Serial Levels Research Articles

Imatinib alleviates lung injury and prolongs survival in ventilated rats.

Imatinib, a tyrosine kinase inhibitor, attenuates pulmonary edema and inflammation in lung injury. However, the physiological effects of this drug and their impact on outcomes are poorly characterized. Using serial computed tomography (CT), we tested the hypothesis that imatinib reduces injury severity and improves survival in ventilated rats. Hydrochloric acid (HCl) was instilled in the trachea (pH 1.5, 2.5 mL/kg) of anesthetized, intubated supine rats. Animals were randomized (n = 17 each group) to receive intraperitoneal imatinib or vehicle immediately prior to HCl. All rats then received mechanical ventilation. CT was performed hourly for 4 h. Images were quantitatively analyzed to assess the progression of radiological abnormalities. Injury severity was confirmed via hourly blood gases, serum biomarkers, bronchoalveolar lavage (BAL), and histopathology. Serial blood drug levels were measured in a subset of rats. Imatinib reduced mortality while delaying functional and radiological injury progression: out of 17 rats per condition, 2 control vs. 8 imatinib-treated rats survived until the end of the experiment (P = 0.02). Imatinib attenuated edema after lung injury (P < 0.05), and survival time in both groups was negatively correlated with increased lung mass (R2 = 0.70) as well as other physiological and CT parameters. Capillary leak (BAL protein concentration) was significantly lower in the treated group (P = 0.04). Peak drug concentration was reached after 70 min, and the drug half-life was 150 min. Imatinib decreased both mortality and lung injury severity in mechanically ventilated rats. Pharmacological inhibition of edema could be used during mechanical ventilation to improve the severity and outcome of lung injury.

Calcium chloride for the prevention of uterine atony during cesarean delivery: A pilot randomized controlled trial and pharmacokinetic study

Study objectiveTo assess the feasibility, patient tolerance, pharmacokinetics, and potential effectiveness of a randomized controlled trial protocol investigating intravenous calcium chloride for the prevention of uterine atony during cesarean delivery. DesignDouble-blind, randomized controlled pilot trial with nested population pharmacokinetic analysis. SettingThis study was performed at Lucile Packard Children's Hospital, from August 2018 to September 2019. PatientsForty patients with at least two risk factors for uterine atony at the time of cesarean delivery. InterventionsOne gram of intravenous calcium chloride (n = 20 patients) or a saline placebo control (n = 20 patients), in addition to standard care with oxytocin, upon umbilical cord clamping. MeasurementsThe primary efficacy-related outcome was the presence of uterine atony defined as the use of a second-line uterotonic medication, surgical interventions for atony, or hemorrhage with blood loss >1000 mL. Blood loss, uterine tone numerical rating scores, serial venous blood calcium levels, hemodynamics, and potential side effects were also assessed. Main resultsThe study protocol proved feasible. The incidence of atony was 20% in parturients who received calcium compared to 50% in the placebo group (relative risk 0.38, P = 0.07, 95% CI 0.15–1.07, NNT 3.3). Calcium recipients tolerated the drug infusion well, with no adverse events and an equal incidence of potential side effects in the calcium and placebo groups. Ionized calcium concentration rose significantly in all patients who received calcium infusion, from baseline 1.18 mmol/L to peak levels 1.50–1.60 mmol/L. One-compartment population pharmacokinetics established clearance of 0.93 (95% CI 0.63–1.52) L/min and volume of distribution 76 (95% CI 49–94) L. ConclusionsIn this pilot study, investigators found that intravenous calcium chloride was well-tolerated by the 20 patients assigned to receive the study drug and may be effective in prevention of uterine atony. A 1-g dose was sufficient to substantially increase calcium levels without any critically elevated lab values or concern for adverse side effects. These encouraging findings warrant further investigation of calcium as a novel agent to prevent uterine atony with an adequately powered clinical trial.Clinical trial registry NCT03867383 https://clinicaltrials.gov/ct2/show/NCT03867383

Effects of Multimodal Bundle with Remote Ischemic Preconditioning and Intrathecal Analgesia on Early Recovery of Estimated Glomerular Filtration Rate after Robot-Assisted Laparoscopic Partial Nephrectomy for Renal Cell Carcinoma.

Simple SummaryThis study suggested that robot-assisted laparoscopic partial nephrectomy (RALPN) may have benefits with regard to the preservation of renal function and few complications postoperatively in patients with renal cell carcinoma (RCC). However, a reduction in the estimated glomerular filtration rate may be unavoidable. Our results suggested that the preservation of renal function may be enhanced by combining robot-assisted nephron-sparing surgery with an intraoperative bundle strategy consisting of remote ischemic preconditioning (RIPC) and an intrathecal morphine block (ITMB), to protect against ischemia–reperfusion injury and the pain-related stress induced by renal artery clamping and surgical insults. It is important to adjust modifiable variables related to the progression of renal impairment in a timely and appropriate manner for the recovery of renal function after RALPN. Together with surgical and pharmacological methods to minimize irreversible injury, RIPC and ITMB combined bundle therapy may relieve ischemia–reperfusion- and pain-induced stress and serve as a safe and efficient method for improving renal outcomes of RALPN in patients with RCC.We investigated the effects of multimodal combined bundle therapy, consisting of remote ischemic preconditioning (RIPC) and intrathecal morphine block (ITMB), on the early recovery of kidney function after robot-assisted laparoscopic partial nephrectomy (RALPN) in patients with renal cell carcinoma (RCC). In addition, we compared the surgical and analgesic outcomes between patients with and without bundle treatment. This prospective randomized double-blind controlled trial was performed in a cohort of 80 patients with RCC, who were divided into two groups: a bundle group (n = 40) and non-bundle group (n = 40). The primary outcome was postoperative kidney function, defined as the lowest estimated glomerular filtration rate (eGFR) on postoperative day (POD) 2. Surgical complications, pain, and length of hospital stay were assessed as secondary outcomes. The eGFR immediately after surgery was significantly lower in the bundle group compared to the preoperative baseline, but serial levels on PODs 1 and 2 and at three and six months after surgery were comparable to the preoperative baseline. The eGFR level immediately after surgery was lower in the non-bundle than bundle group, and serial levels on PODs 1 and 2 and at three months after surgery remained below the baseline. The eGFR level immediately after surgery was higher in the bundle group than in the non-bundle group. The eGFR changes immediately after surgery, and on POD 1, were smaller in the bundle than in the non-bundle group. The non-bundle group had longer hospital stays and more severe pain than the bundle group, but there were no severe surgical complications in either group. The combined RIPC and ITMB bundle may relieve ischemia–reperfusion- and pain-induced stress, as a safe and efficient means of improving renal outcomes following RALPN in patients with RCC.

The Relationship Between Cord Blood Cytokine Levels and Perinatal Characteristics and Bronchopulmonary Dysplasia: A Case-Control Study.

ObjectiveTo establish the association between serial levels of inflammatory cytokines in cord blood and perinatal characteristics and bronchopulmonary dysplasia (BPD) in preterm infants.Methods147 premature infants with gestational age ≤32 weeks who were born and hospitalized in the First Affiliated Hospital of Zhengzhou University between July 2019 and August 2021 were enrolled in this retrospective case–control study. Multiple microsphere flow immunofluorescence was used to detect seven cytokines in cord blood collected within 24 h of birth. Demographics, delivery characteristics, maternal factors, neonatal characteristics, and clinical outcomes were collected for the two groups. An unconditional logistic regression model was used in this study to assess the clinical variables.ResultsIL-6 cord blood levels at birth were significantly higher in the BPD group than in the non-BPD group, but the odds ratio (OR) was very small (OR = 1). No differences in other cytokine concentrations were observed between the two groups. Multivariable logistic regression analysis demonstrated that increased maternal white blood cell (WBC) count on admission and lower birth weight increased the risk of BPD progression.ConclusionsIncreased IL-6 cord blood levels at birth in preterm infants may have trivial significance for predicting BPD. Furthermore, higher maternal WBC count on admission and lower birth weight increased the risk of BPD.

Incidence, Predictors, and Reversibility of Left Ventricular Dysfunction After Brain Death: The Donor Heart Study

<h3>Purpose</h3> Left ventricular (LV) dysfunction after brain death often prompts non-use of potential donor hearts for transplant, but little is known regarding its incidence, reversibility, and impact on outcomes. Shedding light on these unknowns was a primary aim of the Donor Heart Study -a first-of-its-kind, multisite, prospective study of potential heart donors. <h3>Methods</h3> We enrolled potential donors (n = 4333) at 8 organ procurement organizations across the United States from February 2015-May 2020. Data were collected on donor management, serial labs, and diagnostic tests. These included a transthoracic echocardiogram (TTE) performed within 48 hours after brain death and, if LV dysfunction was present, a repeat TTE 24 ± 6 hours later. LV dysfunction was defined as an ejection fraction (LVEF)<50%, as ascertained by a single expert reviewer, and was considered reversible if LVEF was >50% on the second TTE. LASSO models identified predictors of initial LV dysfunction and its reversibility. A conditional inference ("decision") tree was fit to identify threshold values that predict reversibility. <h3>Results</h3> An initial TTE was performed and interpretable for 3794 donors, and 493 (13%) had LV dysfunction. Significant predictors of LV dysfunction included: higher levels of troponin, nt-pro B-type natriuretic peptide (nt-proBNP), and lactate; higher mean arterial pressure, body temperature, use of vasopressors, and thyroid hormone; younger age; low body mass index (BMI≤ 20 kg/m2); and elevated blood urea nitrogen:creatinine ratio. A second TTE was performed for 224 donors with LV dysfunction and 130 (58%) of these demonstrated reversibility. Donors with baseline nt-proBNP levels >11,137 pg/ml were less likely to have LVEF improvement (30% vs 62%, p=0.008). Low BMI and reductions in serial nt-proBNP and lactate levels were the strongest predictors of reversibility. 59% of donor hearts with normal LV function were accepted for transplant, compared to 47% with reversible dysfunction and 29% with persistently low LVEF. <h3>Conclusion</h3> LV dysfunction after brain death is common among potential heart donors, but is reversible in the majority of cases. Commonly measured clinical variables are predictive of LV dysfunction and its subsequent improvement. Our results can better inform decisions made during donor management and evaluation, and can help guide donor heart acceptance.

Comparison of erythrocyte sedimentation rate and C-reactive protein in patients with distal radius fractures according to the prophylactic antibiotic period: 1 day versus 1 week

Purpose: Surgical site infection is a serious postoperative complication. Most surgical site infections after distal radius fracture (DRF) surgery are superficial and early-onset, and they can be prevented by prophylactic antibiotics. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are representative inflammatory markers. The aim of this study was to compare serial serum ESR and CRP levels in DRF patients according to the period of prophylactic antibiotic use.Methods: A retrospective study was conducted on 46 patients with DRF treated with internal fixation. Twenty-two patients treated between September 2019 and March 2020 were in group A and 24 patients who underwent treatment from September 2020 to March 2021 comprised group B. The patients in group A were administered the first-generation cephalosporin for 1 week, as was customary. Group B received 1-day antibiotic prophylaxis. Surgery was performed by a single surgeon using volar locking plates. The surgical wounds and serum ESR and CRP levels were examined before surgery, 2 days after surgery, and 1 week after surgery and compared between the two groups.Results: The CRP level, but not the ESR, changed significantly over time within each group. However, no statistically significant difference was observed between the two groups, and there were no surgical site infections.Conclusion: The use of prophylactic antibiotics for 1 week had no significant effect on reducing ESR and CRP compared to 1-day prophylactic antibiotics in patients with DRFs.

Clinical significance of soluble interleukin-2 receptor measurement in patients with idiopathic retroperitoneal fibrosis.

Idiopathic retroperitoneal fibrosis (iRPF) is a rare chronic fibro-inflammatory disorder of unknown etiology. Activated T-helper cells, which shed soluble interleukin-2 receptor (sIL-2R) into the circulation, may play a pathogenetic role. Hence, measuring sIL-2R may be of value in monitoring disease activity and treatment response in iRPF patients. We performed a prospective inception cohort study of 82 patients with untreated (re)active iRPF stratified by elevated (> 623U/mL) or normal sIL-2R level at baseline and compared disease characteristics among these groups. Baseline and changes in sIL-2R levels following treatment with tamoxifen (TMX) or prednisone (PDN) were analyzed and related to treatment response. Median sIL-2R level was 668 U/mL (IQR 502.8-827.5); 48 patients (59%) had elevated baseline sIL-2R levels. Patients with elevated sIL-2R presented with higher CRP (P = 0.049) and serum creatinine (sCr) levels (P < 0.001) and more often had hydroureteronephrosis (P = 0.01). There was an age and sex adjusted linear association between baseline sIL-2R and both CRP (P = 0.02) and sCr (P < 0.001). Baseline and serial levels of sIL-2R were predictive and concordant, respectively, with clinical response in patients treated with PDN. ROC curve analyses of sIL-2R on a continuous scale and PDN treatment success showed an AUC of 0.84. A serum sIL-2R cut-off value for PDN treatment success of ≤ 703U/mL was found with a sensitivity of 100% and specificity of 72%. Serial measurement of sIL-2R may be of value in monitoring disease activity and PDN treatment response in iRPF patients.

Increased serial levels of platelet‐derived growth factor using hypoxic mesenchymal stem cell‐conditioned medium to promote closure acceler‐ ation in a full‐thickness wound

The healing process of a full‐thickness wound involves a complex cascade of cellular responses to reverse skin integrity formation. These processes require growth factors, particularly platelet‐derived growth factor (PDGF). Conversely, hypoxic mesenchymal stem‐cell‐conditioned medium (HMSC‐CM)‐contained growth factors notably contribute to acceleration of wound healing. This study aims to investigate the role of HMSC‐CM in controlling the serial levels of PDGF associated with accelerated wound closure in full‐thickness wounds. Twenty male Wistar rats with full‐thickness wounds were developed as animal models. The animals were randomly assigned to four groups, comprising two treatment groups (treated using HMSC‐CM at a high dose as P1 and at a low dose as P2), a control group (administration of base gel), and sham group (healthy group). PDGF levels were examined using an enzyme‐linked immunosorbent assay. Using ImageJ software, wound closure percentages were determined photographically. The study showed that there was a significant increase in PDGF levels on days 3 and 6 after HMSC‐CM treatment, followed by a decrease in PDGF levels on day 9. In line with these findings, wound closure percentage also increased significantly on days 6 and 9. In the rat model, HMSC‐CM administration may promote acceleration of wound closure by increasing serial PDGF levels in the full‐thickness wound.

A Diagnosis of Choriocarcinoma in a Parturient Presenting With Intracranial Hemorrhage

Choriocarcinoma in a viable pregnancy is uncommon. The diagnosis can easily be missed when there is an explanation for the clinical symptoms that the cancer can mimic. We present the case of a primigravid patient whose choriocarcinoma was initially missed as a result of seemingly obvious explanations for her atypical history and disease manifestation. The patient is a Caucasian female at 30 weeks and 5 days of gestation who presented with persistent headaches and new-onset tonic-clonic seizures found on brain magnetic resonance imaging (MRI) to have a left intracranial hematoma, a 5 mm midline shift, and multiple foci of restricted diffusion. Cerebral angiogram demonstrated arteriovenous malformations (AVMs). The fetus was emergently delivered 1 week into hospitalization for non-reassuring fetal heart tracings in the setting of maternal lethargy secondary to continued AVM hemorrhage. The patient’s hospital course was complicated by four episodes of intracranial bleeding and edema requiring neurosurgical intervention. Three weeks after hospitalization she was discharged to a rehabilitation center, shortly after which placental biopsy demonstrated choriocarcinoma. MRI after readmission demonstrated extensive metastatic disease and human chorionic gonadotropin (hCG) levels were greater than 225,000 mIU/mL. Despite two additional neurosurgical procedures and extensive chemotherapy the patient died 3 months after initial presentation. Choriocarcinoma is extremely rare in viable pregnancies, but it should be considered when a parturient presents with intracranial bleeding. A high level of suspicion and serial serum hCG levels may lead to early and potentially life-saving multidrug chemotherapy. With a broader differential, earlier hCG measurement, and earlier treatment, our patient may have survived.

The Predictive Value of Shock Index versus Modified Shock Index in Critically Ill COVID-19 Infected Patients

Background/Aim: Having reliable indicators and markers that would help in prognosticating the survival are invaluable and would consequently assist in the course of effective treatment. Our objectives in this study were to compare the ability of SI and mSI to predict the primary outcomes of overall 28-day mortality rate in SARS-CoV-2 infected hemodynamic unstable critically ill patients. Methods: This study was retrospectively conducted and both of confirmed and suspected affected critically ill COVID-19 patients were included in our study. Hemodynamics variables of SI and mSI were mathematically calculated after dividing HR over SBP and MAP. All tested variables and others were comparatively compared across the two studied affected COVID-19 patients; Survivors Cohort (Cohort I) and Non-Survivors Cohort (Cohort II) using One Sample and Independent-T Tests in addition to Chi Square Test for categorical retrievable data. ROC curves were constructed for SI and mSI, and the area under the ROC curves (AUROCs) were statistically compared using proposed Delong Method. The optimal operating cutoffs on each ROC curve for the two tested prognosticators were also investigated by picking the highest youden’s index. Results: The mean age of the whole study cohort was 51.88±16.22 years, and the Non-Survivors Cohort were significantly older than the Survivors Cohort. Significantly, males were distributed in the study in approximately 2.57: 1 ratio compared to female. There were statistically significant differences regarding serum albumin levels profile during the 1st admission week, among the 3 serial albumin day levels. The overall incidences of NOPST were assessed at 65.9% during an average of 14.08±4.06 days. The Non-Survivors Cohort had also significantly higher SI and mSI compared to Survivors Cohort [1.16±0.14 bpm/mmHg and 1.67±0.23 bpm/mmHg versus 0.92±0.04 bpm/mmHg and 1.30±0.07 bpm/mmHg; +0.24±0.01 bpm/mmHg and -0.37±0.01 bpm/mmHg, respectively, p-Value=0.001]. SI had a higher AUROC than mSI with Area±SEM (95% CI; Range) of 0.983±0.002 (95% CI; 0.978-0.987) versus 0.959±0.004 (95% CI; 0.950-0.967) and the best cut-off values for SI and mSI were 0.99 bpm/mmHg and 1.43 bpm/mmHg, respectively. Conclusion: In summary, our stated hemodynamic based mortality prognosticators may be an early effective, no-cost bedside, realistic, reliable triaging modalities with high sensitivity, specificity, performance. Also, SI may be used as an additional or readily available red flag bedside assessment tool for severe disease.

The Predictive Value of Shock Index versus Modified Shock Index in Critically Ill COVID-19 Infected Patients

Background/Aim: Having reliable indicators and markers that would help in prognosticating the survival are invaluable and would consequently assist in the course of effective treatment. Our objectives in this study were to compare the ability of SI and mSI to predict the primary outcomes of overall 28-day mortality rate in SARS-CoV-2 infected hemodynamic unstable critically ill patients. Methods: This study was retrospectively conducted and both of confirmed and suspected affected critically ill COVID-19 patients were included in our study. Hemodynamics variables of SI and mSI were mathematically calculated after dividing HR over SBP and MAP. All tested variables and others were comparatively compared across the two studied affected COVID-19 patients; Survivors Cohort (Cohort I) and Non-Survivors Cohort (Cohort II) using One Sample and Independent-T Tests in addition to Chi Square Test for categorical retrievable data. ROC curves were constructed for SI and mSI, and the area under the ROC curves (AUROCs) were statistically compared using proposed Delong Method. The optimal operating cutoffs on each ROC curve for the two tested prognosticators were also investigated by picking the highest youden’s index. Results: The mean age of the whole study cohort was 51.88±16.22 years, and the Non-Survivors Cohort were significantly older than the Survivors Cohort. Significantly, males were distributed in the study in approximately 2.57: 1 ratio compared to female. There were statistically significant differences regarding serum albumin levels profile during the 1st admission week, among the 3 serial albumin day levels. The overall incidences of NOPST were assessed at 65.9% during an average of 14.08±4.06 days. The Non-Survivors Cohort had also significantly higher SI and mSI compared to Survivors Cohort [1.16±0.14 bpm/mmHg and 1.67±0.23 bpm/mmHg versus 0.92±0.04 bpm/mmHg and 1.30±0.07 bpm/mmHg; +0.24±0.01 bpm/mmHg and -0.37±0.01 bpm/mmHg, respectively, p-Value=0.001]. SI had a higher AUROC than mSI with Area±SEM (95% CI; Range) of 0.983±0.002 (95% CI; 0.978-0.987) versus 0.959±0.004 (95% CI; 0.950-0.967) and the best cut-off values for SI and mSI were 0.99 bpm/mmHg and 1.43 bpm/mmHg, respectively. Conclusion: In summary, our stated hemodynamic based mortality prognosticators may be an early effective, no-cost bedside, realistic, reliable triaging modalities with high sensitivity, specificity, performance. Also, SI may be used as an additional or readily available red flag bedside assessment tool for severe disease.

Frequency and Clinical Significance of Elevated IgG4 in Rheumatoid Arthritis: A Systematic Review.

Immunoglobulin (Ig)G4 is a unique protein molecule and its role in autoimmune diseases remains elusive and controversial. Accumulating evidence suggests a pathogenic role of IgG4 in rheumatoid arthritis (RA). Rheumatoid factors (RF) in RA can recognize the Fc domains of IgG4 to form RF-IgG4 immune complexes that may activate the complement system leading to synovial injury. The aim of this article was to systematically review the literature from the past 2 decades to determine the frequency of elevated IgG4 and its clinical significance in RA. We comprehensively searched the Pubmed, Scopus, and Web of Science databases with the following terms: “IgG4”, “rheumatoid arthritis”, and “immunoglobulin G4”, and scrutinized all of the relevant publications. Based on the selection criteria, 12 studies were incorporated, which involved a total of 1715 RA patients. Out of 328 subjects from three studies, the pooled frequency of elevated non-specific IgG4 was 35.98%. There was a significant positive correlation between the IgG4 levels and the RA disease activity based on DAS-28 measurements (r = 0.245–0.253) and inflammatory markers, i.e., erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (r = 0.262–0.389). Longitudinal studies that measured the serial levels of IgG4 consistently showed a decline in the concentrations (up to 48% less than baseline) with disease modifying anti-rheumatic drug (DMARD) treatment. Current evidence suggests that serum IgG4 levels are significantly elevated in RA compared to the general population. This review indicates that IgG4 is a promising biomarker of disease activity and tends to decline in response to DMARD therapies. Biologic therapies have revolutionized the therapeutic armamentarium of RA in the recent decade, and IgG4 appears to be a potential treatment target.

Abstract P1-18-14: Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study

Abstract Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had &amp;gt;3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations. Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-14.

Abstract OT1-05-01: Glycoprotein 88 (GP-88) serum levels as a marker of response to therapy in patients with metastatic breast cancer

Abstract The ability to detect metastatic breast cancer (MBC) &amp; readily monitor response to therapy is an important goal in the management of breast cancer (BC). Imaging is used for the assessment &amp; monitoring of disease progression. However, this is expensive &amp; represents a late marker of disease status. The disease may progress significantly on ineffective treatment &amp; the patient may have treatment related toxicities due to the lack of knowledge of the progression at earlier times. Circulating tumor associated biomarkers CA15-3 &amp; CEA can be used to track disease status of MBC, however, they are not always a reliable measure of disease progression. The monitoring of disease progression through measurement of drivers of disease may better reflect the disease status &amp; enable proactive management sooner. GP88 (granulin/epithelin precursor or progranulin) has been identified as a driver of tumorigenesis &amp; disease progression through its signaling as an autocrine growth &amp; survival factor for several cancers including BC1. We hypothesized that measurement of circulating serum GP88 levels can serve as a biomarker to monitor MBC disease status &amp; be prognostic to outcome 2. Clinical studies have demonstrated circulating levels of GP88 statistically differ in healthy volunteers, early BC patients (pts), &amp; pts with metastatic disease &amp; levels correlate with overall survival2,3. The primary aim of this prospective study is to identify whether there is a statistically significant change in serum GP88 levels associated with response to treatment &amp; time to progression of BC as measured by RECIST 1.1 criteria in MBC pts. Under an IRB approved protocol at the University of Maryland Greenbaum Comprehensive Cancer Center, a total of 103 female pts with measurable or evaluable metastatic disease who have been re-staged in within 4 weeks &amp; will continue or begin new therapy &amp; meet the additional criteria will be consented &amp; enrolled. Currently, we have enrolled 23 pts. In addition to standard of care laboratory assessment &amp; radiographic imaging/staging every 2-3 months, blood samples will be collected from each patient. The samples will be stored at -70C until tested for GP88 using a GP88 enzyme linked immunoassay. We will analyze the serial GP88 serum levels &amp; correlate with treatment response using RECIST 1.1 criteria (stable, progression, response), time to progression &amp; overall survival. We assume that pts will provide a baseline &amp; 4 follow up visits/GP-88 levels &amp; that 20% of the visits will record a disease progression &amp; time to progression. The probable &amp; clinically relevant GP-88 test performance will then have 75% sensitivity &amp; 46% false positivity with 85% power in a sample of 90 pts.

Imatinib-associated skin rash is related to treatment outcome in patients with unresectable and/or metastatic gastrointestinal stromal tumor.

Imatinib-associated skin rash in gastrointestinal stromal tumor (GIST) patients is one of the most troublesome adverse effects, and can reduce imatinib adherence and persistence. However, the relationship between skin rash and adherence is unknown, and there are few published studies on the clinical outcomes of patients with severe skin rash. Adult patients (≥18 years) who were treated with 400 mg/day imatinib for unresectable or metastatic GIST were enrolled in this retrospective study. The skin rash was graded by physicians according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Progression-free survival (PFS) was compared using the Kaplan-Meier method between groups with and without skin rash. The risk factors for GIST progression were investigated by Cox regression analysis. A total of 125 GIST patients were finally included. Among them, 43 (34.4%) patients developed skin rash during imatinib treatment. Serial blood eosinophil levels were associated with skin rash and severity (P<0.001). Patients with skin rash tended to have poorer PFS than patients with no rash (P=0.035). Moreover, patients with rash had a significantly higher prevalence of non-adherence compared with patients without rash [odds ratio (OR): 3.42, 95% confidence interval (CI): 1.36-8.61, P=0.009 for grades 1-2; OR: 6.07, 95% CI: 1.42-26.11, P=0.015 for grades 3-4). Cox regression analysis indicated that the independent risk factors for GIST progression were non-adherence (OR: 4.20, 95% CI: 1.57-11.25, P=0.004) and medium- and high-risk GIST (OR: 5.38, 95% CI: 1.15-25.09, P=0.032). Non-adherence and medium- and high-risk GIST are independent risk factors for GIST progression. Skin rash can be associated with treatment adherence, which can in turn be associated with poor outcomes of GIST treatment. Measuring the blood eosinophil levels could be helpful in predicting risk of skin rash during imatinib treatment.

Serum Cytokeratin 18 as a Metastatic and Therapeutic Marker for Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with unfavourable prognosis once it becomes invasive. A tumour marker that reflects disease progression is required for adequate management of EMPD. Cytokeratin 18 is highly expressed in many types of cancer and its soluble forms are detected by M30 (for caspase-cleaved form) and M65 (for both caspase-cleaved and intact forms) assays. We report here that tumour cells of EMPD in both lesional skin and lymph node metastasis are immunohistochemically positive for CK18, and the baseline serum M30 and M65 levels in patients with metastatic EMPD are significantly higher than those in non-metastatic patients. In addition, serial serum M30 and M65 levels might reflect recurrence of EMPD and response to chemotherapy. These results suggest that serum CK18 levels may be a useful tumour marker for advanced EMPD.

Prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) predicts complete responses of transarterial chemoembolization for hepatocellular carcinoma

Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) is a diagnostic marker for hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) is the standard management for intermediate stage HCC but lacks effective response predictors. We investigated the utility of PIVKA-II as a predictor of TACE response. This prospective study included consecutive patients with HCC undergoing TACE in Taiwan. Serum PIVKA-II levels were measured before and serially after TACE. Multivariable analyses were conducted to evaluate predictors of mortality, complete responses (CR) to TACE and unTACEable progression. We included 46 patients with HCC (median age: 64 years, men:72%), and Barcelona Clinic Liver Cancer (BCLC) stages A (17%), B (65%), or C (17%). Before TACE, the median PIVKA-II level was 189 mAU/mL. After a median follow-up of 16 months, 27 (59%) patients died. PIVKA-II was positively correlated with tumor burden. Patients with infiltrative HCC or HCC exceeding the up-to-7 criteria had significantly higher baseline PIVKA-II levels than those without. Multivariable analysis indicated the infiltrative HCC independently predicted mortality. In patients BCLC A and B (n=38), low baseline PIVKA-II (<26 mAU/mL) predicted CR to TACE, whereas high PIVKA-II predicted unTACEable tumor progression. Observations from a validation cohort corroborated the initial result that low PIVKA-II predicts CR. Moreover, serial PIVKA-II levels post TACE were significantly lower in patients with a CR to TACE compared with those without. Low baseline PIVKA-II level helps to predict a CR of TACE in patients with HCC.

Sequential blood lactate measurement as death alarm for the patient with sepsis

The lactate levels in the blood are raised in septicemia, signifying reduced oxidative phosphorylation, which secondarily causes hypoxic hypoxia and stagnant tissue hypoxia. Hence, a high rise of the lactate level in blood may be a valuable forecaster of mortality of patients suffering from severe infection along with some biochemical and clinical related factors. Therefore, in the current study, we evaluated the relationship between serial blood lactate levels and mortality among patients with life-threatening sepsis infections admitted to the Critical Care Centre. It was a cross-sectional study. In this descriptive study, we have included 50 septicemic patients above the age of 18 years. At admission, 24 hours and 72 hours, we monitored the blood's lactate levels. Grouping of the patients as survivors and non-survivor was done based on their clinical status for four weeks. To test the difference in mean blood lactate levels among survivors and non-survivors, student's t-test was applied. The statistical analysis was made with Microsoft Excel and SPSS version 20. A p-value of less than 0.05 was considered significant. In the current study, 23 were survivors, and 27 were non-survivors after 28 follow-ups. The mean lactate range for the 23 survivors ranged from 0.43 mmol/l to 5.69 mmol/l, whereas for non-survivors, it was 1.64 mmol/l to 6.14 mmol/l. The mean value of lactate for the survivors and non-survivors during admission time, at 24 hours and 72 hours were 0.9545±0.45798 vs 2.5204±1.51498, 1.2461±1.21360 vs 2.5107±1.63678 and 1.5496±1.66788 vs 2.7904±2.00160. The differences between the mean lactate values between survivors and the fatal group at different time intervals were highly significant. The result reveals serial blood lactate levels as a significant predictor of mortality in patients with sepsis.

Role of High-Sensitivity Troponin-T And N-Terminal Pro B-Type Natriuretic Peptide as an Early Predictor of Myocardial Dysfunction in Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study.

Acute cardiac complications are commonly seen in aneurysmal subarachnoid hemorrhage (aSAH) patients and may vary from subclinical electrocardiographic abnormalities, or reduced ejection fraction on echocardiography, elevated levels of cardiac markers (cardiac troponin and Brain natriuretic peptide) to heart failure. This study was done to evaluate the role of cardiac markers (high-sensitive Troponin-T and N-terminal pro-B-type natriuretic peptide) in early identification of cardiac complications and hence dysfunction. All consecutive patients with aSAH without any previous cardiac history were included. At admission, neurological evaluation using Hunt and Hess grading (H and H grade), with electrocardiography to look for any changes, echocardiography for ejection fraction, and any wall motion abnormalities was also done. The serial serum levels of high-sensitive Troponin-T (hsTnT) and N-terminal pro B-type natriuretic peptide (NT pro-BNP) for 7 consecutive days was measured with hsTnT >0.14 ng/ml and NT pro-BNP >150 pg/mL considered elevated. A total of 69 patients were included. The elevated peak level of hsTnT and NT pro-BNP was seen in 55.1% and 69.6% of patients. A positive correlation was seen between hsTnT (P = 0.033) and NT pro-BNP (P = 0.011) and poor SAH grade (H and H grade 3-5), similarly, abnormal ECG also significantly correlated with elevated peak hsTnT (P = 0.002) and NT proBNP (P = 0.000). Also, significant difference in peak hsTnT (P = 0.000) and NT-proBNP (P = 0.000) in patients with or without reduced ejection fraction (EF). The elevated peak levels of hsTnT and NTproBNP along with ECG and echocardiography abnormalities may help in early identification of myocardial injury, hence cardiac dysfunction.

Medullary Thyroid Cancer: An Experience from a Tertiary Care Hospital of a Developing Country.

Background:Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer that occasionally occurs as part of MEN2A. The universal treatment of MTC is total thyroidectomy with central lymph node dissection. For disease progression, carcinoembryonic antigen (CEA) and calcitonin (CTN) need to be followed. Our aim was to study the presence and patterns of the above-mentioned characteristics of MTC in our population.Methodology:This retrospective study was conducted in a tertiary care hospital of Pakistan in which data of thirty-two medullary thyroid cancer patients over the past 20 years were reviewed and analysed after fulfilment of inclusion criteria. Their clinical, pathological, biochemical and treatment modalities were recorded through a retrospective review of their medical record files.Results:The mean age of patients was 42.88 ± 2.67 years in our study, with a male-to-female ratio of 2:1. Patients with sporadic MTC were 68.8%, while 31.2% were familial. The rates of metastasis were highest in bones followed by lungs and liver. Total thyroidectomy was performed in 26 (81.2%) patients and among those chemotherapy and XRT were performed in one and two patients, respectively. Histologically, the mean tumour size was 7.62 ± 3.64 cm. Median pre-surgery calcitonin was 5756 pg/ml that decreased to 29.3 pg/ml post-surgery. Median pre-surgery CEA level was 246.5 ng/ml that decreased to 6.39 ng/ml post-surgery. Two patients were RET positive.Conclusion:MTC usually presents in the fourth decade of life with male predominance and mostly sporadic occurrence. Total thyroidectomy with subsequent serial calcitonin and CEA levels thereafter are the mainstay of treatment and follow-up.