Citations

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org . Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

Abstract Context. —Bioelectronic sensors, which combine microchip and biological components, are an emerging technology in clinical diagnostic testing. An electronic detection platform using DNA biochip technology (eSensor) is under development for molecular diagnostic applications. Owing to the novelty of these devices, demonstrations of their successful use in practical diagnostic applications are limited. Objective. —To assess the performance of the eSensor bioelectronic method in the validation of 6 Epstein-Barr virus–transformed blood lymphocyte cell lines with clinically important mutations for use as sources of genetic material for positive controls in clinical molecular genetic testing. Two cell lines carry mutations in the CFTR gene (cystic fibrosis), and 4 carry mutations in the HFE gene (hereditary hemochromatosis). Design. —Samples from each cell line were sent for genotype determination to 6 different molecular genetic testing facilities, including the laboratory developing the DNA biochips. In addition to the bioelectronic method, at least 3 different molecular diagnostic methods were used in the analysis of each cell line. Detailed data were collected from the DNA biochip output, and the genetic results were compared with those obtained using the more established methods. Results. —We report the successful use of 2 applications of the bioelectronic platform, one for detection of CFTR mutations and the other for detection of HFE mutations. In all cases, the results obtained with the DNA biochip were in concordance with those reported for the other methods. Electronic signal output from the DNA biochips clearly differentiated between mutated and wild-type alleles. This is the first report of the use of the cystic fibrosis detection platform. Conclusions. —Bioelectronic sensors for the detection of disease-causing mutations performed well when used in a “real-life” situation, in this case, a validation study of positive control blood lymphocyte cell lines with mutations of public health importance. This study illustrates the practical potential of emerging bioelectronic DNA detection technologies for use in current molecular diagnostic applications.

AbstractCOVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Abstract Evidence-based medicine asks us to integrate the best available evidence with clinical experience and patient values. In the modern intensive care unit, the primary focus is on complex technology and electronic health records, often away from the bedside. Excess interventionism is the norm. The term “intensivist” itself implies an intensive management strategy, which can lead us away from a patient-centered practice and toward iatrogenic harm. Under the hashtag #zentensivist, an international, multiprofessional group of clinicians has begun to discuss via Twitter how to apply key principles of history taking, physical examination, physiology, pharmacology, and clinical research in a competent, compassionate, and minimalist fashion. The term “zentensivist” intentionally combines concepts seemingly at odds—Zen philosophy and intensive care—to describe a holistic approach to the art of caring for the critically ill. We describe the key tenets of zentensivist practice and how we may inspire these actions in those we lead and educate.

AbstractCIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC‐DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45‐years‐old, range 14‐65) superficial CIC‐rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next‐generation sequencing was positive for CIC‐DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC‐DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow‐up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC‐rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC‐rearranged sarcomas are aggressive.

We hypothesized that adaptations of the rabbit diaphragm (Dia) after unilateral denervation (DNV) result from removal of a neural influence rather than from passive stress. Length changes of midcostal and sternal Dia regions were measured before and after DNV by using sonomicrometry. Midcostal fibers passively lengthened after DNV, whereas sternal fibers shortened. In both regions, these length changes were associated with minimal stress, as estimated from passive force-length relationships. Morphological and contractile adaptions of midcostal and sternal Dia regions were examined after 1 and 4 wk of DNV. In both Dia regions, type I fibers progressively hypertrophied, whereas type IIb fibers atrophied. After DNV, changes in isometric contraction were similar in both Dia regions. Twitch contraction and half-relaxation times increased, force-frequency relationships shifted leftward, and maximum tetanic force decreased. We conclude that passive length changes and mechanical stress are not the main determinants of the morphological and contractile adaptations of the Dia after unilateral DNV but that these adaptations result from DNV itself.

The purpose of the present study was to evaluate the effects of chronic mass loading produced by obesity on the structural and functional characteristics of the diaphragm in lean and obese Zucker rats. The trapezius muscle served as an internal control. The studies were carried out on 17 lean (303 +/- 24 g) and 16 obese (698 +/- 79 g) Zucker rats. We observed that the diaphragms from obese animals were restructured such that the overall contribution of type I and IIa fibers was significantly increased. As a consequence of this remodeling, overall diaphragm thickness was selectively greater in obese animals. In small isolated diaphragm bundles studied in vitro, we also detected a reduction in specific force in obese animals that was not detected in the trapezius muscle. In vitro fatigue resistance, assessed by repeated stimulation, was similar in muscles of lean and obese animals. Diaphragm fiber oxidative capacity (succinate dehydrogenase activity) was also comparable in lean and obese animals. We conclude that in obesity the diaphragm undergoes modest remodeling that may be beneficial in enhancing force generation.

To assess the mechanical role of the expiratory musculature during eupnea, we recorded the electromyographic (EMG) activity of the triangularis sterni, the external oblique, and the transversus abdominis in eight supine lightly anesthetized dogs and have measured the volume generated by the phasic activation of the expiratory muscles. Activation of the expiratory muscles was invariably associated with a decrease in lung volume below the relaxed position of the respiratory system, a volume equal to 41.3 +/- 8.4 ml. This volume represented roughly 20% of tidal volume generated during spontaneous breathing. The fractional expiratory contribution to the tidal volume was unrelated to the size of the animal. Traction on the forelimbs (limb extension), however, tended to enhance the phasic expiratory activation of both the triangularis sterni and the transversus abdominis in the majority of animals. Moreover, after limb extension, the fractional contribution of tidal volume attributed to the phasic activation of the expiratory muscles increased in all but one animal. During spontaneous breathing with the forelimbs extended, roughly 25% of tidal volume was found to be due directly to phasic expiratory muscle contraction. The present observations firmly establish that in supine lightly anesthetized dogs breathing at rest the expiratory component of tidal volume represents a substantial contribution.

The purpose of the present study was to assess the mechanical role of the expiratory muscles during spontaneous breathing in prone animals. The electromyographic (EMG) activity of the triangularis sterni, the rectus abdominis, the external oblique, and the transversus abdominis was studied in 10 dogs light anesthetized with pentobarbital sodium. EMGs were recorded during spontaneous steady-state breathing in supine and prone suspended animals both before and after cervical vagotomy. We also measured the end-expiratory lung volume [functional residual capacity (FRC)] in supine and prone positions to assess the mechanical role of expiratory muscle activation in prone dogs. Spontaneous breathing in the prone posture elicited a significant recruitment of the triangularis sterni, the external oblique, and the transversus abdominis (P less than 0.05). Bilateral cervical vagotomy eliminated the postural activation of the external oblique and the transversus abdominis but not the triangularis sterni. Changes in posture during control and after cervical vagotomy were associated with an increase in FRC. However, changes in FRC, on average, were 132.3 +/- 33.8 (SE) ml larger (P less than 0.01) postvagotomy. We conclude that spontaneous breathing in prone anesthetized dogs is associated with a marked phasic expiratory recruitment of rib cage and abdominal muscles. The present data also indicate that by relaxing at end expiration the expiratory muscles of the abdominal region are directly responsible for generating roughly 40% of the tidal volume.