Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR's high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs.

A social media analysis of patient-perceived complications following periacetabular osteotomy (PAO): a retrospective observational study.

BACKGROUND: Social media is a popular resource for patients seeking medical information and sharing experiences. Periacetabular osteotomy (PAO) is an accepted treatment for symptomatic acetabular dysplasia with a low published complication profile in specialty centers. Little is known regarding patient reporting of complications on social media following PAO. The purpose of this study was to describe the patient-perceived complications of PAO posted on social media and analyze how additional factors (postoperative timeframe, concomitant surgery) correlate with these complication posts. METHODS: Facebook and Instagram were queried from 02/01/18-02/01/23; Twitter was searched over an extended range back to 02/01/11. Facebook posts (1054) were collected from the two most populated interest groups; "Periacetabular Osteotomy" and "PAO Australia." Instagram posts (1003) and Tweets (502) were found using the same five most popular hashtags: #PAOwarrior, #periacetabularosteotomy, #periacetabularosteotomysurgery, #PAOsurgery, and #PAOrecovery. Posts were assessed for demographic data, perspective, timing (early postoperative or late postoperative), additional surgeries, type of complication, and post engagement. RESULTS: Facebook posts (1054), Instagram posts (1003), and Tweets (502) were assessed; 13.6% of posts included a complication. The majority of complications were reported > 6 months postoperatively with excessive pain being the most common complication (57.2%), including chronic pain (41.8%), acute pain (6.7%), and nerve pain (8.8%). Bony complications (6.7%), neurologic/psychiatric complications (3.8%), swelling (1.7%), infection (1.4%), other specified complications (16.2%), and unspecified complications (10.2%) were reported. Complication posts were found to be correlated with postoperative timeframe and concomitant surgery. Post engagement decreased in complication-related posts. CONCLUSIONS: Few patients posted a perceived complication associated with PAO surgery. Of those who did, the majority reported unmanageable pain during the late postoperative period. Posts including a perceived complication were found to be positively correlated with postoperative timeframe and negatively correlated with concomitant surgery. This study found a higher pain complication rate, but a lower overall complication rate compared to prior studies. Considering the social media reported complications of PAO patients in addition to traditional outcome measures reveals which aspects of postoperative recovery are most important to patients themselves.

Subacute Enteritis Two Months After COVID-19 Pneumonia With Mucosal Bleeding, Perforation, and Internal Fistulas.

Chronic sequelae of COVID-19 remain undetermined. We report a case of postinfection sequelae in a patient presenting with subacute obstruction 2 months after COVID-19 infection. A 34-year-old man with a prior prolonged hospital stay due to COVID-19 complicated by upper gastrointestinal (GI) bleed presented with subacute obstruction and failure to thrive. Upper GI push enteroscopy revealed residual ulcers and multiple proximal jejuno-jejunal fistulae. Midline laparotomy revealed strictures with dense intra-abdominal adhesions, a large jejuno-jejunal fistula, and evidence of prior jejunal perforation following severe COVID-19 infection. The patient recovered after small bowel resection with anastomoses and was discharged home. Histopathological examination of resected specimen confirmed transmural infarction with evidence of prior hemorrhage, diffuse ulcers, and multifocal inflammation. This is the first report of a chronic GI sequelae resulting from COVID-19. As the pandemic evolves, medical professionals must be vigilant to consider alternative GI diagnoses in the COVID-19 survivors.

A review of COVID-19's impact on modern medical systems from a health organization management perspective.

The novel SARS-CoV-2 (COVID-19) disrupted many facets of the healthcare industry throughout the pandemic and has likely permanently altered modern healthcare delivery. It has been shown that existing healthcare infrastructure influenced national responses to COVID-19, but the current implications and resultant sequelae of the pandemic on the organizational framework of healthcare remains largely unknown. This paper aims to review how aspects of contemporary medical systems - the physical environment of care delivery, global healthcare supply chains, workforce structures, information and communication systems, scientific collaboration, as well as policy frameworks - evolved in the initial response to the COVID-19 pandemic.

Chitosan-based lifefoam improves survival in lethal noncompressible abdominal bleeding in swine.

BACKGROUND: In military combat settings, noncompressible closed cavity exsanguination is the leading cause of potentially survivable deaths, with no effective treatment available at point of injury. The aim of this study was to assess whether an expanding foam based on hydrophobically modified chitosan (hm-chitosan) may be used as a locally injectable hemostatic agent for the treatment of noncompressible bleeding in a swine model. METHODS: A closed-cavity, grade V hepato-portal injury was created in all animals resulting in massive noncoagulopathic, noncompressible bleeding. Animals received either fluid resuscitation alone (control, n = 8) or fluid resuscitation plus intraperitoneal hm-chitosan agent through an umbilical port (experimental, n = 18). The experiment was terminated at 180 minutes or death (defined as end-tidal CO2 <8mmHg or mean arterial pressure [MAP] <15mmHg), whichever came first. RESULTS: All animals had profound hypotension and experienced a near-arrest from hypovolemic shock (mean MAP = 24 mmHg at 10 minutes). Mean survival time was higher than 150 minutes in the experimental arm versus 27 minutes in the control arm (P < .001). Three-hour survival was 72% in the experimental group and 0% in the control group (P = .002). Hm-chitosan stabilized rising lactate, preventing acute lethal acidosis. MAP improved drastically after deployment of the hm-chitosan and was preserved at 60 mmHg throughout the 3 hours. Postmortem examination was performed in all animals and the hepatoportal injuries were anatomically similar. CONCLUSION: Intraperitoneal administration of hm-chitosan-based foam for massive, noncompressible abdominal bleeding improves survival in a lethal, closed-cavity swine model. Chronic safety and toxicity studies are required.

Predictors of Operative Intervention in Patients With Lactic Acidosis.

BACKGROUND: Lactate levels in clinical practice are often used as a quantitative indicator for the severity of hypoperfusion and the responsiveness to therapeutic interventions. In the hospital acute care setting, lactic acidosis combined with the appropriate clinical exam signs warrants surgical evaluation. The purpose of our study was to evaluate all surgical consults for lactic acidosis in a single community hospital to identify what cofactors were most often predictive of the need for surgical management and operative intervention. MATERIALS AND METHODS: A retrospective chart review within a 5-year period was conducted on all consultations to general surgery in which patients additionally had lactic acidosis defined as >2mEq. Within this population, various subjective and objective parameters were evaluated. Final analysis compared these parameters between patients with lactic acidosis who underwent surgical intervention and those who did not require operative intervention. RESULTS: Within the 5-year period, 432 patients met our criteria of a surgical consult placed for lactic acidosis. Final results from the highest quality statistical model showed significant variables as diffuse tenderness on physical exam (P-value = .0010, Odds Ratio (OR) = 2.77) and focal tenderness on physical exam (P-value = .0440, OR = 1.76). The presence of peritoneal signs (P-value = .0521, OR = 2.02) resulted in operative intervention twice as often in patients with lactic acidosis. DISCUSSION: To better appropriate health care costs, measures need to be taken to ensure resources are being utilized properly. In patients with lactic acidosis, one should go "back to the basics" with the physical examination to determine which patients truly need a surgical consultation.

How to Optimize Your Research During a Pandemic - A Summary of Discussions From the Association for Academic Surgery Town Hall and Lessons Learned From 2020.

The year 2020 was an unprecedented year for all of us, including for the academic surgery research community. Both stay-at-home and social distancing restrictions posed challenges to our personal and professional lives. The Association for Academic Surgery held its inaugural webinar-based panel discussion titled Association for Academic Surgery Town Hall with its topic on how to optimize research during a pandemic. This article summarizes the highlights from that discussion and lessons learned from the academic surgery research community in 2020.

Multisystem outcomes and predictors of mortality in critically ill patients with COVID-19: Demographics and disease acuity matter more than comorbidities or treatment modalities.

BACKGROUND: We sought to describe characteristics, multisystem outcomes, and predictors of mortality of the critically ill COVID-19 patients in the largest hospital in Massachusetts. METHODS: This is a prospective cohort study. All patients admitted to the intensive care unit (ICU) with reverse-transcriptase-polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 14, 2020, and April 28, 2020, were included; hospital and multisystem outcomes were evaluated. Data were collected from electronic records. Acute respiratory distress syndrome (ARDS) was defined as PaO2/FiO2 ratio of ≤300 during admission and bilateral radiographic pulmonary opacities. Multivariable logistic regression analyses adjusting for available confounders were performed to identify predictors of mortality. RESULTS: A total of 235 patients were included. The median (interquartile range [IQR]) Sequential Organ Failure Assessment score was 5 (3-8), and the median (IQR) PaO2/FiO2 was 208 (146-300) with 86.4% of patients meeting criteria for ARDS. The median (IQR) follow-up was 92 (86-99) days, and the median ICU length of stay was 16 (8-25) days; 62.1% of patients were proned, 49.8% required neuromuscular blockade, and 3.4% required extracorporeal membrane oxygenation. The most common complications were shock (88.9%), acute kidney injury (AKI) (69.8%), secondary bacterial pneumonia (70.6%), and pressure ulcers (51.1%). As of July 8, 2020, 175 patients (74.5%) were discharged alive (61.7% to skilled nursing or rehabilitation facility), 58 (24.7%) died in the hospital, and only 2 patients were still hospitalized, but out of the ICU. Age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.04-1.12), higher median Sequential Organ Failure Assessment score at ICU admission (OR, 1.24; 95% CI, 1.06-1.43), elevated creatine kinase of ≥1,000 U/L at hospital admission (OR, 6.64; 95% CI, 1.51-29.17), and severe ARDS (OR, 5.24; 95% CI, 1.18-23.29) independently predicted hospital mortality.Comorbidities, steroids, and hydroxychloroquine treatment did not predict mortality. CONCLUSION: We present here the outcomes of critically ill patients with COVID-19. Age, acuity of disease, and severe ARDS predicted mortality rather than comorbidities. LEVEL OF EVIDENCE: Prognostic, level III.

Risk Factors for Failure of Splenic Angioembolization: A Multicenter Study of Level I Trauma Centers.

BACKGROUND: Angioembolization (AE) is an adjunct to nonoperative management (NOM) of splenic injuries. We hypothesize that failure of AE is associated with blood transfusion, grade of injury, and technique of AE. METHODS: We performed a retrospective (2010-2017) multicenter study (nine Level I trauma centers) of adult trauma patients with splenic injuries who underwent splenic AE. Variables included patient physiology, injury grade, transfusion requirement, and embolization technique. The primary outcome was NOM failure requiring splenectomy. Secondary outcomes were mortality, complications, and length of stay. RESULTS: A total of 409 patients met inclusion criteria; only 33 patients (8%) required delayed splenectomy. Patients who failed received more blood in the first 24 h (P = 0.009) and more often received massive transfusion (P = 0.01). There was no difference in failure rates for grade of injury, contrast blush on computed tomography, and branch embolized. After logistic regression, transfusion in the first 24 h was independently associated with failure of NOM (P = 0.02). Patients who failed NOM had more complications (P = 0.002) and spent more days in the intensive care unit (P < 0.0001), on the ventilator (P = 0.0001), and in the hospital (P < 0.0001). Patients who failed NOM had a higher mortality (15% versus 3%, P = 0.007), and delayed splenectomy was independently associated with mortality (odds ratio, 4.2; 95% confidence interval, 1.2-14.7; P = 0.03). CONCLUSIONS: AE for splenic injury leads to effective NOM in 92% of patients. Transfusion in the first 24 h is independently associated with failure of NOM. Patients who required a delayed splenectomy suffered more complications and had higher hospital length of stay. Failure of NOM is independently associated with a fourfold increase in mortality.

Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.

Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.

Comparison of outcomes in non-head injured trauma patients using pre-injury warfarin or direct oral anticoagulant therapy.

BACKGROUND: Patients on prehospital anticoagulation with warfarin or direct oral anticoagulants (DOACs) represent a vulnerable subset of the trauma population. While protocolized warfarin reversal is widely available and easily implemented, prehospital anticoagulation with DOAC is cost prohibitive with only a few reversal options. This study aims to compare hospital outcomes of non-head injured trauma patients taking pre-injury DOAC versus warfarin. METHODS: A retrospective cohort study at a level 1 trauma center was performed. All adult trauma patients with pre-injury anticoagulation admitted between January 2015 and December 2018, were stratified into DOAC-using and warfarin-using groups. Patients were excluded if they had traumatic brain injury (TBI). Univariate and multivariable analyses were performed. Outcomes measures included in-hospital mortality, blood transfusion requirements, ICU length of stay (LOS), hospital LOS and discharge disposition. RESULTS: 374 non-TBI trauma patients on anticoagulation were identified, of which 134 were on DOACs and 240 on warfarin. Patients on DOACs had a higher ISS (9 [IQR, 9-10] vs. 9 [IQR, 5-9]; p<0.001), and lower admission INR values (1.2 [IQR, 1.1-1.3] vs 2.4 [IQR, 1.8-2.7]; p<0.001) than warfarin users. Use of reversal agents was higher in warfarin users (p<0.001). Relative to warfarin, DOAC users did not differ significantly with respect to hospital mortality (OR 0.47, 95% CI [0.13-1.73]). Multivariable analysis (not possible for mortality) did not show significant difference for RBC transfusion requirements (OR 0.92 [0.51-1.67]), ICU LOS (OR 1.08 [0.53-2.19]), hospital LOS (OR 1.10 [0.70-1.74]) or discharge disposition (OR 0.56 [0.29-1.11]) between the groups. CONCLUSION: Despite lower reversal rates and higher ISS, non-TBI trauma patients with pre-injury DOAC use had similar outcomes as patients on pre-injury warfarin. There may be equipoise to have larger, prospective studies evaluating the comparative safety of DOACs and warfarin in the population prone to low energy fall type injuries.

Case logging habits among general surgery residents are discordant and inconsistent.

BACKGROUND: General surgery residents log operative case experience as "first assist" (FA) or "primary surgeon" (PS). This study will evaluate their quantitative and qualitative case log practices. METHODS: Modified Delphi technique was used to create a questionnaire and distributed online to institutions via the APDS. Descriptive analyses and example operative scenarios for resident case logging habits were ascertained. RESULTS: There were 363 residents from university (60%) and non-university (40%) programs; 94% did not know the definition of primary surgeon. Over 50% stated they had been encouraged to log a case as surgeon that they did not feel was warranted. Only 4% felt the current logging system is "very accurate." Given an operative scenario, residents varied how they chose to log the case. CONCLUSION: General surgery residents do not know the current definition of PS. Case logging should be an objective measure of resident operative exposure, but may actually be more complex than previously recognized.

Rib Fractures and Mortality: Breaking the Causal Relationship.

Rib fractures have long been considered as a major contributor to mortality in the blunt trauma patient. We hypothesized that rib fractures can be an excellent predictor of mortality, but rarely contribute to cause death. We performed a retrospective study (2008-2015) of blunt trauma patients admitted to our urban, Level I trauma center with one or more rib fractures. Medical records were reviewed in detail. Rib fracture deaths were those from any respiratory sequelae or hemorrhage from rib fractures. There were 4413 blunt trauma patients who sustained one or more rib fractures and 295 (6.8%) died. Rib fracture patients who died had a mean Injury Severity Score = 38 and chest Abbreviated Injury Score = 3.4. Rib fractures were the cause of death in only 21 patients (0.5%). After excluding patients who were dead on arrival, patients dying as a result of their rib fractures were found to be older (P < 0.0001) and had a higher admission respiratory rate (P = 0.02). Multivariable logistic regression found that age ≥65 was the only variable independently associated with mortality directly related to rib fractures (odds ratio 4.1, 95% confidence interval = 1.3-13.3, P value < .0001). Mortality in patients with rib fractures is uncommon (7%), and mortality directly related to rib fractures is rare (0.5%). Older patients are four times more likely to die as a direct result of rib fractures and may require additional resources to avoid mortality.