index was 21 kg/m². To achieve intestinal function, 9 bowel resections with immediate anastomoses were necessary. Eleven patients (37%) received a complete parietal peritonectomy. Overall morbidity was 44%, with minor complications in 2 patients (7%) and major complications in 11 patients (31%). Three patients (10%) died within the first year after operative treatment. CONCLUSION: PEEL is a treatment option that can be performed with low mortality and acceptable morbidity. It is a precondition that these patients are treated in specialized referral centers.

Safety of neural monitoring in thyroid surgery.

During thyroid surgery, the functional integrity of the recurrent laryngeal nerve (RLN) is not only threatened by direct nerve injury resulting from accidental transection, clipping or ligation. In fact, indirect trauma, e.g. traction and compression occurring repeatedly throughout gland dissection, contribute to long-term nerve impairment. In order to avoid RLN lesions and preserve nerve function the surgeon must adhere to and comply with a strict standardized intraoperative neuromonitoring (IONM) technique to preserve results, quality and safety. IONM should be a team work between the surgeon and the anesthesiologist.

Encapsulating peritoneal sclerosis: a rare, serious but potentially curable complication of peritoneal dialysis-experience of a referral centre in Germany.

BACKGROUND: Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), the most severe complication associated with long-term PD. METHODS: In this study, we retrospectively analysed 49 EPS patients regarding clinical presentation, histopathological findings, treatment and long-term clinical outcome at our referral centre. Patients were divided into two clinical categories: severe and mild/moderate. RESULTS: All patients in the severe group and most patients in the mild/moderate group had symptoms consistent with EPS. The most common computed tomographic findings were peritoneal thickening in both groups. Small bowel dilatation was frequently present in the severe group. The time of onset of symptoms consistent with EPS to the surgical procedure was median 5 months with an inter-quartile range of 2-12 months in the severe group. To date, 25 of 31 patients in the severe group (follow-up 45.6 ± 39.0 months after surgery) are alive. In the mild/moderate group, 8 of 11 patients are alive (follow-up 41.6 ± 21.6 months). The histological features were consistent with EPS in all biopsies. CONCLUSIONS: The outcome of patients even with severe EPS is not worse. It is a precondition that these patients are treated in specialized referral centres. The time of first clinical symptoms consistent with EPS to requirement of surgery is very short. Earlier diagnosis of the disease is mandatory, even in asymptomatic patients.

Histological criteria for encapsulating peritoneal sclerosis - a standardized approach.

BACKGROUND: The two most relevant pathologies of long-term peritoneal dialysis (PD) are simple sclerosis and encapsulating peritoneal sclerosis (EPS). The histological differentiation of those two entities is difficult. The Aim of the study was to establish a method to standardize and facilitate the differentiation between simple sclerosis and EPS METHODS: We investigated 58 peritoneal biopsies - 31 EPS patients and 27 PD patients. Two blinded investigators analyzed 20 histological characteristics in EPS and PD patients. RESULTS: THE FOLLOWING FINDINGS WERE SIGNIFICANTLY MORE COMMON IN EPS THAN IN PATIENTS ON PD WITHOUT EPS: fibroblast like cells (FLC) (p<0.0001), mesothelial denudation (p<0.0001), decreased cellularity (p = 0.008), fibrin deposits (p<0.03), Fe deposits (p = 0.05), podoplanin vascular (p<0.0001), podoplanin avascular (p<0.0001). Using all predictor variables we trained the classification method Random Forest to categorize future cases. Podoplanin vascular and avascular were taken together (p<0.0001), FLC (p<0.0001), mesothelial denudation (p = 0.0005), calcification (p = 0.0026), acellular areas (p = 0.0094), and fibrin deposits (p = 0.0336) showed up as significantly important predictor variables. Estimated misclassification error rate when classifying new cases turned out to be 14%. CONCLUSION: The introduced statistical method allows discriminating between simple sclerosis and EPS. The misclassification error will likely improve with every new case added to the database.

Safety analysis of vagal nerve stimulation for continuous nerve monitoring during thyroid surgery.

OBJECTIVES/HYPOTHESIS: Intraoperative neuromonitoring (IONM) facilitates recurrent laryngeal nerve (RLN) identification, but various studies affirm virtually unchanged postoperative RLN palsy rates. Several authors meanwhile suggest continuous intraoperative neuromonitoring (CIONM) via vagal nerve stimulation (VNS) to improve RLN protection. However, knowledge of side effects of electrical VNS derives mainly from its therapeutic applications in the fields of neurology and psychiatry. The presented study was conducted to further evaluate the safety of CIONM and identify possible VNS related side effects. STUDY DESIGN: Prospective nonrandomized controlled trail. METHODS: Forty patients scheduled for thyroid or parathyroid surgery were enrolled in the trail. The intervention group consisted of 22 patients receiving VNS for CIONM. Eighteen patients were operated on with routine IONM. To assess VNS-induced effects on the autonomic nervous system (ANS), heart rate variability analysis (HRVA) was applied. Serum cytokine levels of tumor necrosis factor (TNF)-α were monitored to evaluate immunomodulatory effects of VNS. RESULTS: HRVA revealed significantly increased vagal activity during CIONM. This parasympathetic predominance was not countered by the sympathetic nervous system. Despite a significant increase of vagal tone, no hemodynamic events occurred; in fact, no significant changes in median heart rate or in median arterial blood pressure were detected. Even though anti-inflammatory effects of VNS have been reported, no attenuation of cytokine release of TNF-α was measured. CONCLUSIONS: VNS for CIONM resulted in increased vagal activity assessable via HRVA. The increased parasympathetic tone affected neither hemodynamics nor levels of the proinflammatory cytokine TNF-α. VNS for CIONM appears safe with the applied settings.

New backstrap vagus electrode for continuous intraoperative neuromonitoring in thyroid surgery.

INTRODUCTION: Continuous intraoperative neuromonitoring (CIONM) via vagal nerve stimulation allows real-time surveillance of the recurrent laryngeal nerve during thyroid surgery. However, for effective CIONM, subtle changes in recurrent laryngeal nerve conductivity have to be detected. A newly developed stimulation electrode that provides stable nerve stimulation and safe application is presented. METHODS: For electrode validation, current distribution was simulated with the finite element method. Mechanical characteristics were assessed through bench testing. Clinical evaluation was initiated with 11 thyroid surgeries. RESULTS: Experimental and clinical results led to the development of a tripolar gold/polyimide electrode mounted onto a backstrap-shaped silicone body. It facilitated rapid electrode implantation and extraction (median implantation time 4 ± 19 seconds). Peak extraction force was 570 mN. Median supramaximal stimulation currents were 2.00 ± 0.95 mA and resulted in reliable electromyogram responses (median 3.1 ± 3.0 mV). No intraoperative electrode dislocations occurred, and no postoperative nerve palsy was observed. CONCLUSION: The new backstrap vagal stimulation electrode meets the requirements for reliable CIONM.

Sashimi NOTES--extraction of bulky specimens in no-scar operations.

A major obstacle in no-scar surgery is the extraction of large, bulky or rigid specimen. Thus, a method is needed that allows for extraction of large specimens without situs contamination in women and men. It should enable safe treatment of infectious or malignant disease while preserving pathologic workup. Five patients suffering from diverticulitis with expected bulky and rigid specimen were enrolled into this early series. Preparation was performed transumbilically in single-port technique. To prevent new scar formation, the incision was limited to the base of the umbilicus without extension onto the sound abdominal skin. A functionally and topologically extracorporeal compartment was created within the abdomen by introduction and insufflation of a tear-proof impermeable retrieval bag. The specimen was sliced in a controlled fashion inside the compartment along a pre-marked geometry. Controlled specimen dissection in a dedicated intraabdominal resection compartment was feasible. The dissected specimen could be retrieved through the 1.5 cm umbilical incision without spillage of material. The geometry of the extracted organ was reconstructed in detail allowing for uncompromised pathological workup. Extraction of bulky and rigid specimen is possible through natural orifices by the proposed controlled dissection method enabling the pathologist to reconstruct anatomical affiliation.

Impact of continuous intraoperative neuromonitoring on autonomic nervous system during thyroid surgery.

BACKGROUND: Continuous intraoperative neuromonitoring (CIONM) via vagal nerve stimulation (VNS) is a new option for recurrent laryngeal nerve (RLN) protection during thyroid surgery. The aim of this study was to evaluate the safety of VNS for CIONM and to assess its effects on the autonomic nervous system (ANS) through analyzing heart rate variability (HRV). METHODS: In a prospective, nonrandomized controlled study 5 patients received VNS for CIONM and 5 were operated on with conventional intermittent intraoperative neuromonitoring (IONM). HRV was analyzed in accord with patient-specific reference values. RESULTS: VNS resulted in significantly altered ANS balance. Relative parasympathetic activity increased during VNS. Yet, no relevant cardiac arrhythmias or hemodynamic alterations were observed during VNS. CONCLUSION: HRV analysis revealed a distinct impact of VNS for CIONM on ANS balance. VNS caused parasympathetic predominance that was not countered by increased sympathetic activity.

Difference in the expression of hormone receptors and fibrotic markers in the human peritoneum--implications for therapeutic targets to prevent encapsulating peritoneal sclerosis.

OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal dialysis (PD). The optimal management of patients with EPS is uncertain. In the present study, we investigated differences in the expression of nuclear receptors [progesterone (PR), androgen (AR), vitamin D (VDR), and glucocorticoid (GCR)] in the human peritoneum. We also investigated estrogen receptor (ER), matrix metalloproteinase 9 (MMP9), and transforming growth factor ß1 (TGFß1) in the context of their potential role in tamoxifen therapy. METHODS: We analyzed clinical and histologic characteristics of 72 peritoneal biopsy specimens (22 from EPS patients, 11 from PD patients, 15 from uremic patients, and 24 from control subjects undergoing hernia repair). For immunophenotyping, we used antibodies against VDR, GCR, ER, PR, AR, MMP9, and TGFß1. RESULTS: In human peritoneum, VDR and GCR are highly expressed (98.6% and 87.3% respectively). Except in the case of VDR (p = 0.0012), we observed no significant difference in receptor expression between the groups. Expression of ER and PR was sparse (11.4% and 31% respectively), with higher expression in women, and AR was absent. Minimal MMP9 expression and moderate TGFß1 expression were observed in all groups. The differences between the groups were nonsignificant. CONCLUSIONS: Nuclear receptors are present in human peritoneum. Except in the case of VDR, the pattern for any one group is nonspecific. Glucocorticoids, vitamin D, and angiotensin converting-enzyme inhibitors or angiotensin II receptor blockers (via the vitamin D/angiotensin II pathway) might be suitable interventions for preservation of the integrity of the peritoneal membrane. The mechanism of action of tamoxifen is still not elucidated, ER expression in the peritoneum is sparse, and data about the studied pathways (MMP9, TGFß) are inconsistent.