Change in the value of the QT interval at various stages of the perioperative period in patients with coronary ischemic heart disease under general anesthesia

Objective. To evaluate the status of QT interval derivatives in patients with chronic IHD during different perioperative periods of planned open cholecystectomy under general anaesthesia and to determine the possibility of using meldonium for prevention of QT interval dysfunction. Materials and methods. Patients with the diagnosis of cholelithiasis with verified forms of chronic CHD (angina I and II AC) were divided into 2 groups: Group 1 was the control group with conventional perioperative therapy, and Group 2 was the main group with additional meldonium. The dynamics of the corrected QT interval (QTc) and the variance of the QT interval (DQT) were assessed. Analysis was performed by means of daily Holter ECG monitoring, in which 6 time periods were singled out: 1 - the day before the operation (18 hours); 2 - hours before the operation; 3 - induction into anesthesia; 4 - maintenance of anesthesia; 5 - withdrawal from anesthesia; 6 - the day 2 after the operation (18 hours). Results. The increase in QTc and DQT values during induction, maintenance and withdrawal from anesthesia was detected only in the control group. The inclusion of meldonium in perioperative therapy in patients with CHD was accompanied by the absence of QTc interval prolongation and an increase in DQT values in the periods of induction, exit and maintenance of anaesthesia. Conclusion. The perioperative period was accompanied by a prolongation of the QTc interval and an increase in DQT values in the group receiving conventional therapy. The inclusion of meldonium was accompanied by no increase in QTc and DQT during most follow-up periods.

Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial

Aim To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42–2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. Conclusion CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. Trial registration ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

The Contribution of the Hunger Hormone Leptin in the Aetiology of Postoperative Anorexia after Laparoscopic and Open Gastrectomy in Gastric Cancer Patients

Background: Laparoscopic surgery produces lesser postoperative inflammation with a smaller cytokine and leptin response, and might thus reduce postoperative anorexia compared with open surgery. The aim of the present study was to determine the role of serum leptin in postoperative anorexia after laparoscopic gastric cancer surgery. Methods: Fifty-four consecutive patients with adenocarcinoma of the stomach were operated on either with open or laparoscopic surgery. Correlations were determined between the serum levels of leptin, clinico-pathological characteristics, serum haemoglobin, and albumin. Results: Serum leptin levels on day seven were correlated significantly to gender (p = 0.004), body mass index (BMI) (p = 0.002), and tumour grade (p = 0.033). In the patients with C-reactive protein (CRP) < 100 mg/L (n = 46) the leptin levels on day seven were significantly lower after the laparoscopic operation (p = 0.042) and in patients with lower BMI (p = 0.001). The linear regression model determined a significant correlation between the relative concentration of leptin on day seven and laparoscopic surgery (Beta−0.688; p < 0.0001), gender, BMI, location of the tumour, T stage, N stage, perioperative therapy, tumour grade, perineural invasion, Lauren histological type, and ulceration. In patients with CRP levels below 100 mg/mL, the serum level of albumin on day seven after surgery was significantly higher in patients after laparoscopic surgery. Conclusion: Laparoscopic surgery produced significantly lower relative leptin concentrations on day seven, and higher serum albumin levels in the subgroup with CRP levels below 100 mg/L at discharge. These results suggested that laparoscopic gastric cancer surgery might reduce postoperative leptin response, leading to a better nutritional status at discharge compared with open surgery.

The Contribution of the Hunger Hormone Leptin in the Aetiology of Postoperative Anorexia After Laparoscopic and Open Gastrectomy in Gastric Cancer Patients

Background: Laparoscopic surgery produces lesser postoperative inflammation with a smaller cytokine and leptin response, and might thus reduce postoperative anorexia compared to open surgery. The aim of the present study was to determine the role of serum leptin in postoperative anorexia after laparoscopic gastric cancer surgery. Methods: Fifty-four consecutive patients with adenocarcinoma of the stomach were operated on either with open or laparoscopic surgery. Correlations were determined between the serum levels of leptin, clinico-pathological characteristics, serum haemoglobin and albumin. Results: Serum leptin levels on day seven were correlated significantly to gender (p=0.004), BMI (p=0.002) and tumour grade (p=0.033). In the patients with CRP &lt; 100 mg/l the leptin levels on day seven were significantly lower after the laparoscopic operation (p=0.042) and in patients with lower BMI (p=0.001). The linear regression model determined a significant correlation between the relative concentration of leptin on day seven and laparoscopic surgery (Beta -0.688; p &lt; 0.0001), gender, BMI, location of the tumour, T stage, N stage, perioperative therapy, tumour grade, perineural invasion, Lauren histological type and ulceration. In patients with CRP levels below 100 mg/ml the serum level of albumin on day seven after surgery was significantly higher in patients after laparoscopic surgery. Conclusion: Laparoscopic surgery produced significantly lower relative leptin concentrations on day seven, and higher serum albumin levels in the subgroup with CRP levels below 100 mg/l at discharge. These results suggested that laparoscopic gastric cancer surgery might reduce postoperative leptin response, leading to a better nutritional status at discharge compared to open surgery.

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

Lymph Node Involvement in Advanced Gastric Cancer in the Era of Multimodal Treatment—Oncological and Surgical Perspective

Gastric cancer (GC) continues to be one of the major oncological challenges on a global scale. The role of neoadjuvant chemotherapy (NAC) in GC is to downstage primary tumour, eliminate potential micrometastases, and increase the chance for radical resection. Although systemic treatment prolongs the survival in advanced GC, persistent lymph node (LN) metastases indicate poor prognosis. Further identification of prognostic factors after NAC is urgent and could positively influence clinical outcomes. This article aimed to review the actual trends and future perspectives in multimodal therapy of advanced GC, with a particular interest in the post-neoadjuvant pathological nodal stage. A favourable prognostic impact for ypN0 patients is observed, either due to truly negative LN before the start of therapy or because preoperative therapy achieved a pathologically complete nodal response. Ongoing trials investigating the extent of lymphadenectomy after neoadjuvant therapy will standardise the LN dissection from the multimodal therapy perspective. Since downstaged and primarily node-negative patients show a similar prognosis, the main target for NAC in advanced GC should be nodal clearance. Adequate staging and personalised perioperative therapy seem to be of great importance in the multimodal treatment of GC.

A randomized phase II study comparing cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma.

4507 Background: Cisplatin with gemcitabine (CG) remains the standard upfront chemotherapy regimen for metastatic urothelial cancer (mUC). Preclinical synergy was noted between cisplatin and berzosertib, a selective ATR inhibitor. The current study sought to determine if the combination of berzosertib and CG could improve clinical outcomes in mUC. Methods: An open-label, randomized study was conducted across 23 centers in the United States through the Experimental Therapeutics Clinical Trials Network of the National Cancer Institute. Key eligibility criteria included confirmed mUC, no prior cytotoxic therapy for metastatic disease, ≥ 12 months since perioperative therapy and eligibility for cisplatin based on standard criteria. Patients (pts) were randomized to receive either CG alone (control arm) or CG plus berzosertib (experimental arm). In the control arm, 70 mg/m2 of cisplatin was given on day 1 and gemcitabine at 1000 mg/m2 on days 1 and 8 of a 21-day cycle. In the experimental arm, 60 mg/m2 of cisplatin was given on day 1, gemcitabine at 875 mg/m2 on days 1 and 8 and berzosertib at 90 mg/m2 on days 2 and 9 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized; 41 pts received CG alone while 46 received CG with berzosertib. Visceral metastases were present in 49% of pts and 52%, 45% and 3% of pts were Bajorin risk 0, 1 and 2, respectively. Median PFS was 8.0 months for both arms (Bajorin risk adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.72-2.08). RR was 54%(4 CR, 21 PR) in the CG with berzosertib arm and 63% (4 CR, 22 PR) in CG alone arm (P = 0.66). Median OS was shorter with CG with berzosertib as compared to CG alone (14.4 versus 19.8 months; Bajorin risk adjusted HR 1.42, 95%CI 0.76-2.68). Notably higher rates of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with CG plus berzosertib compared to CG alone. Higher rates of toxicity-related discontinuation were seen in the experimental arm (24% vs 15%), and the median cumulative cisplatin dose in the experimental arm was 250 mg/m2, as compared to 370 mg/m2 in the control arm (P < 0.001). Conclusions: No improvement in PFS was observed with the addition of berzosertib to CG, and a trend towards inferior survival was observed. These results suggest caution in reducing the starting dose of cytotoxic therapy to accommodate addition of a myelosuppressive agent, as in the experimental arm of this study. Clinical trial information: NCT02567409.

The prognostic value of tumor markers in patients (pts) with resectable gastric cancer (GC) receiving perioperative therapy in the CRITICS trial.

4024 Background: Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are well-known tumor markers. Most studies on CEA and CA 19-9 in pts with GC were performed in Asia, and/or in the metastatic setting. The aim of this study was to investigate the prognostic value of blood derived laboratory parameters in a cohort of European pts with resectable non-metastatic GC. Methods: In the CRITICS trial, 788 pts with resectable GC underwent perioperative therapy (preoperative chemotherapy plus either postoperative chemotherapy or postoperative chemoradiotherapy). Blood levels of CEA, CA 19-9, alkaline phosphatase (AP), creatinine, neutrophils, hemoglobin (Hb) and lactate dehydrogenase (LDH) were determined prior to treatment. Data for these variables were available for at least 89% of the pts. Factors significant on univariable cox regression analysis were further explored in multivariable analysis. Probabilities to undergo potentially curative surgery was investigated for factors significant on multivariable analysis. The relationship between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 pts with available ctDNA data. Results: CEA and CA 19-9 were identified as independent prognostic factors for survival (Table). Probabilities to undergo potentially curative surgery were 86%, 77% and 60% for pts with no elevated tumor makers versus those with elevated CEA or elevated CA 19-9 versus those with both tumor markers elevated, respectively (p<0.001). No relationship was found between elevated tumor marker(s) and the presence of ctDNA neither pretreatment nor preoperatively. Conclusions: Pretreatment blood levels of CEA and CA 19-9 were identified as prognostic factors for overall survival in a large cohort of European GC pts with potentially curable disease. These factors may guide treatment choices at an early phase and should be included in future trials to determine their role in clinical decision making.[Table: see text]

P361 No increased postoperative risk of venous thromboembolism in patients with Ulcerative Colitis undergoing colectomy after tofacitinib exposure

Background Colectomy for ulcerative colitis (UC) has been associated with postoperative morbidity and mortality, including venous thromboembolism (VTE). Patients with inflammatory bowel diseases (IBD) have a 2 to 4-fold increased risk for developing VTE, as compared to non-IBD patients. Due to recent concerns on increased VTE associated with tofacitinib exposure, we aimed to evaluate the 180-day postoperative VTE risk in UC patients undergoing colectomy after tofacitinib use in comparison to patients failing biologicals and undergoing the same surgery. Methods This retrospective cohort study included all UC patients who underwent colectomy between 2014 and 2020 in our tertiary IBD center. All medical charts were reviewed, and clinically relevant information extracted, including indication for colectomy, development of postoperative VTE (deep venous thrombosis, pulmonary or extra-pulmonary embolisms) within 180 days of surgery, low-molecular weight heparin (LMWH) prophylaxis and perioperative therapy exposure (steroids within 1 month prior to surgery, biologicals or tofacitinib within 3 months prior to surgery). Results One-hundred seven UC patients (49.5% women, median [IQR] age 38.0 [27.0 – 53.0] years) underwent colectomy due to refractory disease (n=93), dysplasia or carcinoma (n=12) or polyposis (n=2) (Table 1). Thirty-six (33.6%) patients were operated urgently. At the time of surgery, 44 (41.1%) were on steroids, 38 (35.5%) on anti-TNF agents, 27 (25.2%) on vedolizumab/etrolizumab, 6 (5.6%) on anti-IL12/23 agents and 12 (11.2%) on tofacitinib. All patients received antithrombotic prophylactic LMWH postoperatively. During the 180-day postoperative period, 3 (2.8%) patients developed an intra-abdominal thrombosis, none of them had a history of VTE. Two thromboses were found by coincidence on CT scans which were performed in light of postoperative fever and inflammatory blood tests, the other patient was symptomatic. All 3 patients had been exposed to vedolizumab: one had an underlying malignancy (colon adenocarcinoma), the 2 others also had been exposed to corticosteroids prior to colectomy. No VTE was seen in the patients who underwent colectomy while on tofacitinib. Conclusion The overall risk for UC patients to develop VTE after colectomy is low with adequate antithrombotic prophylactic therapy. In particular, we did not observe any VTE in our colectomy patients who were exposed to tofacitinib prior to surgery. The three patients who developed VTE despite LMWH had additional risk factors (concomitant steroid use, active cancer).