COVID-19 in cancer patients: update from the joint analysis of the ESMO-CoCARE, BSMO, and PSMO international databases.

BACKGROUND: COVID-19 has significantly affected patients with cancer and revealed unanticipated challenges in securing optimal cancer care across different disciplines. The European Society for Medical Oncology COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international, real-world database, collecting data on the natural history, management, and outcomes of patients with cancer and SARS-CoV-2 infection. METHODS: This is the 2nd CoCARE analysis, jointly with Belgian (Belgian Society of Medical Oncology, BSMO) and Portuguese (Portuguese Society of Medical Oncology, PSMO) registries, with data from January 2020 to December 2021. The aim is to identify significant prognostic factors for COVID-19 hospitalization and mortality (primary outcomes), as well as intensive care unit admission and overall survival (OS) (secondary outcomes). Subgroup analyses by pandemic phase and vaccination status were carried out. RESULTS: The cohort includes 3294 patients (CoCARE: 2049; BSMO: 928, all hospitalized by eligibility criteria; PSMO: 317), diagnosed in four distinct pandemic phases (January to May 2020: 36%; June to September 2020: 9%; October 2020 to February 2021: 41%; March to December 2021: 12%). COVID-19 hospitalization rate was 54% (CoCARE/PSMO), ICU admission 14%, and COVID-19 mortality 22% (all data). At a 6-month median follow-up, 1013 deaths were recorded with 73% 3-month OS rate. No significant change was observed in COVID-19 mortality among hospitalized patients across the four pandemic phases (30%-33%). Hospitalizations and ICU admission decreased significantly (from 78% to 34% and 16% to 10%, respectively). Among 1522 patients with known vaccination status at COVID-19 diagnosis, 70% were non-vaccinated, 24% had incomplete vaccination, and 7% complete vaccination. Complete vaccination had a protective effect on hospitalization (odds ratio = 0.24; 95% confidence interval [0.14-0.38]), ICU admission (odds ratio = 0.29 [0.09-0.94]), and OS (hazard ratio = 0.39 [0.20-0.76]). In multivariable analyses, COVID-19 hospitalization was associated with patient/cancer characteristics, the first pandemic phase, the presence of COVID-19-related symptoms or inflammatory biomarkers, whereas COVID-19 mortality was significantly higher in symptomatic patients, males, older age, ethnicity other than Asian/Caucasian, Eastern Cooperative Oncology Group performance status ≥2, body mass index <25, hematological malignancy, progressive disease versus no evident disease, and advanced cancer stage. CONCLUSIONS: The updated CoCARE analysis, jointly with BSMO and PSMO, highlights factors that significantly affect COVID-19 outcomes, providing actionable clues for further reducing mortality.

[Remote Monitoring of the QT Interval During Polychemotherapy].

Aim      To evaluate the incidence of prolonged corrected QT interval (QTc) by remote single-channel electrocardiogram (ECG) monitoring in primary oncological patients with elective polychemotherapy (PCT).Material and methods  This study included 49 oncological patients with elective PCT. A single-channel portable CardioQVARK electrocardiograph was used to record single-channel, one-lead ECG between the first and second courses of PCT.Results Analysis of QTc interval detected a prolonged QTc interval >500 msec in 8.2 % of cases, prolonged QTc >480 msec in 18.3 % f cases, and prolonged QTc interval >60 msec compared to baseline in 12.2 % of cases.Conclusion      Remote recording of single-channel ECG using a portable electrocardiograph is an effective method for recording and detecting various forms of heart rhythm disorders.

COVID-19 in patients with cancer: first report of the ESMO international, registry-based, cohort study (ESMO-CoCARE).

BACKGROUND: ESMO COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international collaborative registry-based, cohort study gathering real-world data from Europe, Asia/Oceania and Africa on the natural history, management and outcomes of patients with cancer infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). PATIENTS AND METHODS: ESMO-CoCARE captures information on patients with solid/haematological malignancies, diagnosed with coronavirus disease 2019 (COVID-19). Data collected since June 2020 include demographics, comorbidities, laboratory measurements, cancer characteristics, COVID-19 clinical features, management and outcome. Parameters influencing COVID-19 severity/recovery were investigated as well as factors associated with overall survival (OS) upon SARS-CoV-2 infection. RESULTS: This analysis includes 1626 patients from 20 countries (87% from 24 European, 7% from 5 North African, 6% from 8 Asian/Oceanian centres), with COVID-19 diagnosis from January 2020 to May 2021. Median age was 64 years, with 52% of female, 57% of cancer stage III/IV and 65% receiving active cancer treatment. Nearly 64% patients required hospitalization due to COVID-19 diagnosis, with 11% receiving intensive care. In multivariable analysis, male sex, older age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, body mass index (BMI) <25 kg/m2, presence of comorbidities, symptomatic disease, as well as haematological malignancies, active/progressive cancer, neutrophil-to-lymphocyte ratio (NLR) ≥6 and OnCovid Inflammatory Score ≤40 were associated with COVID-19 severity (i.e. severe/moderate disease requiring hospitalization). About 98% of patients with mild COVID-19 recovered, as opposed to 71% with severe/moderate disease. Advanced cancer stage was an additional adverse prognostic factor for recovery. At data cut-off, and with median follow-up of 3 months, the COVID-19-related death rate was 24.5% (297/1212), with 380 deaths recorded in total. Almost all factors associated with COVID-19 severity, except for BMI and NLR, were also predictive of inferior OS, along with smoking and non-Asian ethnicity. CONCLUSIONS: Selected patient and cancer characteristics related to sex, ethnicity, poor fitness, comorbidities, inflammation and active malignancy predict for severe/moderate disease and adverse outcomes from COVID-19 in patients with cancer.

[Kidney injury associated with antitumor therapy: focus on the adverse events of modern immuno-oncological drugs].

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

[The role of lymphadenectomy for treatment of colorectal liver metastases with regional lymph nodes involvement]. / Rol' limfadenéktomii v lechenii metastaticheskogo kolorektal'nogo raka pecheni s porazheniem regionarnykh limfaticheskikh uzlov.

Liver resection remains the method of choice for treatment of colorectal liver metastases with good long-term results. Regional lymph nodes involvement is significant negative prognostic factor. Moreover, it has been considered as a contraindication for liver resection for a long time. The role of lymphadenectomy remains controversial. Current state of this problem is reviewed in the article. Liver regional lymph nodes involvement takes place in 10-20% of cases. PET/CT is the most sensitive method of preoperative diagnosis. Involvement of liver regional lymph nodes is currently not absolute contraindication for liver resection. Routine lymphadenectomy does not make sense, and, perhaps, is justified only within scientific trials for more accurate disease staging. Indications for lymphadenectomy are suspicious changes of lymph nodes revealed by preoperative visualization methods or by intraoperative exploration. Modern chemotherapy regimens allow to reconsider the prognostic importance of liver regional lymph node metastases and to extend indications for liver resections.

[Impact of preoperative drug therapy on the expression of angiogenesis markers in colorectal liver metastases]. / Vliyanie predoperatsionnoi lekarstvennoi terapii na ekspressiyu markerov angiogeneza v metastazakh kolorektal'nogo raka v pecheni.

AIM: to study changes in the expression of angio- and vasculogenesis markers in colorectal adenocarcinoma metastases to the liver during combined cytotoxic and targeted anti-VEGF therapy versus cytotoxic monotherapy. SUBJECTS AND METHODS: Intraoperative samples from 96 patients with colorectal adenocarcinomas metastases to the liver were immunohistochemically examined. The investigation enrolled patients who had preoperatively received either combined FOLFOX6 cytotoxic therapy and targeted anti-VEGF therapy with bevacizumab or only FOLFOX6 therapy, as well as patients who had not received preoperative anti-tumor drug treatment. The expression of SDF1α, CXCR4, CXCR7, and VEGF-A was compared in these groups. Statistical significance was accepted at p<0.05. RESULTS: The expression of CXCR4 in the vessel endothelial cells was significantly less frequently detected in the patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy as compared to those had not drug therapy. Comparing the patients treated with cytotoxic drugs with those who had not received anti-tumor therapy revealed similar results in the women. CXCR7 expression in the tumor cells and stromal cells from the metastatic foci was significantly more common in the group of male patients treated with cytotoxic drugs according to the FOLFOX6 regimen. The expression of SDF1α in the tumor cells was significantly more often observed in the male patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy than in those who had not drug therapy. VEGF expression in the stromal cells was significantly less frequently seen in the patients who had received the combined therapy. CONCLUSION: Combined cytotoxic therapy and targeted anti-VEGF therapy for colorectal adenocarcinoma metastases to the liver leads to some suppression of the alternative pathway in the formation of new vessels, by reducing the expression of CXCR4 in the vessel endothelial cells and that of VEGF in the stromal cells from the metastatic foci. In men, this therapy simultaneously causes an increase in the expression of SDF1α in the tumor cells and in that of CXCR4 in the stroma. Preoperative FOLFOX6 therapy significantly increases the expression of CXCR7 in the tumor cells and stromal cells in the male patients, which may suggest that this pathway in vessel formation can be activated.

[Impact of preoperative drug therapy on the expression of apoptosis markers in colorectal liver metastases].

AIM: to estimate the expression of p53 protein, effector caspases-3 and -7, and the antiapoptotic protein survivin in colorectal adenocarcinoma metastases to the liver in patients who have received preoperative cytotoxic and combined cytotoxic and target anti-VEGF therapies. SUBJECTS AND METHODS: Intraoperative samples from 122 patients with colorectal carcinoma metastases to the liver were immunohistologically examined. The investigation included patients who had received preoperative treatment with cytotoxic drugs, combined cytotoxic and targeted anti-VEGF therapy. A control group consisted of patients who had not received preoperative anti-tumor drug treatment. RESULTS: Expression of Caspase 3, including that of survivin, was significantly more frequently detected in the patients who had received combined cytotoxic and anti-VEGF therapy as compared to both those treated with only cytotoxic agents (p=0.00004) and the control group (p=0.0008) As compared to the latter, the women who had received cytotoxic therapy were found to have no survivin expression (p=0.015). Investigation of the expression of caspase-7 and p53 revealed no statistically significant differences between the three groups. CONCLUSION: Addition of bevacizumab to preoperative standard therapy regimens for colorectal adenocarcinoma metastases to the liver leads to activated apoptosis in tumor cells, by enhancing the expression of effector caspase 3. At the same time, standard cytotoxic chemotherapy regimens in women results in activated apoptosis, by decreasing the expression of the antiapoptotic protein survivin.

[Impact of preoperative drug therapy on adhesion molecule expression in colorectal cancer liver metastases].

OBJECTIVE: To study E-cadherin and ß-catenin expression in colorectal cancer (CRC) liver metastases in order to assess the impact of different drug therapy regimens on the adhesive properties of tumor cells. MATERIAL AND METHODS: Intraoperative metastatic CRC samples from patients who had received preoperative cytotoxic chemotherapy or combined cytotoxic and targeted anti-VEGF (vascular endothelial growth factor) therapy were immunohistochemically examined using antibodies to E-cadherin and ß-catenin. A comparison group consisted of patients who had not received drug therapy. RESULTS: Combined therapy with cytotoxic and anti-VEGF agents was shown to result in a significant increase in the number of cases of normal membrane localization of E-cadherin as compared with control (p = 0.00043) and cytotoxic therapy-alone (p = 0.01) groups. A comparison of ß-catenin levels in three patient groups revealed no significant differences, but addition of an anti-VEGF agent caused some decrease in the number of cases of abnormal nuclear localization of the protein as compared to both the control group and the cytotoxic therapy groups. The comparison of E-cadherin and ß-catenin localization in tumor cells showed that a combination of normal E-cadherin membrane localization and ß-catenin membrane-cytoplasmic expression prevailed in the combined therapy group compared to the control (p = 0.009) and cytotoxic therapy (p = 0.04) groups. CONCLUSION: The addition of a targeted anti-VEGF agent to the drug therapy of metastatic CRC has a positive impact on the cadherin-catenin complex, leading to increased intercellular contacts and suppressed ß-catenin functioning as a transcription factor that enhances tumor cell proliferation.

[Impact of preoperative chemotherapy on the expression of apoptosis factors in colorectal cancer liver metastases].

OBJECTIVE: To study the effects of cytotoxic and targeted anti-VEGF drugs on some mechanisms of apoptosis. MATERIAL AND METHODS: The effects of cytotoxic and targeted anti-VEGF drugs on the expression of the apoptosis activators Bax and PML and the apoptosis inhibitor Bcl-2 were studied in the colorectal cancer (CRC) liver metastases; a comparison group comprised patients receiving no chemotherapy. RESULTS: Immunohistochemical examination revealed lower Bax and PML expressions and higher Bcl-2 expression in the majority of untreated patients, suggesting the suppressed mechanisms triggering tumor cell apoptosis. Cytotoxic therapy resulted in a statistically significant rise in the expression of the apoptosis activator Bax (p = 0.01), a reduction in the level of the apoptosis inhibitor Bcl-2 (p = 0.04) and a slight increase in PML that controlled the induction of apoptosis. Adding an anti-VEGF agent to cytotoxic therapy exerted no statistically significant impact on Bax and Bcl-2, but caused more frequent positive PML expression than in the control and cytotoxic chemotherapy groups. CONCLUSION: Our study showed that cytotoxic and targeted anti-VEGF agents activate the apoptosis of tumor cells in the CRC liver metastases.

[The colorectal cancer progression after the right branch of vena porta occlusion].

Liver resections by metastatic colorectal cancer are considered to be seldom applicable on the reason of bilobar lesions and insufficient volume of the left liver lobe. The two-stage operations have been suggested for such situations. Of 276 patients, treated in our centre, 52 cases, unsuitable for the single-stage liver resection according to the preoperative data, had been retrospectively chosen. All these patients had the procedure of the right branch of vena porta occlusion, which aimed the compensatory hypertrophy of the left liver lobe. The efficacy of the occlusion was up to 73%. The median left lobe enlargement was 11%. The increase of the summary diameter of metastases was 60,4% (from 53 mm to 85 mm; p < 0,0001). The follow-up time was from 3 to 96 months. The three-year survival time was significantly higher in patients with the completed two-stage surgical treatment in comparison with those, who were refused the liver resection--77 and 43%, respectively. The multifactorial analysis revealed the only independent factor of the survival time--the extrahepatic intraabdominal lesion (p = 0,014).

[True cystic tumors of the pancreas].

Retrospective analysis of treatment results was carried out in 37 patients that had been treated during 1984-2009 years. Mean age of the patients was 50.7 years; among them 94.6% were women. 8 (21.6%) patients had serous cystadenoma, 21 (56.8%) patients - mucinous cystadenoma, 7 (18,9%) patients - cystadenocarcinoma and 1 (2.7%) patient - intraductal papillary-mucinous tumor. Distal pancreatic resection was carried out to 19 patients, pancreatoduodenal resection - in 5 patients, enucleation - in 10 patients, midline resection - in 1 patient, pancreatectomy - in 2 patients. The frequency of complications amounted 35.1%; lethal outcomes were not observed. Pancreatitis (in 7 patients) and pancreatic fistula (in 4 patients) were the most common complications. Re-laparotomy was necessary for destructive pancreatitis in 2 observations. Other complications were treated conservatively. Long-term results were studied in 28 (76%) patients. Mean duration of the observation was 87,3 months (6-120 months). 5-year survival rate amounted 100% among patients with benign cystic tumors of the pancreas and 25% in patients with cystadenocarcinoma. It is drawn a conclusion that complete recovery is quite possible in patients with benign tumors whereas treatment of the patients with invasive cystadenocarcinoma demonstrate poor results in long-term period.

[Intraduct papillar-mucinous pancreatic tumors].

AIM: To inform the surgeons about specific morphologic criteria of pancreatic intraductal papillary mucinous neoplasm, features of diagnosis and surgical treatment of this pathology. RECENT LITERATURE DATA: This article review the foreign papers published in last five years, which are dedicated to the diagnostic, surgical strategy and long-term results. CONCLUSION: Feature of the intraductal papillary-mucinous neoplasm is growth along ductal system of the pancreas. Histological assessment of the resection's margin should be a gold rule. Long-term results of surgical treatment are better than those of the malignant intraductal papillary mucinous neoplasms.

[Methodology of clinical studies in surgery].

Results of clinical studies recently became the guidelines in decision making in medicine including surgical practice. Results of each study could be used generally only if all methodological requirements are fulfilled. In this paper the principles of clinical studies design particularly in surgery and medical publications analysis are described and discussed.