Angiogenic imbalance in pregnancies with preterm prelabor rupture of membranes between 34 and 37 weeks of gestation.

INTRODUCTION: This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. MATERIAL AND METHODS: This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. RESULTS: Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. CONCLUSIONS: Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

Predictive value of the sFlt-1/PlGF ratio and interleukin-6 for the presence of placental lesions in spontaneous preterm labor with intact membranes with delivery within seven days.

INTRODUCTION: To identify predictive values of the soluble fms-like tyrosine kinase / placental growth factor (sFlt-1/ PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively. Methods of Study This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within seven days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys sFlt-1, PlGF, and IL-6 immunoassays. RESULTS: Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p < 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs.8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p < 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL. CONCLUSIONS: Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within seven days.

Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation.

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

Pitx2 is a useful marker of midgut-derived neuroendocrine tumours - an immunohistochemical study of 224 cases.

Pitx2 is a transcription factor responsible for establishment of the right-left axis and development of the gut and pituitary. In mouse embryos, Pitx2 is expressed in the greater curvature of the stomach and midgut. Previously, Pitx2 was studied in pituitary neuroendocrine tumours but not in other NETs. Pitx2 expression was immunohistochemically assessed in whole sections and tissue microarrays in a cohort of 224 neuroendocrine neoplasms, and was analysed in 29 cases. The cohort included 18 cauda equina NETs, 38 paragangliomas, 98 cases of primary visceral NETs from different organs, 23 metastases of visceral NETs and 47 neuroendocrine carcinomas (NECs). Pitx2 expression was observed in 29.5% (29 of 98) NETs and 14.9% (7 of 47) NECs, but was not observed in any paraganglioma or cauda equina NET. Pitx2 was observed only in tumours of midgut-derived organs, including the small intestine (100%, 20 of 20), appendix (88.9%, eight of nine) and large intestine (9.1%, one of 11 - only caecal NET). The NETs of remaining locations were negative. Pitx2 was 96.7% sensitive and 100% specific for NETs of midgut origin. In NECs, Pitx2 positivity was observed in goblet cell adenocarcinoma (75%, three of four), medullary thyroid carcinoma (42.9, three of seven) and one Merkel cell carcinoma (25%, one of four). In metastatic NETs, Pitx2 was observed in all the tumours originating in the small intestine (n = 17) or caecum (n = 1). No positivity was observed in tumours from other locations (four pancreas, one lung). We observed no correlation between immunoreactivity and mRNA expression. Thus, Pitx2 immunohistochemistry can be helpful in assessing the midgut origin of NETs.

Predictive and prognostic significance of tumour subtype, SSTR1-5 and e-cadherin expression in a well-defined cohort of patients with acromegaly.

In somatotroph pituitary tumours, somatostatin analogue (SSA) therapy outcomes vary throughout the studies. We performed an analysis of cohort of patients with acromegaly from the Czech registry to identify new prognostic and predictive factors. Clinical data of patients were collected, and complex immunohistochemical assessment of tumour samples was performed (SSTR1-5, dopamine D2 receptor, E-cadherin, AIP). The study included 110 patients. In 31, SSA treatment outcome was evaluated. Sparsely granulated tumours (SGST) differed from the other subtypes in expression of SSTR2A, SSTR3, SSTR5 and E-cadherin and occurred more often in young. No other clinical differences were observed. Trouillas grading system showed association with age, tumour size and SSTR2A expression. Factors significantly associated with SSA treatment outcome included age, IGF1 levels, tumour size and expression of E-cadherin and SSTR2A. In the group of SGST, poor SSA response was observed in younger patients with larger tumours, lower levels of SSTR2A and higher Ki67. We observed no relationship with expression of other proteins including AIP. No predictive value of E-cadherin was observed when tumour subtype was considered. Multiple additional factors apart from SSTR2A expression can predict treatment outcome in patients with acromegaly.

Cytokeratin 8/18-negative somatotroph pituitary neuroendocrine tumours (PitNETs, adenomas) show variable morphological features and do not represent a clinicopathologically distinct entity.

AIMS: In somatotroph pituitary neuroendocrine tumours (adenomas), a pattern of cytokeratin (CK) 18 expression is used for tumour subclassification, with possible clinical implications. Rare somatotroph tumours do not express CK 18. We aimed to characterise this subset clinically and histologically. METHODS AND RESULTS: Clinical and pathological data for the study were derived from a previously published data set of a cohort of 110 patients with acromegaly. Data included serum levels of insulin-like growth factor 1 (IGF1), growth hormone (GH), prolactin and thyroid-stimulating hormone (TSH), tumour diameter, tumour invasion defined by Knosp grade and immunohistochemical data concerning the expression of Ki67, p53, E-cadherin, somatostatin receptor (SSTR)1, SSTR2A, SSTR3, SSTR5 and D2 dopamine receptor. Additional immunohistochemical analysis (AE1/3, CK 8/18, vimentin, neurofilament light chain, internexin-α) was performed. CK 18 was negative in 10 of 110 (9.1%) tumours. One of these tumours was immunoreactive with CK 8/18 antibody, while the remainder expressed only internexin-α intermediate filament in patterns similar to CK 18 (perinuclear fibrous bodies). CK-negative tumours showed no significant differences with respect to biochemical, radiological or pathological features. They showed significantly higher expression of SSTR2A compared to the sparsely granulated subtype and significantly lower expression of E-cadherin compared to the non-sparsely granulated subtypes of tumours. The tumours showed divergent morphology and hormonal expression: two corresponded to densely granulated tumours and three showed co-expression of prolactin and morphology of either mammosomatotroph or somatotroph-lactotroph tumours. Four tumours showed morphology and immunoprofile compatible with plurihormonal Pit1-positive tumours. CONCLUSIONS: CK-negative somatotroph tumours do not represent a distinct subtype of somatotroph tumours, and can be further subdivided according to their morphology and immunoprofile.

Antibiotic administration reduces the rate of intraamniotic inflammation in preterm prelabor rupture of the membranes.

BACKGROUND: Preterm prelabor rupture of the membranes (PPROM) is frequently complicated by intraamniotic inflammatory processes such as intraamniotic infection and sterile intraamniotic inflammation. Antibiotic therapy is recommended to patients with PPROM to prolong the interval between this complication and delivery (latency period), reduce the risk of clinical chorioamnionitis, and improve neonatal outcome. However, there is a lack of information regarding whether the administration of antibiotics can reduce the intensity of the intraamniotic inflammatory response or eradicate microorganisms in patients with PPROM. OBJECTIVE: The first aim of the study was to determine whether antimicrobial agents can reduce the magnitude of the intraamniotic inflammatory response in patients with PPROM by assessing the concentrations of interleukin-6 in amniotic fluid before and after antibiotic treatment. The second aim was to determine whether treatment with intravenous clarithromycin changes the microbial load of Ureaplasma spp DNA in amniotic fluid. STUDY DESIGN: A retrospective cohort study included patients who had (1) a singleton gestation, (2) PPROM between 24+0 and 33+6 weeks, (3) a transabdominal amniocentesis at the time of admission, and (4) intravenous antibiotic treatment (clarithromycin for patients with intraamniotic inflammation and benzylpenicillin/clindamycin in the cases of allergy in patients without intraamniotic inflammation) for 7 days. Follow-up amniocenteses (7th day after admission) were performed in the subset of patients with a latency period lasting longer than 7 days. Concentrations of interleukin-6 were measured in the samples of amniotic fluid with a bedside test, and the presence of microbial invasion of the amniotic cavity was assessed with culture and molecular microbiological methods. Intraamniotic inflammation was defined as a bedside interleukin-6 concentration ≥745 pg/mL in the samples of amniotic fluid. Intraamniotic infection was defined as the presence of both microbial invasion of the amniotic cavity and intraamniotic inflammation; sterile intraamniotic inflammation was defined as the presence of intraamniotic inflammation without microbial invasion of the amniotic cavity. RESULTS: A total of 270 patients with PPROM were included in this study: 207 patients delivered within 7 days and 63 patients delivered after 7 days of admission. Of the 63 patients who delivered after 7 days following the initial amniocentesis, 40 underwent a follow-up amniocentesis. Patients with intraamniotic infection (n = 7) and sterile intraamniotic inflammation (n = 7) were treated with intravenous clarithromycin. Patients without either microbial invasion of the amniotic cavity or intraamniotic inflammation (n = 26) were treated with benzylpenicillin or clindamycin. Treatment with clarithromycin decreased the interleukin-6 concentration in amniotic fluid at the follow-up amniocentesis compared to the initial amniocentesis in patients with intraamniotic infection (follow-up: median, 295 pg/mL, interquartile range [IQR], 72-673 vs initial: median, 2973 pg/mL, IQR, 1750-6296; P = .02) and in those with sterile intraamniotic inflammation (follow-up: median, 221 pg/mL, IQR 118-366 pg/mL vs initial: median, 1446 pg/mL, IQR, 1300-2941; P = .02). Samples of amniotic fluid with Ureaplasma spp DNA had a lower microbial load at the time of follow-up amniocentesis compared to the initial amniocentesis (follow-up: median, 1.8 × 104 copies DNA/mL, 2.9 × 104 to 6.7 × 108 vs initial: median, 4.7 × 107 copies DNA/mL, interquartile range, 2.9 × 103 to 3.6 × 107; P = .03). CONCLUSION: Intravenous therapy with clarithromycin was associated with a reduction in the intensity of the intraamniotic inflammatory response in patients with PPROM with either intraamniotic infection or sterile intraamniotic inflammation. Moreover, treatment with clarithromycin was related to a reduction in the load of Ureaplasma spp DNA in the amniotic fluid of patients with PPROM <34 weeks of gestation.

Late preterm prelabor rupture of fetal membranes: fetal inflammatory response and neonatal outcome.

BackgroundTo characterize the influence of microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI) on the intensity of the fetal inflammatory response and the association between the presence of the fetal inflammatory response syndrome (FIRS) and short-term neonatal morbidity in the preterm prelabor rupture of membranes (PPROM) between the gestational ages of 34 and 37 weeks.MethodsOne hundred and fifty-nine women were included in the study. The umbilical cord blood interleukin (IL)-6 concentrations were determined using enzyme-linked immunosorbent assay kits. FIRS was defined based on the umbilical cord blood IL-6 concentration and the presence of funisitis and/or chorionic plate vasculitis.ResultsWomen with both MIAC and IAI had the highest median umbilical cord blood IL-6 concentrations and highest rates of FIRS. Women with FIRS had the higher rates of early-onset sepsis and intraventricular hemorrhage grades I and II when FIRS was characterized based on the umbilical cord blood IL-6 concentrations and the histopathological findings.ConclusionThe presence of both MIAC and IAI was associated with a higher fetal inflammatory response and a higher rate of FIRS. Different aspects of short-term neonatal morbidity were related to FIRS when defined by umbilical cord blood IL-6 concentrations and the histopathology of the placenta.

Gastric fluid used to assess changes during the latency period in preterm prelabor rupture of membranes.

OBJECTIVE: To determine changes in the intraamniotic environment during the latency period using paired amniotic and gastric fluid samples in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). METHODS: A total of 34 women with singleton pregnancies complicated by PPROM prior to 34 weeks were included in the study. Amniotic fluid was obtained by transabdominal amniocentesis at the time of admission. Immediately after delivery, umbilical cord blood and gastric fluid were obtained. RESULT: Microorganisms in amniotic and gastric fluid samples were found in 38% and 59% of women, respectively. Bedside IL-6 levels were higher in amniotic than in gastric fluid in pregnancies without fetal inflammatory response syndrome (FIRS) (263 pg/mL vs. 50 pg/mL; p < 0.0001), but not in pregnancies with FIRS (318 pg/mL vs. 444 pg/mL; p = 0.91). Funisitis and FIRS was associated with the highest bedside IL-6 levels in gastric fluid. A gastric fluid bedside IL-6 level of 275 pg/mL was found to be the ideal cutoff value to predict funisitis and FIRS. CONCLUSIONS: The microbial and inflammatory status of the intraamniotic compartment changes during the latency period in PPROM. Bedside IL-6 assessment of gastric fluid may be useful in the rapid diagnosis of funisitis and FIRS.

Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

[Identification of an optimal algorithm for effective diagnostics of non-small cell lung cancer with ALK gene rearrangement - implementation of the method and practical experiences with routine diagnostics]. / Stanovení optimálního vysetrovacího algoritmu pro efektivní vyhledávání nemalobunecných karcinomu plic s prestavbou genu ALK - zavedení metodiky a praktické zkusenosti z rutinního vysetrování.

The aim of the retrospective part of the study was a) to select an optimal clone of immunohistochemical (IHC) antibody against the ALK protein with specificity and sensitivity high enough to use this antibody as a screening method for selecting non-small cell lung cancer (NSCLC) cases for fluorescence in situ hybridization (FISH) testing of ALK gene rearrangement and b) to determine the diagnostic yield of "small" biopsies i.e. endobronchial, transbronchial and transthoracic biopsies and cytoblocks for ALK gene rearrangement testing. The best IHC method of ALK protein detection (clone D5F3, dilution 1:100, Cell Signaling Technology, Danvers, MA, USA) was then verified in prospective routine testing of patients with NSCLC. ALK status was correlated with tumor morphology and clinical data. In the retrospective part of the study, 170 EGFR-nonmutated cases of NSCLC were IHC and FISH tested. In the prospective part, 557 cases of NSCLC were tested by IHC and 76 by FISH. There were 8/154 (5.2%) cases with ALK gene rearrangement detected in the retrospective part and 24/557(4.3 %) in the prospective part. Sensitivity and specificity of the best IHC method were 100 % and 99 % in the retrospective part and 100 % and 80 % in the prospective part. The diagnostic yield of "small" biopsies was between 74 - 80 % retrospectively, depending on IHC variant, and 88 % prospectively. No case with ALK gene rearrangement detected prospectively had EGFR mutation. A high diagnostic yield confirms that ALK status testing can be used in this type of specimen. A prevalence of 5.2 % in the retrospective part (EGFR-nonmutated cases) and 4.3 % in the prospective part (without known EGFR mutation status), tumor morphology (solid and acinar type, mucinous type or at least partial mucin production (extra- and/or intracellular) as well as lower average age and male/female ratio of patients with ALK positive tumors in the prospective part (57.5 y vs. 65.2 y, 8 men and 16 women vs. 336 men and 197 women) are consistent with global data.

[Histopathology of interstitial lung diseases]. / Histopatologické principy vysetrení intersticiálních plicních procesu.

Diffuse interstitial lung disorders include more than 200 different syndroms affecting the space between epithelial basal membrane and endothelial cells. Histopathological investigation of the lung tissue is one of the crucial parts of the multidisciplinary team approach for the investigation of these disorders. The aim of this review is a brief characterization of the pattern of the main subtypes of lung tissue damage.

[Differential diagnosis of granulomatous lung diseases]. / Diferenciální diagnostika granulomatózních procesu v plicích.

Brief review of histopathology of non-tumor pulmonary diseases with nodular or granulomatous morphology. Differential diagnosis of infections, sarcoidosis, vasculitides with a granulomatous component and selected pneumoconioses is presented.

[Interstitial lung diseases associated with smoking]. / Intersticiální plicní onemocnení asociovaná s kourením.

There are many different interstitial lung diseases associated with smoking. This short review describes officially recognized disorders (desquamative interstitial pneumonia, respiratory bronchiolitis and pulmonary Langerhans´cells histiocytosis) and entities with uncertain relationship to smoking, which have recently been published in the literature. Histopathological pictures and differential diagnosis of smoking-related diseases of the lungs are discussed.

[Practical comments on examination of placenta in the second and third trimester of gravidity]. / Praktické poznámky k vysetrení placenty ve druhém a tretím trimestru gravidity.

The authors present a short summary of placental pathology for the general pathologist. Practical tips for macroscopic examination of formalin-fixed material are listed and several cases are presented for illustration of the theoretical text.

[Hopes and pitfalls of the molecular classification of breast cancer]. / Nadeje a úskalí molekulární klasifikace karcinomu prsu.

Traditional histopathological diagnosis of breast cancer has been extended in recent years through the results of additional methods. Today, the results of the detection of hormone receptors, HER-2/neu, and Ki67 antigen are thus an integral part of the histopathological diagnosis. A critical factor for the success of these tests is the fulfillment of pre-analytical phase conditions - i.e. optimal fixation, as well as taking into account the heterogeneous nature of the neoplastic population. In addition to the above-mentioned markers - which have become a routine practice in recent years, there are many efforts to include the molecular characteristics of tumors both in tumor classification as well as in the prediction of results of cancer treatment. Most of the work is based on the use of gene expression profiles. On the basis of the detection of increased or decreased expression of a large number of genes, it is possible to find a set of multiple genes correlating with the biological behavior of the tumor. Using this approach, four basic subgroups of breast cancer have been identified - luminal, basal-like, HER-2 enriched and normal gland-like. Over the course of time, the number of molecular categories has expanded - originally a homogenous group of luminal cancers has been subclassified into the luminal A, B and C. Also within basal-like carcinomas additional subgroups have been identified. However, the results of studies dealing with the analysis of gene expression profiles suggest that our understanding of the biology of breast cancer is far from being complete. The individual categories are defined differently in various publications and thus the comparison of the results of these studies is very difficult. Another approach for the molecular classification of breast cancer is the immunohistochemical detection of various proteins used as a surrogate marker instead of the detection of the mRNA of individual genes. The advantage of this approach is the possibility to use even archive material, as well as much lower costs. On the other hand, its main limitation is the inability of parallel detection of thousands of markers, unlike in genomic profiling. The results of molecular classification are, however, not fundamentally surprising. The fact that breast cancer tumor stem cells can differentiate towards myoepithelial (or basal) and luminal cells has been known for a long time. These two lines of differentiation are - among others - characterized by differential expression of cytoskeletal proteins as well as of other molecules. These findings have been confirmed by the results of molecular studies - either those based on gene expression profiling or immunohistochemical ones. Research results in gene expression profiling have relatively quickly translated into clinical practice. At present, several commercially available certified tests serve as a complementary source of information for decisions about clinical treatment.

Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes.

OBJECTIVE: We sought to determine the influence of microbial invasion of the amniotic cavity (MIAC) and acute histologic chorioamnionitis (HCA) on the intensity of the intraamniotic inflammatory response and neonatal morbidity in preterm prelabor rupture of membranes (PPROM) between 34-37 weeks. STUDY DESIGN: This study included 99 women with singleton pregnancies complicated by PPROM between the gestational ages of 34-37 weeks. Amniocenteses were performed at the time of admission, and MIAC and amniotic fluid interleukin-6 concentrations were determined. After delivery, the placenta was evaluated for the presence of HCA. RESULTS: Women with both MIAC and HCA had the highest intraamniotic inflammatory response, which was mediated by interleukin-6 concentrations (both MIAC and HCA: median 2164.0 pg/mL; HCA alone: median 654.8 pg/mL; MIAC alone: median 784.1 pg/mL; neither MIAC nor HCA: median 383.0 pg/mL; P < .0001) and the highest incidence of newborns with early-onset sepsis (P = .02). CONCLUSION: Both MIAC and HCA affect the intensity of the intraamniotic inflammatory response and the incidence of early-onset sepsis following PPROM between 34-37 weeks. The intensity of the intraamniotic inflammatory response should be considered in the clinical management of PPROM between 34-37 weeks.

Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes.

OBJECTIVE: The objective of the study was to determine the diagnostic indices and predictive values by bedside assessment of amniotic fluid interleukin-6 (IL-6) concentration in the identification of microbial invasion of the amniotic cavity (MIAC) and/or histological chorioamnionitis (HCA) in patients with preterm prelabor rupture of membranes. STUDY DESIGN: One hundred twenty-four women with singleton pregnancies were included in this study. The amniotic fluid was sampled by transabdominal amniocentesis at the time of admission. IL-6 concentrations were assessed with an immunoassay. RESULTS: The presence of MIAC, HCA, or the coexistence of both was associated with higher amniotic fluid concentrations of IL-6 in both a crude and adjusted analysis. The amniotic fluid concentration of IL-6 of 1000 pg/mL was determined to be the best cutoff value for the prediction of MIAC (sensitivity of 50%, specificity of 95%, positive predictive value of 82%, negative predictive value of 81%, and likelihood ratio of 8.4) or both MIAC and HCA (sensitivity of 60%, specificity of 94%, positive predictive value of 75%, negative predictive value of 88%, and likelihood ratio of 9.4). CONCLUSION: The bedside assessment of amniotic fluid IL-6 seems to be an easy, rapid, and inexpensive method for the prediction of MIAC or both MIAC and HCA in pregnancies complicated by preterm prelabor rupture of membranes.

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms.

Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.

Ultrasound measurement of the transverse diameter of the fetal thymus in pregnancies complicated by the preterm prelabor rupture of membranes.

PURPOSE: To determine whether the measurement of the transverse diameter of the fetal thymus is of value in the identification of either histologic chorioamnionitis or funisitis in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). METHODS: The transverse diameter of the fetal thymus was measured in 216 fetuses from PPROM pregnancies. A small thymus was defined as a transverse thymic diameter below the fifth percentile according to a previously published nomogram. The placenta, the fetal membranes, and the umbilical cord were assessed for the presence of inflammation. RESULTS: A small thymus was identified in 69% (150/216) of fetuses. A small thymus was present in 80% (106/133) and 88% (36/41) of women with histologic chorioamnionitis or funisitis, respectively. The presence of a small thymus had a sensitivity of 79%, specificity of 47%, positive predictive value of 71%, negative predictive value of 59% for the identification of chorioamnionitis (p < 0.0001; odds ratio 3.5) and a sensitivity of 88%, specificity of 35%, positive predictive value of 24%, and negative predictive value of 92% in the identification of funisitis (p = 0.004; odds ratio 4.4). CONCLUSIONS: The sonographic finding of a small thymus is a sensitive indicator of histologic chorioamnionitis or funisitis; low specificity excludes it as a possible clinical implication in the management of PPROM pregnancies.