T Cells Expressing a Modified FcγRI Exert Antibody-Dependent Cytotoxicity and Overcome the Limitations of CAR T-cell Therapy against Solid Tumors.

The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.

Association between ionised calcium and severity of postpartum haemorrhage: a retrospective cohort study.

BACKGROUND: Postpartum haemorrhage (PPH) is often complicated by impaired coagulation. We aimed to determine whether the level of ionised calcium (Ca2+), an essential coagulation co-factor, at diagnosis of PPH is associated with bleeding severity. METHODS: This was a retrospective cohort study of women diagnosed with PPH during vaginal delivery between January 2009 and April 2020. Ca2+ levels at PPH diagnosis were compared between women who progressed to severe PPH (primary outcome) and those with less severe bleeding. Severe PPH was defined by transfusion of ≥2 blood units, arterial embolisation or emergency surgery, admission to ICU, or death. Associations between other variables (e.g. fibrinogen concentration) and bleeding severity were also assessed. RESULTS: For 436 patients included in the analysis, hypocalcaemia was more common among patients with severe PPH (51.5% vs 10.6%, P<0.001). In a multivariable logistic regression model, Ca2+ and fibrinogen were the only parameters independently associated with PPH severity with odds ratios of 1.14 for each 10 mg dl-1 decrease in fibrinogen (95% confidence interval [CI], 1.05-1.24; P=0.002) and 1.97 for each 0.1 mmol L-1 decrease in Ca2+ (95% CI, 1.25-3.1; P=0.003). The performance of Ca2+ or fibrinogen was not significantly different (area under the curve [AUC]=0.79 [95% CI, 0.75-0.83] vs AUC=0.86 [95% CI, 0.82-0.9]; P=0.09). The addition of Ca2+ to fibrinogen improved the model, leading to AUC of 0.9 (95% CI, 0.86-0.93), P=0.03. CONCLUSIONS: Ca2+ level at the time of diagnosis of PPH was associated with risk of severe bleeding. Ca2+ monitoring may facilitate identification and treatment of high-risk patients.

Obstetrical outcomes following laparoscopy during pregnancy: a retrospective case-control study.

PURPOSE: To evaluate pregnancy outcome of patients who undergo laparoscopy during pregnancy. METHODS: A retrospective case-control study, conducted in a single university-affiliated tertiary care medical center, comparing pregnancy outcomes of women who underwent laparoscopy during pregnancy to women without operations during pregnancy. The study group (n = 232) included all pregnant women who underwent a single laparoscopic surgery during pregnancy (4-28 weeks of gestation) which culminated in delivery between 2006 and 2017; this study group was matched to a control group (n = 463) without surgical intervention during pregnancy, in a 2:1 ratio by maternal age, parity, and multiple gestation. RESULTS: The main pregnancy outcomes included preterm birth, cesarean section, small for gestational age (≤ 10 percentile), and Apgar score of less than 7 in 5 min. Laparoscopy during pregnancy was associated with an increased risk for cesarean section (32.3% vs. 24.6%, adjusted OR = 1.9, CI 1.2-3.1, p = 0.011). We found no difference between the groups with regard to other outcomes, including rates of preterm birth (12.1% vs. 10.4%, adjusted OR = 1.3, CI 0.64-2.72, p = 0.451). In a subgroup analysis of the study group, various perioperative parameters such as operation duration, hospitalization length, and others, did not correlate with adverse pregnancy outcome. CONCLUSIONS: Laparoscopy during pregnancy may be associated with an increased rate of cesarean section. We did not find an increase in any other pregnancy or neonatal complication. Different perioperative parameters did not appear to predict adverse pregnancy outcome.

Surgical Intervention in Patients with Tubo-Ovarian Abscess: Clinical Predictors and a Simple Risk Score.

STUDY OBJECTIVE: To identify the clinical characteristics associated with surgical intervention in patients with tubo-ovarian abscess (TOA). DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary university-affiliated hospital. PATIENTS: Three hundred thirty-five patients were diagnosed with TOA based on sonographic and clinical criteria. Patients who underwent surgical intervention were compared with patients managed conservatively. INTERVENTION: Electronic medical records were used to identify patients who were diagnosed with TOA between 2007 and 2015. All patients received the same antibiotic regimen upon admission. The data extracted included microbial and pathologic reports. Clinical characteristics such as disease severity and outcomes were compared. The clinical predictors available on patient admission for surgical intervention were identified retrospectively. A logistic regression was used to determine the independent predictors of treatment failure. A risk score was created by giving a nominal weight to each predictor. The score was validated by a random bootstrap analysis. An additional validation cohort that consisted of patients diagnosed with TOA during the 2 years after the original study period was applied to the final score. MEASUREMENTS AND MAIN RESULTS: The following variables of patients who underwent surgical intervention in comparison with those successfully treated and were enrolled into the score analysis differed significantly: age at admission (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.3-3.5), mean leukocytosis at admission (OR, 2.2; 95% CI, 1.3-3.6), ultrasonographic measurement of abscess diameter (OR, 3.6 95% CI, 2.0-6.3), and the presence of bilateral abscess (OR, 2.2; 95% CI, 1.3-3.9). Risk groups A, B, C, and D were positively correlated with the need for surgical intervention. Those in the highest risk group D had an antibiotic failure rate of 92%, as compared with those with the lowest risk group, in which there was a 20% risk of antibiotic failure. CONCLUSIONS: Antibiotic treatment failure for TOA can be predicted on patient admission using a novel risk assessment score.

Maternal and neonatal hyponatremia during labor: a case series.

BACKGROUND: Hyponatremia during labor and delivery may result in severe maternal and neonatal sequelae. Our aim was to describe the direct effect of hyponatremia in labor on pregnancy outcome. METHODS: A case series of parturients diagnosed with hyponatremia during labor and their neonates. Clinical presentation, laboratory workup, and maternal and neonatal outcomes are presented. RESULTS: Four parturients and their corresponding six neonates were diagnosed with hyponatremia. Of these, two cases were caused by water intoxication and two were preeclampsia induced. While two were identified due to maternal or neonatal symptoms, two were diagnosed by routine laboratory testing. In all cases, low maternal sodium resulted in similarly low neonatal sodium. Neonatal symptoms included respiratory distress syndrome (RDS), lethargy, and jaundice. CONCLUSION: Psychogenic drinking during labor and preeclampsia may predispose to maternal hyponatremia, resulting in neonatal hyponatremia. Early recognition and treatment can prevent further maternal deterioration and adverse neonatal sequelae.

Adnexal Torsion in Postmenopausal Women: Clinical Presentation and Risk of Ovarian Malignancy.

STUDY OBJECTIVE: To investigate the clinical presentation, operative outcome, and incidence of malignancy in postmenopausal women who were diagnosed with adnexal torsion. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary university-affiliated hospital. PATIENTS: Postmenopausal women diagnosed with adnexal torsion between 1995 and 2014 (study group) were reviewed and compared with 220 premenopausal patients diagnosed with adnexal torsion during the same time period. INTERVENTION: Demographic data, clinical signs and symptoms, and intra- and postoperative characteristics were compared between the 2 groups. MEASUREMENTS AND MAIN RESULTS: During the study period 44 postmenopausal women were diagnosed with adnexal torsion. Continuous dull pain was the most common presenting symptom in the postmenopausal group (57%), whereas acute-onset sharp pain was the predominant symptom in the premenopausal group (86%). The time interval from admission to surgery was significantly longer in the postmenopausal group (24 vs 6 hours, p < .001). Laparoscopic surgery was performed in 84.5% of the cases in the premenopausal group, whereas it was carried out in only 50% of cases in the postmenopausal group (p < .001). Four women in the postmenopausal group were diagnosed with malignancy, whereas only 1 case of malignancy was found in the premenopausal group (9% vs .4%, respectively; p = .003). CONCLUSIONS: Adnexal torsion in postmenopausal women is an uncommon event with a unique presentation. Because ovarian malignancy is not an uncommon finding in this group of patients, preparation for more extensive surgery should be contemplated.