Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Surgical Management of Non-Malignant Esophageal Perforations: A Single-Center Analysis Over a 15-Year Period.

PURPOSE: Esophageal perforations are associated with high morbidity and mortality. Different nonoperative and operative treatment options have been proposed. This study focuses on the impact of different surgical treatments in nonmalignant esophageal perforations and tries to identify predictors of mortality in a single tertiary center over a 15-year period. METHODS: From 2002 to 2017, patients with surgically managed esophageal perforation were identified from our database. Patients with esophageal malignancies were excluded. Etiology, clinical data, treatment, and outcome were analyzed. A multivariate logistic regression analysis was performed to investigate the impact on mortality. RESULTS: A total of 72 patients were identified. The majority of perforations were iatrogenic (54.2%) followed by Boerhaave's syndrome (23.6%). Most ruptures were found in the distal third of the esophagus (59.7%) measuring <3 cm (61.1%). Patients were treated with exploration and drainage (8.3%), primary suture and patch reinforcement (36.1%), resection and restoration of continuity (25.0%), or resection without restoration of continuity (30.6%). Delayed therapy significantly correlated with sepsis (p < 0.0001) and mortality (p = 0.032). A correlation between an increasing perforation length with sepsis (p = 0.012) was observed. A higher Perforation Severity Score (PSS; OR 4.430; 95% CI 1.143-17.174; p = 0.031) and a higher American Society of Anesthesiologists (ASA) score (OR 2.923; 95% CI 1.011-8.448; p = 0.048) were associated with mortality in multivariate analysis. CONCLUSION: Esophageal perforations are associated with high mortality, and larger ruptures are associated with worse outcome. Rapid diagnosis and treatment are crucial for patient survival. Hence, PSS and ASA score help to identify high-risk patients. The advantage of surgical management lies in the rapid control of the septic focus in an already critically ill patient. Though, the kind of surgical technique needs to be adjusted to the individual situation.

Prognostic Significant or Not? The Positive Circumferential Resection Margin in Esophageal Cancer: Impact on Local Recurrence and Overall Survival in Patients Without Neoadjuvant Treatment.

OBJECTIVE: The aim of this study is to investigate the impact of the circumferential resection margin (CRM) in esophageal cancer on survival and recurrence in patients without pretreatment. BACKGROUND: Whereas the infiltration of the proximal or distal resection margin is associated with poor survival and higher recurrence, studies looking at the role of the circumferential resection margin on survival and local recurrence after esophagectomy are conflicting. METHODS: Influence of CRM infiltration according to the College of American Pathologists (CAP) and Royal College of Pathologists (RCP) on long-term survival of 180 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. RESULTS: A positive CRM was found in 76 (42.4%) patients according to RCP and 44 (24.4%) patients according to CAP. The CRM status had neither according to CAP nor according to RCP a significant impact on overall survival (P = 0.317 and 0.655, respectively), local recurrence (P = 0.716 and 0.900, respectively), or distant tumor relapse (P = 0.303 and 0.471, respectively).Lymphatic tumor spread found in 129 (71.7%) patients was an independent prognosticator (P = 0.002). In 137 (76.1%) patients who had a transthoracic esophagectomy a CRM infiltration was significantly lower according to CAP compared with 43 (23.9%) patients who had a transhiatal esophagectomy (P = 0.026). CONCLUSIONS: CRM was found to have no impact on survival and recurrence in esophageal cancer. Therefore, the possible impact of neoadjuvant pretreatment in locally advanced tumors should be considered with caution in terms of an improved resectability.

Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer.

OBJECTIVE: We evaluated the prognostic significance of circulating tumor cells (CTCs) in patients with esophageal cancer (EC). BACKGROUND: Despite the availability of several preoperative diagnostic techniques, accurate pretreatment staging of EC remains challenging. METHODS: In this single-center, prospective study, peripheral blood samples for CTC analyses were obtained preoperatively from 100 patients who were judged to have resectable EC. CTC detection was performed using the CellSearch System. Data were correlated with clinicopathological parameters and patient outcomes. RESULTS: CTCs were detected in 18% (18/100) of all eligible patients. Patients with CTCs showed significantly shorter relapse-free (P < 0.001) and overall survival (P < 0.001) than CTC-negative patients. Even in patients with lymph node invasion and without distant metastases (pN+, M0, N = 45), CTC detection indicated significantly worse relapse-free (P < 0.001) and overall survival (P = 0.007). Multivariate analyses of eligible patients identified CTCs as a strong, independent, prognostic indicator of tumor recurrence (hazard ratio, 5.063; 95% confidence interval, 2.233-11.480; P < 0.001) and overall survival (hazard ratio, 3.128; 95% confidence interval, 1.492-6.559; P = 0.003). CONCLUSIONS: This is the first study to report that CTCs detected by an automated immunomagnetic detection system are independent, prognostic indicators of patients' outcome in EC. Thus, implementation of CTCs may improve accuracy of preoperative staging in EC.

Effective inhibition of metastases and primary tumor growth with CTCE-9908 in esophageal cancer.

BACKGROUND: In spite of multimodular treatment, the therapeutic options for esophageal carcinoma are limited, and metastases remain the leading cause of tumor-related mortality. Expression of the chemokine receptor CXCR4 significantly correlates with poor survival rates in patients with esophageal carcinoma and is associated with lymph node and bone marrow metastases. The aim of this study was to evaluate the effect of the CXCR4 antagonist CTCE-9908 on metastatic homing and primary tumor growth in vitro and in vivo in an orthotopic xenograft model of esophageal cancer. MATERIALS AND METHODS: OE19 cells were examined for stromal cell-derived factor 1 alpha-mediated migration under CTCE-9908 treatment. The CTCE-9908 treatment was further evaluated in an in vitro proliferation assay and orthotopic esophageal model, accompanied by magnetic resonance imaging. Tumor and metastases were immunohistochemically examined for CXCR4 expression. RESULTS: CTCE-9908 has an inhibitory effect on stromal cell-derived factor 1 alpha-mediated migration and proliferation of OE19 cells. Treatment with CTCE-9908 in the orthotopic esophageal model leads to a reduction of metastatic spread and primary tumor growth. This was confirmed by magnetic resonsance imaging. Treatment with CTCE-9908 results in altered CXCR4 expression pattern exhibiting a high degree of variability. CONCLUSION: CTCE-9908 effectively inhibits OE19 cell migration and proliferation in vitro, reduces metastases to lung, liver, and lymph nodes in vivo, and moreover leads to tumor growth reduction in an orthotopic model of esophageal carcinoma.

Intratumoral heterogeneity of KRAS mutation is rare in non-small-cell lung cancer.

BACKGROUND: Several lines of evidence indicate that mutational activation of KRAS is an early event in the carcinogenesis of non-small cell lung cancer (NSCLC). Nonetheless, previous studies report high frequencies of divergent KRAS mutational status between primary NSCLC and corresponding metastases. This suggests heterogeneity of the primary tumor in respect to its KRAS status. We therefore aimed to examine the frequency and the extent of such intratumoral heterogeneity. METHODS: 40 NSCLC were examined for intratumoral heterogeneity of KRAS mutation (20 adenocarcinomas, 10 squamous cell carcinomas and 10 large cell carcinomas). Three to eight different tumor areas were analyzed for KRAS mutation and up to four corresponding lymph node metastases were included for analysis in nineteen cases. A combination of different methods for screening of heterogeneity and its validation were used including direct sequencing, laser-capture microdissection for tumor cell enrichment and the very sensitive ARMS/S method. RESULTS: Mutations of KRAS were found in 13/30 adenocarcinomas and large cell carcinomas. No mutations were detected in 10 squamous cell carcinomas. Four cases showed heterogeneous KRAS results by direct sequencing. More sensitive methods for KRAS mutation analysis revealed false negative results due to admixture of non-neoplastic cells in all of these samples. Intratumoral heterogeneity of KRAS mutational status was therefore confirmed in none of the analyzed cases. In addition, identical KRAS mutations were present in the primary tumor and the corresponding lymph node metastases in 19 cases examined. CONCLUSIONS: Intratumoral heterogeneity of KRAS mutational status is rare in NSCLC but highly sensitive tools are required to reliably identify these mutations. This finding is in line with the hypothesis that oncogenic activation of KRAS is an early event and a bona fide "driver mutation" in NSCLC. Furthermore, future therapies targeting KRAS will not be limited by intratumoral heterogeneity.

Ultrasonic dissection versus conventional dissection techniques in pancreatic surgery: a randomized multicentre study.

OBJECTIVE: : This prospective randomized multicenter trial was performed to assess the potential benefits of ultrasonic energy dissection compared with conventional dissection techniques in pancreatic surgery. BACKGROUND: : Surgical procedures for tumors of the pancreatic head involve time-consuming manual dissection. The primary hypothesis was that use of ultrasonic tissue and vessel dissection would lead to substantial saving in operative time during pancreatic resection. METHODS: : Patients eligible for pancreaticoduodenectomy (PD) or pylorus-preserving PD (PPPD) were randomized to group A (dissection with ultrasonic device) or group B (conventional dissection) from March 2009 to May 2011. The primary endpoint was overall duration of operation time. Secondary endpoints were time to end of resection phase, intraoperative blood loss, number of transfused units of blood, and postoperative morbidity. RESULTS: : Analysis of primary and secondary endpoints included 101 patients, who received either PD or PPPD. Demographical characteristics and clinical parameters were similar in both groups. The use of an ultrasonic dissection device did not significantly reduce overall operation time (median 316 minutes in group A and 319 minutes in group B, P = 0.95) and did not significantly increase the costs of surgery. Analysis of secondary endpoints revealed no difference in postoperative course. CONCLUSIONS: : Tissue dissection and vessel closure using an ultrasonic device is equivalent to dissection with conventional techniques in pancreatic surgery.

Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung.

The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogeneity of the HER2 status in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung, 590 tumors were analyzed for HER2 overexpression and ERBB2 amplification using FDA-approved reagents for immunohistochemistry and fluorescence in-situ hybridization (FISH). Moderate and strong immunostaining (2+, 3+) was seen in 10% of the tumors. ERBB2 amplification was found in 17 (3%) lung cancer patients including 10 cases (2%) with high-level amplification forming gene clusters. ERBB2 amplification was significantly related to histologic subtype and tumor grade, resulting in 12% ERBB2 amplified tumors in the subgroup of high-grade adenocarcinomas. Heterogeneity was analyzed in all highly amplified tumors. For this purpose, all available tumor tissue blocks from these patients were evaluated. Heterogeneity of ERBB2 amplification was found in 4 of 10 tumors as assessed by FISH. These included two tumors with a mixture of low-level and high-level amplification and two tumors with non-amplified tumor areas next to regions with high-level ERBB2 amplification. High-level ERBB2 amplification occurs in a small fraction of lung cancers with a strong propensity to high-grade adenocarcinomas. Heterogeneity of amplification may limit the utility of anti-HER2 therapy in some of these tumors. Further attempts to assess the utility of HER2-targeting therapy in homogeneously amplified lung cancers appear to be justified.

Long-term results of primary and secondary resections in patients with retroperitoneal soft tissue sarcoma.

BACKGROUND AND OBJECTIVES: The aim of this study was to analyse treatment and long-term outcome for primary and recurrent disease in patients with retroperitoneal soft tissue sarcoma (RSTS). METHODS: Clinicopathological data including tumour stage, grade, and histological subtype, location of the principal tumour, completeness of resection and operative procedure were studied. Kaplan-Meier estimations and Cox regression analyses were performed. RESULTS: Patients comprised a primary resection group (PRG, n = 42), and a secondary resection group (SRG, n = 12) which included patients with recurrent RSTS and/or metastatic RSTS. Postoperative complications occurred in 15 patients (PRG: n = 13 (31%); SRG: n = 2, (16.7%)) and overall 30-day mortality was 5.6% (PRG: n = 2 (4.8%); SRG: n = 1 (8.3%)). Median overall survival was 58 months (PRG 60 months, SRG 50 months) with a 5-year survival rate of 39% (PRG 35.7%, SRG 50%) and a 1-year survival of 74.1% (PRG 71.4%, SRG 83.3%). Multivariate Cox regression analyses indicated that histopathological subtype (P = 0.006), completeness of resection (P < 0.001) and tumour grade (P = 0.018) were independent prognostic variables for overall survival. CONCLUSION: In the absence of effective alternative treatment options, patients with RSTS should undergo extended resection, even in recurrent disease. Complete surgical resection is still the most effective modality for the treatment of retroperitoneal sarcoma.

Developing the multi-dimensional mobility divide index (MDI) as a methodology to assess the accessibility level of public transport systems.

Background: This paper presents the development of a multi-dimensional mobility divide index (MDI) for assessing the accessibility of public transport developed using a co-design approach, directly involving end-users in the index design process. The index measures the gap that persons with disabilities feel they need to over-come to use public transport in the same way non-disabled citizens do. The MDI covers six accessibility-related dimensions: 1) safety, 2) convenience, 3) comfort, 4) affordability, 5) travel time, and 6) autonomy. Methods: The method paper describes the step-by-step approach to create the MDI as a set of indicators to be rated by people with different access needs to 1) provide evidence of the main criticalities to be addressed through the design and implementation of new inclusive mobility solutions, 2) guide the design of new inclusive mobility solutions and measure their impacts, and 3) inform the transport sector encouraging positive changes in transport by providing recommendations for policy-making, new directions for service innovation, improvements and practical advice or highlighting investment priorities to pave the way for a more inclusive mobility. Results: We present our findings in ways that can inform universal design and provide actionable information to researchers, policymakers, transport and urban planners, operators, and stakeholders' representatives to promote inclusive and equitable mobility solutions for all. Conclusions: Finally, we suggest follow up research and innovation, as well as recommendations for its uptake and utilisation in the pursuit of European accessibility standards and requirements for products and services in the mobility sector.

Heme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer.

BACKGROUND: Heme oxygenase-1 (HO-1) correlates with aggressive tumor behavior and chemotherapy resistance in pancreatic cancer (PC). We evaluated the prognostic value of the basal transcription controlling germ line GTn repeat polymorphism (GTn) in the promoter region of the HO-1 gene in PC. PATIENTS AND METHODS: We determined the GTn in 100 controls and 150 PC patients. DNA was extracted from blood leukocytes and GTn determined by PCR, electrophoresis, and sequencing. Clinicopathological parameters, disease-free, and overall survival (DFS, OS) were correlated with GTn. RESULTS: Three genotypes were defined based on short (S) <25 and long (L) ≥25 GTn repeat alleles. In PC patients, a steadily increasing risk was evident between LL, SL, and SS genotype patients for larger tumor size, presence of lymph node metastasis, poor tumor differentiation and higher recurrence rate (P < 0.001 each). The SS genotype displayed the most aggressive tumor biology. The LL genotype had the best and the SS genotype the worst DFS and OS (P < 0.001 each). The GTn genotype was the strongest prognostic factor for recurrence and survival (P < 0.001 each). CONCLUSION: The GTn repeat polymorphism is a strong prognostic marker for recurrence and survival in PC patients.

High surgical morbidity following distal pancreatectomy: still an unsolved problem.

BACKGROUND: High surgical morbidity following distal pancreatectomy, especially pancreatic fistula, remains an unsolved problem. The aim of this study was to identify potential risk factors for surgical morbidity with a focus on the development of pancreatic fistula. METHODS: Clinicopathologic parameters were collected for 283 patients who underwent distal pancreatectomy between January 2000 and May 2010. Logistic regression analyses were performed to identify potential risk factors for surgical morbidity and pancreatic fistula. RESULTS: Spleen-preserving pancreatectomy was carried out in 12% of all cases and multivisceral resections were performed in 37.8%. For closure of the pancreatic remnant, three different techniques were used: hand-sewn suture in 44.5%, pancreaticojejunal anastomosis in 24%, and closure by stapler in 31.5%. Overall morbidity and mortality were 53 and 3.5%. Surgical morbidity was observed in 50.2% of all cases and pancreatic fistula in 24%. The stapling group had significantly higher surgical morbidity at 65.2% (p=0.001) and the most pancreatic fistulas, though this did not reach statistical significance (p=0.189). Univariate and multivariate logistic analyses indicated that closure by stapler [odds ratio (OR)=3.61; p<0.001] is a risk factor for surgical morbidity. CONCLUSION: Closure of the pancreatic remnant by using a stapling device was associated with an increased risk of surgical morbidity. With an increasing number of laparoscopic distal pancreatectomies being performed, further studies analyzing the use of stapling devices and newer closure techniques are needed.

How radical should surgery be for early esophageal cancer?

BACKGROUND: We have compared the oncologic effectiveness of limited resection (LR) techniques such as transhiatal (TH) or limited resection of the esophagogastric junction with intestinal interposition (LREGJ) in the treatment of early esophageal carcinoma with that of the extended resection such as the classical thoracoabdominal (TA) en bloc esophagectomy. METHODS: We performed a retrospective analysis of prospectively collected data of 113 patients with T1 esophageal cancer (57 adeno- and 56 squamous cell carcinomas) who had surgical resection with systematic lymphadenectomy. Forty-one underwent extensive (TA) and 72 limited resection (51 TH and 21 LREGJ). RESULTS: Complete resection (R0) was achieved in all cases. Lymphatic metastases were seen in none of the mucosal but in 26.8% of the submucosal T1 cancers. The median lymph node yield was significantly higher in patients with extensive resection (24 vs. 15 lymph nodes; p=0.036), but this did not affect the overall survival (median=88 vs. 102 months, 5-year survival probability=57.8 vs. 67.7%; log rank=0.578). The median hospital stay and ICU stay were significantly shorter in the LR group (p=0.039 and p = 0.044, respectively). CONCLUSION: Limited resection leads to lower lymph node yield but similar oncologic effectiveness as the extensive surgery. It may represent a valuable alternative in the treatment of patients with early (submucosal) esophageal carcinoma.

Diagnostic accuracy of guided cervical biopsies: a prospective multicenter study comparing the histopathology of simultaneous biopsy and cone specimen.

OBJECTIVE: We sought to determine the validity of colposcopically directed cervical biopsies as a diagnostic test to define the degree of cervical intraepithelial neoplasia (CIN). STUDY DESIGN: In a prospective multicenter trial, patients undergoing excisional procedures of the transformation zone additionally had colposcopy and up to 3 guided cervical biopsies in a single procedure. Cervical biopsies were regarded as a diagnostic test to detect high-grade lesions (CIN 2,3), with the cone specimen as reference standard. RESULTS: In all, 488 biopsies were performed in 244 cases, with 2 biopsies done in 192 cases. Cervical biopsies underestimated the severity of lesions in 46.7% of cases. Sensitivity, specificity, and positive and negative predictive values were 66.2% (95% confidence interval [CI], 59.4-72.3), 95.0% (95% CI, 83.5-98.6), 98.5% (95% CI, 94.8-99.6), and 35.5% (95% CI, 27.1-44.9), respectively. CONCLUSION: Our data suggest that cytologically suspected high-grade lesions (CIN 2,3) can be confirmed by biopsy in many cases, but they cannot be excluded.

Strong impact of micrometastatic tumor cell load in patients with esophageal carcinoma.

BACKGROUND: To assess the role of immunohistochemically detectable nodal microinvolvement of patients with "curatively" resected esophageal carcinoma. METHODS: In 73 patients with resectable esophageal carcinoma [squamous cell carcinoma (SCC), n = 45 (61.6%); adenocarcinoma (AC), n = 28 (38.4%)] a total of 2174 lymph nodes (LN) were removed. In each of the 1958 LN classified as negative on conventional histopathology, immunohistochemistry was performed using the anticytokeratin antibody AE1/AE3. To determine the role of the amount of residual tumor load, the patients were grouped according to the percentage of LN affected with micrometastasis (0%, <11%, and > or =11%). RESULTS: Tumor cells were immunohistochemically detected in 47 LN (2.4%) from 25 (34.2%) patients. Five-year overall survival probability (5-YSP) of 30% in pN(0 )patients with detected occult tumor cells in LN was significantly worse than that in those without nodal microinvolvement (76%, P = 0.021), hereby resembling that of pN1-patients (24%, P = 0.84). Median overall survival in patients with no (0%), low (<11%), and high (>11%) micrometastatic tumor load was 43, 27, and 11 months, respectively. Substratification according to histological type showed that, in patients with AC, the presence of nodal microinvolvement had a significant impact on 5-YSP (0% versus 65%; P = 0.03), whereas in patients with SCC, differences of 5-YSP were only of borderline significance (24% versus 53%; P = 0.081). CONCLUSION: Minimal tumor cell load as assessed by the ratio of micrometastatically affected LN is a complementary tool for better risk stratification of patients with esophageal carcinoma.

Haeme oxygenase-1 promoter polymorphism is an independent prognostic marker of gastrointestinal stromal tumour.

AIMS: Gastrointestinal stromal tumours (GISTs) display genetic alterations on chromosome 22. GTn repeat (GTn) length polymorphism in the promoter of haeme oxygenase-1 gene (HMOX-1) is located on chromosome 22 and associated with malignant growth. The aim was to investigate the role of HMOX-1 promoter polymorphism in GIST patients. METHODS AND RESULTS: Tumour and corresponding healthy tissue DNA of 44 patients who underwent surgical resection of GIST were analysed by polymerase chain reaction, capillary electrophoresis and DNA sequencing. GTn polymorphism was classified into short (S) and long (L) allele. There was no difference detected in GTn genotype between tumour and healthy tissue DNA. Short GTn allele (SGTn) was significantly associated with metastatic disease, higher tumour recurrence rates and high risk GIST (consensus criteria 2001). Furthermore, SGTn allele carriers had significantly shorter disease-free and overall survival (log rank test, P < 0.0001). On multivariate Cox regression analysis, GTn polymorphism was identified as an independent prognostic factor for survival (P = 0.001). CONCLUSIONS: HMOX-1 promoter GTn polymorphism is a potential prognostic marker and may help to allocate patients to different risk groups, customized therapy and follow-up. Haeme oxygenase-1 could represent an important candidate gene in the pathogenesis and growth of GIST.

Pharmacologic Approaches for the Management of Apathy in Neurodegenerative Disorders.

Apathy is one of the most frequent behavioral disturbances in many neurodegenerative disorders and is known to have a negative impact on the disease progression, particularly in Alzheimer's disease. Therapeutic options are currently limited and non-pharmacological approaches should constitute first line treatments. Pharmacological agents likely to reduce apathy levels are lacking. The objective of the present article is to review recent pharmacological treatments for apathy in neurodegenerative disorders. The Pubmed database was searched with a particular focus on articles published as of January 2017. Current main levels of evidence have been reported so far with cholinergic, glutamatergic and dopaminergic agents to reduce levels of apathy, despite several conflicting results. Treatment duration and samples sizes may have however decreased the validity of previous results. Ongoing studies involving more participants/treatment duration or distinct neural pathways may provide new insights in the treatment of apathy in neurodegenerative disorders.

The Association of Childhood Maltreatment With Lipid Peroxidation and DNA Damage in Postpartum Women.

Childhood maltreatment (CM) is associated with an increased risk for the development of psychiatric and somatic disorders in later life. A potential link could be oxidative stress, which is defined as the imbalance between the amount of reactive oxygen species (ROS) and the neutralizing capacity of anti-oxidative defense systems. However, the findings linking CM with oxidative stress have been inconsistent so far. In this study, we aimed to further explore this association by investigating biological markers of DNA and lipid damage due to oxidation in a comprehensive approach over two study cohorts of postpartum women (study cohort I and study cohort II). The severity of CM experiences (maltreatment load) was assessed in both studies using the Childhood Trauma Questionnaire. In study cohort I (N = 30), we investigated whether CM was associated with higher levels of structural DNA damage in peripheral blood mononuclear cells (PBMC) by two methods that are highly sensitive for detecting nuclear DNA strand breaks (comet assay and γH2AX staining). In study cohort II (N = 117), we then assessed in a larger cohort, that was specifically controlled for potential confounders for oxidative stress measurements, two established serum and plasma biomarkers of oxidative stress, one representing oxidative DNA and RNA damage (8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine; 8-OH(d)G) and the other representing lipid peroxidation (8-isoprostane). In study cohort I, the analyses revealed no significant main effects of maltreatment load on cellular measures of nuclear DNA damage. The analyses of peripheral oxidative stress biomarkers in study cohort II revealed a significant main effect of maltreatment load on free 8-isoprostane plasma levels, but not on total 8-isprostane plasma levels and 8-OH(d)G serum levels. Taken together, by combining different methods and two study cohorts, we found no indications for higher oxidative DNA damages with higher maltreatment load in postpartum women. Further research is needed to investigate whether this increase in free 8-isoprostane is a marker for oxidative stress or whether it is instead functionally involved in ROS-related signaling pathways that potentially regulate inflammatory processes following a history of CM.

The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach.

While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene × environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.

Prognostic significance of TPA versus SCC-Ag, CEA and neopterin in carcinoma of the uterine cervix.

INTRODUCTION: Prognostic significance of squamous cell carcinoma antigen (SCC-Ag), tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA) and neopterin in cervical cancer patients was compared. MATERIALS AND METHODS: Pretreatment concentrations were determined in 138 women. RESULTS: Median age was 52 years, 85% squamous cell carcinomas, 15% adeno- or adenosquamous carcinomas were seen. In 36% Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, 24% stage II, 32% stage III and 8% stage IV was diagnosed. TPA was elevated in 22%, SCC in 68%, CEA in 42% and neopterin in 29%. These patients showed significantly worse overall survival in univariate analysis (p<0.001). TPA remained as independent prognostic factor in multivariate analysis. CONCLUSIONS: Elevation of TPA was associated with worse overall survival.