COSMO Study Research Articles

Abstract OT2-15-01: COntinue the SaMe systemic therapy after local ablative therapy for Oligoprogression in metastatic breast cancer - the COSMO study

Abstract Background Patients with metastatic breast cancer (MBC) are usually treated with palliative systemic therapy until progression or unacceptable toxicity. When progression occurs, clinicians typically switch to the next line of systemic therapy. However, this strategy might be suboptimal in case of mixed response or oligoprogression. Oligoprogression refers to a situation in which inter-lesion heterogeneity causes one or few metastatic lesions to progress while the vast majority of the metastatic burden responds to the treatment. Locally ablative treatment of the progressive lesion(s) with radiotherapy, resection or radiofrequency ablation may enable continuation of otherwise effective systemic treatment. Solid data to support this approach, however, is lacking at this moment. Study design The COSMO study is an investigator-initiated single-arm phase 2 study. It is intended to be a multicenter study. Eligibility criteria Patients with MBC and oligoprogression, defined as 1-2 progressive lesions while the majority of the metastatic burden remains stable or in remission, are eligible. Current systemic therapy must be 1st or 2nd line and patients must have responded to this systemic therapy for at least six months prior to the occurence of oligoprogression. The aberrant lesion must be amenable to locally ablative therapy. All eligibility criteria may be found in table 1: eligibility criteria. Aim To investigate efficacy of local ablation of aberrant lesions combined with continuation of the same systemic therapy in patients with oligoprogression of MBC. Primary endpoint: Progression-free survival rate at six months (PFS-6). Secondary endpoints: - PFS - Overall survival - Time to next line of systemic therapy Primary and secondary endpoints will also be stratified by localization of progressive lesion and BC subtype (ER+/HER2- vs. HER2+ vs. TN). - Local control rate of lesion treated with LAT at 12 months - Complications due to LAT - Quality of life - Incidence of visceral crisis Exploratory endpoints: - Biomarkers, including receptor (ER/PR/HER2), PD-L1 and gene expression patterns in biopsies from progressive and responding lesions - Prognostic value of ctDNA at oligoprogression and during the course of treatment Statistical methods An A’hern design was chosen to conduct this study. As null-hypothesis (H0), PFS-6 rate ≤ 25% is set. The alternative hypothesis (H1) is PFS-6-rate ≥ 40%. Hypotheses were set to meet criteria for clinical significance, as stated by experts in the field. Setting one-sided α = 0.05 and a desirable power=95%, 107 evaluable patients are needed. To account for 10% of the patients to be unevaluable, 118 included patients are needed. An early stopping rule for safety is applicable: if out of the first 45 patients ≥4 of these patients have developed visceral crisis, the study will be closed early. Accrual Start: July 2022 Target: 118 patients Estimated accrual time: 2-3 years Further information Corresponding author: c.almekinders@nki.nl Clinicaltrials.gov identifier: NCT05301881 This study is funded by the Maarten van der Weijden foundation. This study was developed during the 21st EORTC/ESMO/AACR workshop on methods in clinical cancer research (MCCR). Table 1. Eligibility criteria. Citation Format: Cornelia AM Almekinders, Tessa G Steenbruggen, Ingrid A. Mandjes, Marta Lopez-Yurda, Monique EMM Bos, Terry G Wiersma, Gabe S. Sonke. COntinue the SaMe systemic therapy after local ablative therapy for Oligoprogression in metastatic breast cancer - the COSMO study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-15-01.

Ionic liquids, the mixture of ionic liquids and their co-solvent with N, N-dimethylformamide as solvents for cellulose using experimental and COSMO study

Efficacy of mixtures of ionic liquids (ILs): 1-butyl-3-methylimidazolium acetate ([BMIM][OAc]) and 1-butyl-3-methylimidazolium thiocyanate ([BMIM][SCN]) with 4:1 mol/mol ratio was investigated to dissolve cellulose and compared with parent ILs. Attempt to reduce the mass transport limitations, viscosity was reduced by adding N, N-dimethylformamide (DMF) as a co-solvent in each system and found that ([BMIM][OAc] + DMF) mixture proved that the addition of a co-solvent enhances cellulose dissolution to 22.3 g per 100 g of solvent which is more than double in [BMIM][OAc] IL. The COSMO analysis study incorporated density functional theory (DFT) calculations which confirmed the experimental results obtained in this study. In addition to the above, a study was also conducted from a thermophysical perspective to confirm the qualitative dissolution. Distilled water was used to regenerate cellulose from the mixtures and characterized using thermogravimetric analysis (TGA), X-ray diffraction (p-XRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR) to confirm the structure identification.

Carbon Capture from Biogas by Deep Eutectic Solvents: A COSMO Study to Evaluate the Effect of Impurities on Solubility and Selectivity

Deep eutectic solvents (DES) are compounds of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) that contain a depressed melting point compared to their individual constituents. DES have been studied for their use as carbon capture media and biogas upgrading. However, contaminants’ presence in biogas might affect the carbon capture by DES. In this study, conductor-like screening model for real solvents (COSMO-RS) was used to determine the effect of temperature, pressure, and selective contaminants on five DES’ namely, choline chloride-urea, choline chloride-ethylene glycol, tetra butyl ammonium chloride-ethylene glycol, tetra butyl ammonium bromide-decanoic acid, and tetra octyl ammonium chloride-decanoic acid. Impurities studied in this paper are hydrogen sulfide, ammonia, water, nitrogen, octamethyltrisiloxane, and decamethylcyclopentasiloxane. At infinite dilution, CO2 solubility dependence upon temperature in each DES was examined by means of Henry’s Law constants. Next, the systems were modeled from infinite dilution to equilibrium using the modified Raoults’ Law, where CO2 solubility dependence upon pressure was examined. Finally, solubility of CO2 and CH4 in the various DES were explored with the presence of varying mole percent of selective contaminants. Among the parameters studied, it was found that the HBD of the solvent is the most determinant factor for the effectiveness of CO2 solubility. Other factors affecting the solubility are alkyl chain length of the HBA, the associated halogen, and the resulting polarity of the DES. It was also found that choline chloride-urea is the most selective to CO2, but has the lowest CO2 solubility, and is the most polar among other solvents. On the other hand, tetraoctylammonium chloride-decanoic acid is the least selective, has the highest maximum CO2 solubility, is the least polar, and is the least affected by its environment.

Overall Survival in Metastatic Breast Cancer Patients in the Third Millennium: Results of the COSMO Study

IntroductionMetastatic breast cancer (MBC) is a life-threatening disease, and although some data suggest a trend in survival improvement, it has not yet been unequivocally demonstrated. This study aimed to evaluate the overall survival (OS) of MBC patients, assessing its correlation with prognostic factors. Patients and MethodsCOSMO (Checking Overall Survival in a MBC Observational study) is an Italian longitudinal retrospective multicenter study that enrolled patients with MBC diagnosed between 2000 and 2008. The primary objective was to detect a temporal difference in OS; the secondary objective was to identify prognostic factors as causal factors of the temporal variation in OS. ResultsA total of 3721 of 3930 patients from 31 centers were distributed in 3 periods: 886 (23.8%), 1302 (35.0%), and 1533 (41.2%) in 2000-2002, 2003-2005, and 2006-2008, respectively. With a median follow-up of 9.3 years, median OS was 2.8 years (95% confidence interval, 2.6-2.9). No difference in OS was found in the 3 cohorts (P for trend = .563). The worst prognosis was observed for patients with triple-negative MBC (OS, 1.5 years) and for those with central nervous system metastases (1.7 years); the best prognosis was observed in those with bone metastases or nonvisceral disease (3.4 and 3.2 years, respectively) and in patients with a disease-free interval, defined as the time between resection of the primary malignancy and diagnosis of MBC, of > 2 years (3 years). ConclusionsThe COSMO study found improvement in OS between 2000 and 2008. Molecular subtype remained the strongest prognostic factor, and the role of other prognostic factors was confirmed, in particular disease-free interval, site of metastasis, and age.

Psychomorbidity, Resilience, and Exacerbating and Protective Factors During the SARS-CoV-2 Pandemic.

The SARS-CoV-2 pandemic has caused mental stress in a number of ways: overstrain of the health care system, lockdown of the economy, restricted opportunities for interpersonal contact and excursions outside the home and workplace, and quarantine measures where necessary. In this article, we provide an overview of psychological distress in the current pandemic, identifying protective factors and risk factors. The PubMed, PsycINFO, and Web of Science databases were systematically searched for relevant publications (1 January 2019 - 16 April 2020). This study was registered in OSF Registries (osf.io/34j8g). Data on mental stress and resilience in Germany were obtained from three surveys carried out on more than 1000 participants each in the framework of the COSMO study (24 March, 31 March, and 21 April 2020). 18 studies from China and India, with a total of 79 664 participants, revealed increased stress in the general population, with manifestations of depression and anxiety, post-traumatic stress, and sleep disturbances. Stress was more marked among persons working in the health care sector. Risk factors for stress included patient contact, female sex, impaired health status, worry about family members and significant others, and poor sleep quality. Protective factors included being informed about the increasing number of persons who have recovered from COVID, social support, and a lower perceived infectious risk. The COSMO study, though based on an insufficiently representative population sample because of a low questionnaire return rate (<20%), revealed increased rates of despondency, loneliness, and hopelessness in the German population as compared to norm data, with no change in estimated resilience. Stress factors associated with the current pandemic probably increase stress by causing anxiety and depression. Once the protective factors and risk factors have been identified, these can be used to develop psychosocial interventions. The informativeness of the results reported here is limited by the wide variety of instruments used to acquire data and by the insufficiently representative nature of the population samples.

Examining the Association Between Psychiatric Disorders and Cocaine Binges: Results From the COSMO Study.

Although cocaine binges and mental health problems have both been identified as significant risk factors for different health hazards, little is known about the relationship between mental health and cocaine binging. Hence, the aim of this study is to examine the association between psychiatric disorders and cocaine binge. Participants were part of a prospective cohort study of individuals who either smoke or inject cocaine. The dependent variable, namely a cocaine binge within the past month, was defined as the repetitive use of large quantities of cocaine until the individual was unable to access more of the drug or was physically unable to keep using. Psychiatric disorders were assessed using the Composite International Diagnostic Interview and the Diagnostic Interview Schedule questionnaires. Logistic regression models were performed to examine the association between cocaine binging and psychiatric disorders, adjusting for potential confounders. Of the 492 participants, 24.4% reported at least 1 cocaine binging episode during the prior month. Among the study population, 48.0% met the criteria for antisocial personality disorder (ASPD), 45.5% for anxiety disorders, and 28.2% for mood disorders. Participants with ASPD were more likely to binge (adjusted odds ratio 1.73, 95% confidence interval 1.10-2.73), whereas those with a mood disorder were not. The association between anxiety disorders and cocaine binging was significant only in univariate analyses. ASPD increased the odds of reporting cocaine binge in our study population. These results highlight the need for a better understanding of the specific dimensions of ASPD that contribute to the increased risk of unsafe drug use behaviors.

Anxiety disorders as a risk factor for needle sharing among cocaine users: Results from the cosmo study

Anxiety disorders as a risk factor for needle sharing among cocaine users: Results from the cosmo study

Prevalence and correlates of prescription opioid residue injection

BackgroundThere is growing evidence of intravenous administration of prescription opioids (POs) in several countries. Preparation of POs for injection may leave residues in containers and filters used by people who inject drugs and may lead to adverse health outcomes if they are injected. MethodsThis exploratory study used cross-sectional data from the COSMO study, a prospective cohort of out-of-treatment cocaine users carried out in Montréal (Canada) between October 2010 and August 2015. For this analysis, only one visit per participant was selected, that is, the first time the participant reported PO injection during the study. The outcome of interest, “injection of PO residues”, was defined as having injected PO residues from a filter and/or a container in the last month. Correlates of this outcome were identified using logistic regression analyses. ResultsOf the 122 participants who reported PO injection during the study period, 41.8% had injected PO residues. Reporting an unstable source of income (AOR=4.26; 95% CI: 1.03-17.69), a recent overdose (AOR=5.45; 95% CI: 1.50-19.88) and a preponderant use of opiates (mostly opiate use versus other drugs excluding alcohol and cannabis) (AOR=2.46; 95% CI: 1.08-5.63) increased the risk of PO residue injection. The odds of reporting PO residue injection rose by 7% per unit increase in the score of psychological distress (AOR=1.07 per unit increase; 95% CI: 1.01-1.12). ConclusionsThe findings of this study suggest that PO residue injection is associated with markers of vulnerability. Further investigation is needed in order to better understand this understudied drug injection practice.

Anxiety, mood disorders and injection risk behaviors among cocaine users: Results from the COSMO study.

Despite being common among cocaine users, mental health problems and their relationship with HIV and hepatitis C high risk injection behaviors are poorly documented. This study was undertaken to examine the relationships between mood and anxiety disorders and the sharing of drug injection equipment among cocaine users who inject drugs. The sample was drawn from a prospective cohort study and comprised of 387 participants. The outcome of interest was "sharing injection material" in the past 3 months. The presence of mood and anxiety disorders during the past year was assessed using the CIDI questionnaire. Statistical analyses were conducted on baseline data using logistic regression. Most participants were male (84.5%) and were aged 25 or over (92.2%); 43.0% qualified for an anxiety disorder diagnosis and 29.3% for a mood disorder diagnosis. Participants with anxiety disorders were more likely to share needles (Adjusted Odds Ratio [AOR]: 2.13, 95%CI: 1.15-3.96) and other injection material (AOR: 1.81, 95%CI: 1.12-2.92). No significant association was found between mood disorders and sharing behaviors. Primary anxiety disorders but not mood disorders increases injection risk behaviors among cocaine users. These results bring to light another negative outcome of mental health comorbidity in this vulnerable population. This study underlines the need to fine-tune therapeutic approaches targeting specific mental health problems in individuals with cocaine use disorders. Longitudinal studies that assess impulsivity and other correlates of psychiatric disorders are needed to examine underlying mechanisms of high risk injection behaviors in comorbid populations.

Psychological Distress Increases Needle Sharing among Cocaine users: Results from the COSMO Study

Objective: Cocaine use and mental health disorders have both been separately identified as risk factors for blood borne virus infection. However, the contribution of specific underlying aspects of mental health to risks is not well documented. The aim of this study was to examine the association between psychological distress and risk behaviors for HIV and Hepatitis C infection among cocaine users. Methods: Individuals who either smoked or injected cocaine were recruited in community-based and addiction treatment programs located in downtown Montreal. Participants were asked to complete an interviewer-administered questionnaire assessing psychological distress based on the Kessler scale (K10). Three-month risk behaviors outcomes included drug injection material sharing (needle, dilution water, cooker, filters, backloading, frontloading or wash), and smoking equipment sharing. Socio-demographic data, severity of cocaine dependence and other substances use information were also collected. Statistical analyses were conducted using logistic regression. Results: Severe psychological distress was reported by 202 (34.3%) out of 589 participants (86.2% male; 76.6% ≥ 30y.o.). The prevalence of sharing was: 14.8% for needles, 24.9% for other injection equipment (378 injectors) and 68.3% for smoking material (508 smokers). Multivariate analysis showed that injectors with severe psychological distress were more likely to report needle sharing (Adjusted Odds Ratio (AOR): 2.1, 95% CI: 1.1-3.8). No significant association was found between K10 score and sharing of other paraphernalia. Conclusion: Severe psychological distress increases the risk of needle sharing, a major risk factor for HIV and HCV infection, but not sharing of other paraphernalia. These results suggest differential psychological mechanisms according to sharing practices. They also support the importance of screening for psychological distress in order to implement adequate preventive interventions aimed at cocaine users.

Observational case-control study of the prevalence of chronic cerebrospinal venousinsufficiency in multiple sclerosis: results from the CoSMo study

Background: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a possible cause ofmultiple sclerosis (MS). Objectives: The CoSMo study evaluated the association between CCSVI and MS. Methods: The primary end-point of this multicentric, case-control study was to compare the prevalence ofCCSVI between patients with MS, patients with other neurodegenerative diseases (ONDs) and healthycontrols (HCs). Color-coded duplex sonography was performed by a sonologist and the images were sentto one of three central sonologists for a second reading. Agreement between local and centralsonologists or, in case of disagreement, the predominant judgment among the three central readers,was required for a diagnosis of CCSVI. All readings, data collection and analysis were blinded. Results: The study involved 35 MS centers across Italy and included 1874 subjects aged 18–55. 1767 (94%)were evaluable: 1165 MS patients, 226 patients with ONDs and 376 HCs. CCSVI prevalence was 3.26%,3.10% and 2.13% for the MS, OND and HC groups, respectively. No significant difference in CCSVIprevalence was found amongst the three cohorts (MS versus HC, OR = 1.55, 95%CI = 0.72–3.36,p = 0.30; OND versus HC, OR = 1.47, 95%CI = 0.53–4.11, p = 0.46;MS versus OND, OR = 1.05, 95%CI = 0.47–2.39, p = 0.99). High negative and lowpositive agreement was found between the local and centralized readers. Conclusions: CCSVI is not associated with MS.

Italian multicentre observational study of the prevalence of CCSVI in multiple sclerosis (CoSMo study): rationale, design, and methodology

Chronic cerebro-spinal venous insufficiency (CCSVI) has been proposed as a “congenital malformation” implicated in the pathogenesis of multiple sclerosis (MS). However, numerous studies failed to confirm its presence in MS patients. This paper presents the rationale, design, and methodology adopted in the CoSMo study, conducted with the aim of verifying whether or not CCSVI is linked to MS. The primary endpoint of the CoSMo study is to compare the prevalence of CCSVI in patients with MS versus patients affected by other neurodegenerative diseases (OND) and healthy volunteers. CoSMo is a multicenter, blinded, prevalence study recruiting 2,000 adult subjects, involving 43 MS centers across Italy. Assessment of the presence or absence of CCSVI is performed by color-coded duplex (CCD) sonography and two out of the five criteria according to Zamboni are necessary for the diagnosis of CCSVI. Local CCD examination carried out by a certified sonologist and the central image readings performed by experts in the field are blinded. An advanced protocol is also described in this paper. The application of a rigorous methodological design will definitively confirm whether an association exists between CCSVI and MS. Should an association be observed, this study also further examines the link between CCSVI and the severity of MS. The addition of subgroups without MS and OND also provides information on whether CCSVI is specific to MS only. Results from the CoSMo study will play a crucial role in the possible studies concerning the potential treatment of CCSVI in MS.