Outpatient vs inpatient induction of labor with oral misoprostol: A retrospective study.

INTRODUCTION: Induction of labor is one of the most common obstetrical procedures today, with a successively rising rate. With a limited number of hospital beds, the option of starting induction at home has gained increasing attention. The primary aim of this study was to compare the proportion of women achieving vaginal delivery and the duration of hospital stay before delivery in induction of labor with oral misoprostol starting at home and induction with oral misoprostol at the hospital, in a low-risk population. MATERIAL AND METHODS: Women with home induction (n = 282) were individually matched to controls induced at the hospital during the same time period regarding parity, age, body mass index, labor unit and indication for induction. RESULTS: The rates of vaginal birth were similar in outpatients and inpatients (84.8% vs 86.2%; p = 0.5). Time from hospital admission to delivery in the outpatient group was significantly shorter than in the inpatient group (12.8 vs 20.6 h; p < 0.001), as was total hospital stay (2 vs 3 days; p < 0.001). There were no significant differences between the groups in neonatal or maternal outcomes. One patient undergoing outpatient induction had an unplanned home birth. CONCLUSIONS: Starting induction at home reduced the time spent in hospital without affecting the vaginal delivery rate. Although underpowered to assess safety, this study did not show any differences in adverse maternal and perinatal outcomes between inpatients and outpatients. Further research is needed to evaluate the safety of outpatient induction of labor with misoprostol.

A follow up on the feasibility after national implementation of magnesium sulfate for neuroprotection prior to preterm birth.

INTRODUCTION: The risk for brain injury manifested as cerebral palsy is higher in very preterm born children than in term. Prenatal administration of magnesium sulfate (MgSO4 ) has been shown to be neuroprotective and reduces the proportion of very preterm born children later diagnosed with cerebral palsy. A Swedish national clinical practice guideline was implemented in March 2020, stipulating the administration of a single intravenous dose of 6 g MgSO4 1-24 h prior to delivery before gestational age 32+0, aiming for 90% treatment coverage. The aim of this study was to evaluate the feasibility of this new clinical practice guideline in the first year of its implementation. MATERIAL AND METHODS: Data on MgSO4 treatment were collected by reviewing the medical charts of women who gave birth to live born children in gestational age 22+0-31+6 during the period of March 1, 2020 to February 28, 2021, at five Swedish university hospitals. Women with pre-eclampsia, eclampsia, or high elevated liver enzymes low platelets (HELLP) were excluded. RESULTS: A total of 388 women were eligible and 79% received treatment with MgSO4 . Of the 21% not receiving treatment, 9% did not receive treatment due to lack of knowledge about the clinical practice guideline, 9% were not possible to treat and 3% had missing data. The proportion treated increased from 72% to 87% from the first to the last 3 months. Of those treated, 81% received the drug within the stipulated timeframe (mean 8.7 h, median 3.4 h). CONCLUSIONS: There was a positive trend over time in the proportion of women receiving MgSO4 treatment, but the a priori target of 90% was not reached during the first year of implementation. Our findings indicate that this target could be reached with additional information to clinicians.

Relation between perinatal outcome and gestational duration in term primiparous pregnancies stratified by body mass index.

INTRODUCTION: There is growing evidence that induction of labor at 41 completed weeks improves neonatal outcome, at least among primiparous women. This study was performed to investigate whether maternal body mass index (BMI) should be considered when deciding on timing of intervention in term pregnancies. MATERIAL AND METHODS: The study design was a historical cohort study using data from the Swedish Medical Birth Register, singletons in cephalic presentation with births 39+0 to 41+6 weeks, with available information on maternal BMI 2005-2017 (n = 352 567). Modified Poisson regression analyses were used to investigate the association between gestational duration and stillbirth or death before 45 postmenstrual weeks (primary outcome) and Apgar score <7 at 5 minutes (secondary outcome) by BMI, respectively. Adjustments were made for maternal age, smoking, country of birth and educational level. RESULTS: The adjusted relative risk (ARR) of stillbirth or death before 45 weeks among infants born at 41+0 to 41+6 vs 40+0 to 40+6 weeks, was 1.26 with a 95% confidence interval (CI) of 1.07-1.48. Among women with BMI ≥30, the offspring mortality risk in pregnancies lasting 39+0 to 39+2 weeks was significantly above the corresponding risk among women of normal BMI who delivered at 41+0 to 41+2 weeks (ARR = 1.95; 95% CI 1.07-3.56) but no statistically significant heterogeneity was found regarding the magnitude of the association between gestational duration and offspring mortality. The ARR, for Apgar <7 at 5 minutes (41+0 to 41+6 vs 40+0 to 40+6 weeks, regardless of BMI), was 1.36 (95% CI 1.27-1.45). The risk for low Apgar score at 41+0 weeks was 1.5% among all children regardless of maternal BMI. Among children to women with BMI ≥30, this magnitude of risk was found already at 39+3 weeks. CONCLUSIONS: In primiparous women with obesity the risk of stillbirth or death before 45 postmenstrual weeks were increased throughout all full-term gestational age categories, compared with women with overweight or normal BMI. Children to obese women had the same risk for Apgar scores <7 at 5 minutes compared with women overall at earlier gestational age. The results suggest that maternal BMI needs to be considered when discussing timing of elective induction in term healthy pregnancies of primiparous women.

Time to reconsider: Have the 2015 FIGO and 2017 Swedish intrapartum cardiotocogram classifications led us from Charybdis to Scylla?

In 2015, FIGO revised the 1987 intrapartum cardiotocography (CTG) classification (FIGO1987). A less radical FIGO2015 version was introduced in Sweden 2017 (SWE2017). Now, post hoc simulation studies show that FIGO2015 and SWE2017 are less reliable than (a modified) FIGO1987. FIGO2015 shows significantly better interobserver agreement for normal CTG traces than FIGO1987, but significantly worse for pathological traces. Agreements between templates are moderate to good, but different classifications of mainly variable decelerations and tachycardia cause significant heterogeneities. FIGO2015 shows insufficient sensitivity to identify fetal acidemia compared with FIGO1987. In connection with fetal electrocardiogram ST analysis, one study showed no template was superior in identifying fetal acidemia, but in a series of only academia, FIGO1987 had significantly higher sensitivity than FIGO2015 (73% vs. 43%) and set of an alarm for fetal acidemia considerably earlier. With SWE2017, operative interventions declined significantly in Sweden but several adverse neonatal outcomes increased significantly. It remains to investigate the development with FIGO2015.

Serial Circulating Tumor DNA Mutational Status in Patients with KRAS-Mutant Metastatic Colorectal Cancer from the Phase 3 AIO KRK0207 Trial.

BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC). METHODS: Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2-3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters. RESULTS: mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20-2.95; HR = 2.15, 95% CI 1.47-3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44-4.46; HR = 1.90, 95% CI 1.23-2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40-3.25). CONCLUSIONS: Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy. CLINICALTRIALSGOV IDENTIFIER: NCT00973609.

Complicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery.

BACKGROUND: It has been proposed that pregnant women and their fetuses may be particularly at risk for poor outcomes due to the coronavirus (COVID-19) pandemic. From the few case series that are available in the literature, women with high risk pregnancies have been associated with higher morbidity. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection. CASE PRESENTATION: A 26-year old Somalian woman (G2P1) presented with a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever. A nasopharyngeal swab returned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Her condition rapidly worsened leading to severe liver and coagulation impairment. An emergency Caesarean section was performed at gestational week 32 + 6 after which the patient made a rapid recovery. Severe COVID-19 promptly improved by the termination of the pregnancy or atypical HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelet Count) exacerbated by concomitant COVID-19 infection could not be ruled out. There was no evidence of vertical transmission. CONCLUSIONS: This case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy and advocates for pregnant women to be recognized as a vulnerable group during the current pandemic.

Dro1/Ccdc80 inactivation promotes AOM/DSS-induced colorectal carcinogenesis and aggravates colitis by DSS in mice.

Colorectal carcinogenesis is a progressive multistep process involving the sequential accumulation of genetic alterations in tumor suppressor genes and oncogenes. Downregulated by oncogenes 1 (Dro1/Ccdc80) has been shown to be a potent tumor suppressor of colorectal carcinogenesis in the genetic ApcMin/+ mouse model. In ApcMin/+ mice, loss of DRO1 strongly increases colonic tumor multiplicity and leads to the regular formation of adenocarcinoma in the colon. To investigate DRO1's role in chemically induced as well as inflammation-associated colorectal carcinogenesis, the effect of Dro1 inactivation was studied in mice subjected to the carcinogen azoxymethane (AOM) and upon combined treatment with AOM and the proinflammatory agent dextran sodium sulfate (DSS), respectively. Loss of DRO1 increases multiplicity of preneoplastic aberrant crypt foci and colonic tumors upon administration of AOM. Combined treatment with AOM and DSS leads to increased colonic tumor number and promotes formation of adenocarcinoma in the colon. Moreover, Dro1 inactivation aggravates histological signs of acute and chronic DSS-induced colitis, strongly enlarges the size of ulcerative lesions in the intestinal lining, and exacerbates clinical signs and morbidity by DSS. Our results demonstrate DRO1 to be a strong tumor suppressor in the chemically induced colon carcinogenic mouse model. Additionally, we demonstrate DRO1 to inhibit colitis-associated colon cancer formation and uncover a novel putative role for DRO1 in inflammatory bowel disease.

Correlation Between Baseline Osteoprotegerin Serum Levels and Prognosis of Advanced-Stage Colorectal Cancer Patients.

BACKGROUND/AIMS: Osteoprotegerin (OPG) is a soluble receptor of the pro-apoptotic cytokine TRAIL which is thought to contribute to tumour development by inhibiting apoptosis or affecting other aspects of tumour biology, including cell proliferation and immune response. Although immunohistochemical studies suggest that OPG correlates with survival in metastatic colorectal cancer (mCRC), only scarce data are available on serum OPG in CRC patients. METHODS: In this pilot study, we assessed the prognostic significance of serum OPG and CEA (Carcinoembryonic antigen) in 81 patients with UICC (Union for International Cancer Control) stage-IV mCRC. OPG was additionally assessed by immunohistochemistry in primary tissue samples from 33 patients of the same cohort. RESULTS: Baseline serum OPG correlated with CEA (r=0.36, p=0.0011), but independently predicted survival of mCRC patients. Life expectancy was poorer in patients with OPG levels above the median concentration of 51ng/ml (median overall survival [95% confidence interval] 1.8 years [1.3-3.0] vs. 1.0 [0.7-1.2] p=0.013). Patients with high levels of both OPG and CEA had an even poorer life expectancy vs. low-OPG/low-CEA patients (0.9 years [0.6-1.5] vs. 3 years [1.2-4.4], p=0.015), indicating that CEA and OPG have additive prognostic significance. Immunohistochemical analysis of OPG failed to show a correlation between OPG staining and survival (p=0.055) or OPG concentration from matched serum samples. CONCLUSIONS: This pilot study provides evidence of independent prognostic significance of serum OPG in patients with advanced mCRC and warrants its further prospective validation.

Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice.

OBJECTIVE: ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease. APPROACH AND RESULTS: Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17ex/ex), which have low residual Adam17 expression. To induce atherosclerosis, mice were crossed onto the low-density lipoprotein receptor (Ldlr)-deficient background. We found that Adam17ex/ex.Ldlr-/- mice developed ≈1.5-fold larger atherosclerotic lesions, which contained more macrophages and vascular smooth muscle cells than wild-type littermate controls (Adam17wt/wt.Ldlr-/-). Reduced Adam17-mediated shedding led to significantly increased protein levels of membrane-resident TNFα (tumor necrosis factor) and TNFR2 (tumor necrosis factor receptor 2), resulting in a constitutive activation of TNFR2 signaling. At the same time, Adam17 deficiency promoted proatherosclerotic cellular functions, such as increased proliferation and reduced apoptosis in cultured macrophages and vascular smooth muscle cells and increased adhesion of macrophages to vascular endothelial cells. Because siRNA (small interfering RNA)-mediated knockdown of Tnfr2 rescued from aberrant proliferation and from misregulation of apoptosis in Adam17-depleted cells, our data indicate that TNFR2 is an important effector of ADAM17 in our mouse model. CONCLUSIONS: Our results provide evidence for an atheroprotective role of ADAM17, which might be mediated by cleaving membrane-bound TNFα and TNFR2, thereby preventing overactivation of endogenous TNFR2 signaling in cells of the vasculature.

Deep brain stimulation: custom-made silicone-coated pulse-generator implantation after allergic reaction to generator compounds.

Deep brain stimulation for Parkinson's disease has become an established treatment option in recent years. The method and its application in clinical practice has proved to be safe and effective. Nevertheless, procedure-related and hardware-related complications occur. We present a rare case of a patient with an allergic reaction to the impulse generator. The patient suffered from delayed wound-healing deficits with several wound revisions and generator repositionings. After diagnosis of an allergic reaction to components of the generator, a custom-made silicon-coated model was implanted. Hereafter, no wound healing-deficit occurred throughout long-term follow-up. Allergic reaction to hardware components may lead to wound-healing deficits. In such cases, custom-made silicon-coated models may be an effective treatment option.

Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.

Improved neonatal outcome after active management of prolonged pregnancies beyond 41+2 weeks in nulliparous, but not among multiparous women.

INTRODUCTION: Prolonged pregnancies are associated with adverse maternal and fetal outcome. In Sweden, no national guidelines exist for when to induce prolonged pregnancies. MATERIAL AND METHODS: Singleton cephalic prolonged pregnancies (defined as ≥ 41+3 gestational weeks) during 2001-2013 (n = 199 770) were identified using the Swedish Medical Birth Register. The maternity units were divided into three groups (tertiles) based on the proportion of pregnancies ≥ 42+3 gestational weeks among all pregnancies ≥ 41+3  weeks. The pregnancy outcome among women delivered at the units with the most expectant management of prolonged pregnancies (> 17.6% proceeding to 42+3  weeks), was compared with that among women delivered at units with the most active management (< 12.6% proceeding to 42+3  weeks). Odds ratios (OR) were calculated using simple and multiple logistic regression. Adjustments were made for year of delivery, hospital level, maternal age, body mass index, and smoking. RESULTS: Among primiparas, an increased risk of Apgar score < 7 at 5 minutes [odds ratio (OR) 1.27, 95% CI 1.16-1.41] and meconium aspiration (OR 1.49, 95% CI 1.14-1.95) was found after birth at most expectant units compared with most active units, but among multiparas, no such associations were detected. A decreased rate of cesarean section was found for both primiparas (OR 0.83, 95% CI 0.80-0.86) and multiparas (OR 0.82, 95% CI 0.77-0.86) at units with expectant vs. active management. No association between perinatal death and delivery-unit specific management of prolonged pregnancies was detected. CONCLUSIONS: Offspring to primiparas might gain from a more active management of prolonged pregnancies, whereas no such improvement of neonatal outcome among multiparous women was detected.

miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression.

BACKGROUND: Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies. METHODS: Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples. RESULTS: MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/ß-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT profiler analysis identified a substantial dysregulation of 4 Wnt/ß-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2. CONCLUSION: MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/ß-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC.

Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks.

BACKGROUND: Observational data shows that postterm pregnancy (≥42 gestational weeks, GW) and late term pregnancy (≥41 GW), as compared to term pregnancy, is associated with an increased risk for adverse outcome for the mother and infant. Standard care in many countries is induction of labour at 42 GW. There is insufficient scientific support that induction of labour at 41 GW, as compared with expectant management and induction at 42 GW will reduce perinatal mortality and morbidity without an increase in operative deliveries, negative delivery experiences or higher costs. Large randomised studies are needed since important outcomes; such as perinatal mortality and hypoxic ischaemic encephalopathy are rare events. METHODS/DESIGN: A total of 10 038 healthy women ≥18 years old with a normal live singleton pregnancy in cephalic presentation at 41 GW estimated with a first or second trimester ultrasound, who is able to understand oral and written information will be randomised to labour induction at 41 GW (early induction) or expectant management and induction at 42 GW (late induction). Women will be recruited at university clinics and county hospitals in Sweden comprising more than 65 000 deliveries per year. Primary outcome will be a composite of stillbirth, neonatal mortality and severe neonatal morbidity. Secondary outcomes will be other adverse neonatal and maternal outcomes, mode of delivery, women's experience, cost effectiveness and infant morbidity up to 3 months of age. Data on background variables, obstetric and neonatal outcomes will be obtained from the Swedish Pregnancy Register and the Swedish Neonatal Quality Register. Data on women's experiences will be collected by questionnaires after randomisation and 3 months after delivery. Primary analysis will be intention to treat. The statistician will be blinded to group and intervention. DISCUSSION: It is important to investigate if an intervention at 41 GW is superior to standard care in order to reduce death and lifelong disability for the children. The pregnant population, >41 GW, constitutes 15-20% of all pregnancies and the results of the study will thus have a great impact. The use of registries for randomisation and collection of outcome data represents a unique and new study design. TRIAL REGISTRATION: The study was registered in Current Controlled Trials, ISRCTN26113652 the 30(th) of March 2015 (DOI 10.1186/ISRCTN26113652 ).

Inactivation of Itf2 promotes intestinal tumorigenesis in Apc(Min/+) mice.

Deregulation of Wnt/ß-catenin signaling following inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is frequently found in colorectal cancer. We have previously shown that levels of ITF-2B, encoded by the ß-catenin target gene ITF2 that is located on the tumor suppressor gene locus 18q21, are increased in colonic adenomas with deregulated ß-catenin activity. However, during tumor progression ITF-2B levels are reduced, suggesting that ITF-2B interferes with tumor development. To investigate the role of ITF2 in intestinal tumorigenesis, we specifically inactivated Itf2 in the intestinal epithelium of Apc(Min/+) mice. We found that genetic disruption of Itf2 on the Apc(Min/+) background results in earlier death and a significant increase in tumor number and size in the small intestine. Based on these data Itf2 acts as a tumor suppressor gene of the intestinal tract that inhibits tumor initiation and growth.

Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men.

The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamine, we demonstrate that loss of E-cadherin expression in hepatocytes results in acceleration of the growth of hepatocellular carcinoma (HCC). In contrast, liver regeneration is not disturbed in mice lacking E-cadherin expression in hepatocytes. In human HCC, we observed four different expression patterns of E-cadherin. Notably, atypical cytosolic expression of E-cadherin was positively correlated with a poorer patient prognosis. The median overall survival of patients with HCC expressing E-cadherin on the membrane only was 221 weeks (95% confidence interval: 51-391) compared with 131 weeks in patients with cytosolic expression (95% confidence interval: 71-191 weeks; P < 0.05). In conclusion, we demonstrate that impaired expression of E-cadherin promotes hepatocellular carcinogenesis and is associated with a worse prognosis in humans.

Comprehensive analysis of ß-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/ß-catenin signaling.

BACKGROUND: Deregulation of Wnt/ß-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein ß-catenin. ß-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by ß-catenin in colorectal cancer cell lines, we analyzed ß-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to ß-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. RESULTS: Treatment of DLD1 and SW480 cells with ß-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published ß-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed ß-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines. CONCLUSIONS: Based on the large number of potential ß-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed ß-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/ß-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential ß-catenin target genes are useful starting points for further studies.

ß-catenin regulates NF-κB activity via TNFRSF19 in colorectal cancer cells.

Wnt/ß-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors. Under physiological conditions, ß-catenin activity is tightly controlled. However, the majority of sporadic forms of colorectal cancer are characterized by inactivation of the tumor suppressor gene APC due to loss of heterozygosity (LOH), resulting in deregulation of the protein ß-catenin. Apart from known ß-catenin target genes like MYC, OPG, and DKK4, the gene TNFRSF19, a member of the TNF receptor superfamily, is regulated by ß-catenin in mesenchymal stem cells (hMSC). We found that TNFRSF19 is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. Further characterization revealed that both isoforms of TNFRSF19, TNFRSF19.1 and TNFRSF19.2, are regulated in a ß-catenin dependent manner. The transcript TNFRSF19.2 encodes a 417 amino acid long protein containing a TRAF-binding site that links the TNFRSF19.2 to NF-κB signaling, whereas the isoform TNFRSF19.1 lacks this TRAF-binding site. Nevertheless both isoform 1 and 2 induced the activity of an NF-κB reporter gene. NF-κB signaling is important for inflammatory processes and chronic inflammatory diseases like ulcerative colitis and Crohn's disease, which are associated with increased risk for developing colorectal cancer. The observation that TNFRSF19 is a ß-catenin target gene and TNFRSF19 receptor molecules activate NF-κB signaling shows that ß-catenin regulates NF-κB activity via TNFRSF19, suggesting that TNFRSF19 may contribute to the development of colorectal tumors with deregulated ß-catenin activity.

Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer.

BACKGROUND: Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes NEUROG1, HLTF and HPP1 in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined. METHODS: Pretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes HLTF, HPP1, and NEUROG1 was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test. RESULTS: Hypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for HLTF [p = 0.004]; 0.49 [p < .0001] for HPP1). No correlation between methylation of NEUROG1 and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients. CONCLUSIONS: We were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both HLTF and HPP1 as well as LDH. In sum, determining the methylation of HLTF and HPP1 in serum might be useful in order to identify patients with more aggressive tumors.

Sporadic accelerations during labor strongly indicate normal pH, whereas periodic accelerations do not: a case-control study.

PURPOSE: To determine the association between the occurrence of sporadic and periodic fetal heart rate accelerations during labor and acidemia at birth. MATERIALS AND METHODS: This is a case-control study of fetal heart rate patterns from 364 neonates with acidemia at birth (cord blood pH <7.05 at vaginal birth, or pH <7.10 at birth after first stage cesarean delivery) and 731 controls with pH ≥7.15. The last 30-60 min of the cardiotocographic traces before birth from the neonates born with acidemia and from the corresponding stage in labor for the controls were scrutinized. Odds ratios (OR) with 95% confidence interval for acidemia at birth were determined. RESULTS: During the first stage, ≥2 sporadic accelerations were present in 16% of cases and 78% of controls; OR for acidemia (compared to 0-1 accelerations) 0.05 (0.02-0.10). In the second stage, the corresponding rates were 13% and 60%, OR 0.09 (0.06-0.14). Isolated periodic accelerations were infrequent. A weak negative association between ≥2 periodic accelerations and acidemia (compared with 0-1 accelerations) was found in the second stage, OR 0.51 (0.30-0.86), but was not significant in the first stage, OR 0.24 (0.04-1.4). Even among fetuses with normal fetal heart rate variability (5-25 beats per minute) the occurrence of less than two sporadic accelerations was associated with an increased risk of acidemia, OR 10.3 (7.2-14.8). CONCLUSIONS: Sporadic accelerations indicate a very low probability of acidosis but are absent in 40% of fetuses with normal pH during a 30-60 min second-stage recording.