Clinical Outcomes of Immune Checkpoint Inhibitors in Unique Cohorts Underrepresented in Clinical Trials.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

BACKGROUND: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. METHODS: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. RESULTS: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01). CONCLUSIONS: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

The Risk of Opportunistic Infections and the Role of Antibiotic Prophylaxis in Patients on Checkpoint Inhibitors Requiring Steroids.

BACKGROUND: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs. METHODS: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs. RESULTS: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs. CONCLUSIONS: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.

Enhancing the REMBRANDT MRI collection with expert segmentation labels and quantitative radiomic features.

Malignancy of the brain and CNS is unfortunately a common diagnosis. A large subset of these lesions tends to be high grade tumors which portend poor prognoses and low survival rates, and are estimated to be the tenth leading cause of death worldwide. The complex nature of the brain tissue environment in which these lesions arise offers a rich opportunity for translational research. Magnetic Resonance Imaging (MRI) can provide a comprehensive view of the abnormal regions in the brain, therefore, its applications in the translational brain cancer research is considered essential for the diagnosis and monitoring of disease. Recent years has seen rapid growth in the field of radiogenomics, especially in cancer, and scientists have been able to successfully integrate the quantitative data extracted from medical images (also known as radiomics) with genomics to answer new and clinically relevant questions. In this paper, we took raw MRI scans from the REMBRANDT data collection from public domain, and performed volumetric segmentation to identify subregions of the brain. Radiomic features were then extracted to represent the MRIs in a quantitative yet summarized format. This resulting dataset now enables further biomedical and integrative data analysis, and is being made public via the NeuroImaging Tools & Resources Collaboratory (NITRC) repository ( https://www.nitrc.org/projects/rembrandt_brain/ ).

SPRD: a surface plasmon resonance database of common factors for better experimental planning.

BACKGROUND: Surface plasmon resonance is a label-free biophysical technique that is widely used in investigating biomolecular interactions, including protein-protein, protein-DNA, and protein-small molecule binding. Surface plasmon resonance is a very powerful tool in different stages of small molecule drug development and antibody characterization. Both academic institutions and pharmaceutical industry extensively utilize this method for screening and validation studies involving direct molecular interactions. In most applications of the surface plasmon resonance technology, one of the studied molecules is immobilized on a microchip, while the second molecule is delivered through a microfluidic system over the immobilized molecules. Changes in total mass on the chip surface is recorded in real time as an indicator of the molecular interactions. MAIN BODY: Quality and accuracy of the surface plasmon resonance data depend on experimental variables, including buffer composition, type of sensor chip, coupling chemistry of molecules on the sensor surface, and surface regeneration conditions. These technical details are generally included in materials and methods sections of published manuscripts and are not easily accessible using the common internet browser search engines or PubMed. Herein, we introduce a surface plasmon resonance database, www.sprdatabase.info that contains technical details extracted from 5140 publications with surface plasmon resonance data. We also provide an analysis of experimental conditions preferred by different laboratories. These experimental variables can be searched within the database and help future users of this technology to design better experiments. CONCLUSION: Amine coupling and CM5 chips were the most common methods used for immobilizing proteins in surface plasmon resonance experiments. However, number of different chips, capture methods and buffer conditions were used by multiple investigators. We predict that the database will significantly help the scientific community using this technology and hope that users will provide feedback to improve and expand the database indefinitely. Publicly available information in the database can save a great amount of time and resources by assisting initial optimization and troubleshooting of surface plasmon resonance experiments.

Acoustic and language analysis of speech for suicidal ideation among US veterans.

BACKGROUND: Screening for suicidal ideation in high-risk groups such as U.S. veterans is crucial for early detection and suicide prevention. Currently, screening is based on clinical interviews or self-report measures. Both approaches rely on subjects to disclose their suicidal thoughts. Innovative approaches are necessary to develop objective and clinically applicable assessments. Speech has been investigated as an objective marker to understand various mental states including suicidal ideation. In this work, we developed a machine learning and natural language processing classifier based on speech markers to screen for suicidal ideation in US veterans. METHODOLOGY: Veterans submitted 588 narrative audio recordings via a mobile app in a real-life setting. In addition, participants completed self-report psychiatric scales and questionnaires. Recordings were analyzed to extract voice characteristics including prosodic, phonation, and glottal. The audios were also transcribed to extract textual features for linguistic analysis. We evaluated the acoustic and linguistic features using both statistical significance and ensemble feature selection. We also examined the performance of different machine learning algorithms on multiple combinations of features to classify suicidal and non-suicidal audios. RESULTS: A combined set of 15 acoustic and linguistic features of speech were identified by the ensemble feature selection. Random Forest classifier, using the selected set of features, correctly identified suicidal ideation in veterans with 86% sensitivity, 70% specificity, and an area under the receiver operating characteristic curve (AUC) of 80%. CONCLUSIONS: Speech analysis of audios collected from veterans in everyday life settings using smartphones offers a promising approach for suicidal ideation detection. A machine learning classifier may eventually help clinicians identify and monitor high-risk veterans.

Fractal Structure in Silica and Composites Aerogels.

Silica aerogels are known to be materials with exceptional characteristics, such as ultra-low density, high surface area, high porosity, high adsorption, and low-thermal conductivity. In addition, these unique properties are mainly related to their specific processing. Depending on the aerogel synthesis procedure, the aerogels texture can be tailored with meso and/or macroporosity. Fractal geometry has been observed and used to describe silica aerogels at nanoscales in certain conditions. In this review paper, we describe the fractal structure of silica aerogels that can develop depending on the synthesis conditions. X-ray and neutron scattering measurements allow to show that silica aerogels can exhibit a fractal structure over one or even more than two orders of magnitude in length. The fractal dimension does not depend directly on the material density but can vary with the synthesis conditions. It ranges typically between 1.6 and 2.4. The effect of the introduction of silica particles or of further thermal treatment or compression of the silica aerogels on their microstructure and their fractal characteristics is also resumed.

An Internet-based writing intervention for PTSD in veterans: A feasibility and pilot effectiveness trial.

[Correction Notice: An Erratum for this article was reported in Vol 9(4) of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2016-54154-001). In the article, the names of authors Adil Alaoui and Anas Belouali were misspelled as Adil Aloui and Anas Beloui respectively. All versions of this article have been corrected.] Objective: Veterans suffering from posttraumatic stress disorder (PTSD) may avoid or fail to follow through with a full course of face-to-face mental health treatment for a variety of reasons. We conducted a pilot effectiveness trial of an online intervention for veterans with current PTSD to determine the feasibility, safety, and preliminary effectiveness of an online writing intervention (i.e., Warriors Internet Recovery & EDucation [WIRED]) as an adjunct to face-to-face psychotherapy. Method: Veterans (N = 34) who had served in Iraq or Afghanistan with current PTSD subsequent to deployment-related trauma were randomized to Veterans Affairs (VA) mental health treatment as usual (TAU) or to treatment as usual plus the online intervention (TAU + WIRED). All research participants were recruited from the Trauma Services Program, VA Medical Center, Washington, DC. They completed baseline assessments as well as assessments 12 weeks and 24 weeks after the baseline assessment. The online intervention consisted of therapist-guided writing, using principles of prolonged exposure and cognitive therapy. The intervention was adapted from an evidence-based treatment used in The Netherlands and Germany for individuals who had been exposed to nonmilitary traumas. Results: In addition to showing that the online intervention was both feasible to develop and implement, as well as being safe, the results showed preliminary evidence of the effectiveness of the TAU + WIRED intervention in this patient population, with particular evidence in reducing PTSD symptoms of hyperarousal. Conclusion: With minor modifications to enhance the therapeutic alliance, this intervention should be tested in a larger clinical trial to determine whether this method of online intervention might provide another alternative to face-to-face treatment for veterans with PTSD. (PsycINFO Database Record

[Classic and aggressive Kaposi sarcoma with bone involvement]. / L'atteinte osseuse dans le sarcome de Kaposi classique et agressif: à propos d'un cas.

Classic Kaposi sarcoma is a multifocal rare tumor originating from vascular endothelial cells with progressive evolution and little malignant predisposition. Although Kaposi sarcoma with extensive visceral involvement is sometimes observed among HIV-positive patients, tumor dissemination to visceral lymph nodes in classic SK remains very rare. We report a rare case of aggressive classic Kaposi sarcoma of the hand with a rapid and destructive development.

[Bilateral rupture of the anterior cruciate ligament in a ski player treated with DIDT by arthroscopic surgery in one time]. / Rupture bilatérale du ligament croisé antérieur chez un joueur de ski traitée par une ligamentoplastie DIDT sous arthroscopie en un seul temps opératoire.

We report the case of a 25-year-old patient who suffered a ski accident that causing a serious knees sprain. The patient underwent immobilization by plaster knees. After 12 rehabilitation sessions, good progress was noticed in terms of pain. However, the patient is unstable when walking and a positive Trillat Lachman sign at both knees is observed. MRI of Knees confirmed a bilateral rupture of the anterior cruciate ligament (figures A, B). We conducted a ligament ACL with the DIDT technique on both knees, beginning with the left- side. After the surgery, everything was normal. X-ray controls (face and profile views) of both knees showed a good positioning of implants (figures C, D). Rehabilitation was undertaken the day following the surgery. Six months later, the patient was able to return to sport.

Intertrochanteric fracture non-unions with implant failure of the gamma nail.

Failure of internal fixation of intertrochanteric fracture is associated with delayed union or malunion resulting in persistent pain and diminished function. We report a rare case of implant failure of the gamma nail with intertrochanteric fracture non union treated by DCS plate screw and bone graft.

G-DOC Plus - an integrative bioinformatics platform for precision medicine.

BACKGROUND: G-DOC Plus is a data integration and bioinformatics platform that uses cloud computing and other advanced computational tools to handle a variety of biomedical BIG DATA including gene expression arrays, NGS and medical images so that they can be analyzed in the full context of other omics and clinical information. RESULTS: G-DOC Plus currently holds data from over 10,000 patients selected from private and public resources including Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and the recently added datasets from REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT), caArray studies of lung and colon cancer, ImmPort and the 1000 genomes data sets. The system allows researchers to explore clinical-omic data one sample at a time, as a cohort of samples; or at the level of population, providing the user with a comprehensive view of the data. G-DOC Plus tools have been leveraged in cancer and non-cancer studies for hypothesis generation and validation; biomarker discovery and multi-omics analysis, to explore somatic mutations and cancer MRI images; as well as for training and graduate education in bioinformatics, data and computational sciences. Several of these use cases are described in this paper to demonstrate its multifaceted usability. CONCLUSION: G-DOC Plus can be used to support a variety of user groups in multiple domains to enable hypothesis generation for precision medicine research. The long-term vision of G-DOC Plus is to extend this translational bioinformatics platform to stay current with emerging omics technologies and analysis methods to continue supporting novel hypothesis generation, analysis and validation for integrative biomedical research. By integrating several aspects of the disease and exposing various data elements, such as outpatient lab workup, pathology, radiology, current treatments, molecular signatures and expected outcomes over a web interface, G-DOC Plus will continue to strengthen precision medicine research. G-DOC Plus is available at: https://gdoc.georgetown.edu .