Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA-Seq

Abstract

The promotion of tumor development by Dickkopf 4 (DKK4) is receiving increased attention. However, the association between DKK4 and pancreatic cancer remains unclear. DKK4 expression was measured in pancreatic ductal adenocarcinoma tissues using qRT-PCR and immunohistochemistry. A DKK4-overexpressing pancreatic cancer cell line was established, and the differentially expressed genes (DEGs) that were induced by DKK4 were identified using transcriptome sequencing. The association between the identified DEGs and pancreatic cancer was assessed using gene ontology (GO), pathway analysis, pathway interaction networks, differentially expressed gene interaction network analysis, and co-expression gene networks. Finally, the accuracy of the analyses was validated using serial paraffin and frozen sections of clinical samples. DKK4 is highly expressed in pancreatic cancer tissues. DEGs of overexpression DKK4 of PANC-1 are mostly upregulated. GO and pathway analysis showed that DKK4 are associated with tumor and organ development and immune inflammation. The mitogen-activated protein kinase (MAPK) signaling pathway was the main signal transduction pathway that showed significant enrichment in overexpression DKK4 of PANC-1. The results of GO, pathway analyses, and differentially expressed gene interaction network identified genes that are closely associated with tumor development, including MAPK3, PIK3R3, VAV3, JAG1, and Notch3. The immunohistochemistry and immunofluorescence results suggested that DKK4 is co-expressed with MAPK3 and VAV3 in pancreatic cancer tissues. The results presented here show for the first time that DKK4 is highly expressed in pancreatic cancer tissues. Bioinformatics analysis of a DKK4-overexpressing of PANC-1 identified several oncogenes that are closely associated with tumors, and the MAPK signaling pathway is the core signal transduction pathway. DKK4 can be co-expressed with MAPK3 and VAV3 in pancreatic ductal adenocarcinoma tissues. Thus, DKK4 may have function on the development and progression of pancreatic cancer.

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Comparison of in vitro antileukemic activity of obatoclax and ABT-737

Abstract

Obatoclax and ABT-737 belong to a new class of anticancer agents known as BH3-mimetics. These agents antagonize the anti-apoptotic members of Bcl-2 family. The Bcl-2 proteins modulate sensitivity of many types of cancer cells to chemotherapy. Therefore, the objective of the present study was to examine and compare the antileukemic activity of obatoclax and ABT-737 applied alone, and in combination with anticancer agent, mafosfamide and daunorubicin. The in vitro cytotoxic effects of the tested agents on human leukemia cells were determined using the spectrophotometric MTT test, Coulter electrical impedance method, flow cytometry annexin V–fluorescein/propidium iodide assay, and light microscopy technique. The combination index analysis was used to quantify the extent of agent interactions. BH3 mimetics significantly decreased the leukemia cell viability and synergistically enhanced the cytotoxic effects induced by mafosfamide and daunorubicin. Obatoclax affected the cell viability to a greater degree than did ABT-737. In addition, various patterns of temporary changes in the cell volume and count, and in the frequency of leukemia cells undergoing apoptosis, were found 24 and 48 h after the tested agent application. ABT-737 combined with anticancer agents induced apoptosis more effectively than obatoclax when given in the same combination regimen. The results of the present study point to the different antileukemic activities of obatoclax and ABT-737, when applied alone, and in combination with anticancer agents. A better understanding of the exact mechanisms of BH3 mimetic action is of key importance for their optional use in cancer therapy.

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The interplay between microRNAs and Twist1 transcription factor: a systematic review

Abstract

Twist1 (also known as Twist) is a transcription factor that belongs to the family of basic helix-loop-helix (bHLH) proteins. It functions as a negative regulator of epithelial gene expression and a positive regulator of mesenchymal gene expression, thereby leading to induction of the epithelial mesenchymal transition (EMT), a process in which epithelial cells acquire the motile and migratory characteristics of mesenchymal cells. In addition to regulating the expression of protein-coding genes, Twist1 regulates the expression of microRNAs (miRNAs), adding a regulatory layer to EMT induction. Interestingly, the mRNA of Twist1 represents a downstream target of miRNAs, indicating an intricate network between miRNAs and Twist1. This network was shown to play multiple roles in cancer cell migration, invasion, and metastasis. The network can induce angiogenesis, protect cells from oncogene-induced apoptosis and senescence, enhance cancer cell resistance to conventional therapies, and increase cancer stem cell (CSC) populations. Recently, miRNAs have attracted considerable attention as potential promising tools in cancer therapies. Thus, this systematic review was conducted to clarify the reciprocal link between Twist1 and miRNAs in order to provide potential candidate miRNAs for diagnostic and therapeutic approaches in cancer treatment.

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Association of toll-like receptor 2 ∆22 and risk for gastric cancer considering main effects and interactions with smoking: a matched case-control study from Mizoram, India

Abstract

Toll-like receptors (TLRs) are evolutionary conserved cell surface receptors of the innate immune system. Smoking has significant immunological effects which are mediated via TLRs on various receptor-mediated innate response pathways. Polymorphisms of TLR genes are associated with susceptibility toward various malignancies. The present study was undertaken to examine the association between TLR2 ∆22 and gastric cancer. In this study, we also investigated the interaction between TLR2 ∆22 and smoking. A total of 133 histologically confirmed gastric cancer cases and 266 age-sex-matched controls were selected for this study. TLR2 ∆22 genotypes were determined by allele-specific polymerase chain reaction (PCR). Binary conditional logistic regression analysis was used to find the association of TLR2 ∆22 with risk of gastric cancer. Logistic regression using hierarchically well-formulated models was used for interaction analysis between smoking and TLR2 ∆22. Persons having TLR2 ∆22 heterozygous genotype had two times increased risk of gastric cancer in multivariate logistic regression model. The interaction analysis using hierarchical logistic regression models between smoking and TLR2 ∆22 by calculating separate X ² for interaction model and only main effect model, the difference of X ² 57.68−47.70 = 9.98 and degrees of freedom (df) 5−3 = 2, revealed significant (α = 0.05, df = 2) omnibus interaction. Our present study revealed TLR2 ∆22 to be significantly and independently associated with gastric cancer risk in Mizoram, and there is also evidence of significant interaction between smoking and TLR2 ∆22 with risk of gastric cancer.

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Hypoxia inducible factor: a potential prognostic biomarker in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is the most common oral cancer. Hypoxia inducible factor (HIF) is involved in many malignant tumors’ growth and metastasis and upregulated by hypoxia, including oral cancer. Many studies have studied about the prognostic value of HIF expression in OSCC; however, they do not get the consistent results. Therefore, this study explored the correlation between the HIF expression and the prognosis of OSCC. It conducted a meta-analysis of relevant publications searched in the Web of Science, PubMed, and ISI Web of Knowledge databases. Totally, this study identified 12 relevant articles reporting a total of 1112 patients. This analysis revealed a significant association between increased risk of mortality (RR = 1.20; 95 % CI 0.74–1.95; I ² 85.4 %) and overexpression of HIFs. Furthermore, different HIF isoforms were associated with overall survival [HIF-1α (RR = 1.18; 95 % CI 0.66–2.11; I ² 87.2 %) and HIF-2α (RR = 1.40; 95 % CI 0.93–2.09; I² 0.0 %)]. These results show that overexpression of HIFs, regardless of whether the HIF-1α or HIF-2α isoforms are overexpressed is significantly associated with increased risk of mortality in OSCC patients. In this study, the funnel is symmetric, suggesting existed no publication bias.

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Tumor suppressor NGX6 inhibits the growth and metastasis of multiple cancers

Abstract

Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a membrane protein primarily located in the nuclear membrane and cell membrane. Several groups reported that NGX6 gene was down-regulated in nasopharyngeal carcinoma (NPC), gastric cancer, lung cancer, liver cancer, and colorectal cancer and even less in the carcinomas with metastasis. Current studies have demonstrated that NGX6 possesses various biological functions, such as regulating protein expression of related genes, involving cell signal transduction pathways, negatively controlling cell cycle progression, inhibiting angiogenesis, and increasing the sensitivity of patients to anti-cancer drugs. Some factors regulating the expression level of NGX6 gene also have been studied. The methylation of promoter of NGX6 and histone H3K9 negatively regulates its expression, similar to the function of transcription factor special protein-1 (Sp1). However, the regulatory factor early growth response gene 1 (Egr-1) is provided with positive regulation function. This review will summarize the progress of those studies on NGX6 and elucidate the potential application of NGX6 for some malignant diseases.

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Colon cancer screening guidelines - STLtoday.com

Colon cancer screening guidelines STLtoday.com My maternal grandmother died of colon cancer, my brother is presently getting chemo for colon cancer, a double cousin had it and my father's double cousin also has had a couple of bouts. ... The tonsils and sinuses are the most likely places for this. and more »

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Another local mom claims son was attacked at Westside library - ActionNewsJax.com

ActionNewsJax.com

Another local mom claims son was attacked at Westside library ActionNewsJax.com "It's devastated my life," said Kathleen Morgan, Rex Morgan's widow. In 2010, doctors found a growth on Rex Morgan's tonsil. It was cancer. Rigorous treatment began and he was told he was disease-free. In 2011, doctors found another lump – this time on ...

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Bikers riding to benefit Jason - Athens Daily Review

Athens Daily Review

Bikers riding to benefit Jason Athens Daily Review Jason McCloud, 31, of Cross Roads, has suffered with Adenoid Cystic Carcinoma (ACC) since 2013. ACC is an uncommon form of malignant neoplasm that arises within secretory glands, most commonly the major and minor salivary glands of the head and ...

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Toll-like receptor-mediated immune response inhibits prion propagation

Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion diseases is neuroinflammation characterized by activation of neuroglia surrounding prion deposition. The cause and effect of this cellular response, however, is unclear. We investigated innate immune defenses against prion infection using primary mixed neuronal and glial cultures. Conditional prion propagation occurred in glial cultures depending on their immune status. Preconditioning of the cells with the toll-like receptor (TLR) ligand, lipopolysaccharide, resulted in a reduction in prion propagation, whereas suppression of the immune responses with the synthetic glucocorticoid, dexamethasone, increased prion propagation. In response to recombinant prion fibrils, glial cells up-regulated TLRs (TLR1 and TLR2) expression and secreted cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, granulocyte-macrophage colony-stimulating factor, and interferon-β). Preconditioning of neuronal and glial cultures with recombinant prion fibrils inhibited prion replication and altered microglial and astrocytic populations. Our results provide evidence that, in early stages of prion infection, glial cells respond to prion infection through TLR-mediated innate immunity. GLIA 2016

Main Points

Preconditioning of glial cells with a sterile ligand, recombinant prion fibril, inhibits prion propagation. Prion-sensing is mediated by toll-like receptors triggering protective innate immune responses in early stage of prion infection.

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An orthostatic hypotension mimic: The inebriation-like syndrome in Parkinson disease

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Imaging synucleinopathies

ABSTRACT

In this review the structural and functional imaging changes associated with the synucleinopathies PD, MSA, and dementias associated with Lewy bodies are reviewed. The role of imaging for supporting differential diagnosis, detecting subclinical disease, and following disease progression is discussed and its potential use for monitoring disease progression is debated. © 2016 International Parkinson and Movement Disorder Society

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Validation of “laboratory-supported” criteria for functional (psychogenic) tremor

ABSTRACT

Background

In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Objectives

This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a “laboratory-supported” level of certainty.

Methods

For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor.

Results

We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%.

Conclusion

We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice. © 2016 International Parkinson and Movement Disorder Society

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Alterations of putaminal shape in de novo Parkinson's disease

ABSTRACT

Introduction

Several neuroimaging studies have been carried out to gain insight on the pathological processes that cause PD, but literature findings are inconsistent. The aim of this study was to combine information carried by functional imaging with DA transporter ligands and structural MRI.

Methods

Forty-two untreated, de novo-PD patients and 30 control subjects were involved in this study. Patients were divided in subgroups according to the presence of uni- or bilateral reduction of ligand uptake in the putamen, as observed on DA transporter single-photon emission tomography: 12 patients had abnormal uptake in the right putamen and 11 in the left, whereas 19 had bilateral abnormal uptake. Voxel-based morphometry and shape analysis were used to compare healthy subjects to all de novo-PD or to patients with either right or left abnormal uptake.

Results

Shape analysis identified significant differences between de novo-PD and controls in putaminal regions. In patients with unilateral abnormal uptake, only the medial surface of the structure was involved. When patients with bilateral uptake reduction were also considered, changes extended from the medial to the lateral surface of putamina. Voxel-based morphometry showed similar results to those detected with shape analysis, but it failed to identify the putaminal subfield involved in patients with asymmetric or symmetric damage on DA transporter single-photon emission tomography.

Conclusions

Shape analysis in de novo-PD patients suggested a progressive medial-to-lateral involvement of the putamina that paralleled an asymmetric-to-bilateral distribution of DA transporter depletion. © 2016 International Parkinson and Movement Disorder Society

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Location, Location, Location: Validating the Position of Deep Brain Stimulation Electrodes

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Alpha-synuclein gene variants may predict neurostimulation outcome

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Corticostriatal plasticity modulation: New roads for therapeutic targets

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Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease

ABSTRACT

Objective

The purpose of this study was to investigate whether cerebrospinal fluid (CSF) levels of tau, phosphorylated tau, β-amyloid₄₂, α-synuclein, neurofilament light, and YKL-40 change over time and if changes correlate with motor progression and/or cognitive decline in patients with PD and controls.

Methods

We included 63 patients with PD (nondemented) and 21 neurologically healthy controls from the prospective and longitudinal Swedish BioFINDER study, all of whom had clinical assessments and lumbar punctures at baseline and after 2 years.

Results

CSF tau levels correlated strongly with α-synuclein. The levels of CSF α-synuclein, tau, phosphorylated tau, neurofilament light, and YKL-40, but not β-amyloid₄₂, increased in CSF over 2 years in PD. No changes were seen in the control group. Studying patients with a short disease duration ( ≤ 5 years) and patients with a long disease duration ( > 5 years) separately, α-synuclein and tau only increased in the PD group with long disease duration. In the PD group, an increase in phosphorylated tau over 2 years correlated with faster motor progression and faster cognitive decline. An increase in YKL-40 over 2 years correlated with faster cognitive decline.

Conclusion

CSF biomarkers reflecting Lewy body pathology and neurodegeneration (α-synuclein), neuronal degeneration (tau, phosphorylated tau, and neurofilament light), and inflammation (YKL-40) increase significantly over 2 years in PD. CSF levels of α-synuclein and tau correlate and remain stable in the early symptomatic phase of PD but increase in the later phase. We hypothesize that CSF α-synuclein levels might increase as a result of more intense neurodegeneration in PD with long disease duration. © 2016 International Parkinson and Movement Disorder Society

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Parkinson's disease-related fatigue: A case definition and recommendations for clinical research

ABSTRACT

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society

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Exponentially growing osteosarcoma of mandible with acromegaly

ABSTRACT

Background

Osteosarcoma of the head and neck is aggressive malignancy that might be affected by growth hormone. The purpose of this study was to demonstrate an unusual case of osteosarcoma with acromegaly.

Methods and Results

This case is about a 39-year-old woman with an osteosarcoma of the mandible, who had a history of exponential tumor growth in spite of chemotherapy at another hospital. She transferred to Samsung Medical Center and underwent a wide resection of tumor and free flap reconstruction. During postoperative care, a brain MRI and hormonal test revealed a growth hormone-secreting pituitary adenoma, and then a transsphenoidal approach pituitary tumor removal was performed. Immunohistochemistry of the osteosarcoma indicated positive for insulin-like growth factor (IGF)−2 and somatostatin receptor.

Conclusion

This study proved the IGF-2 and somatostatin receptor from the osteosarcoma of the patient with acromegaly, and this could explain that the growth hormone secreting from the pituitary adenoma might be a risk factor of therapeutic intractability and growth acceleration of osteosarcoma. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

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Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma

Abstract

Background

Because immune responses within the tumor microenvironment are important predictors of tumor biology, correlations of types of tumor infiltrating lymphocytes (TILs) with clinical outcomes were determined in 278 patients with head and neck squamous cell carcinoma (HNSCC).

Methods

Infiltrating levels of CD4 (helper T cells), CD8 (cytotoxic/suppressor T cells), FoxP3 (regulatory T cells), CD68 (myeloid-derived suppressor cells,) and CD1a (Langerhans) cells were measured in tissue microarrays (TMAs). Cox models tested associations with patient outcomes after adjusting for all known prognostic factors. Median follow-up was 36.6 months.

Results

Higher CD4 and CD8 TIL levels were associated with improved overall survival (OS; hazard ratio [HR] = 0.77; 95% confidence interval [CI]  = 0.65–0.93; p = .005 and HR = 0.77; 95% CI = 0.64–0.94; p = .008, respectively), and relapse-free survival (RFS; p = .03 and .05, respectively). After controlling for prognostic factors, higher CD4 levels predicted improved OS and disease-specific survival (DSS; p = .003 and p = .004, respectively).

Conclusion

The findings suggest that TILs are a significant independent prognostic factor for HNSCC that differ by treatment. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

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Salvage total laryngectomy after external-beam radiotherapy: A 20-year experience

Abstract

Background

The purpose of this study was to present our evaluation of the clinical and functional outcomes after salvage total laryngectomy (STL).

Methods

We conducted a retrospective review of 218 patients who underwent STL between 1994 and 2014.

Results

Seventy percent of patients originally had T1 or T2, N0 tumors and 73% had definitive external-beam radiotherapy (EBRT) alone. A majority utilized tracheoesophageal prosthesis (77%) and were gastrostomy free (80%) at last follow-up. The 5-year disease control and overall survival (OS) rates were 65% and 57%, respectively. Patients with a disease-free interval after initial treatment <2 years were more likely to develop a recurrence (p = .001) and die of disease (p = .032) after STL. The disease-free interval after EBRT impacted disease control (p < .001), with 5-year disease control of 92% for >5-year disease-free interval and 60% for <2-year disease-free interval.

Conclusion

Most patients remain disease-free after STL, achieve intelligible tracheoesophageal speech, and maintain an oral diet. Delayed recurrence after initial treatment portends better survival and may indicate a distinct biological profile. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

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Anaplastic thyroid carcinoma: Failure of conventional therapy but hope of targeted therapy

Abstract

Background

Anaplastic thyroid cancer has a median survival between 1.2 and 10 months. The purpose of our study was to evaluate the outcomes of patients with anaplastic thyroid cancer in Ireland.

Methods

We carried out a retrospective analysis of the Irish National Cancer Database for patients with anaplastic thyroid cancer between 2000 and 2010.

Results

Of a total of 64 patients (40 women, 24 men), the median age was 69 years, and 29.7% of the patients had distant metastases. The overall median survival was 2.3 months and the 1, 2, and 5-year survival was 12.5%, 6.25%, and 4.69%, respectively. On univariate analysis age, sex, metastases at diagnosis, and multimodality treatment were statistically significant indicators of prognosis, and metastases at diagnosis remained statistically significant on multivariate analysis.

Conclusion

These results correlate with the American Thyroid Association (ATA) guidelines, in which, when possible, multimodality therapy offers a survival advantage to a select group of patients. Novel therapies may offer the greatest hope for these patients. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

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Psychological factors associated with failure of detoxification treatment in chronic headache associated with medication overuse

Aim

The aim of this study was to evaluate the psychological factors associated with a negative outcome following detoxification in a 2-month follow-up in medication-overuse headache.

Methods

All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion. Psychiatric conditions and personality characteristics were assessed using the Structured Clinical Interview for DSM-IV Disorders (SCID-I) and the Minnesota Multiphasic Personality Inventory (MMPI)-2. ² tests, one-way analyses of variance, and odds ratios (ORs) were used.

Results

A total of 248 patients completed the follow-up: 156 stopped overuse and their headaches reverted to an episodic pattern (Group A); 23 kept overusing without any benefit on headache frequency (Group B); and 51 stopped overuse without any benefit on headache frequency (Group C). The prognostic factors for the outcome of Group B were higher scores on the correction (OR 1.128; p = 0.036), depression (OR 1.071; p = 0.05), hysteria (OR 1.106; p = 0.023), and overcontrolled hostility (OR 1.182; p = 0.04) MMPI-2 scales, whereas those for Group C were psychiatric comorbidities (OR 1.502; p = 0.021) and higher scores on the hysteria scale (OR 1.125; p = 0.004).

Conclusions

The outcome of detoxification is influenced by psychological factors that should be considered when considering treatment strategies.

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