Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation.

New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD.

The Effects of Humor in Clinical Settings on Medical Trainees and the Implications for Medical Educators: A Scoping Review.

Background: Clinical settings represent the site of patient care and clinical training for medical students and residents. Both processes involve social interaction, and humor is a fundamental component of social interaction that remains underexplored in medical education. This study investigated the impact of humor on medical trainees in the context of the clinical learning environment and examined the implications for medical educators. Methods: Following scoping review methodology, the authors systematically searched six databases and Google Scholar in February 2021 and March 2022. Articles were screened and selected according to inclusion/exclusion criteria, and findings from included articles were synthesized using procedures of metasynthesis. Results: Fifteen articles met inclusion criteria. Six themes emerged relating to the functions and effects of humor in clinical training settings: (1) managing emotions; (2) demarcating insider vs outsider status; (3) facilitating camaraderie; (4) ensuring conformity; (5) negotiating power differentials; and (6) fostering discrimination. Conclusions: The use of humor by medical educators plays an integral role in trainees' everyday experiences. Positive humor helps with coping and communication, while negative humor serves as an indirect medium for communicating ridicule and prejudice. Further research drawing on social psychology theories may identify ways to reduce effects of negative humor and promote well-being and diversity in medical education. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01769-0.

Work-hour restrictions as an ethical dilemma for residents.

BACKGROUND: We propose that the standardized work-hour limitations have created an ethical dilemma for residents. METHODS: A survey tool was designed to assess factors that influence the number of hours residents work and report. The program directors of pediatrics, internal medicine, and general surgery at our institution supported their residents' participation. A voluntary, anonymous survey of these residents was performed. RESULTS: One hundred seventy of 265 eligible residents were surveyed. Eighty-one percent of residents surveyed responded. Eighty percent of respondents reported exceeding work-hour restrictions at least once within the past 6 months. The factor of greatest influence measured was concern for patient care (80%). Forty-nine percent of respondents admitted underreporting their work hours. CONCLUSIONS: The Accreditation Council for Graduate Medical Education work-hour restrictions have created an ethical dilemma for residents. Our data show that a significant number of residents feel compelled to exceed work-hour regulations and report those hours falsely.

Influence of broad-spectrum antibiotic prophylaxis on intracranial pressure monitor infections and subsequent infectious complications in head-injured patients.

BACKGROUND: The benefit of antibiotic prophylaxis for intracranial pressure (ICP) monitors remains controversial, and clinical practice varies widely. Whether any antibiotic coverage, particularly broad-spectrum coverage, reduces monitor-related infections remains unproved, and exposure to antibiotics may affect the susceptibility patterns of pathogens producing subsequent infectious complications. Despite the lack of data supporting its use, our level I trauma center had a long-standing ICP monitor prophylaxis protocol that provided broad-spectrum coverage that included ceftriaxone. In April 2002, a protocol change was instituted that substituted cefazolin for ceftriaxone as single-agent prophylaxis for ICP monitors. HYPOTHESIS: Broader-spectrum antibiotic prophylaxis does not reduce ICP monitor-related infections but is associated with acquisition of more drug-resistant infections than narrow-spectrum prophylaxis. METHODS: To evaluate the influence of broad- versus narrow-spectrum prophylaxis, a three year period encompassing each practice was selected. All injured patients with ICP monitors placed between January 1, 2001, and December 31, 2003 (n = 279), were identified using the Vanderbilt trauma database. Antibiotic prophylaxis for ICP monitors was determined using the hospital financial database to identify all antibiotics given to individual patients and subsequent chart review to identify those antibiotics given solely for ICP prophylaxis. A total of 119 patients received narrow-spectrum (either cefazolin or vancomycin; n = 100) or no (n = 19) prophylaxis, whereas 160 received broad-spectrum prophylaxis (ceftriaxone or ciprofloxacin). The two groups did not differ with respect to baseline demographics, type of ICP monitor, or duration of monitor placement. Infectious complications were determined by continuous infection surveillance utilizing standard U.S. Centers for Disease Control and Prevention National Nosocomial Infection Surveillance System (CDC-NNIS) definitions and maintained in a contemporary database. The influence of broad-spectrum antibiotic prophylaxis on both ICP monitor infections and subsequent infections outside the central nervous system (CNS) was determined. RESULTS: Nine patients (3.2%) developed CNS infections; two of 119 patients (1.7%) who received narrow-spectrum or no prophylaxis versus seven of 160 patients (4.4%) who received broad-spectrum prophylaxis (p = NS). Only the duration of monitor placement and Injury Severity Score were associated with the infection rate. In the total population, 185 infections occurred in 93 patients (33%). Infection rates did not differ between patients who received narrow-spectrum or no prophylaxis (32%) and those who received broad-spectrum prophylaxis (34%). However, patients who received broad-spectrum prophylaxis acquired gram-negative infections with significantly greater antibiotic resistance. CONCLUSIONS: Broad-spectrum antibiotic prophylaxis of ICP monitors does not reduce CNS infections, but is associated with a shift to resistant gram-negative pathogens in subsequent infectious complications. Thus, broad-spectrum antibiotic prophylaxis of ICP monitors should be eliminated or minimized unless data from randomized trials prove its utility.

Missed opportunities: a descriptive assessment of teaching and attitudes regarding communication skills in a surgical residency.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires that "residents must be able to demonstrate interpersonal and communication skills that result in effective information exchange and teaming with patients, their patients' families, and professional associates." The authors sought to assess current methods of teaching and attitudes regarding communication skills in their surgical residency. METHODS: After obtaining Institutional Review Board (IRB) exemption, voluntary anonymous surveys were completed by a sample of convenience at the Vanderbilt University Medical Center: surgical residents at Grand Rounds and attending surgeons in a faculty meeting. Data were evaluated from 49 respondents (33 of 75 total surgical residents, 16 representative attending surgeons). RESULTS: One hundred percent of respondents rated the importance of communication to the successful care of patients as "4" or "5" of 5. Direct attending observation of residents communicating with patients/families was confirmed by residents and faculty. Residents reported varying levels of comfort with different types of conversations. Residents were "comfortable" or "very comfortable" as follows: obtaining informed consent, 91%; reporting operative findings, 64%; delivering bad news, 61%; conducting a family conference, 40%; discussing do not resuscitate (DNR) orders, 36%; and discussing transition to comfort care, 24%. Resident receptiveness to communication skills education varied with proposed venues: 84% favored teaching in the course of routine clinical care, 52% via online resources, and 46% in workshops. Residents were asked how frequently they received feedback specific to their communication skills during the past 6 months: Most residents reported 0 (39%) or 1 (21%) feedback episode. Only 30% of resident respondents reported receiving feedback that they perceived helpful. Attending surgeons reported that they did provide residents feedback specific to their communication skills. When asked to estimate the number of feedback episodes in the last 6 months, 16 faculty members reported a total of 67 feedback episodes, whereas 33 residents reported a total of only 24 episodes. Most faculty members rated their comfort with providing feedback specific to communication skills as "very comfortable" (56%) or "comfortable" (19%). "Time constraints" was the most frequently cited barrier to teaching communication skills. CONCLUSIONS: Communication skills are valued as integral to patient care by both residents and faculty in this study. Residents are most receptive to teaching of communication skills in the clinical setting. Faculty members report they are providing feedback to residents. Although residents report direct observation by faculty, currently only a minority (30%) are receiving feedback regarding communication that they consider helpful. A need exists to facilitate the feedback process to resolve this discrepancy. The authors propose that an evaluation instrument regarding communication skills may strengthen the feedback process.

Work hours restrictions as an ethical dilemma for residents: a descriptive survey of violation types and frequency.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) implemented requirements regarding allowable duty hours for resident training in the United States in July 2003. In a previous pilot study at Vanderbilt University Medical Center, a significant number of residents reported violation of requirements. In addition, almost half of those individuals admitted under-reporting their hours worked. The authors' goal was to further delineate the type and frequency of violations and under-reporting. METHODS: A survey tool was designed to assess specific types of violations as well as factors that influence the number of hours residents worked and reported. Approval was obtained from the Vanderbilt Institutional Review Board and Office of Graduate Medical Education before enrollment of subjects. The program directors of Pediatrics, Internal Medicine, Medicine-Pediatrics, and General Surgery supported the participation of their residents. A voluntary anonymous survey of these residents was conducted 1 year after the pilot study. RESULTS: Of 263 eligible residents, 175 were surveyed. Of 175 residents, 125 (71%) residents responded. Eighty-five percent of residents reported violation of duty-hour requirements within the preceding 3 months. Residents reported violation of specific requirements as follows: 1 day off in 7, 28%; 80-hour weekly average, 65%; and "24+6" consecutive hours, 85%. Residents were asked to estimate the number of hours by which they exceeded requirements. Hours over the 80-hour weekly requirement were reported as follows: 1 hour, 12%; 2 hours, 15%; 3 hours, 21%; 4 hours, 5%; 5 hours, 14%; and 6 or more hours, 33%. Hours over the "24+6" requirement were reported as follows: 1 hour, 30%; 2 hours, 42%; 3 hours, 18%; 4 hours, 7%; 5 hours, 1%; and 6 or more hours, 2%. Forty-eight percent of respondents admitted under-reporting violations to their program director. CONCLUSIONS: Eighty-five percent of residents reported at least 1 violation, and 48% admitted under-reporting violations. These results support the previous findings of 80% and 49%, respectively. Of the various requirements, the "24+6" rule was most frequently violated. Of those in violation of the "24+6" requirement, the majority (90%) exceeded limits by no more than 3 hours. Of those in violation of the 80-hour weekly average requirement, the majority (57%) exceeded limits by no more than 5 hours. Per the ACGME website, "an RRC may grant exceptions for up to 10% of the 80-hour limit, to individual programs based on a sound educational rationale." Although the overall percent of residents reporting violation remains high, the number of excess hours worked is small relative to established standards (within 10%). The authors propose that systems adaptations could be developed to improve compliance. Special attention is warranted to investigate the activities of residents in the post-call period.

Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.

PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/µL. CONCLUSION: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.

A comparison of postoperative effects of bariatric surgery on medical markers of morbidity.

BACKGROUND: Bariatric surgery reduces the prevalence of diabetes and improves lipid profiles. Low-density lipoprotein particle (LDL-P) is a more accurate predictor of cardiovascular events than high-density lipoprotein (HDL) and LDL cholesterol. The effects of bariatric procedures on LDL-P have not been previously reported. METHODS: Two hundred thirty patients undergoing bariatric surgery, including gastric bypass, sleeve gastrectomy, and laparoscopic adjustable gastric band placement at a single institution were included. HDL, LDL, hemoglobin A1c, and LDL-P were measured preoperatively and at 3, 6, and 12 months postoperatively. Weight was recorded at baseline and after 1 year. RESULTS: There was a decrease in serum LDL-P levels, averaging 472.58 (P < .0001) over 1 year. HDL levels increased. Hemoglobin A1c and LDL levels declined. On average, patients lost 58% of excess weight. CONCLUSION: LDL-P significantly decreased after bariatric surgery in relation to weight loss. It may be inferred that bariatric surgery decreases the risk of cardiovascular events.

What is the future of training in surgery? Needs assessment of national stakeholders.

BACKGROUND: The Curriculum Committee of the American College of Surgeons-Accredited Educational Institutes conducted a need assessment to (1) identify gaps between ideal and actual practices in areas of surgical care, (2) explore educational solutions for addressing these gaps, and (3) shape a vision to advance the future of training in surgery. METHODS: National stakeholders were recruited from the committee members' professional network and interviewed via telephone. Interview questions targeted areas for improving surgical patient care, optimal educational solutions for training in surgery including simulation roles, and entities that should primarily bear training costs. We performed an iterative, qualitative analysis including member checking to identify key themes. RESULTS: Twenty-two interviewees included state/national board representatives, risk managers, multispecialty faculty/program directors, nurses, trainees, an industry representative, and a patient. Surgeons' communication with patients, families, and team members was raised consistently by stakeholders as a way to establish clear expectations regarding pre-, peri-, and postoperative care. Other comments highlighted the surgeon's development and demonstration and maintenance of cognitive and technical skills, including surgical judgment. Stakeholders also reiterated the critical need for surgeons to engage in on-going self-assessment and professional development to identify and remediate recognized limitations. Recommended learning modalities for meeting surgeons' needs included active learning (deliberate practice, diverse patient experiences), experiential learning (simulation), and peer and mentored learning (preceptorship). CONCLUSION: This first formal needs assessment of education for surgeons points to opportunities for educational programs in patient-centered communication, learning models that match preferences of new generations of trainees, and training in interprofessional/interdisciplinary team communication and teamwork.

B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

PURPOSE: Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T-cell therapies for multiple myeloma has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. EXPERIMENTAL DESIGN: We conducted an assessment of BCMA expression in normal human tissues and multiple myeloma cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs. RESULTS: BCMA had a restricted RNA expression pattern. Except for expression in plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34(+) hematopoietic cells. We detected uniform BCMA cell-surface expression on primary multiple myeloma cells from five of five patients. We designed the first anti-BCMA CARs to be reported and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary multiple myeloma cells. CONCLUSIONS: BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating multiple myeloma.

Characterization of sarcoplasmic calcium binding protein (SCP) variants from freshwater crayfish Procambarus clarkii.

Sarcoplasmic calcium binding protein (SCP) is an invertebrate EF-hand calcium buffering protein that has been proposed to fulfill a similar function in muscle relaxation as vertebrate parvalbumin. We have identified three SCP variants in the freshwater crayfish Procambarus clarkii. The variants (pcSCP1a, pcSCP1b, and pcSCP1c) differ across a 37 amino acid region that lies mainly between the second and third EF-hand calcium binding domains. We evaluated tissue distribution and response of the variants to cold exposure, a stress known to affect expression of parvalbumin. Expression patterns of the variants were not different and therefore do not provide a functional rationale for the polymorphism of pcSCP1. Compared to hepatopancreas, expression of pcSCP1 variants was 100,000-fold greater in axial abdominal muscle and 10-fold greater in cardiac muscle. Expression was 10-100 greater in fast-twitch deep flexor and extensor muscles compared to slow-twitch superficial flexor and extensors. In axial muscle, no significant changes of pcSCP1, calmodulin (CaM), or sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) expression were measured after one week of 4°C exposure. In contrast, large decreases of pcSCP1 were measured in cardiac muscle, with no changes in CaM or SERCA. Knockdown of pcSCP1 by dsRNA led to reduced muscle activity and decreased expression of SERCA. In summary, the pattern of pcSCP1 tissue expression is similar to parvalbumin, supporting a role in muscle contraction. However, the response of pcSCP1 to cold exposure differs from parvalbumin, suggesting possible functional divergence between the two proteins.

Moral distress in the third year of medical school; a descriptive review of student case reflections.

BACKGROUND: Medical students may find certain clinical experiences particularly difficult. Moral distress occurs when a trainee sees a situation or behavior as undesirable, but, because of a position in the hierarchy, declines to address the problem. To prompt our students to reflect on such experiences, students are required to submit a brief case description and are assigned to mentor groups to discuss cases. METHODS: After exemption from our Institutional Review Board, a database of student submissions was de-identified. A total of 192 case descriptions were analyzed by a single reviewer to identify recurrent themes. Submissions were categorized in a binary fashion as higher or lower levels of distress. Frequency and correlation with levels of distress were assessed for each theme. RESULTS: Sixty-seven percent of the submissions were classified as higher distress. Seven major themes were identified, the most common being problems of communication (n = 179). Those students taking action correlated to lower distress. CONCLUSIONS: Our review shows that specific situations can be expected to generate moral distress in trainees. Addressing such distress may support the ongoing professional growth of trainees.

Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients.

BACKGROUND: Timely diagnosis and treatment of adrenal insufficiency (AI) dramatically reduces mortality in trauma patients. We sought to identify risk factors and populations with a high risk of developing AI. DESIGN: Retrospective registry study. SETTING: Academic level I trauma center. PATIENTS: All trauma patients in the intensive care unit who underwent cosyntropin stimulation testing (CST) for presumed AI from January 1, 2002, through December 31, 2004. INTERVENTIONS: Cosyntropin stimulation testing, in which response was defined as an increase of 9 mug/dL (248 nmol/L) or more in cortisol level. MAIN OUTCOME MEASURES: Risk factors for developing AI in critically ill trauma patients. RESULTS: In 137 patients, CST was performed; 83 (60.6%) were nonresponders and 54 (39.4%) were responders. Age, sex, race, trauma mechanism, Injury Severity Score, and Revised Trauma Score were not statistically different between the groups. Rates of sepsis/septic shock, mechanical ventilation, and mortality were also similar between the 2 groups. However, rates of hemorrhagic shock on admission (45 [54%] vs 16 [30%]), requirement of vasopressor support (65 [78%] vs 28 [52%]), and etomidate exposure (59 [71%] vs 28 [52%]) were all significantly higher in the nonresponder group (P < .01). The increased risk of AI remained after controlling for potential confounding covariates (age, mechanism, Injury Severity Score, and Revised Trauma Score). CONCLUSIONS: Exposure to etomidate is a modifiable risk factor for the development of AI in this sample of critically injured patients. The use of etomidate for procedural sedation and rapid-sequence intubation in this patient population should be reevaluated.

Beta-blocker exposure is associated with improved survival after severe traumatic brain injury.

BACKGROUND: Beta-blocker use in elective noncardiac surgery has been associated with a reduction in mortality and cardiovascular complications. Traumatic brain injury (TBI) is often associated with a hyperadrenergic state. We hypothesized that adrenergic blockade would confer improved survival among TBI patients. METHODS: Retrospective review of the Trauma Registry of the American College of Surgeons database at a Level I trauma center was conducted. All trauma patients admitted from January 2004 to March 2005 with head Abbreviated Injury Scale score of 3 or greater were evaluated. Patients with length of stay <4 or >30 days were excluded. Beta-blocker exposure was defined as receiving beta-blockers for 2 or more consecutive days. RESULTS: In all, 420 patients met inclusion criteria: 174 patients exposed to beta-blockers [BB(+)] and 246 not exposed [BB(-)]. Mean age in BB(+) group was 50 years and 36 years in BB(-) group (p < 0.001). Mean Injury Severity Score was 33.6 for BB(+) group and 30.8 for BB(-) group (p = 0.01). Predicted survival (by Trauma and Injury Severity Score) for BB(+) group was 59.1% compared with 70.3% for BB(-) group (p < 0.001). Observed mortality for BB(+) group was 5.1%, 10.8% for BB(-) group (p = 0.036). Adjusted incidence rate ratio of mortality among those exposed to beta-blockers compared with those not exposed was 0.29 (95% confidence interval). CONCLUSIONS: Beta-blocker exposure was associated with a significant reduction in mortality in patients with severe TBI. This reduction in mortality is even more impressive, considering that the BB(+) group was older, more severely injured, and had lower predicted survival.