David Spiegel

Bio: David Spiegel is an academic researcher from Stanford University. The author has contributed to research in topics: Medicine & Breast cancer. The author has an hindex of 106, co-authored 733 publications receiving 46276 citations. Previous affiliations of David Spiegel include Tel Aviv University & University of Adelaide.

De novo EGFR T790M mutations in a community-based oncology practice.

Abstract: 3146 Background: With the 2018 FDA approval of osimertinib for first-line treatment in EGFR-mutated lung cancers, the prevalence of acquired EGFR T790M mutations is expected to decrease, heightening the significance of de novo T790M mutations. Previous studies have reported a wide range of de novo T790M prevalence, and smaller retrospective studies have indicated that germline T790M may comprise the majority of de novo T790M mutations. Here, we assess the frequency of de novo T790M mutations in a community-based setting and report on germline T790M mutations occurring within this population. Methods: Patients with T790M-positive lung cancer were identified using Sarah Cannon’s clinicogenomics database containing information for patients treated within the Sarah Cannon research network. All T790M mutations were detected on tissue- and plasma-based NGS tests delivered as part of routine care. De novo and germline EGFR T790M status was determined via manual electronic health record chart review. When available, allele fraction and %cfDNA values were extracted from the structured NGS report and analyzed separately. Results: Of T790M-positive lung cancers with available pretreatment testing results, 36% (16/44) were confirmed to be T790M+ prior to EGFR TKI exposure; five of these patients received germline testing, and all five were confirmed to have originated in the germline. Two patients with germline T790M mutations detected on testing ordered by external providers were added to our de novo T790M+ patient analysis after chart review. Co-occurring EGFR mutations, including L858R, were detected in pre-TKI samples for 78% (14/18) of de novo T790M+ patients (Table). Co-occurring mutations in TP53, KRAS, PTEN, or RB1 were detected in pre-TKI samples of all patients without co-occurring EGFR mutations. EGFR C797S was observed after osimertinib treatment in one of four patients with post-TKI testing results. Of confirmed germline T790M+ cases with available allele frequencies, 100% (4/4) had allele fractions >0.5 (tissue) and/or %cfDNA values >50% (plasma). Average allele fraction and %cfDNA values were higher for de novo T790M mutations (allele fraction: 0.5 ± 0.2; %cfDNA: 40% ± 20%) than for acquired T790M mutations (allele fraction: 0.3 ± 0.2; %cfDNA: 2% ± 2%). Conclusions: Roughly one-third of T790M mutations detected in real-world settings occur before EGFR TKI exposure and may be associated with germline inheritance. Allele frequency may be a potential indicator of de novo T790M mutations in scenarios where pre-treatment data is not available. Future studies will investigate the impact of de novo T790M mutations on treatment response and evolution of resistance mechanisms in osimertinib-treated patients. [Table: see text]

Circadian rest-activity rhythm as a predictor of survival in metastatic colorectal cancer.

Abstract: e14006 Background: Experimental disruption of the Circadian Timing System (CTS) accelerates cancer progression. The relative amount of activity in-bed versus out-of-bed (I

Impact of Workforce Challenges and Funds Flow on Cancer Clinical Trial Development and Conduct.

Abstract: The conduct of clinical cancer research has faced considerable challenges in recent years, and the situation has only been exacerbated by the global pandemic. The growing complexity of clinical trials and rising administrative burdens had been causing greater expense and difficulty in recruiting and retaining an appropriately trained workforce even before the well-publicized increase in turnover caused by the pandemic. Longstanding issues such as restrictive inclusion criteria and complicated trial designs have negatively affected already low clinical trial accrual rates, limited sites capable of opening studies and enrolling patients, and worsened disparities in trial participation. Opposing these elements are efforts by ASCO and other organizations to increase affordability, access, and equity in clinical trial enrollment. To provide diverse perspectives on how these challenges are affecting cancer research as we emerge from the pandemic, we asked a panel of experienced clinical research leaders from both academic and community cancer centers to answer questions they felt most pressing about the business of conducting clinical research today and where they felt the field was moving in the near future.

Open Reduction and Suture Fixation of Acute Sternoclavicular Fracture-Dislocations in Children.

Abstract: Background Acute sternoclavicular fracture-dislocation is associated with high-energy trauma and is being increasingly recognized in children1. These injuries are associated with compression of mediastinal structures and can be life-threatening1. The management of acute sternoclavicular fracture-dislocation includes closed reduction or open surgical stabilization; however, limited success is reported with closed reduction2,3. To our knowledge, there are no detailed descriptions of open reduction and suture fixation of acute sternoclavicular fracture-dislocation in children. Description Following diagnosis of acute sternoclavicular fracture-dislocation, the timing of surgical treatment is determined according to several patient and surgical factors. Among patients with hemodynamic instability, respiratory compromise, or evidence of asymmetric perfusion, surgical treatment is needed on an emergency basis. In the absence of these factors, surgical treatment can be performed on an urgent basis. It is important to communicate with vascular or thoracic surgeons prior to proceeding to the operating room because of the rare case in which advanced surgical access or vascular repair is required. In the operating room, general anesthesia and large-bore intravenous access are required. Patients are positioned supine on a radiolucent table, and a small bump is placed between the scapulae to elevate the medial aspect of the clavicle. The contralateral sternoclavicular joint and medial aspect of the clavicle should be prepared into the sterile field, as well as both sides of the groin in case vascular access is needed. A 6 to 8-cm incision is centered on the medial aspect of the clavicle, extending to the manubrium. Standard dissection to the clavicle is performed, and care is taken to maintain the integrity of the sternoclavicular ligament complex. Circumferential dissection of the medial clavicular metaphysis is usually required in order to mobilize the dislocated fragment. Reduction of the physeal fracture usually requires axial traction and extension of the ipsilateral shoulder with the aid of a reduction clamp on the medial clavicular metaphysis. In some cases, a Freer elevator can be placed between the metaphysis and epiphysis to shoehorn the clavicle from posterior to anterior. Once reduced, the fracture-dislocation is usually stable; however, the reduction is augmented with suture fixation. The sternoclavicular joint capsule should be repaired if disrupted, and the incision should be closed in layers. Postoperatively, the arm is placed in a sling, and range of motion is commenced at 4 weeks. Alternatives Alternative management of acute sternoclavicular fracture-dislocation includes closed reduction, plate fixation4, and ligament reconstruction5. Rationale In our experience, closed reduction is often unsuccessful, which is consistent with the experiences reported by other authors2,3. In addition, suture fixation is sufficient and plate fixation is not required because this injury is relatively stable following reduction. Lastly, ligament reconstruction with use of autograft or allograft may be indicated but is more relevant in chronic cases with injury or attenuation of the sternoclavicular ligament complex. Open reduction allows for direct visualization of the fracture reduction, and suture fixation allows for increased stability without the need for hardware or secondary surgical procedures. Expected Outcomes We expect patients to achieve full range of motion and strength without any joint instability as reported by Waters et al.3. Important Tips There is an inherent risk of vascular injury with open reduction and suture fixation. This risk is mitigated with perioperative planning and consultation with vascular or thoracic surgeons. General surgeons should always be available when these procedures are performed in case of vascular issues or emergencies.It is sometimes difficult to reduce the dislocation, but additional maneuvers allow for controlled reduction of the displaced clavicle, such as using a Freer elevator and serrated clamp.Assessing fracture reduction can be difficult intraoperatively. Including the contralateral sternoclavicular joint in the sterile surgical field can be helpful in assessing fracture reduction and osseous contour.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The Benefits of Being Present: Mindfulness and Its Role in Psychological Well-Being

Abstract: Mindfulness is an attribute of consciousness long believed to promote well-being. This research provides a theoretical and empirical examination of the role of mindfulness in psychological well-being. The development and psychometric properties of the dispositional Mindful Attention Awareness Scale (MAAS) are described. Correlational, quasi-experimental, and laboratory studies then show that the MAAS measures a unique quality of consciousness that is related to a variety of well-being constructs, that differentiates mindfulness practitioners from others, and that is associated with enhanced selfawareness. An experience-sampling study shows that both dispositional and state mindfulness predict self-regulated behavior and positive emotional states. Finally, a clinical intervention study with cancer patients demonstrates that increases in mindfulness over time relate to declines in mood disturbance and stress. Many philosophical, spiritual, and psychological traditions emphasize the importance of the quality of consciousness for the maintenance and enhancement of well-being (Wilber, 2000). Despite this, it is easy to overlook the importance of consciousness in human well-being because almost everyone exercises its primary capacities, that is, attention and awareness. Indeed, the relation between qualities of consciousness and well-being has received little empirical attention. One attribute of consciousness that has been much-discussed in relation to well-being is mindfulness. The concept of mindfulness has roots in Buddhist and other contemplative traditions where conscious attention and awareness are actively cultivated. It is most commonly defined as the state of being attentive to and aware of what is taking place in the present. For example, Nyanaponika Thera (1972) called mindfulness “the clear and single-minded awareness of what actually happens to us and in us at the successive moments of perception” (p. 5). Hanh (1976) similarly defined mindfulness as “keeping one’s consciousness alive to the present reality” (p. 11). Recent research has shown that the enhancement of mindfulness through training facilitates a variety of well-being outcomes (e.g., Kabat-Zinn, 1990). To date, however, there has been little work examining this attribute as a naturally occurring characteristic. Recognizing that most everyone has the capacity to attend and to be aware, we nonetheless assume (a) that individuals differ in their propensity or willingness to be aware and to sustain attention to what is occurring in the present and (b) that this mindful capacity varies within persons, because it can be sharpened or dulled by a variety of factors. The intent of the present research is to reliably identify these inter- and intrapersonal variations in mindfulness, establish their relations to other relevant psychological constructs, and demonstrate their importance to a variety of forms of psychological well-being.

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.