Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis.

BACKGROUND: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation. METHODS: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use. RESULTS: Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q-value = 7.29 × 10-5. Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001). CONCLUSIONS: Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Radiographic Findings and Association With Clinical Severity and Outcomes in Critically Ill Patients With COVID-19.

PURPOSE: To describe evolution and severity of radiographic findings and assess association with disease severity and outcomes in critically ill COVID-19 patients. MATERIALS AND METHODS: This retrospective study included 62 COVID-19 patients admitted to the intensive care unit (ICU). Clinical data was obtained from electronic medical records. A total of 270 chest radiographs were reviewed and qualitatively scored (CXR score) using a severity scale of 0-30. Radiographic findings were correlated with clinical severity and outcome. RESULTS: The CXR score increases from a median initial score of 10 at hospital presentation to the median peak CXR score of 18 within a median time of 4 days after hospitalization, and then slowly decreases to a median last CXR score of 15 in a median time of 12 days after hospitalization. The initial and peak CXR score was independently associated with invasive MV after adjusting for age, gender, body mass index, smoking, and comorbidities (Initial, odds ratio [OR]: 2.11 per 5-point increase, confidence interval [CI] 1.35-3.32, P= 0.001; Peak, OR: 2.50 per 5-point increase, CI 1.48-4.22, P= 0.001). Peak CXR scores were also independently associated with vasopressor usage (OR: 2.28 per 5-point increase, CI 1.30-3.98, P= 0.004). Peak CXR scores strongly correlated with the duration of invasive MV (Rho = 0.62, P< 0.001), while the initial CXR score (Rho = 0.26) and the peak CXR score (Rho = 0.27) correlated weakly with the sequential organ failure assessment score. No statistically significant associations were found between radiographic findings and mortality. CONCLUSIONS: Evolution of radiographic features indicates rapid disease progression and correlate with requirement for invasive MV or vasopressors but not mortality, which suggests potential nonpulmonary pathways to death in COVID-19.

Effect of Obesity on Perioperative Outcomes After Robotic-Assisted Pulmonary Lobectomy.

OBJECTIVE: We investigated whether higher body mass index (BMI) affects perioperative and postoperative outcomes after robotic-assisted video-thoracoscopic pulmonary lobectomy. METHODS: We retrospectively studied all patients who underwent robotic-assisted pulmonary lobectomy by one surgeon between September 2010 and January 2015. Patients were grouped according to the World Health Organization's definition of obesity, with "obese" being defined as BMI >30.0 kg/m2. Perioperative outcomes, including intraoperative estimated blood loss (EBL) and postoperative complication rates, were compared. RESULTS: Over 53 months, 287 patients underwent robotic-assisted pulmonary lobectomy, with 7 patients categorized as "underweight," 94 patients categorized as "normal weight," 106 patients categorized as "overweight," and 80 patients categorized as "obese." Because of the relatively low sample size, "underweight" patients were excluded from this study, leaving a total cohort of 280 patients. There was no significant difference in intraoperative complication rates, conversion rates, perioperative outcomes, or postoperative complication rates among the 3 groups, except for lower risk of prolonged air leaks ≥7 days and higher risk of pneumonia in patients with obesity. CONCLUSIONS: Patients with obesity do not have increased risk of intraoperative or postoperative complications, except for pneumonia, compared with "normal weight" and "overweight" patients. Robotic-assisted pulmonary lobectomy is safe and effective for patients with high BMI.

Effect of advanced age on peri-operative outcomes after robotic-assisted pulmonary lobectomy: Retrospective analysis of 287 consecutive cases.

OBJECTIVES: We investigated whether advanced age affects peri-operative outcomes after robotic-assisted pulmonary lobectomies. MATERIALS AND METHODS: We retrospectively analyzed patients who underwent robotic-assisted lobectomy by one surgeon over a 5-year period. Rates of postoperative complications were compared according to age group. Other outcomes, such as intraoperative complications, hospital length of stay (LOS), and in-hospital mortality, were also compared. RESULTS: A total of 287 patients were included (mean age 67.1yr). Group A had 65 patients of advanced age≥75yr (range 75-87yr; 37 men, 28 women); Group B had 222 patients aged <75yr (range 29-74yr; 95 men, 127 women). Group A had 10/65 (15.4%) patients with robotic-related intraoperative complications, compared to 10/222 (4.5%) for Group B (p=0.002), with the most frequent intraoperative complications being bleeding from a pulmonary vessel (10.8% vs. 4.5%, p=0.06), bronchial injury (3.1% vs. 0.9%, p=0.18), and injury to the phrenic or recurrent laryngeal nerve (1.5% vs. 0.4%, p=0.33). There were 28/65 (43.1%) patients in Group A with postoperative complications compared to 76/222 (34.2%) in Group B (p=0.19). While operative times were similar (p=0.42), Group A had longer median hospital LOS of 6±0.9days compared to 4±0.3days for Group B (p=0.02). CONCLUSION: While younger patients have lower risk of robotic-related intraoperative complications and shorter hospital LOS, elderly patients do not have increased overall or emergent conversion rates to open lobectomy, overall postoperative complications rates, or in-house mortality compared to younger patients. Thus, robotic-assisted pulmonary lobectomy is feasible and relatively safe for patients of advanced age.

Effect of body mass index on operative outcome after robotic-assisted Ivor-Lewis esophagectomy: retrospective analysis of 129 cases at a single high-volume tertiary care center.

The impact of body weight on outcomes after robotic-assisted esophageal surgery for cancer has not been studied. We examined the short-term operative outcomes in patients according to their body mass index following robotic-assisted Ivor-Lewis esophagectomy at a high-volume tertiary-care referral cancer center and evaluated the safety of robotic surgery in patients with an elevated body mass index. A retrospective review of all patients who underwent robotic-assisted Ivor-Lewis esophagectomy between April 2010 and June 2013 for pathologically confirmed distal esophageal cancer was conducted. Patient demographics, clinicopathologic data, and operative outcomes were collected. We stratified body mass index at admission for surgery according to World Health Organization criteria; normal range is defined as a body mass index range of 18.5-24.9 kg/m2. Overweight is defined as a body mass index range of 25.0-29.9 kg/m2 and obesity is defined as a body mass index of 30 kg/m2 and above. Statistics were calculated using Pearson's Chi-square and Pearson's correlation coefficient tests with a P-value of 0.05 or less for significance. One hundred and twenty-nine patients (103 men, 26 women) with median age of 67 (30-84) years were included. The majority of patients, 76% (N = 98) received neoadjuvant therapy. When stratified by body mass index, 28 (22%) were normal weight, 56 (43%) were overweight, and 45 (35%) were obese. All patients had R0 resection. Median operating room time was 407 (239-694) minutes. When stratified by body mass index, medians of operating room time across the normal weight, overweight and obese groups were 387 (254-660) minutes, 395 (310-645) minutes and 445 (239-694), respectively. Median estimated blood loss (EBL) was 150 (25-600) cc. When stratified by body mass index, medians of EBL across the normal weight, overweight and obese groups were 100 (50-500) cc, 150 (25-600) cc and 150 (25-600), respectively. Obesity significantly correlated with longer operating room time (P = 0.05) but without significant increased EBL (P = 0.348). Among the three body mass index groups there was no difference in postoperative complications including thrombotic events (pulmonary embolism and deep venous thrombosis) (P = 0.266), pneumonia (P = 0.189), anastomotic leak (P = 0.090), wound infection (P = 0.390), any cardiac events (P = 0.793) or 30 days mortality (P = 0.414). Our data study demonstrates that patients with esophageal cancer and an elevated body mass index undergoing robotic-assisted Ivor-Lewis esophagectomy have increased operative times but no significantly increased EBL during the procedure. Other potential morbidities did not differ with the robotic approach.

Efficacy of lymph node dissection during robotic-assisted lobectomy for non-small cell lung cancer: retrospective review of 159 consecutive cases.

BACKGROUND: We investigated whether robotic-assisted surgery improves mediastinal lymph node dissection (MLND). METHODS: We analyzed patients (pts) who underwent robotic-assisted video-assisted thoracoscopic surgery (R-VATS) lobectomy for non-small cell lung cancer (NSCLC) over 36 months. Perioperative outcomes, tumor histology, numbers, locations, and status of all lymph nodes (LNs), and TNM (tumor, nodal, and metastasis) stage changes were analyzed. RESULTS: One hundred fifty-nine pts had mean tumor size 3.3±0.2 cm, most commonly being adenocarcinoma. Assessment of ≥3 N2 stations occurred in 156 (98.1%) pts, with 141 (88.7%) pts having >3 N2 stations reported. Mean total N1 + N2 stations assessed was 5.6±0.1 stations, including mean 4.1±0.1 N2 stations assessed. Mean N2 LNs reported was 7.2±0.3 LNs, and mean total N1 + N2 LNs reported was 13.4±0.4 LNs. There were 118 (74.2%) clinical stage-I pts versus 96 (60.4%) pathologic stage-I pts. Overall, 48 (30.2%) pts were upstaged, including 13 pts with cN0-pN1, 13 pts with cN0-pN2, 4 pts with cN1-pN2, and 18 pts with changes in T. CONCLUSIONS: R-VATS lobectomy is safe and results in perioperative outcomes comparable to those reported for conventional VATS. R-VATS MLND is effective at detecting occult metastatic disease during lobectomy for NSCLC.

Surgical outcomes associated with postoperative atrial fibrillation after robotic-assisted pulmonary lobectomy: retrospective review of 208 consecutive cases.

BACKGROUND: In this study, we sought to investigate the effect of post-operative atrial fibrillation (POAF) after robotic-assisted video-thoracoscopic pulmonary lobectomy on comorbid postoperative complications, chest tube duration, and hospital length of stay (LOS). METHODS: We retrospectively analyzed prospectively collected data from 208 consecutive patients who underwent robotic-assisted pulmonary lobectomy by one surgeon for known or suspected lung cancer. Postoperatively, 39 (18.8%) of these patients experienced POAF during their hospital stay. The occurrence of postoperative complications other than POAF, chest tube duration, and hospital LOS were analyzed in patients with POAF and without POAF. Statistical significance (P≤0.05) was determined by unpaired Student's t-test or by Chi-square test. RESULTS: Of patients with POAF, 46% also had other concurrent postoperative complications, while only 31% of patients without POAF experienced complications. The average number of postoperative complications experienced by patients with POAF was significantly higher than that experienced by those without POAF (0.9 vs. 0.4, P<0.05). Median chest tube duration in POAF patients (6 days) was significantly higher than in patients without POAF (4 days). A similar result was also seen with hospital LOS, with the median hospital LOS of 8 days in POAF patients being significantly longer than in those without POAF, whose median hospital LOS was 4 days. No other significant difference was detected between the two groups of patients. CONCLUSIONS: This study demonstrated the association between the incidence of POAF and a more complicated hospital course. Further studies are needed to determine whether confounders were involved in this association.

Effect of small body habitus on peri-operative outcomes after robotic-assisted pulmonary lobectomy: retrospective analysis of 208 consecutive cases.

BACKGROUND: Patients with smaller body surface area (BSA) have smaller pleural cavities, which limit visualization and instrument mobility during video-assisted thoracoscopic surgery (VATS). We investigated the effects of BSA on outcomes with robotic-assisted VATS lobectomy. METHODS: We analyzed 208 consecutive patients who underwent robotic-assisted lobectomy over 34 months. Patients were separated into group A (BSA ≤1.65 m(2)) and group B (BSA >1.65 m(2)). Operative times, estimated blood loss (EBL), conversions to thoracotomy, complications, hospital length of stay (LOS), and in-hospital mortality were compared. RESULTS: Group A had 40 patients (BSA 1.25-1.65 m(2)), and group B had 168 patients (BSA 1.66-2.86 m(2)). Median skin-to-skin operative times [± standard error of the mean (SEM)] were 169±16 min for group A and 176±6 min for group B (P=0.34). Group A had median EBL of 150±96 mL compared to 200±24 mL for group B (P=0.37). Overall conversion rate to thoracotomy was 8/40 (20.0%) in group A versus 12/168 (7.1%) in group B (P=0.03); while emergent conversion for bleeding was 2/40 (5.0%) in group A versus 5/168 (3.0%) in group B (P=0.62). Postoperative complications occurred in 12/40 (30.0%) in group A, compared to 66/168 (39.3%) in group B (P=0.28). Patients from both groups had median hospital LOS of 5 days (P=0.68) and had similar in-hospital mortality. CONCLUSIONS: Patients with BSA ≤1.65 m(2) have similar perioperative outcomes and complication risks as patients with larger BSA. Patients with BSA ≤1.65 m(2) have a higher overall conversion rate to thoracotomy, but similar conversion rate for bleeding as patients with larger BSA. Robotic-assisted pulmonary lobectomy is feasible and safe in patients with small body habitus.

Antioxidant enzymes mediate survival of breast cancer cells deprived of extracellular matrix.

Metastasis by cancer cells relies upon the acquisition of the ability to evade anoikis, a cell death process elicited by detachment from extracellular matrix (ECM). The molecular mechanisms that ECM-detached cancer cells use to survive are not understood. Striking increases in reactive oxygen species (ROS) occur in ECM-detached mammary epithelial cells, threatening cell viability by inhibiting ATP production, suggesting that ROS must be neutralized if cells are to survive ECM-detachment. Here, we report the discovery of a prominent role for antioxidant enzymes, including catalase and superoxide dismutase, in facilitating the survival of breast cancer cells after ECM-detachment. Enhanced expression of antioxidant enzymes in nonmalignant mammary epithelial cells detached from ECM resulted in ATP elevation and survival in the luminal space of mammary acini. Conversely, silencing antioxidant enzyme expression in multiple breast cancer cell lines caused ATP reduction and compromised anchorage-independent growth. Notably, antioxidant enzyme-deficient cancer cells were compromised in their ability to form tumors in mice. In aggregate, our results reveal a vital role for antioxidant enzyme activity in maintaining metabolic activity and anchorage-independent growth in breast cancer cells. Furthermore, these findings imply that eliminating antioxidant enzyme activity may be an effective strategy to enhance susceptibility to cell death in cancer cells that may otherwise survive ECM-detachment.