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Morphoea is a spectrum of disorders characterized by inflammation and sclerosis of the skin and potentially underlying tissues. There are no specific licensed treatments for morphoea and prospective studies on commonly used therapies are lacking. We describe a case of progressive, recalcitrant pansclerotic morphoea with a rapid response to abatacept.

Background Treatment resistant hypertension (TRH) is defined as uncontrolled blood pressure (>140/90 mm Hg) after treatment with the intensified dose of three standard antihypertensive drugs. Management of TRH involves addition of fourth line drugs on standard care or interventional therapies (Renal denervation, Baroreceptor activation, Central venous anastomosis). However, evidence concerning cost-effectiveness of interventional therapies is inconclusive. Objective: This systematic review was conducted to extract the level of evidence on cost-effectiveness of interventional therapies for TRH. Method We systematically searched articles written in English language since January 2000 to January 2020 from the following databases: PubMed/Medline, Ovid/Medline, Embase, Scopus, Web of Science, Google scholar and other relevant sources. Key findings Twelve pharmacoeconomic studies were included in this systematic review. Renal denervation (RDN) is the most commonly studied intervention therapy for treatment of TRH. Participants included in the study vary from age 18-99 years. The incremental cost-effectiveness ratio (ICER) of RDN ranged from $1,709.84 per QALY gained in Netherlands to 66,380.3 per QALY gained in Australia. RDN was cost-effective in high-risk patients in UK, Australia, Canada, Netherlands, USA, Germany, Russia and Korea. The cost-effectiveness was influenced by the magnitude of effect of RDN on systolic blood pressure, the rate of RDN nonresponders, and the procedure costs of RDN and assumption of long-term time horizon. However, the ICER of RDN in Mexico was above MXN$ 139,000 GDP/capita of the country. The ICER of implantable carotid body stimulator was $64,400 per QALYs gained. The cost-effectiveness of baroreceptor activation didn’t improve with age. Conclusion Overall cost-effectiveness of interventional therapies for treatment of TRH was inconclusive based on the current available evidence. Therefore, strong clinical trials and pharmacoeconomic evaluations from different perspectives in various candidate populations are needed to generate adequate clinical and cost-effectiveness evidence for using interventional therapies in treatment of treatment resistant hypertension.

Introduction In oesophageal adenocarcinoma with an apparent pathological complete response (pCR) to neoadjuvant therapy (NAT) there remains debate as to whether oesophagectomy is required. Single Cell RNA sequencing (scRNAseq) enables identification and characterisation of cell populations at higher resolution than diagnostic techniques. Method ScRNAseq was used to determine transcriptomic profiles of cell populations in 24 OAC tumours and 13 matched normal samples. Five were also analysed using bulk RNA sequencing and high-precision mass spectrometry proteomics. Immunohistochemistry (IHC) was used to validate pCR. Paired scRNAseq analysis of pre-and post-treatment specimens from three further patients was used to compare transcriptomic profiles before and after NAT. Cancer cells (CCs) were assigned a cancer stem cell (CSC) score curated from published gene sets. Result We analysed a total of 22,738 single cells forming 29 different cell phenotypes. In two samples with apparent pCR, IHC staining, bulk RNA sequencing and proteomics of post-treatment samples failed to identify CCs. ScRNAseq, conversely, revealed persistent CCs (12/978 and 45/774). Transcriptomic analysis identified upregulation of stem cell markers and high CSC scores in these cells. Conclusion We have shown that CCs persist beneath the lower detection limit of standard approaches in apparent pCR. These cells express marker genes and expression programs consistent with CSCs. CSCs are a critical subpopulation that drive tumour initiation, growth, invasion, metastasis and resistance to therapy. These gene expression programs are not enriched in non-responders and straight to surgery samples. Oesophagus sparing treatment algorithms in pCR may subject patients to unnecessary risk of progression. Take-home message Cancer cells remain within tumours after apparent complete pathological response. These cells express stem cell markers associated with resistance to therapy and cancer progression.

BACKGROUND Uncontrolled treatment-resistant hypertension (TRH), i.e., blood pressure (BP, mm Hg) ≥140/≥90mm Hg in and out of office on ≥3 different BP medications at optimal doses, is common and has a poor prognosis. Aldosterone antagonist (AA) and renin-guided therapy (RGT) are effective strategies for improving BP control in TRH but have not been compared. METHODS A comparative effectiveness TRH pilot study of AA vs. RGT was conducted in 4 primary care clinics with 2 each randomized to AA or RGT. The primary outcome was change in clinic BP defined by means of 5 automated office BP values. Eighty-nine patients with apparent TRH were screened and 44 met criteria for true TRH. RESULTS Baseline characteristics of 20 patients in the AA (70% Black, 45% female, mean age: 57.4 years) and 24 patients in RGT (79% Black, 50% female, 57.8 years) arms were similar with baseline BP 162±5/90±3 vs. 153±3/84±3, respectively, P = 0.11/0.20. BP declined to 144±5/86±4 in AA vs. 132±4/75±3 in RGT, P = 0.07/0.01; BP was controlled to JNC7 (Seventh Joint National Committee Report) goal in 25% vs. 62.5%, respectively, P < 0.01. Although BP changes from baseline, the primary outcome, were not different (-17.6±5.1/-4.0±3.0 AA vs. -20.4±3.8/-9.7±2.0 RGT, P = 0.65/0.10.), more BP medications were added with AA than RGT (+0.9±0.1 vs. +0.4±0.1 per patient, P < 0.01). CONCLUSIONS In this TRH pilot study, AA and RGT lowered BP similarly, although fewer additional medications were required with RGT. A larger comparative effectiveness study could establish the utility of these treatment strategies for lowering BP of uncontrolled TRH patients in primary care.

BACKGROUND Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer death. Recurrence after therapy is a major challenge, since recurrent pHGG proliferates aggressively and resists therapy. We developed and validated preclinical models of matched primary and recurrent tumors, providing a method to study recurrence and potential therapies. METHODS We irradiated H3K27M thalamic pHGG cells (BT245) (8 Gy/week,2Gy fractions x3 weeks) and propagated the surviving cells (BT245R). We developed a murine recurrence model by orthotopically implanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d) and propagating irradiated (BT245RM) or control (BT245CM) tumor cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug testing. RESULTS BT245R cells were more stemlike than BT245, with an 8-fold greater rate of neurosphere formation (p CONCLUSIONS Our neurosphere and murine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.

BACKGROUND Sex differences independent from acute hormone action are evident in the incidence and tumorigenesis of several cancers, including glioblastoma (GBM). Malignant brain tumors with mesenchymal, proneural, and neural GBM subtypes occur twice as frequently in males than in females, implying a molecular basis for the sex disparities observed. Accordingly, response to therapy and overall survival, may also differ between male and female GBM patients. Further elucidation of these differences would benefit from a robust preclinical testing system, such as the one described here. METHODS Adult (U87-MG) GBM cells were exposed to a total radiation dose of 10 Gy, effecting an epithelial to mesenchymal transition. The resultant irradiated U87-10Gy cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. In vivo advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics™ Software (IQ-AI, Ltd.). RESULTS Tumor take was 90% in males and 60% in females, indicating an ‘incidence’ ratio of 1.5. Overall survival was significantly higher in females (median = 48, range = 40-72 days) than in males (median = 28, range = 27-30 days) (p = 0.024). Immunohistochemical and imaging analyses are pending and will be discussed. CONCLUSION The outcomes noted in this pilot study mirror incidence and survival outcomes noted in GBM patients undergoing standard care. Our model of treatment-resistant glioma provides a robust testing system to study underlying sex differences in GBM biology and treatment response in parallel analyses of male and female data.

Background The prevalence of schizophrenia in the United States ranges between 0.5% and 1%. This difficult-to-treat disorder is marked by the presentation of symptoms that are both positive (i.e. hallucinations) and negative (i.e. blunted affect), as well as disturbances in cognition and affect. Several second-generation antipsychotics (i.e. olanzapine, risperidone.) have been utilized for their varying effects on the symptoms of schizophrenia, yet 20% to 60% of patients with schizophrenia are considered treatment-resistant. While clozapine is shown to be the most effective antipsychotic, negative symptoms commonly persist in clozapine-treated patients. Research shows that oxytocin has neuromodulatory effects on social perception and enhances empathy and attentional engagement in individuals with schizophrenia, suggesting it may have therapeutic effects on negative symptoms. The present study presents a pilot prospective research study evaluating the efficacy of combining clozapine and sublingual oxytocin for the reduction of positive and negative symptoms. Methods Prospective research study evaluated 25 treatment resistant schizophrenic patients who were admitted to the persistent psychotic disorder unit at a private hospital, with an average treatment duration of 2.9 months with a range between 1 and 9 months. All have been followed as outpatient for up to 30 months after discharge. All patients were 18 years or older and met the DSM-5 criteria for schizophrenia. The Positive and Negative Syndrome Scale (PANSS) was used to assess the efficacy of the combination treatment. Clozapine was prescribed to all 25 patients after they had failed to improve in three different trials of other antipsychotic medications. Sublingual oxytocin (10 IU 2x per day; 20 IU 3x per day) was prescribed to 25 of the patients only after the improvement in positive symptoms on the PANSS with clozapine had plateaued. Due to a history of intranasal substance use in all the patients, oxytocin was administered sublingual to ensure adequate and less variable absorption of the neuropeptide. Results A time-series analysis demonstrated a significant decrease in PANSS scores across admission, stabilization of clozapine and stabilization of oxytocin (p Discussion The combined effect extends the current research of augmenting sublingual oxytocin and clozapine for individuals with previously treatment-resistant symptoms. Though each patient benefitted from clozapine alone, negative symptoms persisted. Patients, their families, and treatment program staff all observed a significant reduction in the patients’ anxiety and an improvement in the patients’ relatedness. While this case series cannot establish that oxytocin is responsible for the clinical improvements seen here, it does suggest that it may improve negative symptoms and social functioning in patients with treatment-resistant schizophrenia showing incomplete improvement with clozapine alone. The present study suggests the need for future research to explore the possibility that oxytocin can mitigate the negative symptoms of schizophrenia.

Background Clozapine is the gold standard for Treatment Resistant Schizophrenia (TRS) and its use is strongly recommended after failure of two/three antipsychotics. Nonetheless, prescribing trends do not appear to follow the global guidelines and switching to clozapine is often delayed or improper. Reasons for clozapine underuse are quite understood, whereas little is known on clozapine misuse. In fact, more stringent operative criteria to define TRS should be used in clinical practice, taking advantage of standardized assessment tools in order to avoid false TRS positive. In these perspectives, we studied the patterns of clozapine prescription in a sample of TRS and non-TRS patients, in order to identify psychopathological variables associated with lifetime exposure to clozapine. Methods 198 consecutive patients have been screened for eligibility criteria from 2016 until 2019 at Treatment Resistant Psychosis Centre of the University of Naples “Federico II”. Only stabilized schizophrenic patients aged between 18 and 65 were enrolled. All relevant clinical-demographic data were recorded. TRS diagnosis was based on TRRIP working group operational criteria and clear pseudo-resistance factors were excluded. Patients were subdivided into two groups: those having received or currently under clozapine treatment (eCLZ) and those never treated by clozapine (nCLZ). Patients were assessed for psychotic symptoms (PANSS), cognitive performances (BACS), neurological soft signs (NES), functional capacity (UPSA), social functioning (PSP and SLOF scales), and severity of illness (CGI-S). Results Among the patients included (92), eCLZ were 50 (54.3%), of which 20% being non-TRS. Compared to nCLZ, eCLZ had a significantly earlier age at onset, more hospitalizations, higher daily antipsychotic doses; eCLZ patients had significantly higher scores on the CGI-S, PANSS total, PANSS Negative, General Psychopathology and PAUSS subscale and, according to the Five Factor PANSS Model, higher score on Negative and Disorganization Factors; eCLZ had also more impaired Working Memory performances, higher NES Total score, lower PSP and all SLOF areas scores, except Area4. Then we use univariate and multivariate analysis to delineate predictors of clozapine exposure and to evaluate whether these factors may organize in proximal (independent) and distal (mediated) associations. We found five independently associated variables that mediate all the other ones: high antipsychotic doses, higher disease severity, suicide attempts, impaired working memory, more severe Stereotyped Thinking. Discussion While it is expected that some TRS patients might not receive clozapine, the observation that non-TRS patients had been exposed to clozapine may surprise. A possible explanation may be the lack of systematized procedure to diagnose TRS, which is often merely coincident with a nonspecific lack of response to antipsychotics. Due to mediation analysis, we further gained insights into the hierarchy of these variables’ impact on clozapine prescription and we finally compose a complex network of proximal and distal factors predicting clozapine exposure in schizophrenic patients. The above-mentioned independent variables significantly associated with clozapine exposure let intend that eCLZ patients may belong to a subset of more severely ill ones, beyond reaching the response threshold. Earlier onset patients may suffer from a more severe disease, be more prone to suicide attempts, and less responsive to antipsychotics. This result needs to be replicated in wider samples, and this relevant therapeutic issue should be further debated in order to gather robust evidence to support or discourage clozapine off-label use and misuse.

Background About one-third of patients with schizophrenia are treatment-resistant (TRS). They cause a significative burden for their caregivers (1). Our objective is to compare caregiver burden in TRS versus non-TRS outpatients with schizophrenia. Methods Patients with diagnosis of schizophrenia (DSM-5), 18–50 years, both sexes, and a relative/caregiver, both sexes, aged 18 to 70 years, living in contact with the patient ≥30 hours/week. The use of clozapine for more than 6 months, in stable daily dosage was used as a proxy for TRS; non-TRS were patients using other antipsychotics, with stable dosage for at least 6 months. Psychopathology was evaluated with the CGI-Schizophrenia Scale (2). Family burden was assessed with the Family Burden Interview Schedule (FBIS-BR), objective and subjective total and subscores (3). Student’s t-test and chi-square test were used to compare TRS versus non-TRS patients and caregivers. Results TRS patients: n = 45; (31 male, 14 female); mean age: 37.11 ± 8.93 years; age at onset of illness 20.84 ± 6.20 years; duration of disease: 16.51 ± 9.14 years. CGI: positive: 3.96 ± 1.22; negative: 3.62 ± 1.17; depressive: 2.36 ± 0.98; cognitive: 3.76 ± 1.26; total: 13.66 ± 3.31. TRS Caregivers: n=45 (12 male, 33 female); mean age: 56.7 ± 11.04 years; in contact with the patient 82.53 ± 36.98 hours/week. Non-TRS patients: n= 15 (9 male, 6 female); mean age: 36.00 ± 12.49 years; age onset of illness 21.93 ± 9.73 years; duration of disease: 14.20 ± 13.66 years. CGI: positive: 2.40 ± 1.40; negative: 3.40 ± 1.24; depressive: 2.33 ± 1.11; cognitive: 3.20 ± 0.86; total: 11.33 ± 3.51. Non TRS Caregivers: n=15 (2 males, 13 female); mean age: 53.13 ± 13.61 years; in contact with the patient 106.13 ± 62.47 hours/week. Sociodemographic variables showed no significant differences were observed between TRS and non-TRS groups. CGI positive and total scores were significantly higher in TRS patients compared to non-TRS patients (p FBIS-BR Scores: TRS caregivers: The mean total score of the objective burden was 2.41 ± 0.66 and subjective burden was 2.00 ± 0.64. Assistance to the patient in daily life (objective) was 2.99 ± 0.55 and its subjective score was 1.56 ± 0.80. Supervision of patients’ problematic behaviors was 1.81 ± 0.61 and its subjective score was 1.00 ± 1.00. Impact on family routine was 2.43 ± 1.13 and worries about the patients’ present and future life (subjective) was 3.45 ± 0.70. Non TRS caregivers: The mean total score of the objective burden was 2.42 ± 0.58 and subjective burden was 2.18 ± 0.51. Assistance to the patient in daily life (objective) was 3.30 ± 0.80 and its subjective score was 1.91 ± 0.93. Supervision of patients’ problematic behaviors was 1.80 ± 0.51 and its subjective score was 0.94 ± 0.59. Impact on family routine was 2.16 ± 0.86 and worries about the patients’ present and future life (subjective) 3.68 ± 0.55. No significant differences were observed between the TRS and non-TRS caregivers’ groups. Discussion Contrary to our initial expectation (1), TRS and non-TRS caregivers showed similar burden, even though TRS patients had higher positive scores on the CGI. This lack of difference may be due to small number of patients in the non-TRS group; non-TRS patients might be refractory but did not receive clozapine yet. It is also possible that TRS caregivers adapt to the caring of these severe patients and learn to deal with the burden the disease.

BACKGROUND: Chemo- and radioresistance are characteristic features of post-treatment high-grade glioma (HGG). The cell populations responsible for this treatment-resistant phenotype are glioma stem cells (GSCs). These GSCs have a high requirement for iron which is essential for tumor cell viability. Intriguingly, the transferrin receptors that play a crucial role in iron uptake by both adult and pediatric astrocytomas exhibit a high affinity for gallium maltolate (GaM), a novel iron mimetic. Given the added commonality between adult and pediatric glioma stem cell signatures, especially post-treatment, we believe targeting treatment-resistant cell populations via their inherent iron metabolism is a viable approach to combat treatment-resistant HGG in adults and children. Here, we demonstrate the profound effects of GaM in a novel in vivo model of recurrent glioblastoma. METHODS: Irradiated human GBM cells (adult or pediatric) were stereotactically implanted into the right striatum of male athymic rats. Following confirmation of in vivo tumor growth by MRI at 9.4T, animals received GaM (50 mg/kg/day) in an oral preparation for voluntary ingestion. Tumor growth was monitored weekly by MRI, and lesion volume and associated advanced MRI parameter maps were determined using enhancing tumor ROIs. RESULTS: In a first set of animals, the mean weekly tumor growth rates of enhancing lesions were 65.8% and 156% in GaM-treated and control rats, respectively (p=0.002). Median disease-specific survival was 51 days in GaM-treated animals and 28 days in controls (p=0.004). Complete response was observed in 20% of the animals, with complete resolution of the disease confirmed histologically. A partial response was observed in 40% of the animals. Follow-up data is being collected in a second set of animals for verification and updated results will be discussed. CONCLUSION: We present compelling evidence that iron-targeted therapy using the novel iron mimetic GaM is highly effective in treatment-resistant HGG.

Thomas Munzel takes his crusade to stop airport expansion to politicians after discovering that noise directly harms blood vessels.

This double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 wk of risperidone augmentation of serotonin reuptake inhibitor (SRI) treatment in adult subjects with treatment-resistant obsessive–compulsive disorder (OCD) (failure of at least two SRI trials). Sixteen adult treatment-resistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone ( n =10) (0.5–3.0 mg/d) or placebo ( n =6) following at least 12 wk of SRI treatment. Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression – Improvement (CGI-I) score of 1 or 2 and a Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) decrease [ges ]25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this.

Malignant gliomas are composed of heterogeneous cell populations and the clonal evolution of these cells is one of the key reasons for treatment resistance and tumor recurrence. A fundamental challenge in studying clonal evolution in these tumors is the difficulty in isolating the phenotype-associated (e.g. treatment resistant) sub-populations from the heterogeneous population. We developed an approach to individually barcode and isolate specific cell subpopulations using a CRISPR (clustered, regularly interspaced, short palindromic repeat)-Cas9D10A targetable, single-cell barcoding library with a complexity of 36 million unique barcodes. This approach enabled us to uniquely barcode > 1 million cells, identify enriching barcoded sub-populations following treatment and then isolate the resistant subpopulation using the subpopulation-specific barcode. Each barcode sequence carrying two guide RNAs so that CRISPR-Cas9D10A targeting can lead to “switching” (i.e. frameshift) of an EGFP (Enhanced Green Fluorescent Protein) reporter. Thus, targeted cells lose their EGFP signal and can be specifically isolated by cell sorting. Proof of principle studies showed that specific barcoding cells could be efficiently targeted to turn off EGFP and subpopulations isolated. Subsequent large-scale implementation of this approach has been performed to isolate resistant subpopulations following radiation and temozolomide. Our approach will lead to identification of the both pre-existing and acquired specific somatic genetic or epigenetic changes driving treatment resistance in patients with malignant gliomas.

Background: Positive symptoms and specifically paranoid delusions in psychosis are characterized by a fundamental luck of trust. A number of studies show that dopaminergic dysfunction modulating the cortico-striatal reward network underlies psychosis. However, antipsychotic medication is not effective in approximately a third of schizophrenia patients. Recent evidence suggest that their dysfunction might be primarily glutamatergic, hence might affect reward networks differentially.

Background: Longitudinal studies are essential for understanding the trajectory and prognosis of patients diagnosed with schizophrenia, in particular those who are treatment resistant as this outcome is difficult to predict. However, follow-up is challenging within this patient population due to high relapse rates, difficulties recontacting participants due to regular change of address, and patients’ symptoms leading to their refusal to take part.

Primary glioblastoma (GBM) tumours recur following treatment. This is likely due to selection and expansion of treatment resistant cells during therapy. Details of the patterns of therapy-driven genomic evolution of these tumours are emerging, but less is known about how transcriptional profiles are altered between paired samples during treatment. The latter will reveal the gene expression signatures that are selected for during therapy and can give insights into convergent treatment resistance mechanisms. To investigate this, we have applied high-depth RNAseq to capture coding and non-coding gene expression in a preliminary set of eight pairs of primary (P) and recurrent (R) GBM from the same patient. We will discuss the results of our preliminary analyses of these data in the context of translational opportunities for inhibiting relapse-promoting clones in primary tumours.

Patients with stage II and III colorectal cancer whose tumors possessed more stem cell–like properties had worse 5-year disease-free survival rates than individuals with more differentiated tumors, 6.9% compared to 93.1%, according to a new study. The presence of the CDX2 transcription factor in tumors, which drives differentiation of intestinal cells, statistically correlated with the least aggressive cancers and highest rates of survival in the validation set. The research, which appeared in the New England Journal of Medicine in February, was conducted by Michael Clarke, M.D., Karel H. and Avice N. Beekhuis Professor of Cancer Biology at Stanford University in Palo Alto, Calif., and colleagues (N. Engl. J. Med. 2016;374:211–22; doi: 10.1056/ NEJMoa1506597). “This study, which indicates that tumors with a stem cell–like signature are more aggressive and is highly predictive of survival, may be the first to demonstrate clinical utility in cancer stem cell research,” Clarke said. “We have known that these cells, in contrast to other cancer cells, are treatment resistant,” he said. Clarke’s discovery “sets the field of cancer stem cell research on firmer currently approved drug. Neither result was expected.

Background: This open trial was conducted to evaluate the effectiveness of intravenous clomipramine (CMI) in refractory obsessive-compulsive disorder (OCD). Methods: Thirty OCD poor responders to previous multiple trials of anti-obsessive medications were selected and admitted to the hospital. Severity of the illness and response to treatment were primarily assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). CMI was gradually administered intravenously for one week. All patients were thereafter switched to oral CMI with a maximum dose of 225mg/day. Results: The Y-BOCS total score mean at admission was in the severe range (24–31), and dropped on discharge and follow-ups to the moderate range (16–23). At discharge, 23 patients (76.7%) had a decrease in Y-BOCS ≥25% and were considered responders, while only 18 (60%) were still responders at 24 weeks. No relevant persistent side effects were reported. Conclusion: Intravenous clomipramine could be of benefit for severe OCD cases that have not adequately responded to several therapies, including oral clomipramine.