Vol 53, No 2 (2025)
ARTICLES
The ejection fraction and the cardiac index in the perioperative period of coronary artery bypass grafting: what is worth relying on?
Abstract
Rationale: Ejection fraction (EF) has been recognized as a key echocardiographic parameter describing the systolic function of the heart. Nevertheless, its accuracy for the assessment of the hemodynamic status in the perioperative period of cardiac surgery remains a debate.
Aim: To compare the EF values assessed by different techniques and to map those against the left ventricular systolic function parameters in the perioperative period of the off-pump coronary artery bypass grafting (OPCABG).
Methods: We performed a post hoc analysis of two consequential randomized studies. EF was assessed with echocardiography in 115 patients in the perioperative period of OPCABG and its changes over time at the following timepoints: before admission to the hospital (EFscreening), on the day before surgery (EFsimpson) (transthoracic approach), before sternotomy, at the end of the surgery (transesophageal echocardiography, TEE), as well as at the end of the first postoperative day (POD1) and before discharge from the hospital (transthoracic approach). Preoperatively and at the end of POD1, the EF values were compared with those of the global longitudinal strain (GLS) and with the EF measured automatically (EFauto, QLAB 10.0), as well as with hemodynamic parameters measured by thermodilution (TD), such as cardiac index (CI) and stroke volume index (SVI).
Results: There were no postoperative changes in the EFscreening and EFsimpson values. EFauto decreased from 48.4 ± 6.4 to 41.6 ± 7.3% (p < 0.001), while EFtee increased from 49.7 [46.0; 57.0] to 53.0 [46.1; 58.1]% (p = 0.047) and was associated with a decrease in GLS from -14.6 ± 2.5 to -11.7 ± 2.6% (p < 0.001). The bias in the measurement of EFsimpson and EFauto assessed a day before surgery and on POD1 according to the Bland-Altman test was 29.3% and 34.0%. There was a correlation between GLS and EFauto preoperatively (rho = -0.791, p < 0.001) and on the POD1 (rho = -0.723, p < 0.001), while EFscreening and EFsimpson did not show such a correlation. There was no correlation of EF or GLS with CI, as well. The bias in the measurement of the SVItd and SVIecho values was 11% (rho = 0.301, p = 0.001).
Conclusion: The echocardiographic assessment of the EF in the perioperative period of OPCABG does not characterize the systolic function of the heart reliably and depends on the method of its measurement. These limitations of echocardiographic parameters require their critical evaluation, including a comparison with thermodilution variables.
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Immunohistochemical analysis of PD-L1, CD4, CD8, CD20, and PU.1 expression in a dedifferentiated chondrosarcoma: the clinical and prognostic value
Abstract
Background: Dedifferentiated chondrosarcoma (DDCS) is a rare and extremely aggressive variant of mesenchymal bone tumors, with a biphasic structure represented by the classical chondrosarcoma elements, usually of low or intermediate grade, combined with a sharp transition to a highly malignant (high grade) non-cartilaginous sarcoma. The DDCS is associated with a poor outcome, low effectiveness of medical therapy and high mortality rates. One of promising areas of treatment for these tumors is immunotherapy, which requires a more profound understanding of the immunological status of the tumor and composition of its microenvironment.
Aim: To analyze the expression of PD-L1, CD4, CD8, CD20 and PU.1 markers in the inflammatory infiltrate of the tumor stroma in the samples of primary DDCS to search for new treatment and prognostic targets, as well as potential predictors of treatment efficacy.
Methods: We retrospectively analyzed the results of the immunohistochemical (IHC) studies of the tumor samples obtained from 42 patients with DDCS (18 men and 24 women aged 24 to 94 years; median age 65 years). The study samples of DDCS demonstrated two components, namely, well-differentiated chondrosarcoma and poorly differentiated non-cartilaginous sarcoma represented by pleomorphic undifferentiated sarcoma (n = 33), osteosarcoma (n = 6), rhabdomyosarcoma (n = 2) and angiosarcoma (n = 1). The IHC analysis was performed in the automated mode with a Ventana Bench Mark ULTRA IHC stainer (Ventana Medical Systems, USA) using an optimized protocol and anti-PD-L1 antibodies (clone SP142) and in the manual mode for staining with anti-PU.1, CD4, CD8 and CD20 antibodies. The PD-L1 expression was assessed separately in the dedifferentiated and chondroid components of the tumor. Samples containing PD-L1 expressing lymphocytes were counted separately.
Results: PD-L1 was expressed in the dedifferentiated component of 40% of the cases (17/42), in the chondroid component of 26% of the cases (11/42), and in both components in 17% of the cases (7/42). There was no association between PD-L1 expression in different tumor components and clinical and morphological characteristics of the disease. Median survival of the PD-L1 non-expressing patients was 68.6 months, while of those with the expression 7.7 months (p = 0.096). The mean macrophage count in the dedifferentiated tumor component was 17.3 ± 12.8%, that of CD4+ T-cells 4 ± 3.5%, CD8+ T-cells 4 ± 2.4%, and B cells 6.7 ± 3.8%. The analysis of an association between immune cell counts and clinical and morphological characteristics showed that higher tumor infiltration with B-cells was typical for an earlier stage of the disease (p = 0.045). The stromal markers studied did not have any prognostic significance, however there was a trend towards an unfavorable course of the disease (p = 0.112) for those with high macrophagal infiltration of the DDCS samples. The PU.1+ cell counts in the tumor stroma positively correlated with PD-L1 expression both in the chondroid (r = 0.357, p = 0.028) and in the dedifferentiated tumor components (r = 0.343, p = 0.033), as well as with the T cell numbers (r = 0.365, p = 0.026).
Conclusion: The results of our IHC studies on the expression of PD-L1, CD4, CD8, CD20, and PU.1 indicate the clinical and prognostic significance of the immune microenvironment of DDCS, opening additional prospects for predicting of the disease outcomes and development of immune therapies. Nevertheless, a more precise delineation of the clinical value of the identified markers requires that studies on larger patient samples should be continued.
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The differential diagnosis of adrenal incidentalomas with non-benign appearence on unenhanced computed tomography: a retrospective study
Abstract
Background: Сomputed tomography (CT) is considered as the gold standard for imaging the adrenal tumors. Tumor size and native density in unenhanced CT images are widely used to predict tumor malignancy, however, their diagnostic accuracy and the added value of clinical and anamnestic data remain uncertain.
Objective: To identify clinical markers that possibly could differentiate pheochromocytoma (PCC), adrenocortical cancer (ACC), and hormonally non-functioning adrenal adenoma (NAA) in patients with adrenal masses of non-benign appearance on unenhanced CT.
Methods: This was a single-center observational retrospective selective non-controlled study of 123 patients who underwent adrenalectomy between January 2011 and December 2023. All lesions showed native density ≥ 10 Hounsfield units [HU] or maximum diameter ≥ 4 cm, or both features on pre-operative CT. Histology examination confirmed 63 PCC, 30 ACC and 30 NAA. Clinical presentation, comorbidities, laboratory tests and imaging findings were reviewed.
Results: Paroxysmal type of arterial hypertension (AH) was common across all groups; its presence did not aid discrimination. AH grade 3, however, prevailed in the patients with PCC only. Patients with an adrenal mass and AH grade 3 had the high probability of PCC presence (odds ratio, OR: 5.978, 95% confidence interval, CI [2.620–13.640]; p < 0.001). AH grade distribution was similar in the ACC and NAA groups. Headache (57.1%), palpitations (48.3%) and a history of peptic ulcer disease (25.4%) were also characteristic of PCC. In contrast, generalized weakness and lumbar pain predominated in ACC (63.3% and 60%, respectively) and NAA (56.7% and 73.3%). Tumors with native density of ≥ 10 HU and size > 4 cm (the malignant CT phenotype) were found in 90% (27/30) of ACC, 62% (39/63) of PCC, and 36.7% (11/30) of NAA cases. This CT appearance detected a malignant lesion (PCC or ACC) with 71% sensitivity and 63% specificity, while the chance to find NAA was low (OR: 0.237, 95% CI [0.097–0.555]; р < 0.001). Tumors with native density ≥ 10 HU and tumor size of < 4 cm were found in similar proportions in PCC (36.5%, 23/63) and NAA (30%, 9/30) groups, indicating a low probability of ACC (OR: 0.212, 95% CI [0.048–0.659]; р = 0.016) and focusing the differential diagnosis on PCC versus NAA. Tumors with native density < 10 HU and size ≥ 4 cm were rare in PCC (1/63, 1.6%) and absent in ACC, yet presented in 10/30 (33.3%) NAA cases. This CT phenotype is associated with low risk of malignancy (OR: 0.022, 95% CI [0.001–0.123]; р < 0.001), although insensitive (33%), it had a specificity of 98.9% for benign NAA.
Conclusion: In adrenal tumors of the malignant CT phenotype, the differential diagnosis should be made between ACC and PCC, while the presence of NAA is highly unlikely. In tumors with native density of > 10 HU and tumor size of < 4 cm, the differential diagnosis should first consider PCC and NAA, while the chance to identify ACC is low. The adrenal masses with the native density of < 10 HU and tumor size of ≥ 4 cm were strongly suggestive of benign NAA, with an exceedingly low risk of cancer.
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The association of the TNFα gene rs1800629 and TLR3 gene rs3775291 polymorphisms with cervical cancer risk and its survival outcomes
Abstract
Background: Cervical cancer (CC) ranks fourth in the cancer morbidity and mortality in women. In 2022, in the Russian Federation the standardized incidence and mortality rates are 13.8 and 4.67 cases per 100 000 of the female population, respectively, which are lower than in the Eastern Europe (15.7 and 6.3), but higher that in the Northern (8.2 и 2.2) and Western Europe (6.6 и 2.1). The human papillomavirus (HPV) plays a key role in the CC carcinogenesis. The mechanisms of carcinogenesis are related to genetic variations in immunoregulatory factors involved in the induction of proliferation, invasion and metastasis of tumor cells with weakening of the immune control. Among the potential immunogenetic risk factors for the CC development, genetic variants of the TNFα gene rs1800629 and the TLR3 gene rs3775291 have been highlighted, whose associations with CC may be different in various populations and ethnic groups.
Aim: To identify the association the -308A TNFα (rs1800629) and 1234C/T TLR3 (rs3775291) genetic polymorphisms with CC development in the patients of the Donbass region of the Russian Federation and to establish the link between these genetic variants and survival.
Methods: From February 2021 to December 2024, 320 female patients (the main study group, median age 55 [47; 64] years) with CC stage I to II (TNM) were consecutively recruited to the study. From January 2005 to January 2021, all of them had undergone a radical hysterectomy (Wertheim procedure) in a specialized oncology center, followed by radiation therapy. The control group included 200 healthy women comparable by age (median age 55 [44.75; 63] years, p = 0.101), body mass index (p = 0.513) and smoking status (р = 0.586). In both groups, cervical HPV was diagnosed with polymerase chain reaction (PCR). The genetic variants of TNFα rs1800629 and TLR3 rs3775291 were determined by the SNP-express PCR test systems, TNFα (-308G/A) and TLR3 (Leu412Phe) (Litech, Russia).
Results: The incidence of HPV infection in the study group was more than 6.4-fold higher than in the control group (74.1% versus 11.5%, p < 0.001). There was an association between СС and the TNFα rs1800629 polymorphism in the co-dominant (χ2 = 8.33; p = 0.016), multiplicative (χ2 = 9.12; p = 0.003), and dominant (χ2 = 7.17; p = 0.008) models; and also with TLR3 rs3775291 polymorphism in the co-dominant (χ2 = 7.47; p = 0.025), multiplicative (χ2 = 6.61; p = 0.011), and dominant (χ2 = 7.17; p = 0.008) models. The patients with the TNFα rs1800629 AA (odds ratio [OR] 2.39, 95% confidence interval [CI)] 0.951–5.994) and GA genotypes (OR 1.46, 95% CI 0.978–2.181), A allele (OR 1.66, 95% CI 1.192–2.311), and the combination of GA + AA genotypes (OR 1.69, 95% CI 1.149–2.481) were at increased risk of СС. In the patients with TLR3 rs3775291 polymorphism, an increased risk of СС was found in the CT (OR 1.42, 95% CI 0.995–2.031) and TT (OR 1.53, 95% CI 0.796–2.932) genotype carriers, in those with the T allele (OR 1.43, 95% CI 1.088–1.878) and the combination of CT + TT (OR 1.63, 95% CI 1.138–2.321). The CC HPV-positive patients with the combination of TNFα rs1800629 GA + AA genotypes, compared to the carriers of the GG genotype, had a decreased overall survival (OS) (p < 0.001) and relapse-free survival (RFS) (p = 0.002). The 5-year OS and RFS of the patients with the TNFα rs1800629 GG genotype were 96.13 and 93.55%, and of those with the GA + AA genotypes, 84.15 and 79.27%, respectively. The TLR3 rs3775291 СТ + ТТ carriers, compared to СС, had poorer OS (р = 0.039) and RFS (р = 0.045). The 5-year OS and RFS in the HPV-positive CC patients with the TLR3 rs3775291 СС genotype were 93.94 and 91.92%, and in those with СТ + ТТ genotypes, 90.58 and 86.23%, respectively.
Conclusion: The study has shown an association of the genetic variants -308A TNFα (rs1800629) and 1234C/T (rs3775291) with the development of СС and its survival outcomes in the patients of the Donbass region of the Russian Federation. The negative effect of the risk alleles A TNFα rs1800629 and T TLR3 rs3775291 was more common for the CC patients infected with HPV and was associated with worse OS and RFS.
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Comparison of the results of regional chemotherapy alone and in combination with conform radiotherapy in patients with curable pancreatic head cancer and high surgical risk
Abstract
Rationale: Curative surgery with subsequent adjuvant chemotherapy is the main combination treatment for pancreatic cancer (PC). However, there is the group of patients with resectable tumors who cannot be resected due to severe comorbidities and as such are subjects for palliative anti-tumor treatment.
Aim: To evaluate safety and efficacy of regional chemotherapy (RCT) combined with distant radiation therapy (DRT) at daily dose split regimen, compared to RCT alone in PC patients assessed as inoperable.
Methods: This retrospective analysis included 71 patients with a resectable ductal adenocarcinoma of the pancreatic head without distant metastases (T2–3N0–2M0), with American Society of Anesthesiologists (ASA) physical status III (a patient with severe systemic disease, inoperable), Eastern Cooperative Oncology Group performance status (ECOG) 1 to 2, who had received RCT alone from 2010 to 2015 (n = 38) or in combination with conform DRT from 2016 to 2024 (n = 33). The subsequent follow-up was censored at February 1, 2025. All patients have received RCT as chemoembolization of the pancreatic head with suspension of gemcitabine and lipiodol followed by intra-arterial infusion of gemcitabine and oxaliplatin during at least 2 cycles. At the 2nd step of treatment, the patients of the main study group received 3D conform daily split-dose DRT (single dose 2 Gy, 4 Gy daily, up to a total physical dose of 50 Gy).
Results: The mean age of the patients in the combination chemoradiation therapy group (n = 33) was 70 years, in the RCT alone group (n = 38) 66.5 years (p = 0.8). The study groups were comparable for the ECOG status (p = 0.6), CA 19-9 (p = 0.6), and disease stage (p = 0.6). There were no deaths and adverse events above NCI CTCAE, v. 5.0 grade 2 in both study groups. CTCAE v. 5.0 grade 1–2 toxicities were seen in 31 (93.9%) patients in the RCT + DRT group and in (84.2%) patients of the RCT alone group (p = 0.27), and did not affect the time schedule and dose of treatments. The median time to progression was 7.8 (95% confidence interval [CI] 6.9–8.4) months in the RCT + DRT group and 6.0 (95% CI 5.2–6.3) months in the RCT alone group (p < 0.05). The median overall survival was 12.4 (95% CI 10.5–17.8) months and 10.2 (95% CI 8.9–12.2) months, respectively (p = 0.006), and one year survival, 50% and 29%, respectively (p = 0.006).
Conclusion: The palliative combination of RCT with daily split-dose DRT is safe and relatively effective treatment and can be viewed as an alternative to surgery in the patients with high surgical risk.
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