Citations

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti–programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.

AbstractBackgroundAn increasing demand of minimally‐invasive aesthetic procedures of the forehead concomitantly leads to higher numbers of adverse events. Adequate application of anatomical knowledge is required to increase safety and efficacy of different minimally‐invasive aesthetic procedures in this anatomical region.ObjectiveTo describe the layered anatomy of the forehead soft tissues with respect to their thicknesses and how they relate to different minimally‐invasive aesthetic treatments.MethodsA total of n = 85 healthy study participants (69 females and 16 males) with a mean age of 40.84 ± 10.9 years and a mean body mass index of 22.65 ± 2.6 kg/m2 were investigated with ultrasound‐based imaging to measure the thickness of different forehead soft tissues.ResultsThe mean overall soft tissue thickness of the forehead was measured to be 4.18 ± 0.7 mm for the entire study population. Increasing BMI values correlated statistically significantly with increasing thickness of all measured forehead soft tissues with exception of the frontalis muscle. On a statistically significant level, males showed thicker forehead soft tissues than females, with exception of the retrofrontalis fat and the frontalis muscle.ConclusionOn basis of the findings obtained in this study, basic treatment principles can be derived and improved for the injection of neuromodulators, hyaluronic acid as well as the application of polydiaxonane (PDO) threads and micro‐focused ultrasound. Precise knowledge and thorough understanding of the layers and soft tissues of the forehead is required to guarantee safe and effective procedures in this aesthetically important facial region.

Although great improvements have been achieved in the fields of diagnosing and treating patients with giant-cell arteritis (GCA) in the last decades, several questions remain unanswered. The progressive increase in the number of older people, together with growing awareness of the disease and use of advanced diagnostic tools by healthcare professionals, foretells a possible increase in both prevalence and number of newly diagnosed patients with GCA in the coming years. A thorough clarification of pathogenetic mechanisms and a better definition of clinical subsets are the first steps toward a better understanding of the disease and, subsequently, toward a better use of existing and future therapeutic options. Examination of the role of different imaging techniques for GCA diagnosing and monitoring, optimization, and personalization of glucocorticoids and other immunosuppressive agents, further development and introduction of novel drugs, identification of prognostic factors for long-term outcomes and management of treatment discontinuation will be the central topics of the research agenda in years to come.

Acute ischemic stroke is a critical condition that can result in disability and death. The consequences of this medical condition depend on various factors, including the size of the stroke, affected brain region, treatment onset, and the type of treatment. The primary objective of stroke treatment is to restart ischemic penumbra tissue perfusion and reduce infarct volume by sustaining blood flow. Recent research on the condition’s pathological pathways and processes has significantly improved treatment options beyond restoring perfusion. Many studies have concentrated on limiting injury severity via the manipulation of molecular mechanisms of ischemia, particularly in animal research. This article reviews completed and ongoing research on the development of acute ischemic stroke drugs. This study focuses on three main categories of antithrombotic drugs, thrombolytic drugs, and neuroprotective agents. The paper outlines findings from animal and clinical trials and explores the working mechanisms of these drugs.

Objective Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache. Methods Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points. Results After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14–67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia. Conclusion Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

Patients with delayed and normal gastric emptying (GE) had similar symptom profiles during gastric emptying scintigraphy (GES). Idiopathic patients with symptoms of gastroparesis had less gastric retention by GES; but more symptoms after GES meal and after water load satiety test (WLST) compared with diabetic patients. In patients with symptoms of gastroparesis, symptoms after WLST increased with decreasing water consumption. Early satiety and loss of appetite were associated with decreased water consumption during WLST. Thus, impaired accommodation and perhaps visceral hypersensitivity are important in explaining postprandial symptoms in gastroparesis.

This clinical case report describes surgical management of a giant left ventricular fibroma and postoperative venoarterial extracorporeal membrane oxygenation support in a newborn male. Transthoracic echocardiography performed at 9-month follow-up showed an ejection fraction of 33% and a cardiac index of 4.5 liters per minute per square meter.

Accurate and precise monitoring of kidney function is critical for a timely and reliable diagnosis of chronic kidney disease (CKD). The determination of kidney function usually involves the estimation of the glomerular filtration rate (eGFR). We recently reported the clinical performance of a new eGFR equation (GFRNMR) based on the nuclear magnetic resonance (NMR) measurement of serum myo-inositol, valine, and creatinine, in addition to the immunoturbidometric quantification of serum cystatin C, age and sex. We now describe the analytical performance evaluation of GFRNMR according to the Clinical and Laboratory Standards Institute guidelines. Within-laboratory coefficients of variation (CV%) of the GFRNMR equation did not exceed 4.3%, with a maximum CV% for repeatability of 3.7%. Between-site reproducibility (three sites) demonstrated a maximum CV% of 5.9%. GFRNMR stability was demonstrated for sera stored for up to 8 days at 2–10°C and for NMR samples stored for up to 10 days in the NMR device at 6 ± 2°C. Substance interference was limited to 4/40 (10.0%) of the investigated substances, resulting in an underestimated GFRNMR (for glucose and metformin) or a loss of results (for naproxen and ribavirin) for concentrations twice as high as usual clinical doses. The analytical performances of GFRNMR, combined with its previously reported clinical performance, support the potential integration of this NMR method into clinical practice.