Elevated Risk Of Relapse Research Articles

Clinical and sociodemographic characteristics associated with relapse following electroconvulsive therapy for bipolar disorder.

Electroconvulsive therapy (ECT) is an effective treatment for bipolar disorder, but relapse following a successful ECT series is common. We aimed to identify clinical and sociodemographic characteristics associated with the risk of relapse following ECT in bipolar disorder. Using data from nationwide Danish registers, we identified all patients receiving their first ECT series with an indication diagnosis of bipolar disorder between 2006 and 2018. We then followed these patients for relapse, defined as either psychiatric admission or a new ECT series, for 6 months following ECT. Associations between clinical and sociodemographic characteristics and relapse were examined via multivariable Cox proportional-hazards regression, yielding adjusted hazard rate ratios (aHRR). Of the 1473 patients receiving ECT for bipolar disorder (62% females, mean age = 53 years), 34% met the relapse criterion. The following characteristics were associated with an elevated risk of relapse; age <40 (aHRR = 1.54, 95% CI = 1.05-2.26); being a pensioner (aHRR = 1.73, 95% CI = 1.29-2.32), indication diagnosis for ECT being psychotic mania (aHRR = 1.63, 95% CI = 1.16-2.28), psychotic bipolar depression (aHRR = 1.37, 95% CI = 1.06-1.80), mixed episode (aHRR = 1.51, 95% CI = 1.13-2.02), or other bipolar episodes (aHRR = 1.68, 95% CI = 1.28-2.21); and treatment with antipsychotics prior to the course of ECT (aHRR = 1.32, 95% CI = 1.04-1.67). Patients with bipolar disorder face a particularly high risk of relapse following ECT if they present with the following characteristics when initiating ECT: age <40, being a pensioner, having received treatment with an antipsychotic before initiating ECT, or having psychotic bipolar depression, psychotic mania, mixed episodes, or other bipolar episodes as the indication for ECT. These findings may guide relapse monitoring following ECT in bipolar disorder.

Pregnancy and reproductive health in women with multiple sclerosis: an update.

Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, neuro-degenerative disease of the central nervous system, prevalent in women of reproductive age. Today, many women want to start a family after MS diagnosis. There are over 20 treatments for MS, and safely navigating family planning is important. We review updated information on family planning, preconception, and peri-partum considerations, and reproductive concerns in special populations with MS. There are no MS-related restrictions on any available and appropriate contraceptive method in women with MS. The question of MS and pregnancy outcomes following assisted reproduction, remains somewhat unsettled. In many studies, no elevated relapse risk is confirmed regardless of the type of fertility treatment. MRI status may offer better assessment of postpartum disease stability than relapse rate alone. Ongoing effective MS treatments during fertility assistance and before pregnancy, can further reduce the relapse risk. B-cell depleting therapies are emerging as safe and effective treatments for peripartum MS patients. Patients with MS should receive accurate support and counseling related to their reproductive options. The general outlook on pregnancy and MS remains positive. The ever-increasing therapeutic complexity of MS calls for ongoing education and updated guidance for neuroimmunology and obstetrics healthcare providers.

Sleep disorders in patients with bipolar disorder: age and tobacco consumption correlates

IntroductionSleep disruptions are frequently observed in individuals with bipolar disorder and have been linked to various unfavorable consequences, such as an elevated risk of relapse and lower quality of life. Nonetheless, the impact of sociodemographic factors on the development and progression of these disruptions remains largely unexplored. Gaining insight into the relationship between sleep disruptions and sociodemographic factors is essential for designing effective interventions and enhancing clinical outcomes for individuals affected by bipolar disorderObjectivesThe objective of this study is to examine the association between sleep disorders in patients with bipolar disorder II (BDII) and sociodemographic characteristics.MethodsThis is a cross-sectional, descriptive, and analytical study that was conducted over a one-month period from October 1 to October 31, 2022, with patients attending the follow-up unit of the mental health department at Nabeul Hospital ,Tunisia.The study employed a questionnaire as a tool for data collection, and participants provided voluntary and informed consent before responding. The protection of participant confidentiality and anonymity was carefully observed during all stages of the study.ResultsIn this study, we enrolled patients who satisfied the following eligibility criteria: age range of 18 to 60 years, a confirmed diagnosis of type II bipolar disorder based on DSM V criteria, and psychiatric stability as demonstrated by no hospitalization within the preceding 6-month period.Our study included a sample of 40 male patients diagnosed with type II bipolar disorder. The participants had a mean age of 36 ± 13.2 years, and the majority were unmarried and living with their families or alone. Over two-thirds of the participants had attained a university level of education, while a large proportion of the patients, specifically 80%, reported being regular smokers.The results of the study revealed that the mean global score on the Pittsburgh Sleep Quality Index (PSQI) was 7.28 ± 3.35, indicating an overall low quality of sleep. The majority of the participants, that is 65% (26), had poor sleep quality scores (&gt; 5), while 45% (18) reported experiencing poor sleep (PSQI ≥ 8).Our analyses further demonstrated that there was a significant association between tobacco consumption and PSQI scores (p=0.003). Additionally, we found that participants who were above 40 years old had a higher likelihood of experiencing sleep disturbances (p=0.0017).ConclusionsAccording to the findings of our study, it appears that patients diagnosed with type II bipolar disorder may experience impaired sleep quality, which can be influenced by age and tobacco consumption. These results underscore the need for a holistic approach to patient care that addresses both the biological and sociodemographic factors that can impact sleep in this population.Disclosure of InterestNone Declared

Evaluating the safety and efficacy of cryopreserved ovarian tissue transplantation in leukemia patients with different bone marrow remission status using xenotransplantation.

Leukemia patients undergoing cryopreserved ovarian tissue transplantation (OTT) may carry a high risk of disease induction. Measurable residual disease (MRD) in bone marrow is linked to an elevated risk of relapse. It is controversial whether leukemia patients must be allowed to achieve measurable residual disease negative (MRD-negative) status instead of measurable residual disease positive (MRD-positive) status before ovarian tissue cryopreservation (OTC). To explore the safety and efficacy of OTT in acute leukemia patients with different MRD status by using xenotransplantation. Cryopreserved ovarian tissue from 19 leukemia patients was thawed and xenotransplanted to ovariectomized BALB/C nude mice (n=36). The mice were divided into 2 groups based on the patient's MRD status before OTC: MRD-negative group (n=18) and MRD-positive group (n=18), additionally, a control group consisted of ovariectomized mice (n=9). Body weight was measured weekly and mortality, emaciation, and other abnormalities were recorded. Twenty-six weeks post-surgery, livers, spleens, uteruses, and ovarian grafts were removed for macroscopic and histological examinations to evaluate the efficacy of xenotransplantation and assess malignant cell contamination in mice. Follicle growth was visible in the ovarian grafts of the MRD-negative and MRD-positive groups. Compared with the ovariectomized group, a significant decrease in body weight (p<0.01) was noted, the uterine volume was notably larger, estradiol (E2) levels were significantly higher (p<0.01), and follicle-stimulating hormone (FSH) levels were significantly lower (p<0.001) in the other two groups. Mice in the MRD-positive group showed a significantly higher incidence of death (p<0.001) and emaciation (p<0.01), compared to the MRD-negative group. Histological observation revealed the presence of malignant cells in the grafts, livers, and spleens of 3 mice in the MRD-positive group. No abnormalities were observed in the mice from the MRD-negative group in both macroscopic and histological observations except one mouse was sacrificed for ascites unrelated to leukemia relapse. For leukemia patients having ovarian tissue preserved in the first and only centralized human ovarian tissue cryobank in China, immunodeficient mice xenotransplantation can be a method to evaluate the safety and efficacy of OTT; the risk of malignant cell reimplantation due to OTT is higher in leukemia patients with MRD-positive status than those with MRD-negative status before OTC.

Metformin Potentiates Gilteritinib Sensitivity Via Targeting PLK1 Signaling: A Strategy to Improve Outcomes and Reduce Costs in Treating FLT3-Mutated Acute Myeloid Leukemia

FLT3 mutations (including FLT3-ITD and FLT3-TKD), occurring in ~30% of acute myeloid leukemia (AML) patients, signal poor prognosis due to elevated relapse risk. Albeit FLT3 tyrosine kinase inhibitors (FLT3 TKI) demonstrated efficacy in treating FLT3-mutated AML in the clinic, there are issues such as high cost, side effects, and high rate of drug resistance/relapse. Hence, an affordable, efficient treatment with lower side effects is needed. Metformin (MET), a cost-effective anti-diabetic drug with minimal side effects, has demonstrated anti-tumor effects (Dowling R et al. Cancer Res. 2007). Here we aimed to determine if combining MET with FLT3 TKI, like Gilteritinib (GLT), could enhance efficacy, reduce side effects and costs in treating FLT3-mutated AML. To this end, we first assessed the IC50 values of MET and GLT across various AML cell lines including those carrying FLT3/ITD (MOLM13, MV4-11, and MA9.3-ITD), FLT3 TKI resistant cells (MOLM13-RES) and those carrying FLT3 wild-type (FLT3/WT) (THP1, NOMO1 and Kasumi-1). MET's IC50 S were consistent (7.284 -12.76 mM) (Fig. 1A), while GLT's varied, with lower values in FLT3/ITD cells (10 nM) and higher in FLT3 TKI resistant (241 nM) and FLT3/WT cells (334-1,053 nM) (Fig. 1B). Using the Chou-Talalay Method, a Combination Index (CI) below 1 in FLT3/ITD and MOLM13-RES cells indicated synergy, whereas it showed antagonism (CI&amp;gt;1) in FLT3/WT cells (Fig. 1C). Both MET and GLT induced cell cycle arrest and apoptosis, with Combo1 (GLT 5 nM + MET 5 mM) matching GLT 10 nM effects; Combo2 (GLT 10 nM + MET 10 mM) amplified these effects (Fig. 1D and E). We next evaluated the potential synergistic effect of MET and GLT in treating TKI-resistance AML in vivo using NRGS mice xeno-transplanted with MOLM13-RES cells. Both bioluminescence imaging and flow cytometry assays showed each treatment alone reduced leukemia burden, and their combination had a synergistic effect, reducing AML burden dramatically (Fig. 1F). While MET or GLT alone doubled overall survival compared to vehicle treatment (56-62 days vs. 26 days), ~90% of the mice treated with the Combo survived over 120 days (Fig. 1G) and their leukemia burden was still minimal, highlighting the synergistic effect and the promising therapeutic potential of this combination in treating FLT3-mutated AML (even with TKI-resistance). To understand the underlying molecular mechanism(s), we performed RNA-seq with vehicle- or drug-treated MOLM13-RES cells, followed by pathway analysis and validation/mechanistic studies, we identified Polo-like kinase 1 (PLK1) as a key target of MET and GLT (Fig. 1H). PLK1's expression is notably suppressed by both treatments (Fig. 1I). Mimicking MET treatment, PLK1 knockdown enhanced GLT sensitivity, reducing IC50 from 259.2 nM to 47-60 nM (Fig. 1J). Conversely, PLK1 overexpression increased GLT's IC50 7-fold (13.07 nM to 95.94 nM) (Fig. 1K), largely reversing MET's effect (data not shown). PLK1, a crucial serine/threonine-protein kinase, influences multiple signaling pathways such as MAPK and mTOR pathways. Upon treating MOLM13 or MOLM13-RES cells with MET and GLT alone or combined, the PLK1 levels and phosphorylation levels of FLT3, STAT5, ERK, and mTOR were decreased, with the most significant decrease occurred upon the combined treatment (Fig. 1L). Depletion and overexpression of PLK1 decreased and increased these phosphorylation levels, respectively (data not shown). Together, our findings suggest that the synergistic therapeutic effect of MET and GLT in treating FLT3-mutated AML is likely through synergistically targeting PLK1 and its downstream pathways. Meanwhile, we executed a retrospective clinical study of FLT3/ITD AML patients who were also diagnosed with diabetes. Metformin users showed a notably longer median OS (13.2 months) than non-MET users (4.5 months, P=0.0197) (Fig. 1M). Despite FLT3/ITD status, FLT3 TKIs were seldom used in China due to high cost. Additionally, PLK1 level was dramatically higher in FLT3/ITD AML cases than in both healthy and FLT3/WT cases (P&amp;lt;0.001) (Fig. 1N), implying PLK1's role in FLT3/ITD's poor prognosis. In summary, our findings suggest a potential synergistic approach in treating FLT3-mutated AML using MET and GLT. This approach could reduce side effects and costs (crucial for developing countries) and improve outcomes. Larger clinical trials are needed to confirm these promising initial findings.

Incidence and Predictors of Relapse After Weaning Immune Suppressive Therapy in Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is a relapsing-remitting disease, and immune suppression (IS) is the mainstay of therapy. Predictors of relapse for patients with CS in remission are not well characterized. We assessed incidence of relapse in consecutive patients with CS treated with high-dose steroids and/or steroid-sparing agents (SSA) in our center from 2000 to 2020. Remission was defined as reaching maintenance therapy (no IS, SSA, and/or prednisone ≤5mg/d) for ≥1month. Relapse was defined as recurrence of CS syndrome requiring IS intensification: heart failure, ventricular arrhythmia, decrease in left ventricular ejection fraction, or increased disease burden on imaging. Among 68 patients, the mean age was 50.7±9.0years; 25 (37%) were women, and 32 (47%) were Black. In total, 59 patients (87%) reached remission. Over a median follow-up of 39.5months (interquartile range 17.6, 92.5), 28 (48%) relapsed. Greater percentage of late gadolinium enhancement (LGE) on pretreatment magnetic resonance imaging corresponded with increased likelihood of relapse (odds ratio 1.396 per 5% increase [95% confidence interval (CI) 1.04 to 1.88]; p=0.028). LGE ≥11% predicted elevated risk of relapse (adjusted odds ratio 4.998 [1.34 to 18.64]; p=0.017). Shorter time to relapse was observed with isolated CS (adjusted hazard ratio 4.084 [1.44,11.56]; p=0.008) and LGE ≥11% (adjusted hazard ratio 3.007 [1.01, 8.98]; p=0.049). Approximately 1 in 2 patients with CS in remission experienced relapse. Greater burden of LGE on cardiac magnetic resonance imaging and isolated CS are associated with greater risk of relapse. Future work is needed to refine risk stratification for relapse and to optimize surveillance strategies on the basis of the burden of disease.

Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.

Effects of heroin self-administration and forced withdrawal on the expression of genes related to the mTOR network in the basolateral complex of the amygdala of male Lewis rats

RationaleThe development of substance use disorders involves long-lasting adaptations in specific brain areas that result in an elevated risk of relapse. Some of these adaptations are regulated by the mTOR network, a signalling system that integrates extracellular and intracellular stimuli and modulates several processes related to plasticity. While the role of the mTOR network in cocaine- and alcohol-related disorders is well established, little is known about its participation in opiate use disorders.ObjectivesTo use a heroin self-administration and a withdrawal protocol that induce incubation of heroin-seeking in male rats and study the associated effects on the expression of several genes related to the mTOR system and, in the specific case of Rictor, its respective translated protein and phosphorylation.ResultsWe found that heroin self-administration elicited an increase in the expression of the genes Igf1r, Igf2r, Akt2 and Gsk3a in the basolateral complex of the amygdala, which was not as evident at 30 days of withdrawal. We also found an increase in the expression of Rictor (a protein of the mTOR complex 2) after heroin self-administration compared to the saline group, which was occluded at the 30-day withdrawal period. The activation levels of Rictor, measured by the phosphorylation rate, were also reduced after heroin self-administration, an effect that seemed more apparent in the protracted withdrawal group.ConclusionsThese results suggest that heroin self-administration under extended access conditions modifies the expression profile of activators and components of the mTOR complexes and show a putative irresponsive mTOR complex 2 after withdrawal from heroin use.

Copy-number intratumor heterogeneity increases the risk of relapse in chemotherapy-naive stage II colon cancer.

Optimal selection of high-risk patients with stage II colon cancer is crucial to ensure clinical benefit of adjuvant chemotherapy. Here, we investigated the prognostic value of genomic intratumor heterogeneity and aneuploidy for disease recurrence. We combined targeted sequencing, SNP arrays, fluorescence in situ hybridization, and immunohistochemistry on a retrospective cohort of 84 untreated stage II colon cancer patients. We assessed the clonality of copy-number alterations (CNAs) and mutations, CD8+ lymphocyte infiltration, and their association with time to recurrence. Prognostic factors were included in machine learning analysis to evaluate their ability to predict individual relapse risk. Tumors from recurrent patients displayed a greater proportion of CNAs compared with non-recurrent (mean 31.3% versus 23%, respectively; p = 0.014). Furthermore, patients with elevated tumor CNA load exhibited a higher risk of recurrence compared with those with low levels [p = 0.038; hazard ratio (HR) 2.46], which was confirmed in an independent cohort (p = 0.004; HR 3.82). Candidate chromosome-specific aberrations frequently observed in recurrent cases included gain of the chromosome arm 13q (p = 0.02; HR 2.67) and loss of heterozygosity at 17q22-q24.3 (p = 0.05; HR 2.69). CNA load positively correlated with intratumor heterogeneity (R = 0.52; p < 0.0001). Consistently, incremental subclonal CNAs were associated with an elevated risk of relapse (p = 0.028; HR 2.20), which we did not observe for subclonal single-nucleotide variants and small insertions and deletions. The clinico-genomic model rated an area under the curve of 0.83, achieving a 10% incremental gain compared with clinicopathological markers (p = 0.047). In conclusion, tumor aneuploidy and copy-number intratumor heterogeneity were predictive of poor outcome and improved discriminative performance in early-stage colon cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Prognostic Significance of PD1 and PDL1 Gene Expression in Lung Cancer: A Meta-Analysis.

BackgroundImmune checkpoint blockade therapy represents an extraordinary advance in lung cancer treatment. It is important to determine the expression of immune checkpoint genes, such as programmed cell death 1 (PD1) and programmed cell death-ligand 1 (PDL1), to develop immunotherapeutic strategies. The aim of this study was to explore the association between PD1 and PDL1 gene expression and prognoses and outcomes in lung cancer.MethodsThis meta-analysis analyzed 1,251 patients from eight different microarray gene expression datasets and were evaluated for their prognostic implications and verified using another independent research.ResultsThe mean expression levels of PDL1 in adenocarcinoma (AD) and squamous cell carcinoma (SC) were significantly higher in patients who died than in patients who did not. There was a trend toward incremental increases in PD1 and PDL1 expression significantly decreasing the risk of relapse and death among AD patients (HR = 0.69; 95% CI = 0.53 ~ 0.91; HR = 0.68; 95% CI = 0.54 ~ 0.84, respectively) and SC patients (HR = 0.53; 95% CI = 0.32 ~ 0.89; HR = 0.78; 95% CI = 0.57 ~ 1.00 respectively), as early-stage patients in this study were more likely to have high expression of both PD1 and PDL1 than late-stage patients (P-trend < 0.05). In contrast, late-stage SC patients expressing one or more of the genes at a high level had a significantly elevated risk of relapse (HR = 1.51; 95% CI = 1.07 ~ 2.11) and death (HR = 1.41; 95% CI = 1.08 ~ 1.84). This result was consistent with the validation data set.ConclusionThese findings indicate that high expression of PD1 and PDL1 is associated with superior outcome in early-stage lung cancer but an adverse outcome in late-stage lung cancer. The expression levels of PD1 and PDL1 individually or jointly are potential prognostic factors for predicting patient outcomes in lung cancer.

MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates

BackgroundWilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized.MethodsWe screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes.ResultsMutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential.ConclusionsThe strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.

Oxidative stress-mediated particulate matter affects the risk of relapse in schizophrenia patients: Air purification intervention-based panel study

Particulate matter (PM) exposure increased the risk of hospital admission and was related to symptoms of schizophrenia (SCZ). However, there are limited studies on the relationship between PM exposure and SCZ relapse risk, and the underlying biological mechanisms remain unclear. We designed an air purification intervention study under a 16-day real air purifier scenario and another 16-day sham air purifier scenario, with a 2-day washout period. Twenty-four chronic stable male patients were recruited. The oxidative stress biomarkers were measured including serum catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), malondialdehyde (MDA), and nitric oxide (NO). The relapse risk was evaluated by the early signs scale (ESS). Linear mixed effect models were fitted to establish the associations between PM exposure and ESS and oxidative stress. Mediation model was performed to explore the mediation effect of oxidative stress on the PM-ESS association. Higher concentrations of PM2.5/PM10 exposure were associated with an elevated risk of relapse of SCZ. For each 10 μg/m3 in PM2.5 concentration, the scores of ESS and subscales of incipient psychosis (ESS-IP), depression/withdrawal (ESS-N), anxiety/agitation (ESS-A), and excitability/disinhibition (ESS-D) were increased by 4.112 (95% CI: 3.174, 5.050), 1.516 (95%CI: 1.178, 1.853), 1.143 (95%CI: 0.598, 1.689), 1.176 (95%CI: 0.727, 1.625) and 0.238 (95%CI: 0.013, 0.464), while logCAT, SOD and T-AOC were reduced by 0.039 U/ml (95% CI: 0.017, 0.060), 1.258 U/ml (95% CI: 0.541, 1.975), and 0.076 mmol/l (95% CI: 0.026, 0.126). In addition, pathways of “PM2.5→T-AOC→ESS-A″ and “PM2.5→T-AOC→ESS-D″ were found, with significant T-AOC mediated effects 15.70% (P = 0.02) and 52.99% (P = 0.04). Our findings suggest that PM may increase the risk of anxiety, depression, excitability, and incipient psychosis behaviors in SCZ patients, while reducing the function of the antioxidant system. The decrease of T-AOC may medicate the PM-ESS association in SCZ.

Relapses in Patients Treated with High-Dose Biotin for Progressive Multiple Sclerosis.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.

Right prefrontal function and coping strategies in patients with remitted major depressive disorder

BackgroundPatients with remitted major depressive disorder (rMDD) generally rely on maladaptive coping strategies for stressful situations. These maladaptive copings are associated with an elevated relapse risk of rMDD; however, their neural basis remains poorly understood. MethodsWe enrolled (1) 45 patients with rMDD (17-item Hamilton Depression Rating Scale [HRSD17] total score ≤ 3) and (2) 56 healthy controls (HCs). Coping styles were measured using the Coping Inventory for Stressful Situations (CISS) according to three coping dimensions: avoidance-, emotion-, and task-oriented copings. The cognitive strategic processes of the prefrontal cortex were measured using a verbal fluency task (VFT). Furthermore, regional frontotemporal hemodynamic responses were monitored by near-infrared spectroscopy (NIRS). ResultsPatients with rMDD had significantly lower task-oriented coping scores and significantly higher avoidance- and emotion-oriented coping scores than HCs. Predominantly in the left frontotemporal region, patients with rMDD had lower frontotemporal hemodynamic responses during a VFT than HCs. Hemodynamic responses in the right inferior frontal gyrus of patients with rMDD were significantly and negatively associated with avoidance-oriented coping scores, but not of HCs. Conversely, those responses of HCs were significantly and positively associated with task-oriented coping scores, but not of patients with rMDD. DiscussionAlteration in the right inferior frontal cortex plays an important role in dysfunction to stress response in patients with rMDD. Differential functioning patterns of the right inferior frontal cortex associated with coping strategies may link to MDD recurrence vulnerability.

Molecular Analysis of Oncogenic Mutations in Resected Margins by Next-Generation Sequencing Predicts Relapse in Non-Small Cell Lung Cancer Patients.

ObjectiveTo investigate the genetic mutations in both tumor and marginal tissues in patients with non-small cell lung cancer (NSCLC), and to evaluate the potential prognostic value in patients with margins gene positive.MethodsNext-generation sequencing (NGS) technique was used to detect genetic mutation in tumor and marginal tissues of the bronchus in 88 patients with NSCLC. Correlation of genetic mutations with pathology, lymph node metastasis, disease-free survival and overall survival was analyzed.ResultsOf the 88 patients, 83 cases (94.3%) had gene mutations in the tumor samples and 12 cases (13.6%) had genetic alterations in their margins. Most of the gene mutations detected were cancer drivers. Six common driver genes between tumor and marginal tissues were identified, including EGFR, TP53, CDKN2A, CTNNB1, BRAF, and NF1. Kaplan–Meier analysis revealed that the median disease-free survival (DFS) was significantly shorter in patients with detectable gene mutations in marginal tissues compared with patients without mutations in margins (30.7 versus 24.4 months, log-rank χ2 = 4.78, P =0.029). Consistently, a shorter median OS was observed in patients harboring gene mutations in margins compared with patients with no mutations in margins (49.1 versus 32.2 months, log-rank χ2 = 3.669, P =0.055).ConclusionThese findings identify the presence of oncogenic alterations in microscopically negative margins in NSCLC patients associated with elevated risk of relapse and shorter survival time. Thus, examination of microscopically negative margins by NGS represents a valuable approach to predict the clinical outcome of NSCLC patients.

Cognitive profiles in persons with opioid use disorder enrolled in methadone treatment

Cognitive impairment is common in persons with opioid use disorder and associated with poor treatment outcomes, including elevated risk for relapse. Much less is known about the underlying structure of these deficits and the possible presence of cognitive phenotypes. A total of 177 adults (average 42.2 years of age, 52.0% male, 65.5% Caucasian) enrolled in a methadone maintenance treatment program completed the NIH Toolbox as part of a larger project. Cluster analyses revealed a 2-cluster solution–persons with intact cognitive function in all domains (n = 93; Intact) and those with impairments on tests of attention and executive function (n = 83; Impaired). Follow-up analyses revealed that the Impaired group was slightly older, more likely to self-identify as a racial/ethnic minority, and less likely to report consuming alcohol four or more times per week. These findings suggest the existence of distinct cognitive profiles in persons with opioid use disorder and encourage further examination, particularly studies to examine the possible benefits of routine screening for cognitive impairment as part of substance use treatment.

Commentary on Strickland et al. (2020): Do commodity purchase tasks provide clinically meaningful indices of motivation to consume drugs?

Drug purchase tasks have the potential to measure clinically meaningful between- and intra-individual differences in strength of motivation to use drugs. These differences may guide decisions about degree of risk and need for treatment. Alcohol and drug purchase tasks are brief self-report measures that are modeled after laboratory drug self-administration paradigms used to quantify the strength of drugs as reinforcers, also known as drug demand. Individuals complete 10–20 hypothetical questions that ask how many standard units of a drug they would purchase and consume across a range of prices. Their responses are then used to generate three relatively distinct indices of strength of desire or motivation to use drugs that are central to theoretical and diagnostic models of addiction, but are not routinely collected as part of clinical assessments. First, the amount of the drug the individual would purchase/use if the drug was free (referred to as demand intensity) is collected; secondly, the greatest drug expenditure across the task items is collected (referred to as Omax, or output maximum). For example, purchasing five drinks priced at $10 would result in a $50 expenditure, which might be an individual's peak expenditure value. Thirdly, the rate of decrease in consumption as a function of increases in price (i.e. price sensitivity or elasticity of demand) is collected. A number of studies have demonstrated that alcohol and cigarette purchase tasks provide reliable and valid assessments of individual differences in these demand parameters. These differences then predict change in level of use over time and are acutely responsive to laboratory manipulations 1, 2 and clinical interventions 3-5. Strickland et al. 6 extend this literature with their timely and rigorous meta-analytical summary of the smaller but growing body of literature examining illicit drug purchase tasks. A relative challenge with drug purchase tasks is the lack of standardization of drug doses and varieties compared to alcohol standard drinks. This challenge may impact the accuracy of the specific quantities purchased more so than the validity of demand parameters as indicators of elevated risk for relapse or high-risk consumption. Strickland et al.’s results are generally consistent with the alcohol purchase task literature 7 and suggest that individual differences in demand show consistent medium effect size associations with cannabis and cocaine use and problems. One important conclusion of this meta-analysis, also consistent with the alcohol purchase task literature, is that demand intensity and Omax may be more clinically relevant indices of strength of motivation or problem severity than demand elasticity. An important research direction is to determine the extent to which drug purchase tasks have the potential to provide information beyond that offered by standard clinical measures of actual recent consumption in the same way that alcohol purchase tasks have. Given that there are myriad contextual factors that influence one's recent drinking and drug use (e.g. availability of drugs and alcohol for those who are underage or in an environment that prohibits use), purchase tasks may provide informative data on the likelihood of future consumption that could be useful in determining change in degree of clinical risk and need for intervention services. For example, an individual may report a desire to consume large amounts of an opiate if it were available or to drink at a level that could lead to a blackout, even if neither behavior occurred recently due to external constraints. Willingness to spend large amounts of money on drugs also indicates a level of motivation for use that may portend stable or increasing drug use over time, even if recent drug use levels are relatively low. Conversely, the presence of relatively low drug demand for an individual with high levels of recent drug use may suggest an impending reduction in drug use due to a shift in motivation or environmental context. Future research is needed to evaluate the utility of drug purchase tasks as dynamic indices of motivation that are responsive to both value enhancing stimuli (negative affect, drug and social context cues) and value reducing stimuli (treatment, next-day responsibilities, cognitive/visceral manipulations such as episodic future thinking or mindfulness 8). Alcohol demand can reduce immediately following an intervention and the extent of the reduction predicts subsequent changes in use 9, suggesting the potential clinical utility of these very brief measures for guiding drug use treatment planning and stepped-care decisions. Given that the availability and price of illicit drugs may fluctuate more than alcohol, and that self-reports of actual illicit drug use may expose individuals to legal or occupational sanctions, hypothetical drug purchasing scenarios may have unique utility in gauging strength of desire to use drugs. None.

NEDD4 expression is associated with breast cancer progression and is predictive of a poor prognosis

BackgroundA role for neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) in tumorigenesis has been suggested. However, information is lacking on its role in breast tumor biology. The purpose of this study was to determine the role of NEDD4 in the promotion of the growth and progression of breast cancer (BC) and to evaluate the clinicopathologic and prognostic significance of NEDD4.MethodsThe impact of NEDD4 expression in BC cell growth was determined by Cell Counting Kit-8 and colony formation assays. Formalin-fixed paraffin-embedded specimens were collected from 133 adjacent normal tissues (ANTs), 445 BC cases composed of pre-invasive ductal carcinoma in situ (DCIS, n = 37), invasive ductal carcinomas (IDC, n = 408, 226 without and 182 with lymph node metastasis), and 116 invaded lymph nodes. The expression of NEDD4 was analyzed by immunohistochemistry. The association between NEDD4 expression and clinicopathological characteristics was analyzed by chi-square test. Survival was evaluated using the Kaplan–Meier method, and curves were compared using a log-rank test. Univariate and multivariate analyses were performed using the Cox regression method.ResultsNEDD4 promoted BC growth in vitro. In clinical retrospective studies, 16.5% of ANTs (22/133) demonstrated positive NEDD4 staining. Strikingly, the proportion of cases showing NEDD4-positive staining increased to 51.4% (19/37) in DCIS, 58.4% (132/226) in IDC without lymph node metastasis, and 73.1% (133/182) in BC with lymph node metastasis (BCLNM). In addition, NEDD4-positive staining was associated with clinical parameters, including tumor size (P = 0.030), nodal status (P = 0.001), estrogen receptor status (P = 0.035), and progesterone receptor status (P = 0.023). Moreover, subset analysis in BCLNM revealed that high NEDD4 expression correlated with an elevated risk of relapse (P = 0.0276). Further, NEDD4 expression was an independent prognostic predictor. Lastly, the rates for 10-year overall survival and disease-free survival were significantly lower in patients with positive NEDD4 staining than those in BC patients with negative NEDD4 staining BC (P = 0.0024 and P = 0.0011, respectively).ConclusionsNEDD4 expression is elevated in BC and is associated with BC growth. NEDD4 correlated with clinicopathological parameters and predicts a poor prognosis. Thus, NEDD4 is a potential biomarker of poor prognosis and a potential therapeutic target for BC treatment.

Setting the stage: Contemporary staging of non-melanomatous skin cancer and implementation of the new American Joint Committee on cancer eighth edition staging manual

Non-melanomatous skin cancer (NMSC) generally refers to basal cell and squamous cell carcinoma of the skin. The majority of patients are curatively treated with simple excision. Only few present with locally advanced disease or have evidence of high-risk features, placing them at an elevated risk of relapse. In such cases, further investigations may guide the multidisciplinary management plan. There are no universally agreed on indications for recommending additional staging investigations, due to a lack of prospective data reporting their impact on patient outcomes. Some generally agreed upon indications are discussed in this review article. Most commonly, computed tomography (CT) and magnetic resonance imaging (MR) are used in cases of locally advanced NMSC for staging purposes and surgical planning. While Positron Emission Tomography (PET)/CT and sentinel lymph node biopsy have shown utility, data is lacking to establish their roles in the staging algorithm. An updated NMSC system was included in The American Joint Committee for Cancer eighth edition staging manual (AJCC8). Under AJCC8 the majority of patients with regional disease are upstaged by the presence of extranodal extension, however, this updated system appears to provide limited prognostic discrimination between the nodal categories and the overall TNM stages. This review article will explore the contemporary role of staging investigations, including evolving technologies, and review the changes implemented in AJCC8. It will also discuss the implications of the AJCC8 decision to assign patients with p16-positive cervical nodal SCC with an unknown primary to the oropharyngeal staging system, with particular relevance to clinicians working in areas of high NMSC incidence.

Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system

ObjectiveInsulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES)...