Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Cyst fluid glycoproteins accurately distinguishing malignancies of pancreatic cystic neoplasm.

Pancreatic cystic neoplasms (PCNs) are recognized as precursor lesions of pancreatic cancer, with a marked increase in prevalence. Early detection of malignant PCNs is crucial for improving prognosis; however, current diagnostic methods are insufficient for accurately identifying malignant PCNs. Here, we utilized mass spectrometry (MS)-based glycosite- and glycoform-specific glycoproteomics, combined with proteomics, to explore potential cyst fluid diagnostic biomarkers for PCN. The glycoproteomic and proteomic landscape of pancreatic cyst fluid samples from PCN patients was comprehensively investigated, and its characteristics during the malignant transformation of PCN were analyzed. Under the criteria of screening specific cyst fluid biomarkers for the diagnosis of PCN, a group of cyst fluid glycoprotein biomarkers was identified. Through parallel reaction monitoring (PRM)-based targeted glycoproteomic analysis, we validated these chosen glycoprotein biomarkers in a second cohort, ultimately confirming N-glycosylated PHKB (Asn-935, H5N2F0S0; Asn-935, H4N4F0S0; Asn-935, H5N4F0S0), CEACAM5 (Asn-197, H5N4F0S0) and ATP6V0A4 (Asn-367, H6N4F0S0) as promising diagnostic biomarkers for distinguishing malignant PCNs. These glycoprotein biomarkers exhibited robust performance, with an area under the curve ranging from 0.771 to 0.948. In conclusion, we successfully established and conducted MS-based glycoproteomic analysis to identify novel cyst fluid glycoprotein biomarkers for PCN. These findings hold significant clinical implications, providing valuable insights for PCN decision-making, and potentially offering therapeutic targets for PCN treatment.

Serum protein N-glycome patterns reveal alterations associated with endometrial cancer and its phenotypes of differentiation.

Background: Aberrant N-glycosylation and its involvement in pathogenesis have been reported in endometrial cancer (EC). Nevertheless, the serum N-glycomic signature of EC remains unknown. Here, we investigated serum N-glycome patterns of EC to identify candidate biomarkers. Methods: This study enrolled 34 untreated EC patients and 34 matched healthy controls (HC) from Peking Union Medical College Hospital. State-of-the-art MS-based methods were employed for N-glycans profiling. Multivariate and univariate statistical analyses were used to identify discriminative N-glycans driving classification. Receiver operating characteristic analyses were performed to evaluate classification accuracy. Results: EC patients displayed distinct differences in serum N-glycome and had abnormal high-mannose and hybrid-type N-glycans, fucosylation, galactosylation, and linkage-specific sialylation compared with HC. The glycan panel built with the four most discriminative and biologically important derived N-glycan traits could accurately identify EC (random forest model, the area under the curve [AUC]=0.993 [95%CI 0.955-1]). The performance was validated by two other models. Total hybrid-type N-glycans significantly associated with the differentiation types of EC could effectively stratify EC into well- or poorly-differentiated subgroups (AUC>0.8). Conclusion: This study provides the initial evidence supporting the utility of serum N-glycomic signature as potential markers for the diagnosis and phenotyping of EC.

Comprehensive analysis of tissue proteomics in patients with papillary thyroid microcarcinoma uncovers the underlying mechanism of lymph node metastasis and its significant sex disparities.

Background: Lymph node metastasis (LNM) in papillary thyroid microcarcinoma (PTMC) is associated with an increased risk of recurrence and poor prognosis. Sex has been regarded as a critical risk factor for LNM. The present study aimed to investigate the molecular mechanisms underlying LNM and its significant sex disparities in PTMC development. Methods: A direct data-independent acquisition (DIA) proteomics approach was used to identify differentially expressed proteins (DEPs) in PTMC tumorous tissues with or without LNM and from male and female patients with LNM. The functional annotation of DEPs was performed using bioinformatics methods. Furthermore, The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) dataset and immunohistochemistry (IHC) were used to validate selected DEPs. Results: The proteomics profile in PTMC with LNM differed from that of PTMC without LNM. The metastasis-related DEPs were primarily enriched in categories associated with mitochondrial dysfunction and may promote tumor progression by activating oxidative phosphorylation and PI3K/AKT signaling pathways. Comparative analyses of these DEPs revealed downregulated expression of specific proteins with well-established links to tumor metastasis, such as SLC25A15, DIRAS2, PLA2R1, and MTARC1. Additionally, the proteomics profiles of male and female PTMC patients with LNM were dramatically distinguishable. An elevated level of ECM-associated proteins might be related to more LNM in male PTMC than in female PTMC patients. The upregulated expression levels of MMRN2 and NID2 correlated with sex disparities and showed a positive relationship with unfavorable variables, such as LNMs and poor prognosis. Conclusions: The proteomics profiles of PTMC show significant differences associated with LNM and its sex disparities, which further expands our understanding of the functional networks and signaling pathways related to PTMC with LNM.

Nomograms Based on Serum N-glycome for Diagnosis of Papillary Thyroid Microcarcinoma and Prediction of Lymph Node Metastasis.

Non-invasive biomarkers for the diagnosis and prognosis of papillary thyroid microcarcinoma (PTMC) are still urgently needed. We aimed to characterize the N-glycome of PTMC, and establish nomograms for the diagnosis of PTMC and the prediction of lymph node metastasis (LNM). N-glycome of PTMC (LNM vs. non-LNM, capsular invasion (CI) vs. non-CI (NCI)) and matched healthy controls (HC) were quantitatively analyzed based on mass spectrometry. N-glycan traits associated with PTMC/LNM were used to create binomial logistic regression models and were visualized as nomograms. We found serum N-glycome differed between PTMC and HC in high-mannose, complexity, fucosylation, and bisection, of which, four N-glycan traits (TM, CA1, CA4, and A2Fa) were significantly associated with PTMC. The nomogram based on four traits achieved good performance for the identification of PTMC. Two N-glycan traits (CA4 and A2F0S0G) showed strong associations with LNM. The nomogram based on two traits showed relatively good performance in predicting LNM. We also found differences between CI and NCI in several N-glycan traits, which were not the same as that associated with LNM. This study reported serum N-glycosylation signatures of PTMC for the first time. Nomograms constructed from aberrant glycans could be useful tools for PTMC diagnosis and stratification.

Gene Expression Analysis Reveals Prognostic Biomarkers of the Tyrosine Metabolism Reprogramming Pathway for Prostate Cancer.

Background: Tyrosine metabolism pathway-related genes were related to prostate cancer progression, which may be used as potential prognostic markers. Aims: To dissect the dysregulation of tyrosine metabolism in prostate cancer and build a prognostic signature based on tyrosine metabolism-related genes for prostate cancer. Materials and Method. Cross-platform gene expression data of prostate cancer cohorts were collected from both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Based on the expression of tyrosine metabolism-related enzymes (TMREs), an unsupervised consensus clustering method was used to classify prostate cancer patients into different molecular subtypes. We employed the least absolute shrinkage and selection operator (LASSO) Cox regression analysis to evaluate prognostic characteristics based on TMREs to obtain a prognostic effect. The nomogram model was established and used to synthesize molecular subtypes, prognostic characteristics, and clinicopathological features. Kaplan-Meier plots and logrank analysis were used to clarify survival differences between subtypes. Results: Based on the hierarchical clustering method and the expression profiles of TMREs, prostate cancer samples were assigned into two subgroups (S1, subgroup 1; S2, subgroup 2), and the Kaplan-Meier plot and logrank analysis showed distinct survival outcomes between S1 and S2 subgroups. We further established a four-gene-based prognostic signature, and both in-group testing dataset and out-group testing dataset indicated the robustness of this model. By combining the four gene-based signatures and clinicopathological features, the nomogram model achieved better survival outcomes than any single classifier. Interestingly, we found that immune-related pathways were significantly concentrated on S1-upregulated genes, and the abundance of memory B cells, CD4+ resting memory T cells, M0 macrophages, resting dendritic cells, and resting mast cells were significantly different between S1 and S2 subgroups. Conclusions: Our results indicate the prognostic value of genes related to tyrosine metabolism in prostate cancer and provide inspiration for treatment and prevention strategies.

Serum Linkage-Specific Sialylation Changes Are Potential Biomarkers for Monitoring and Predicting the Recurrence of Papillary Thyroid Cancer Following Thyroidectomy.

Background: Although papillary thyroid cancer (PTC) could remain indolent, the recurrence rates after thyroidectomy are approximately 20%. There are currently no accurate serum biomarkers that can monitor and predict recurrence of PTC after thyroidectomy. This study aimed to explore novel serum biomarkers that are relevant to the monitoring and prediction of recurrence in PTC using N-glycomics. Methods: A high-throughput quantitative strategy based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to obtain serum protein N-glycomes of well-differentiated PTC, postoperative surveillance (PS), postoperative recurrence (PR), and matched healthy controls (HC) including linkage-specific sialylation information. Results: Serum N-glycan traits were found to differ among PTC, PS, PR, and HC. The differentially expressed N-glycan traits consisting of sixteen directly detected glycan traits and seven derived glycan traits indicated the response to surgical resection therapy and the potential for monitoring the PTC. Two glycan traits representing the levels of linkage-specific sialylation (H4N3F1L1 and H4N6F1E1) which were down-regulated in PS and up-regulated in PR showed high potential as biomarkers for predicting the recurrence after thyroidectomy. Conclusions: To the best of our knowledge, this study provides comprehensive evaluations of the serum N-glycomic changes in patients with PS or PR for the first time. Several candidate serum N-glycan biomarkers including the linkage-specific sialylation have been determined, some of which have potential in the prediction of recurrence in PTC, and others of which can help to explore and monitor the response to initial surgical resection therapy. The findings enhanced the comprehension of PTC.

Diagnostic Potential of Plasma IgA1 O-Glycans in Discriminating IgA Nephropathy From Other Glomerular Diseases and Healthy Participants.

Background: Aberrant O-glycosylation of IgA1 plays an important role in IgA nephropathy pathogenesis. Previous proteomic studies analyzed O-glycans of the circulating IgA1 hinge region and found that the N-acetylgalactosamine (GalNAc) and galactose numbers in the hinge region of IgA1 of patients with IgA nephropathy were lower than those in healthy participants. However, the diagnostic performance of the O-glycosylation traits in the hinge region of plasma IgA1 for IgA nephropathy remains unelucidated. The present study aimed to determine the difference in plasma IgA1 hinge region O-glycoforms among IgA nephropathy, non-IgA nephropathy disease controls, and healthy participants, and to further evaluate the diagnostic performance of plasma IgA1 glycosylation traits. Methods: Sixty-two patients with biopsy-proven primary IgA nephropathy, 30 age- and sex-matched non-IgA nephropathy disease controls (10 patients with membranous nephropathy, 10 with focal segmental glomerulosclerosis, and 10 with minimal change disease), and 30 healthy participants were prospectively recruited. Plasma galactose deficient-IgA1 levels were measured using a KM55 kit. Plasma IgA was extracted using IgA immunoaffinity beads. After de-N-glycosylation, reduction, alkylation, trypsin digestion, and O-glycopeptide enrichment via hydrophilic interaction liquid chromatography, liquid chromatography tandem mass spectrometry (LC-MS/MS) was applied to analyze the IgA1 O-glycosylation patterns and we derived the plasma IgA1 O-glycosylation traits. Results: Plasma IgA1 O-glycosylation patterns were significantly changed in IgA nephropathy patients compared to those with non-IgA nephropathy disease controls and healthy participants. The GalNAc number was lowest in IgA nephropathy patients. In addition, a similar result was observed for the galactose number in the IgA1 hinge region. These values showed moderate potential for discriminating between IgA nephropathy and the controls. When these values were combined, the area under the curve increased compared to when they were considered individually. When further adding a clinical indicator, the area under the curve of the GalNAc-galactose-IgA panel exceed 0.9 in discriminating IgA nephropathy from the controls. Conclusion: The amount of GalNAc and galactose in plasma IgA1 hinge region identified by glycoproteomics could be used as a diagnostic biomarker for IgA nephropathy. The panel containing GalNAc, galactose, and circulating IgA displayed excellent diagnostic performance and is promising for practical clinical applications.

Transforming growth factor-ß challenge alters the N-, O-, and glycosphingolipid glycomes in PaTu-S pancreatic adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-ß (TGF-ß) plays a key role in PDAC tumor progression, which is often associated with aberrant glycosylation. However, how PDAC cells respond to TGF-ß and the role of glycosylation therein is not well known. Here, we investigated the TGF-ß-mediated response and glycosylation changes in the PaTu-8955S (PaTu-S) cell line deficient in SMA-related and MAD-related protein 4 (SMAD4), a signal transducer of the TGF-ß signaling. PaTu-S cells responded to TGF-ß by upregulating SMAD2 phosphorylation and target gene expression. We found that TGF-ß induced expression of the mesenchymal marker N-cadherin but did not significantly affect epithelial marker E-cadherin expression. We also examined differences in N-glycans, O-glycans, and glycosphingolipid-linked glycans in PaTu-S cells upon TGF-ß stimulation. TGF-ß treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in agreement with TGF-ß-induced changes in the expression of glycosylation-associated genes. In addition, we observed differences in O glycosylation and glycosphingolipid glycosylation profiles after TGF-ß treatment, including lower levels of sialylated Tn antigen and neoexpression of globosides. Furthermore, the expression of transcription factor sex-determining region Y-related high-mobility group box 4 was upregulated upon TGF-ß stimulation, and its depletion blocked TGF-ß-induced N-glycomic changes. Thus, TGF-ß-induced N-glycosylation changes can occur in a sex-determining region Y-related high-mobility group box 4-dependent and SMAD4-independent manner in the pancreatic PaTu-S cancer cell line. Our results open up avenues to study the relevance of glycosylation in TGF-ß signaling in SMAD4-inactivated PDAC.

Down-regulated LINC00115 inhibits prostate cancer cell proliferation and invasion via targeting miR-212-5p/FZD5/Wnt/ß-catenin axis.

Prostate cancer is the second most frequent malignancy in men worldwide, and its incidence is increasing. Therefore, it is urgently required to clarify the underlying mechanisms of prostate cancer. Although the long non-coding RNA LINC00115 was identified as an oncogene in several cancers, the expression and function of LINC00115 in prostate cancer have not been explored. Our results showed that LINC00115 was significantly up-regulated in prostate cancer tissues, which was significantly associated with a poor prognosis for prostate cancer patients. Functional studies showed that knockdown LINC00115 inhibited cell proliferation and invasion. In addition, LINC00115 served as a competing endogenous RNA (ceRNA) through sponging miR-212-5p to release Frizzled Family Receptor 5 (FZD5) expression. The expression of miR-212-5p was noticeably low in tumour tissues, and FZD5 expression level was down-regulated with the knockdown of LINC00115. Knockdown LINC00115 inhibited the Wnt/ß-catenin signalling pathway by inhibiting the expression of FZD5. Rescue experiments further showed that LINC00115 inhibits prostate cancer cell proliferation and invasion via targeting miR-212-5p/ FZD5/ Wnt/ß-catenin axis. The present study provided clues that LINC00115 may be a promising novel therapeutic target for prostate cancer patients.

Diagnostic Potential of Plasma IgG N-glycans in Discriminating Thyroid Cancer from Benign Thyroid Nodules and Healthy Controls.

BACKGROUND: Novel biomarkers are urgently needed to distinguish between benign and malignant thyroid nodules and detect thyroid cancer in the early stage. The associations between serum IgG N-glycosylation and thyroid cancer risk have been revealed. We aimed to explore the potential of IgG N-glycan traits as biomarkers in the differential diagnosis of thyroid cancer. METHODS: Plasma IgG N-glycome analysis was applied to a discovery cohort followed by independent validation. IgG N-glycan profiles were obtained using a robust quantitative strategy based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. IgG N-glycans were relatively quantified, and classification performance was evaluated based on directly detected and derived glycan traits. RESULTS: Four directly detected glycans were significantly changed in thyroid cancer patients compared to that in non-cancer controls. Derived glycan traits and a classification glycol-panel were generated based on the directly detected glycan traits. In the discovery cohort, derived trait BN (bisecting type neutral N-glycans) and the glyco-panel showed potential in distinguishing between thyroid cancer and non-cancer controls with AUCs of 0.920 and 0.917, respectively. The diagnostic potential was further validated. Derived trait BN and the glycol-panel displayed "accurate" performance (AUC>0.8) in discriminating thyroid cancer from benign thyroid nodules and healthy controls in the validation cohort. Meanwhile, derived trait BN and the glycol-panel also showed diagnostic potential in detecting early-stage thyroid cancer. CONCLUSIONS: IgG N-glycome analysis revealed N-glycomic differences that allow classification of thyroid cancer from non-cancer controls. Our results suggested that derived trait BN and the classification glyco-panel rather than single N-glycans may serve as candidate biomarkers for further validation.

Distinguishing Benign and Malignant Thyroid Nodules and Identifying Lymph Node Metastasis in Papillary Thyroid Cancer by Plasma N-Glycomics.

Background: Biomarkers are needed for patient stratification between benign thyroid nodules (BTN) and thyroid cancer (TC) and identifying metastasis in TC. Though plasma N-glycome profiling has shown potential in the discovery of biomarkers and can provide new insight into the mechanisms involved, little is known about it in TC and BTN. Besides, several studies have indicated associations between abnormal glycosylation and TC. Here, we aimed to explore plasma protein N-glycome of a TC cohort with regard to their applicability to serve as biomarkers. Methods: Plasma protein N-glycomes of TC, BTN, and matched healthy controls (HC) were obtained using a robust quantitative strategy based on MALDI-TOF MS and included linkage-specific sialylation information. Results: Plasma N-glycans were found to differ between BTN, TC, and HC in main glycosylation features, namely complexity, galactosylation, fucosylation, and sialylation. Four altered glycan traits, which were consecutively decreased in BTN and TC, and classification models based on them showed high potential as biomarkers for discrimination between BTN and TC ("moderately accurate" to "accurate"). Additionally, strong associations were found between plasma N-glycans and lymph node metastasis in TC, which added the accuracy of predicting metastasis before surgery to the existing method. Conclusions: We comprehensively evaluated the plasma N-glycomic changes in patients with TC or BTN for the first time. We determined several N-glycan biomarkers, some of them have potential in the differential diagnosis of TC, and the others can help to stratify TC patients to low or high risk of lymph node metastasis. The findings enhanced the understanding of TC.

A rare case of a cystic renal mass with heterotopic ossification and a mini literature review.

INTRODUCTION: It is a challenge to make accurate pre-surgical diagnosis for renal tumors. This study is to report the findings, management, and outcome of one rare case of ossification in a cystic renal mass. We present and discuss the pathological characteristics, radiologic features, and treatment alternatives of the patient. PATIENTS AND METHODS: A 38 years old female patient had intermittent epigastric pain and microscopic hematuria for two months. Computerized tomography (CT) scan and Magnetic Resonance imaging (MRI) showed a mass with rough edge and dense calcification in the upper pole of the right kidney and normal left kidney. Pre-operative diagnosis is cystic nephroma or cystic renal mass (Bosniak III type, Bosniak renal cyst classification). GFR was within normal limits for age and no other significant laboratory aberrations were noted. Patient underwent a right retroperitoneal laparoscopic partial nephrectomy (margin status was negative). A mini literature review was performed to highlight the principals of diagnosis and treatment of cystic renal mass with heterotopic ossification. RESULTS: The entire renal mass was successfully removed from upper pole of the right kidney by laparoscopic nephron sparing surgery. The size of renal mass is 38×35×30 mm3 with thick and hard capsular wall. The cystic cavity contains yellow lipid-like substances without stone. Histological examination revealed renal cyst in which the cyst wall reveals fibrosis and no obvious lining epithelium. The additional unique feature includes the presence of dense calcification and ossification in the renal mass. Localization tissue of yellow bone marrow was detected. No complications occurred in 9 months after surgery during follow-up. CONCLUSIONS: Cystic renal mass with heterotopic ossification is a rare case of non-malignant renal tumor. Whether surgery is needed depends to whether patients have symptoms. For symptom renal tumors, laparoscopic nephron sparing surgical procedure is recommended. Furthermore, complete surgical resection of the lesion is needed when the mass is suspected to be malignant. An accurate histologic diagnosis is key in its diagnosis.

Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro.

Clear cell renal cell carcinoma (ccRCC) is the most aggressive urologic tumor, and its incidence and diagonosis have been continuously increasing. Identifying novel molecular biomarker for inhibiting the progression of ccRCC will facilitate developing new treatment strategies. Although methyltransferase-like 7B (METTL7B) was identified as a Golgi-associated methyltransferase, the function and mechanism of METTL7B in ccRCC development and progression has not been explored. METTL7B expression were significantly upregulated in ccRCC tissues (n = 60), which significantly associated with TNM classification, tumor size, lymph node metastasis, and poor prognosis for ccRCC patients. Functional studies showed downregulation of METTL7B inhibited cell proliferation, migration in vitro, and xenograft tumor formation in vivo. In addition, METTL7B knockdown promoted cell cycle arrest at G0/G1phase and induced cellular apoptosis. Taken together, downregulation of METTL7B inhibits ccRCC cell proliferation and tumorigenesis in vivo and in vitro. These findings provide a rationale for using METTL7B as a potential therapeutic target in ccRCC patients.

Iatrogenic ureteral injury during retroperitoneal laparoscopy for large renal cysts: What we learned and a review of the literature.

PURPOSE: To avoid Iatrogenic ureteral injury during retroperitoneal laparoscopy for large renal cyst (diameter > 70 mm), we present two cases of iatrogenic ureteral injury and discuss their clinical courses and final outcomes. PATIENTS AND METHODS: Two male patients (47 years old and 74 years old) with large left simple renal cysts underwent a retroperitoneal laparoscopic operation to treat the cysts. In the first patient, the left proximal ureter was partially transected (Grade 3) during the operation. The injury was identified intraoperatively. The transection was managed with a primary ureteroureterostomy (end to end) along with a double J ureteral stent. In the second patient, the left proximalureter was partially transected (Grade 4). However, the injury was unrecognized postoperatively for two days. After recognition of the complication, the injury was managed with an early primary ureteroureterostomy, which followed a failed attempt to place ureteral stent endoscopically. RESULTS: In the first patient, a postoperative urinary leakage developed and lasted for 13 days. During long term follow-up of the first patient after the urine leak resolved, there were no reports of pain in the lumbar region or other discomfort. No recurrence of the renal cyst occurred, which was confirmed with an ultrasound at one year postoperatively. In the second patient a ureteral fistula and severe perirenal infection occurred and lasted for 86 days. The patient ultimately underwent a left nephrectomy after conservative management for this surgical complication failed. This patient developed a chronic wound infection that lasted for 3.14 months following the nephrectomy. During follow-up post nephrectomy, the patient developed stage 3B moderate chronic kidney disease (CKD) (GFR = 30 -44 ml/min). CONCLUSIONS: For single large (diameter > 70 mm) renal cysts located at the lower pole of the kidney, it is recommended to not completely dissect out and mobilize the entire renal cyst for cyst decortication in order to avoid injuring the ureter. Iatrogenic ureteral injury increases the risk of readmission and serious life-threatening complications. The immediate diagnosis and proper management ureteric injury can reduce complications and long term sequalae.

A Modified Endoscopic Primary Realignment of Severe Bulbar Urethral Injury.

Purpose: Male urethral injury is a common urologic emergency in developing countries. Whether early or late treatment of urethral injuries is often multifactorial and controversial. The goal of this study is to determine whether early realignment can reduce postsurgical complications and evaluate the clinical feasibility of emergency endoscopic urethroplasty using single rigid ureteroscopy in the treatment of bulbar urethral severe injury. Patients and Methods: Between September 2013 and March 2019, 15 male adult patients (mean age 35 years; from 21 to 62 years) with severe bulbar urethral injury were enrolled into the current study. The patients mainly presented with dysuria or painful urination (15/15, 100%), urethral bleeding (13/15, 86.7%), and urinary retention (11/15, 73.3%). Six of them had swelling of perineal or scrotal soft tissue, while four had testicular contusion. No pelvic fracture was found in all cases with CT scanning of the pelvic cavity. The bulbar urethral at grade IV was confirmed to be completely ruptured in all cases by endoscopy during operation. The modified endoscopic primary realignment was performed. Results: This new urethral repair technique was effectively performed in all patients and none converted to open operation. Mean operation time was 42.3 ± 11.5 minutes (28-52 minutes) and the mean Foley catheter indwelling time was 34.5 ± 6.9 days (28-42 days). During a follow-up of 41.3 ± 22.8 months (12-64 months), mild urethral strictures (grade I) (19.7 ± 9.5 weeks, 10-27 weeks postsurgery) developed in 8 patients (53.3%) and then were all improved 2.1 ± 0.8 months (1.3-2.9 months) after periodic dilatations of the urethra (4-10 times). Erectile dysfunction (ED) occurred in three patients (20%) after surgery, who recovered from mild ED to normal by administration with oral sildenafil (100 mg, three times a week) for 12 weeks. The International Index of Erectile Function-5 (IIEF-5) score was significantly improved after surgery (M ± SD, 25 ± 3) compared with before (16.4 ± 3.5) (p < 0.05). No incontinence and other complications occurred in all cases. Conclusions: Early endoscopic realignment via suprapubic puncture cystostomy by single rigid ureteroscopy provides an effective, feasible, and safe procedure for severe bulbar urethral injury.

Challenges in the diagnosis of testicular infarction in the presence of prolonged epididymitis: Three cases report and literature review.

INTRODUCTION: Testicular infarction is a rare complication of prolonged epididymitis and may be misdiagnosed as testicular torsion. In this study, we present three cases of testicular infarction and discuss their clinical characteristics, imaging features and clinical management. PATIENTS AND METHODS: Three adult males with prolonged epididymitis presented with chronic unilateral testicular pain, tenderness, and palpable swelling, including left varicocele in one case and hydrocele in the other two cases. Patient's symptoms were not relieved after antibiotic therapy. We analyzed the diagnosis, management, and outcome of these three cases of testicular infarction resulting from prolonged epididymitis. This includes the clinical characteristics, features of color doppler ultrasound imaging for diagnosis, and treatment strategy for testicular infarction from prolonged epididymitis. RESULTS: Complete blood count (CBC) indicated a small leukocytosis (10.6±0.4×109/L; normal arrange 3.5-9.5 WBC×109/L). Color doppler images demonstrated appropriate blood flow to areas of interest at patient's initial visit. At follow up visit several months later, the increased blood flow was detected at the edges of the involved testes with no blood flow to the center. The sizes of the involved testis (27±4 ml) was significantly larger compared to the non affected side (17±2 ml) (p < 0.05). Unilateral simple orchiectomy was performed on the involved testis in all three cases. Grossly, abscess cavities with caseous necrosis were found at the center of the testicle and epididymis in two patients. Histopathologic examination showed chronic inflammation with lymphocytic and macrophage infiltration of the involved testicle in two cases. The third case stained positive for acid fast bacteria. Left varicocele disappeared postoperatively in one patient. No pain, wound infection or other discomfort were noted 12 months after surgery. COMMENTS: This series revealed that testicular infarction may result from inappropriately treated prolonged epididymitis. Epididymal tuberculosis should be considered in cases with epididymitis not responding to broad spectrum antibiotics. Testicular infarction induced by prolonged epididymitis is easily missed due to a lack of symptom changes. Color doppler images are helpful in the diagnosis. This usually presents as a decrease in blood flow at the center of the testis with the increased flow at the periphery differentiating this from testicular torsion.

Monoclonal immunoglobulins promote bone loss in multiple myeloma.

Most patients with multiple myeloma develop a severe osteolytic bone disease. The myeloma cells secrete immunoglobulins, and the presence of monoclonal immunoglobulins in the patient's sera is an important diagnostic criterion. Here, we show that immunoglobulins isolated from myeloma patients with bone disease promote osteoclast differentiation when added to human preosteoclasts in vitro, whereas immunoglobulins from patients without bone disease do not. This effect was primarily mediated by immune complexes or aggregates. The function and aggregation behavior of immunoglobulins are partly determined by differential glycosylation of the immunoglobulin-Fc part. Glycosylation analyses revealed that patients with bone disease had significantly less galactose on immunoglobulin G (IgG) compared with patients without bone disease and also less sialic acid on IgG compared with healthy persons. Importantly, we also observed a significant reduction of IgG sialylation in serum of patients upon onset of bone disease. In the 5TGM1 mouse myeloma model, we found decreased numbers of lesions and decreased CTX-1 levels, a marker for osteoclast activity, in mice treated with a sialic acid precursor, N-acetylmannosamine (ManNAc). ManNAc treatment increased IgG-Fc sialylation in the mice. Our data support that deglycosylated immunoglobulins promote bone loss in multiple myeloma and that altering IgG glycosylation may be a therapeutic strategy to reduce bone loss.

Minimally invasive management of acute ureteral obstruction and severe infection caused by upper urinary tract calculi.

PURPOSETo evaluate therapeutic efficacy of two minimally invasive surgical methods in managing acute ureteral obstruction and severe infection caused by upper urinary tract calculi (UUTC).PATIENTS AND METHODSData of 47 patients diagnosed with acute upper urinary tract obstruction and severe infection caused by ureteral calculus using X-ray CT between September 2014 and January 2019 were retrospectively analyzed. All patients were treated with immediate renal drainage and, after infection and ureteral obstruction were relieved, UUTC removal. Renal drainage was performed by ultrasound-guided percutaneous nephrostomy and retrograde ureteral catheterization was performed using cystoscopy. Kidney and ureteral stones were removed; renal function and the urinary tract were examined by X-ray during follow-up.RESULTSPercutaneous nephrostomy was performed in 29 patients in a critical condition including intolerance to surgery, high-grade hydronephrosis, or failure of retrograde ureteric stent placement. In other 18 patients diagnosed with small stones (≤10 mm) and low-grade hydronephrosis, indwelling double-J ureteral stents were temporally installed by a cystoscope. Acute infection and ureteral obstruction were relieved; white blood cell counts returned to normal values within 3 to 7 days after drainage in all patients. In the second-stage treatment, percutaneous nephrolithotomy (PCNL), ureteroscopic lithotripsy, extracorporeal shock wave lithotripsy and nephrectomy were performed in 24, 10, 8 and 5 patients, respectively. No patients developed severe complication after stone removal surgery. All patients were followed up for 3 months to 4.5 years. Renal function was significantly recovered; 17/29 (59%) patients with elevated serum creatinine returned to normal and serum creatinine in 12/29 (41%) patients improved significantly after drainage, with a pre-operation level of 285±169µM vs 203±91µM post-operation (P = 0.014). Five patients were lost during follow-up.CONCLUSIONThis study demonstrated an optimal approach for relieving upper urinary tract obstruction and acute infection in which percutaneous nephrostomy drainage is preferred for patients with severe pyonephrosis, large stones (>10 mm) with high-grade hydronephrosis, steinstrasse, or failure in retrograde ureteric stent placement, while retrograde ureteral catheterization using cystoscopy is suitable for patients diagnosed with small stones (≤10 mm) and low-grade hydronephrosis.