Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.

Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21low T-bet+ CD11c+ subset along with decreased regulatory T cells, impaired T-cell proliferation and T-cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.

YB-1 regulates mesothelioma cell migration via snail but not EGFR, MMP1, EPHA5 or PARK2.

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y-box-binding protein-1 (YB-1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB-1 on target gene regulation and PM cell behavior. Whereas siRNA-mediated YB-1 knockdown reduced cell motility, YB-1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB-1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB-1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB-1. Finally, we identified snail as a critical regulator of YB-1-mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB-1 in this cancer. In this context, we found that YB-1 closely regulates EGFR and snail, and, moreover, that YB-1-induced cell migration depends on snail.

Safe and Effective Treatment of Compromised Clavicle Fracture of the Medial and Lateral Third Using Focused Shockwaves.

A delay or failure to heal is the most common possible complication in clavicle fractures, especially in cases primarily treated conservatively. As the current standard therapy, surgical revision achieves good healing results, but is associated with potential surgery-related complications. Shockwave therapy as a non-invasive therapy shows similar reasonable consolidation rates in the non-union of different localizations, but avoids complications. Compromised clavicle fractures in the middle and lateral third treated with focused high-energy shockwave therapy were compared with those treated with surgical revision (ORIF). In addition, a three-dimensional computer simulation for evaluating the pressure distribution during shockwave application accompanied the clinical study. A comparable healing rate in bony consolidation was achieved in both groups. Significantly fewer complications, however, occurred in the shockwave group. The simulations showed safe application in this instance, particularly in avoiding lung tissue affection. When applied correctly, shockwaves represent a safe and promising therapy option for compromised clavicle fractures in the middle and lateral third.

Changing Metabolic Patterns along the Colorectal Adenoma-Carcinoma Sequence.

Colorectal cancer (CRC) is a major public health burden and one of the leading causes of cancer-related deaths worldwide. Screening programs facilitate early diagnosis and can help to reduce poor outcomes. Serum metabolomics can extract vital molecular information that may increase the sensitivity and specificity of colonoscopy in combination with histopathological examination. The present study identifies serum metabolite patterns of treatment-naïve patients, diagnosed with either advanced adenoma (AA) or CRC in colonoscopy screenings, in the framework of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program. We used a targeted flow injection analysis and liquid chromatography-tandem mass spectrometry metabolomics approach (FIA- and LC-MS/MS) to characterise the serum metabolomes of an initial screening cohort and two validation cohorts (in total 66 CRC, 76 AA and 93 controls). The lipidome was significantly perturbed, with a proportion of lipid species being downregulated in CRC patients, as compared to AA and controls. The predominant alterations observed were in the levels of lyso-lipids, glycerophosphocholines and acylcarnitines, but additionally, variations in the quantity of hydroxylated sphingolipids could be detected. Changed amino acid metabolism was restricted mainly to metabolites of the arginine/dimethylarginine/NO synthase pathway. The identified metabolic divergences observed in CRC set the foundation for mechanistic studies to characterise biochemical pathways that become deregulated during progression through the adenoma to carcinoma sequence and highlight the key importance of lipid metabolites. Biomarkers related to these pathways could improve the sensitivity and specificity of diagnosis, as well as the monitoring of therapies.

Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A+CD207+ cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAFV600E). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, making BRAF-inhibitors an attractive treatment option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib and salvage chemotherapy who achieved sustained clinical and molecular remission. We show that there is no relationship between peripheral blood BRAFV600E levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of systemic inflammation. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping analysis identified the BRAFV600E mutation in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analyses of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH such as IL1B and CXCL8. Together, our data suggest that while the CD1A+CD207+ histiocytes are the hallmark of LCH, other BRAF-mutated cell populations may contribute significantly to morbidity in patients with multisystem LCH.

Local MRI-based measures of thigh adipose tissue derived from fully automated deep convolutional neural network-based segmentation show a comparable responsiveness to bidirectional change in body weight as from quality controlled manual segmentation.

BACKGROUND: Thigh intermuscular (IMF) and subcutaneous (SCF) fat are associated with joint function, inflammation and knee osteoarthritis. Fully automated segmentation from MRI is important to study the above relationship in larger cohorts. However, such algorithms are not clinically evaluated for longitudinal studies. Our aim was to evaluate a fully automated U-Net segmentation approach and its ability to detect longitudinal changes in thigh IMF and SCF during weight changes compared to manual segmentation. METHODS: 103 Osteoarthritis Initiative subjects, were studied, 52 with> 10% weight loss, and 51 with> 10% weight gain over 2-years. Longitudinal change in IMF and SCF were determined from baseline and year-2 axial thigh MRIs using U-Net segmentation. The standardised response mean (SRM) was used as measure of sensitivity to change. RESULTS: The U-Net took substantially less time (single-slice MRI:< 1 s) and IMF and SCF showed very similar sensitivity to change as manual segmentation: With an average weight gain of + 14%, we observed an + 12% /+ 26% increase in IMF / SCF (SRM=0.99 /1.03) using the U-Net, compared with + 21% /+ 27% (SRM=0.60 /1.07) for manual segmentation. During an average weight loss of - 18%, we observed an - 14% /- 22% reduction in IMF /SCF (SRM = - 1.04 /-1.20) using the U-Net, compared with - 16% /- 22% (SRM = - 0.70 /-1.23) for manual segmentation. CONCLUSION: U-Net segmentation replicates longitudinal changes of IMF and SCF associated with weight changes with a similar sensitivity to change as manual segmentation. This method is applicable to large databases for studying relationships between IMF and SCF and various disease conditions.

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects.

BACKGROUND AND AIMS: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects. METHODS: 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated. RESULTS: Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01). CONCLUSION: Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.

Deep Learning-Based Detection of Endothelial Tip Cells in the Oxygen-Induced Retinopathy Model.

Proliferative retinopathies, such as diabetic retinopathy and retinopathy of prematurity, are leading causes of vision impairment. A common feature is a loss of retinal capillary vessels resulting in hypoxia and neuronal damage. The oxygen-induced retinopathy model is widely used to study revascularization of an ischemic area in the mouse retina. The presence of endothelial tip cells indicates vascular recovery; however, their quantification relies on manual counting in microscopy images of retinal flat mount preparations. Recent advances in deep neural networks (DNNs) allow the automation of such tasks. We demonstrate a workflow for detection of tip cells in retinal images using the DNN-based Single Shot Detector (SSD). The SSD was designed for detection of objects in natural images. We adapt the SSD architecture and training procedure to the tip cell detection task and retrain the DNN using labeled tip cells in images of fluorescently stained retina flat mounts. Transferring knowledge from the pretrained DNN and extensive data augmentation reduced the amount of required labeled data. Our system shows a performance comparable to the human level, while providing highly consistent results. Therefore, such a system can automate counting of tip cells, a readout frequently used in retinopathy research, thereby reducing routine work for biomedical experts.

Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of mild-to-moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established. METHODS & RESULTS: For this retrospective study, 299 consecutive patients with biopsy-proven NAFLD and a mean follow-up of 8.4 (±4.1; range: 0.3-18.0) years were allocated to one of four groups according to presence of hepatic iron in the reticuloendothelial system (RES) and/or hepatocytes (HC): 156 subjects (52%) showed no stainable iron (NONE), 58 (19%) exclusively reticuloendothelial (xRES), 19 (6%) exclusively hepatocellular (xHC) and 66 (22%) showed a mixed (HC/RES) pattern of iron deposition. A long-term analysis for overall survival, hepatic, cardiovascular or extrahepatic-malignant events was conducted. Based on multivariate Cox proportional hazards models any reticuloendothelial iron was associated with fatal and non-fatal hepatic events. Specifically, xRES showed a cause-specific hazard ratio (csHR) of 2.4 (95%-CI, 1.0-5.8; P = .048) for hepatic as well as cardiovascular fatal and non-fatal events combined (csHR 3.2; 95%-CI, 1.2-8.2; P = .015). Furthermore, the mixed HC/RES iron pattern showed a higher rate of combined hepatic fatal and non-fatal events (csHR 3.6; 95%-CI, 1.4-9.5; P = .010), while xHC iron deposition was not associated with any defined events. CONCLUSIONS: The presence of reticuloendothelial-accentuated hepatic iron distribution patterns is associated with detrimental long-term outcomes reflected in a higher rate of both liver-related and cardiovascular fatal and non-fatal events.

Clinical evaluation of fully automated thigh muscle and adipose tissue segmentation using a U-Net deep learning architecture in context of osteoarthritic knee pain.

OBJECTIVE: Segmentation of thigh muscle and adipose tissue is important for the understanding of musculoskeletal diseases such as osteoarthritis. Therefore, the purpose of this work is (a) to evaluate whether a fully automated approach provides accurate segmentation of muscles and adipose tissue cross-sectional areas (CSA) compared with manual segmentation and (b) to evaluate the validity of this method based on a previous clinical study. MATERIALS AND METHODS: The segmentation method is based on U-Net architecture trained on 250 manually segmented thighs from the Osteoarthritis Initiative (OAI). The clinical evaluation is performed on a hold-out test set bilateral thighs of 48 subjects with unilateral knee pain. RESULTS: The segmentation time of the method is < 1 s and demonstrated high agreement with the manual method (dice similarity coeffcient: 0.96 ± 0.01). In the clinical study, the automated method shows that similar to manual segmentation (- 5.7 ± 7.9%, p < 0.001, effect size: 0.69), painful knees display significantly lower quadriceps CSAs than contralateral painless knees (- 5.6 ± 7.6%, p < 0.001, effect size: 0.73). DISCUSSION: Automated segmentation of thigh muscle and adipose tissues has high agreement with manual segmentations and can replicate the effect size seen in a clinical study on osteoarthritic pain.

Trans-Iliac Bypass Grafting for Vascular Groin Complications.

OBJECTIVES: Groin complications following vascular reconstruction, extensive trauma, or severe radiation induced scarring may complicate future revascularisation procedures of the lower limb. Although several techniques have been described, only few cases of trans-iliac bypass grafting have been published. The aim of this study was to perform a review of the literature on trans-ilac bypass grafting and add the authors' experience. METHODS: A single centre retrospective data analysis and a literature review of all trans-iliac bypass procedures was performed. Data on indication, patency, limb salvage, and survival were collected. Study endpoints were patency, limb salvage, and patient survival. RESULTS: Eight trans-iliac wing bypass grafting procedures were performed in our institution between 2003 and 2018, which represents the largest single centre series. Twenty-three procedures were reported in the literature between 1989 and 2018. Prior to the bypass procedure in the eight patients, six had local infection and two irradiation of the groin. The indication for operation was ischaemia in six cases, bleeding in one case, and infection in another case. The external iliac artery was most often used for the proximal (6 cases) and the superficial femoral artery for distal anastomosis (6 cases). Great saphenous vein was the most commonly used graft material (6 cases). The median follow up was five years with three bypass occlusions after 1, 2, and 8 months, followed by two successful thrombectomy procedures. There were no major amputations and only one death after five months, which was not procedure related. CONCLUSIONS: Trans-iliac bypass grafting is a viable alternative extra-anatomic bypass technique in patients with vascular groin complications. Patency as well as limb salvage and survival are good and may be comparable to those reported for autologous in situ repair and obturator canal bypass grafting.

Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients.

A small proportion of lean patients develop non-alcoholic fatty liver disease (NAFLD). We aimed to report the histological picture of lean NAFLD in comparison to overweight and obese NAFLD patients. Biopsy and clinical data from 466 patients diagnosed with NAFLD were stratified to groups according to body mass index (BMI): lean (BMI ≤ 25.0 kg/m², n confirmed to be appropriate = 74), overweight (BMI > 25.0 ≤ 30.0 kg/m², n = 242) and obese (BMI > 30.0 kg/m², n = 150). Lean NAFLD patients had a higher rate of lobular inflammation compared to overweight patients (12/74; 16.2% vs. 19/242; 7.9%; p = 0.011) but were similar to obese patients (25/150; 16.7%). Ballooning was observed in fewer overweight patients (38/242; 15.7%) compared to lean (19/74; 25.7%; p = 0.014) and obese patients (38/150; 25.3%; p = 0.006). Overweight patients had a lower rate of portal and periportal fibrosis (32/242; 13.2%) than lean (19/74; 25.7%; p = 0.019) and obese patients (37/150; 24.7%; p = 0.016). The rate of cirrhosis was higher in lean patients (6/74; 8.1%) compared to overweight (4/242; 1.7%; p = 0.010) and obese patients (3/150; 2.0% p = 0.027). In total, 60/466; 12.9% patients were diagnosed with non-alcoholic steatohepatitis (NASH). The rate of NASH was higher in lean (14/74; 18.9% p = 0.01) and obese (26/150; 17.3%; p = 0.007) compared to overweight patients (20/242; 8.3%)). Among lean patients, fasting glucose, INR and use of thyroid hormone replacement therapy were independent predictors of NASH in a multivariate model. Lean NAFLD patients were characterized by a severe histological picture similar to obese patients but are more progressed compared to overweight patients. Fasting glucose, international normalized ratio (INR) and the use of thyroid hormone replacement may serve as indicators for NASH in lean patients.

Tibiodistal vein bypass in critical limb ischemia and its role after unsuccessful tibial angioplasty.

OBJECTIVE: Technical progress in angioplasty expanded its application to very distal arterial lesions of the lower extremity. In cases of unsuccessful angioplasty tibiodistal bypass surgery may be required for limb salvage. We investigated the long-term outcome of this technique in patients with critical limb ischemia. The purpose of this study was to evaluate whether tibiodistal bypasses done after unsuccessful tibial angioplasty had inferior patency, limb salvage, or survival rates compared with primary tibiodistal bypasses. METHODS: This single-center, retrospective data analysis included all distal bypass procedures originating from a tibial artery. Primary study end points were primary patency, secondary patency, and limb salvage. Secondary end points included survival, wound healing, and systemic and local complications. Society for Vascular Surgery reporting standards were applied. RESULTS: There were 61 tibiodistal vein bypasses for critical limb ischemia performed in 23 years. Indications for tibiodistal bypass was Rutherford category 5 in 41 cases (67%) and category 6 in 20 cases (33%). Procedures were allocated to group A (primary bypass; n = 28) and group B (bypass after unsuccessful tibial angioplasty; n = 33). Primary patency was 55% versus 53% at 1 year and 47% versus 44% at 3 years (P = .58). Secondary patency was 59% versus 64% at 1 year and 52% versus 55% at 3 years (P = .36). Limb salvage was 96% versus 90% at 1 year and 91% versus 85% at 3 years (P = .44). Overall survival rates were 91% versus 97% at 1 year and 85% versus 92% at 3 years (P = .76). The median follow-up was 4.0 years in group A and 4.9 years in group B. In multivariate analyses for loss of primary patency and limb loss, no significant predictors could be identified. CONCLUSIONS: This study showed that tibiodistal vein bypass is a feasible, efficient, and safe technique in patients with critical limb ischemia. It provides acceptable primary and secondary patency rates to prevent major amputation and ensure survival. Previous unsuccessful tibial angioplasty had no significant impact on tibiodistal vein bypass outcome. This technique should be part of the armamentarium of vascular surgeons.

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.

OBJECTIVE: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways. METHODS: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach. RESULTS: Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites). CONCLUSIONS: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.

Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD. METHODS: Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m2, no steatosis, N=71), lean NAFLD (BMI≤25 kg/m2, steatosis, N=55), obese NAFLD (BMI≥30 kg/m2, steatosis; N=61). All subjects received a detailed clinical and laboratory examination including oral glucose tolerance test. The serum metabolome was assessed using the Metabolomics AbsoluteIDQ p180 kit (BIOCRATES Life Sciences). Genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD was performed. RESULTS: Lean NAFLD subjects had fasting insulin concentrations similar to lean healthy subjects but had markedly impaired glucose tolerance. Lean NAFLD subjects had a higher rate of the mutant PNPLA3 CG/GG variant compared to lean controls (P=0.007). Serum adiponectin concentrations were decreased in both NAFLD groups compared to controls (P<0.001 for both groups) The metabolomics study revealed a potential role for various lysophosphatidylcholines (lyso-PC C18:0, lyso-PC C17:0) and phosphatidylcholines (PCaa C36:3; false discovery rate (FDR)-corrected P-value<0.001) as well as lysine, tyrosine, and valine (FDR<0.001). CONCLUSIONS: Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.

Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men.

Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.4 ± 9.6 years and 701 women, 59.1 ± 10.6 years, undergoing screening colonoscopy were allocated to PTH serum concentrations either above or below 55 ng/L. The number, localization, size, and histology of the polypoid lesions detected during screening colonoscopy were recorded according to PTH serum concentrations. Serum PTH concentrations were not different between men and women. Women with PTH serum concentrations above the cut-off had significantly more adenomas (13/40; 32.5%) of the distal colon compared to women below the cut-off (91/659; 13.8%; P = 0.001). Additionally, the rate of dysplasia in adenomas of the distal colon was higher in women with high compared to low PTH concentrations (P = 0.001). These findings remained robust after adjustments for serum vitamin D, age, plasma creatinine, BMI, diabetes, and liver steatosis. No associations were observed between serum PTH concentrations and colorectal lesions in men. These data suggest that elevated PTH serum concentrations might have a role in colorectal cancer development as indicated by higher rates of adenomas, specifically with dysplasia, in women. The role of PTH in colon carcinogenesis and its sex specificity deserve further study.