Variation of modulation and expression of biomarkers associated with inflammation in bariatric surgery patients: A systematic review and meta-analysis.

BACKGROUND: Bariatric surgery is an effective intervention that causes a series of metabolic changes related to inflammatory processes; however, the variation of biomarkers related to these processes is not entirely understood. Our objective was to investigate the variation of modulation and expression of biomarkers associated with inflammation in patients who underwent bariatric surgery. METHODS: We searched the MEDLINE (via PubMed), EMBASE (via Elsevier), Cochrane Central Register of Controlled Trials, Latin American and Caribbean Literature on Health Sciences (via virtual health library), Cumulative Index to Nursing and Allied Health Literature (via EBSCO), Web of Science core collection, and Scopus (via Elsevier) databases, and the gray literature was examined from inception to January 2022. Three pairs of reviewers performed data screening, extraction, and quality assessment independently. Meta-analysis with random effects models was used for general, subgroup, and sensitivity analyses. The I2 statistic was used to assess heterogeneity between studies. RESULTS: In total, 96 articles were included in this systematic review; of these, 87 studies met the criteria for the meta-analysis, involving 3,533 participants. Five biomarkers were included in the meta-analysis (tumor necrosis factor alpha; interleukin 6; leptin; interleukin 1 beta, and lipopolysaccharides). Only leptin showed a significant decrease in the first month after surgery (mean difference -20.71; [95% confidence interval: -28.10 to -13.32, P < .0001; I2 = 66.7%), with moderate heterogeneity. The 12 months after surgery showed a significant decrease in tumor necrosis factor alpha (mean difference -0.89; [95% confidence interval: -1.37 to -0.42], P = .0002; I2 = 94.7%), interleukin 6 (mean difference -1.62; [95% confidence interval: -1.95 to -1.29], P < .0001; I2 = 94.9%), leptin (mean difference -28.63; [95% confidence interval: -34.02 to -23.25], P < .0001; I2 = 92.7%), and interleukin 1 beta (mean difference -2.46; [95% confidence interval: -4.23 to -0.68], P = .006; I2 = 98.3%), all with high heterogeneity. The type of surgery did not show significant differences for the biomarkers at the first month and 12 months, and the results have not changed with high-quality studies. In the 12-month measurement, variations in tumor necrosis factor alpha and leptin were associated with body mass index. CONCLUSION: The findings of this meta-analysis suggest that Roux-en-Y gastric bypass and sleeve gastrectomy bariatric surgeries are associated with a significant reduction in leptin at 1 month after bariatric surgical intervention and tumor necrosis factor alpha, leptin, and interleukin 1 beta after 12 months.

Association of Biomarkers for Human Papillomavirus With Survival Among Adults With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma.

Importance: The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. Objective: To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. Design, Setting, and Participants: This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Main Outcomes and Measures: Disease-free survival and overall survival. Results: Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). Conclusions and Relevance: This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status.

Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages.

OBJECTIVE AND DESIGN: Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. METHODS: We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. RESULTS: We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. CONCLUSIONS: In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.

Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection.

Importance: High-risk human papillomavirus (HPV) has been associated with Barrett dysplasia and esophageal adenocarcinoma. Nevertheless, the prognostic significance of esophageal tumor HPV status is unknown. Objective: To determine the association between HPV infection and related biomarkers in high-grade dysplasia or esophageal adenocarcinoma and survival. Design, Setting, and Participants: Retrospective case-control study. The hypothesis was that HPV-associated esophageal tumors would show a favorable prognosis (as in viral-positive head and neck cancers). Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction, in situ hybridization for E6 and E7 messenger RNA (mRNA), and immunohistochemistry for the proteins p16INK4A and p53. Sequencing of TP53 was also undertaken. The study took place at secondary and tertiary referral centers, with 151 patients assessed for eligibility and 9 excluded. The study period was from December 1, 2002, to November 28, 2017. Main Outcomes and Measures: Disease-free survival (DFS) and overall survival (OS). Results: Among 142 patients with high-grade dysplasia or esophageal adenocarcinoma (126 [88.7%] male; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, and wild-type TP53. There were more Tis, T1, and T2 tumors in HPV-positive patients compared with HPV-negative patients (75.7% vs 54.3%; difference, 21.4%; 95% CI, 4.6%-38.2%; P = .02). Mean DFS was superior in the HPV-positive group (40.3 vs 24.1 months; difference, 16.2 months; 95% CI, 5.7-26.8; P = .003) as was OS (43.7 vs 29.8 months; difference, 13.9 months; 95% CI, 3.6-24.3; P = .009). Recurrence or progression was reduced in the HPV-positive cohort (24.3% vs 58.1%; difference, -33.8%; 95% CI, -50.5% to -17.0%; P < .001) as was distant metastasis (8.1% vs 27.6%; difference, -19.5%; 95% CI, -31.8% to -7.2%; P = .02) and death from esophageal adenocarcinoma (13.5% vs 36.2%; difference, -22.7%; 95% CI, -37.0% to -8.3%; P = .01). Positive results for HPV and transcriptionally active virus were both associated with a superior DFS (hazard ratio [HR], 0.33; 95% CI, 0.16-0.67; P = .002 and HR, 0.44; 95% CI, 0.22-0.88; P = .02, respectively [log-rank test]). Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS. On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95% CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95% CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95% CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95% CI, 0.27-0.89; P = .02). Conclusions and Relevance: Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are positive for HPV are distinct biological entities with a favorable prognosis compared with viral-negative esophageal tumors. Confirmation of these findings in larger cohorts with more advanced disease could present an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival.

Nodular hyperplasia of Bartholin's gland.

AIMS: There has been very little mention of benign solid lesions of the Bartholin's gland (BG) in pathology and gynaecology textbooks, and very few cases have been reported in the literature. Among these lesions, the distinction between nodular hyperplasia (NH) and adenoma has not been well defined. We report ten cases of NH of the BG, describe their clinicopathological, immunohistochemical and ultrastructural findings, and review the literature. METHODS: We examined retrospectively all lesions involving BGs from our surgical pathology records from 1990 to 2004 with emphasis on NH. To separate NH from adenoma, we applied the criteria proposed by Koenig and Tavassoli. Special stains (PAS with and without prior digestion, Mayer's mucicarmine and Alcian blue with and without hyaluronidase) and immunohistochemistry (CAM5.2, AE1/AE3, HMWK, monoclonal CEA, EMA, ER, PR, ALA, SMA, Ki-67, p53 and polyclonal CEA) were performed on NHs. Two cases were examined ultrastructurally. RESULTS: Using specific criteria, ten cases (age range 23-45 years; mean 36.1) of NH were identified, two of which were diagnosed previously as adenoma, but re-classified as NH. Clinically, these lesions were described either as Bartholin's duct cysts (BDCs) or vulvar lumps. Grossly, NHs were solid, tan and unencapsulated, measuring 12.5-45.0 mm in maximum dimension (mean 23.8). Histologically, the NHs were composed of a proliferation of mucus-secreting acini with preservation of the normal duct-to-acinar relationship. Chronic inflammation and squamous metaplasia were present. Eight lesions focally involved the surgical margins. Intracytoplasmic and intra-luminal secretions were positive for PAS with and without digestion, Alcian blue with and without hyaluronidase and mucicarmine. All lesions showed positive staining for CAM5.2, AE1/AE3, HMWK, EMA, and polyclonal CEA. There was negative staining for Ki-67, ER, PR, ALA, p53 and monoclonal CEA. Periacinar myoepithelial cells stained for SMA. Ultrastructurally, the findings included abundant intracytoplasmic secretory granules, granulofibrillar bodies, prominent Golgi and ribosomes. Myoepithelial cells were identified. There was no tumour recurrence or malignant transformation in eight patients with clinical follow-up. CONCLUSION: NH of the BG is a rare lesion with benign behaviour. It is a distinct entity and can be separated histologically from an adenoma.

Applications of monoclonal anti-human inhibin alpha subunit in endometrial curettings.

AIMS: Using archival material, we studied the immunoreactivity and utility of monoclonal anti-human inhibin alpha subunit in the identification of chorionic villi (CV) and trophoblastic subpopulations in endometrial curettings (EC) from patients who had intra-uterine, ectopic, molar and, particularly, probable intra-uterine pregnancies. We also compared its expression with those of betaHCG, HPL and CAM 5.2. METHODS: The four groups of EC investigated included: Group 1, 15 patients with intra-uterine pregnancies (IUP); Group 2, 15 patients with tubal pregnancies (TP); Group 3, 15 patients with hydatidiform moles (HM); and Group 4, 20 patients with purported history of intra-uterine pregnancies (PIUP). Positive and negative control cases were from Groups 1 and 3 and Group 2, respectively. The test cases were from Group 4. Immunohistochemistry was performed on each case testing for expression of inhibin alpha, betaHCG, HPL and CAM 5.2. RESULTS: Trophoblastic populations, which included syncytiotrophoblast (ST), cytotrophoblast (CT) and intermediate trophoblast (IT), were absent in all 15 negative control cases (Group 2). The 30 positive control cases (Groups 1 and 3) revealed the following: (a) ST, CT and IT were identified in all cases and were positive for CAM 5.2, (b) inhibin alpha, betaHCG and HPL (except one case) were reactive for all cases with ST, but not CT, and (c) IT positivity for betaHCG, HPL and inhibin alpha was 67, 80-93 and 100%, respectively. From the 20 test cases (Group 4), the findings were: (a) CT was absent in all cases, (b) scattered ST cells, which were identified only in 10 cases, were positive for all antibodies, (c) scattered IT cells were present in 17 cases and showed 100% CAM 5.2 positivity, and (d) IT positivity for betaHCG, inhibin alpha and HPL was 58.8% (10/17), 76.5% (13/17) and 82.4% (14/17), respectively. Background staining was observed in 22 of 65 cases (33.8%) stained with betaHCG and HPL; half of these cases came from Group 3. Inhibin alpha and CAM 5.2 staining did not show this problem. CONCLUSIONS: We suggest that inhibin alpha is a useful antibody in diagnosing IUP and HM and in documenting intra-uterine gestations in cases with PIUP because it is a sensitive marker in immunolabelling IT and ST. Combined application of inhibin alpha and CAM 5.2 might be more useful than betaHCG and HPL because the latter showed background staining in one third of the cases.

Glomus coccygeum may mimic glomus tumour.

We reviewed all cases of pilonidal sinus excision specimens from our surgical pathology records from 1990 to 2000 to determine the presence of glomus coccygeum. We found only two cases of glomus coccygeum, also known as coccygeal body. We describe the histology and immunohistochemical findings of two glomera coccygea incidentally discovered in pilonidal sinus excision specimens, and review the world's English literature.

Serous oligocystic adenoma of the pancreas: a clinicopathological and immunohistochemical study of three cases with ultrastructural findings.

AIMS: Serous oligocystic adenoma of the pancreas is an uncommon benign neoplasm and is a recently described entity. To date, there are 19 adult cases of this tumour. We report three additional cases, two with macrocystic and one with unilocular types. We describe their clinicopathological, immunohistochemical and ultrastructural findings and review the world's literature. METHODS: For a 10-year period, we reviewed all benign cystic lesions of the pancreas with emphasis on serous oligocystic adenoma. We characterised serous oligocystic adenoma as an ill-demarcated or encapsulated mass, composed largely or exclusively of macrocysts (cysts measuring 20mm or more) but few in number (oligolocular). Grossly, it may contain only a single cyst (unilocular) of any size with a few satellite cysts observed on histological examination. Special stains and immunohistochemistry as well as electron microscopy were performed on three and two cases of serous oligocystic adenoma, respectively. RESULTS: Between 1990 and 2000, we collected 26 benign cystic lesions of the pancreas, three of which were serous oligocystic adenomas (two with macrocystic and one with unilocular types). Many of the cells lining the cysts showed PAS positivity. There was negative staining for PAS with diastase digestion, Alcian blue and mucicarmine. All cases showed positive staining for CAM5.2, AE1/AE3, EMA and CK7. The proliferation index marker was low. There was negative staining for CK20, insulin, glucagon, somatostatin, synaptophysin, chromogranin A, CEA and p53. Ultrastructural studies on two cases revealed similar findings. The single row of uniform epithelial cells lining the cysts was composed of simple cuboidal to flat cells which rested on a thin basal lamina. Their nuclei were round to ovoid. Glycogen granules were identified in the cytoplasm. Short microvilli emerged from the epithelial apical surface. Adjacent tumour cells were connected by microfilaments. CONCLUSIONS: Serous oligocystic adenomas of the pancreas are uncommon benign tumours. Prior to this study, 19 adults with these lesions were reported in the world's literature. No correct pre-operative diagnosis was carried out on all 22 cases. The 20 patients with follow-up ranging from 2 months to 5 years did not show tumour recurrence or malignant transformation.