Busulfan, melphalan and carfilzomib high-dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

Treating Acquired Factor VIII Inhibitor and Tumor-Induced Hypoglycemia in a Case of Relapsed Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLCBL) is a heterogenous disease, with many phenotypic subtypes and occasional paraneoplastic syndromes being present. Herein, we describe a case of a 63-year-old woman, with relapsed/refractory DLBCL (RR-DLBCL) with artifactual hypoglycemia on laboratory testing, likely related to the mechanical effects of a new factor VIII inhibitor. We demonstrate our workup, consideration, treatment, and her clinical course. This patient did not present with a bleeding phenotype despite her aberrant laboratory results, and therefore determining her risk of bleeding to weigh against further diagnostic procedures presented a difficult decision. We utilized rotational thromboelastometry (ROTEM) to assist with clinical decision making regarding her paraneoplastic factor VIII inhibitor and the patient's bleeding risk. This led to a short course of dexamethasone. Her ROTEM improved, and an excisional biopsy was performed without any bleeding. To our knowledge, this is the only reported instance where this technology was utilized in this setting. We believe utilizing ROTEM to determine bleeding risk may be a beneficial tool for clinical practice in such additional rare cases.

Robotic Autonomy for Magnetic Endoscope Biopsy.

Magnetically actuated endoscopes are currently transitioning in to clinical use for procedures such as colonoscopy, presenting numerous benefits over their conventional counterparts. Intelligent and easy-to-use control strategies are an essential part of their clinical effectiveness due to the un-intuitive nature of magnetic field interaction. However, work on developing intelligent control for these devices has mainly been focused on general purpose endoscope navigation. In this work, we investigate the use of autonomous robotic control for magnetic colonoscope intervention via biopsy, another major component of clinical viability. We have developed control strategies with varying levels of robotic autonomy, including semi-autonomous routines for identifying and performing targeted biopsy, as well as random quadrant biopsy. We present and compare the performance of these approaches to magnetic endoscope biopsy against the use of a standard flexible endoscope on bench-top using a colonoscopy training simulator and silicone colon model. The semi-autonomous routines for targeted and random quadrant biopsy were shown to reduce user workload with comparable times to using a standard flexible endoscope.

ACE Inhibitor Induced Isolated Angioedema of the Small Bowel: A Rare Complication of a Common Medication.

Angioedema is a subcutaneous or submucosal tissue swelling due to capillary leakage and transudation of fluid into the interstitial tissue. It can be localized or generalized as part of a widespread reaction known as anaphylaxis. Millions of people in United States and all over the world receive ACEI antihypertensive therapy. ACEI is known to cause angioedema with an incidence of 0.7 percent. We present a case of 40-year-old female who was started on lisinopril three days prior to presentation for newly diagnosed hypertension. She presented with nonspecific severe abdominal pain, nausea, and vomiting. She denied having difficulty breathing or swelling anywhere in the body. On exam, she did not have facial, lip, tongue, or throat swelling. Her abdomen was tender without guarding or rigidity. Laboratory examination was unrevealing except for mild leukocytosis. Computed tomography scan (CT scan) of the abdomen with oral and IV contrast revealed a moderate amount of ascites with diffuse wall thickening, hyperenhancement, and mucosal edema of the entire small bowel. In the absence of any other pathology, matching history, and imaging findings highly suggestive of angioedema, she was diagnosed with isolated small bowel angioedema as a result of ACEI therapy. She was managed conservatively, and lisinopril was discontinued. A week later on follow-up, all her symptoms had resolved, and repeat CT scan showed resolution of all findings.

Circular dumbbell miR-34a-3p and -5p suppresses pancreatic tumor cell-induced angiogenesis and activates macrophages.

Angiogenesis is a tightly regulated biological process by which new blood vessels are formed from pre-existing blood vessels. This process is also critical in diseases such as cancer. Therefore, angiogenesis has been explored as a drug target for cancer therapy. The future of effective anti-angiogenic therapy lies in the intelligent combination of multiple targeting agents with novel modes of delivery to maximize therapeutic effects. Therefore, a novel approach is proposed that utilizes dumbbell RNA (dbRNA) to target pathological angiogenesis by simultaneously targeting multiple molecules and processes that contribute to angiogenesis. In the present study, a plasmid expressing miR-34a-3p and -5p dbRNA (db34a) was constructed using the permuted intron-exon method. A simple protocol to purify dbRNA from bacterial culture with high purity was also developed by modification of the RNASwift method. To test the efficacy of db34a, pancreatic cancer cell lines PANC-1 and MIA PaCa-2 were used. Functional validation of the effect of db34a on angiogenesis was performed on human umbilical vein endothelial cells using a tube formation assay, in which cells transfected with db34a exhibited a significant reduction in tube formation compared with cells transfected with scrambled dbRNA. These results were further validated in vivo using a zebrafish angiogenesis model. In conclusion, the present study demonstrates an approach for blocking angiogenesis using db34a. The data also show that this approach may be used to targeting multiple molecules and pathways.

Celiac Disease in an Adult Presenting as Behavioral Disturbances.

BACKGROUND Celiac disease is very common, with some estimates placing the prevalence at approximately 1: 300 worldwide. Typified by autoimmune degradation of the duodenal brush border due to reactivity with dietary gluten, causing malabsorption, it classically presents with both gastrointestinal and extra-intestinal symptoms. Gastrointestinal symptoms commonly include diarrhea, constipation, foul steatorrhea, flatulence, and bloating. With increased awareness and availability of testing, it is rare that a patient would present with celiac crisis, which is a syndrome of profuse diarrhea and severe metabolic/nutritional disturbances. In children, interestingly, celiac disease can present primarily as behavioral disturbance, such as increased aggression or anxiety, with milder or absent gastrointestinal symptoms. CASE REPORT A 25-year-old man with a history of schizophrenia and autism spectrum disorder presented for behavioral disturbance after breaking into a neighbor's house to eat food. He also reported several months of diarrhea and fecal incontinence and was noted to have severe malnutrition on exam, despite dramatic food intake. Tissue transglutaminase IgA antibody (TTG) and gliadin IgA were highly suggestive of celiac disease, which was confirmed by biopsy. He was started on a lactose-free and gluten-free diet, and required a short course of total parenteral nutrition (TPN) for nutritional resuscitation. He improved rapidly with this intervention, and returned to nutritional and behavioral baseline. CONCLUSIONS We report a unique case in which an adult with psychiatric comorbidities presented with predominantly behavioral disturbances, a more common presentation in children with the disorder. These patients may present in an atypical fashion, and the clinician should have a high index of suspicion.

Enabling the future of colonoscopy with intelligent and autonomous magnetic manipulation.

Early diagnosis of colorectal cancer significantly improves survival. However, over half of cases are diagnosed late due to demand exceeding the capacity for colonoscopy - the "gold standard" for screening. Colonoscopy is limited by the outdated design of conventional endoscopes, associated with high complexity of use, cost and pain. Magnetic endoscopes represent a promising alternative, overcoming drawbacks of pain and cost, but struggle to reach the translational stage as magnetic manipulation is complex and unintuitive. In this work, we use machine vision to develop intelligent and autonomous control of a magnetic endoscope, for the first time enabling non-expert users to effectively perform magnetic colonoscopy in-vivo. We combine the use of robotics, computer vision and advanced control to offer an intuitive and effective endoscopic system. Moreover, we define the characteristics required to achieve autonomy in robotic endoscopy. The paradigm described here can be adopted in a variety of applications where navigation in unstructured environments is required, such as catheters, pancreatic endoscopy, bronchoscopy, and gastroscopy. This work brings alternative endoscopic technologies closer to the translational stage, increasing availability of early-stage cancer treatments.

Multiple Drug-Resistant CLABSI from an Extremely Rare Bacterium, Chryseobacterium gleum.

Chryseobacterium gleum is a lactose nonfermenting Gram-negative bacillus (NFGNB) found in soil, plants, and some water sources but rarely implicated as a human pathogen. Its scarcity in the medical literature and resistance to numerous broad-spectrum antibiotics such as carbapenems, cephalosporins, and beta-lactam/lactamase inhibitors pose a diagnostic and therapeutic challenge. We present the first reported case, to the best of our knowledge, of sepsis from central line-associated blood stream infection from Chryseobacterium gleum in the United States.

Macro-Scale Tread Patterns for Traction in the Intestine.

GOAL: Tread patterns are widely used to increase traction on different substrates, with the tread scale, geometry and material being tailored to the application. This work explores the efficacy of using macro-scale tread patterns for a medical application involving a colon substrate - renowned for its low friction characteristics. METHODS: Current literature was first summarized before an experimental approach was used, based on a custom test rig with ex vivo porcine colon, to assess different macro-scale tread patterns. Performance was based on increasing traction while avoiding significant trauma. Repeated testing (n = 16) was used to obtain robust results. RESULTS: A macro-scale tread pattern can increase the traction coefficient significantly, with a static traction coefficient of 0.74 ± 0.22 and a dynamic traction coefficient of 0.35 ± 0.04 compared to a smooth (on the macro-scale) Control (0.132 ± 0.055 and 0.054 ± 0.015, respectively). Decreasing the scale and spacing between the tread features reduced apparent trauma but also reduced the traction coefficient. CONCLUSION: Significant traction can be achieved on colon tissue using a macro-scale tread but a compromise between traction (large feature sizes) and trauma (small feature sizes) may have to be made. SIGNIFICANCE: This work provides greater insight into the complex frictional mechanisms of the intestine and gives suggestions for developing functional tread surfaces for a wide range of clinical applications.

Adaptive Dynamic Control for Magnetically Actuated Medical Robots.

In the present work we discuss a novel dynamic control approach for magnetically actuated robots, by proposing an adaptive control technique, robust towards parametric uncertainties and unknown bounded disturbances. The former generally arise due to partial knowledge of the robots' dynamic parameters, such as inertial factors, the latter are the outcome of unpredictable interaction with unstructured environments. In order to show the application of the proposed approach, we consider controlling the Magnetic Flexible Endoscope (MFE) which is composed of a soft-tethered Internal Permanent Magnet (IPM), actuated with a single External Permanent Magnet (EPM). We provide with experimental analysis to show the possibility of levitating the MFE - one of the most difficult tasks with this platform - in case of partial knowledge of the IPM's dynamics and no knowledge of the tether's behaviour. Experiments in an acrylic tube show a reduction of contact of the 32% compared to non-levitating techniques and 1.75 times faster task completion with respect to previously proposed levitating techniques. More realistic experiments, performed in a colon phantom, show that levitating the capsule achieves faster and smoother exploration and that the minimum time for completing the task is attained by the proposed approach.

Intelligent magnetic manipulation for gastrointestinal ultrasound.

Diagnostic endoscopy in the gastrointestinal tract has remained largely unchanged for decades and is limited to the visualization of the tissue surface, the collection of biopsy samples for diagnoses, and minor interventions such as clipping or tissue removal. In this work, we present the autonomous servoing of a magnetic capsule robot for in-situ, subsurface diagnostics of microanatomy. We investigated and showed the feasibility of closed-loop magnetic control using digitized microultrasound (µUS) feedback; this is crucial for obtaining robust imaging in an unknown and unconstrained environment. We demonstrated the functionality of an autonomous servoing algorithm that uses µUS feedback, both on benchtop trials as well as in-vivo in a porcine model. We have validated this magnetic-µUS servoing in instances of autonomous linear probe motion and were able to locate markers in an agar phantom with 1.0 ± 0.9 mm position accuracy using a fusion of robot localization and µUS image information. This work demonstrates the feasibility of closed-loop robotic µUS imaging in the bowel without the need for either a rigid physical link between the transducer and extracorporeal tools or complex manual manipulation.

Magnetic Levitation for Soft-Tethered Capsule Colonoscopy Actuated With a Single Permanent Magnet: A Dynamic Control Approach.

The present letter investigates a novel control approach for magnetically driven soft-tethered capsules for colonoscopy-a potentially painless approach for colon inspection. The focus of this work is on a class of devices composed of a magnetic capsule endoscope actuated by a single external permanent magnet. Actuation is achieved by manipulating the external magnet with a serial manipulator, which in turn produces forces and torques on the internal magnetic capsule. We propose a control strategy which, counteracting gravity, achieves levitation of the capsule. This technique, based on a nonlinear backstepping approach, is able to limit contact with the colon walls, reducing friction, avoiding contact with internal folds, and facilitating the inspection of nonplanar cavities. The approach is validated on an experimental setup, which embodies a general scenario faced in colonoscopy. The experiments show that we can attain 19.5% of contact with the colon wall, compared to the almost 100% of previously proposed approaches. Moreover, we show that the control can be used to navigate the capsule through a more realistic environment-a colon phantom-with reasonable completion time.

Explicit Model Predictive Control of a Magnetic Flexible Endoscope.

In this paper, explicit model predictive control is applied in conjunction with nonlinear optimisation to a magnetically actuated flexible endoscope for the first time. The approach is aimed at computing the motion of the external permanent magnet, given the desired forces and torques. The strategy described here takes advantage of the nonlinear nature of the magnetic actuation and explicitly considers the workspace boundaries, as well as the actuation constraints. Initially, a simplified dynamic model of the tethered capsule, based on the Euler-Lagrange equations is developed. Subsequently, the explicit model predictive control is described and a novel approach for the external magnet positioning, based on a single step, nonlinear optimisation routine, is proposed. Finally, the strategy is implemented on the experimental platform, where bench-top trials are performed on a realistic colon phantom, showing the effectiveness of the technique. The work presented here constitutes an initial exploration for model-based control techniques applied to magnetically manipulated payloads, the techniques described here may be applied to a wide range of devices, including flexible endoscopes and wireless capsules. To our knowledge, this is the first example of advanced closed loop control of magnetic capsules.

Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation.

Immune-mediated colitis is an uncommon but well-documented adverse event in patients receiving nivolumab or ipilimumab therapy. In this report, we present a 69-year-old man who developed severe hypokalemia and colitis with significant corrected Q-T segment (QTc) prolongation as a result of combination nivolumab-ipilimumab immunotherapy for clear cell renal cell carcinoma.

New Immunotherapies in Oncology Treatment and Their Side Effect Profiles.

BACKGROUND: Immunotherapies in cancer treatment have a long history going all the way back to the very beginning of the field, and recent advances are extremely promising. These therapies are becoming a larger part in many patients' oncology treatment as the number of approaches, individual medicines, and indications increase. Furthermore, these novel therapies have different side effect profiles from those traditional chemotherapies which have, until recently, typified the oncologist's approach to treatment together with surgery and radiation. METHODS: An electronic literature search was conducted in May and June 2017 and March 2018 with the PubMed and Ebscohost databases. Articles were chosen for their relevance to the drugs in question, cancer physiology, or historic significance. CONCLUSIONS: Checkpoint inhibitors are becoming very common and possess autoimmune side effects such as pneumonitis, hypothyroidism, and colitis. These may present at any time the patient is on the medications but are more common several weeks to several months from beginning therapy. Chimeric antigen receptor T-cell therapies are powerful but have strong side effects such as cytokine release syndrome. Neoantigens are currently in the early stages of clinical trials and may become an exciting avenue for personalized cancer treatment but are not yet typical.

Steric control of the donor/acceptor interface: implications in organic photovoltaic charge generation.

The performance of organic photovoltaic (OPV) devices is currently limited by modest short-circuit current densities. Approaches toward improving this output parameter may provide new avenues to advance OPV technologies and the basic science of charge transfer in organic semiconductors. This work highlights how steric control of the charge separation interface can be effectively tuned in OPV devices. By introducing an octylphenyl substituent onto the investigated polymer backbones, the thermally relaxed charge-transfer state, and potentially excited charge-transfer states, can be raised in energy. This decreases the barrier to charge separation and results in increased photocurrent generation. This finding is of particular significance for nonfullerene OPVs, which have many potential advantages such as tunable energy levels and spectral breadth, but are prone to poor exciton separation efficiencies. Computational, spectroscopic, and synthetic methods were combined to develop a structure-property relationship that correlates polymer substituents with charge-transfer state energies and, ultimately, device efficiencies.

Molecular understanding of organic solar cells: the challenges.

Our objective in this Account is 3-fold. First, we provide an overview of the optical and electronic processes that take place in a solid-state organic solar cell, which we define as a cell in which the semiconducting materials between the electrodes are organic, be them polymers, oligomers, or small molecules; this discussion is also meant to set the conceptual framework in which many of the contributions to this Special Issue on Photovoltaics can be viewed. We successively turn our attention to (i) optical absorption and exciton formation, (ii) exciton migration to the donor-acceptor interface, (iii) exciton dissociation into charge carriers, resulting in the appearance of holes in the donor and electrons in the acceptor, (iv) charge-carrier mobility, and (v) charge collection at the electrodes. For each of these processes, we also describe the theoretical challenges that need to be overcome to gain a comprehensive understanding at the molecular level. Finally, we highlight recent theoretical advances, in particular regarding the determination of the energetics and dynamics at organic-organic interfaces, and underline that the right balance needs to be found for the optimization of material parameters that often result in opposite effects on the photovoltaic performance.

Polarization energies in oligoacene semiconductor crystals.

Characterization of the electronically polarized environment and the nuclear relaxation that accompanies charge carriers is fundamental to charge transport in crystalline, polycrystalline, and amorphous organic solids. To study the polarization effects of localized charged carriers, we use quantum/classical QM/MM approaches with charge redistribution and polarizable force field schemes and apply them to crystals of naphthalene through pentacene. We describe the results of a comprehensive investigation of the electronic polarization energies in molecular crystal structures of these oligoacenes and discuss as well the evolution of the nuclear relaxation energies calculated for model oligoacene systems.

Experimental and theoretical study of temperature dependent exciton delocalization and relaxation in anthracene thin films.

The spectroscopy of solid anthracene is examined both experimentally and theoretically. To avoid experimental complications such as self-absorption and polariton effects, ultrathin polycrystalline films deposited on transparent substrates are studied. To separate the contributions from different emitting species, the emission is resolved in both time and wavelength. The spectroscopic data are interpreted in terms of a three-state kinetic model, where two excited states, a high energy state 1 and a low energy state 2, both contribute to the luminescence and are kinetically coupled. Using this model, we analyze the spectral lineshape, relative quantum yield, and relaxation rates as a function of temperature. For state 1, we find that the ratio of the 0-0 vibronic peak to the 0-1 peak is enhanced by roughly a factor of 3.5 at low temperature, while the quantum yield and decay rates also increase by a similar factor. These observations are explained using a theoretical model previously developed for herringbone polyacene crystals. The early-time emission lineshape is consistent with that expected for a linear aggregate corresponding to an edge-dislocation defect. The results of experiment and theory are quantitatively compared at different temperatures in order to estimate that the singlet exciton in our polycrystalline films is delocalized over about ten molecules. Within these domains, the exciton's coherence length steadily increases as the temperature drops, until it reaches the limits of the domain, whereupon it saturates and remains constant as the temperature is lowered further. While the theoretical modeling correctly reproduces the temperature dependence of the fluorescence spectral lineshape, the decay of the singlet exciton appears to be determined by a trapping process that becomes more rapid as the temperature is lowered. This more rapid decay is consistent with accelerated trapping due to increased delocalization of the exciton at lower temperatures. These observations suggest that exciton coherence can play an important role in both radiative and nonradiative decay channels in these materials. Our results show that the spectroscopy of polyacene solids can be analyzed in a self-consistent fashion to obtain information about electronic delocalization and domain sizes.