Regorafenib in metastatic colorectal cancer: more data for clinical decisions

Regorafenib is a multiple kinase inhibitor. It influences/blocks angiogenesis (VEGFR1-3, TIE2), proliferation (KIT, RET, RAF-1, BRAF), metastatic activity (VEGFR2-3, PDGFR), tumor immunogenicity (CSF1R), tumor microenvironment (PDGFR-, PDGFR-, FGFR1-2). Regorafenib has several indications including metastatic colorectal cancer. Efficacy and safety of regorafenib data from clinical trials (CORRECT, CONCUR, CONSIGN) and observational trials from real world (REBECCA, CORRELATE, RECORA, PMS, REGOTAS) are summarized and presented in this issue. State of the matter of molecular-biologic predictors (KRAS, PIK3CA ANG-2, VEGF-A, LDH, CCL5/CCR5, CA 19-9) and radiological predictors (RadioCORRECT and other trials) is highlighted. Regimens with dose modification and its influence on effectiveness and tolerability of regorafenib are described according to the data from ReDOS, RESET, REARRANGE trials. The results from retrospective trials comparing regorafenib and another approved for refractory metastatic colorectal cancer drug trifluridine/tipiracil are presented.

Telephone interventions for symptom management in adults with cancer (Russian Translation of Cochrane Plain Language Summary – PLS)

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Ream E, Hughes AE, Cox A, Skarparis K, Richardson A, Pedersen VH, Wiseman T, Forbes A, Bryant A. Telephone interventions for symptom management in adults with cancer. Cochrane Database of Systematic Reviews 2020, Issue 6. Art. No.: CD007568. DOI: 10.1002/14651858.CD007568.pub2

Dual immunological blockade in the treatment of metastatic non-small cell lung cancer: reality and perspectives

Nowadays immunotherapy is a crucial option in the treatment of non-small cell lung cancer. There are a lot of actual options of the first-line therapy for the patients with metastatic lung cancer, including dual immunological blockade of PD-1/PD-L1 and CTLA-4 pathways. This review is an attempt to clarify the place of dual immunological blockade now and in the future. The scientific rationale for dual immunotherapy is a possible synergy and overcome resistance to single-drug therapy. The review collected information from open sources, both current studies with dual immunological blockade, and already obtained results of the trials for nivolumab and ipilimumab, tremelimumab and durvalumab, and other combinations for the treatment of patients with metastatic non-small cell lung cancer. This approach is promising for the possible overcoming of resistance to monoimmunotherapy with anti-PD1/PD-L1 antibodies, especially in the population with low and negative PD-L1 status.

Can any breast skin thickening be staged as T4?

Data analysis showed that many diagnostic issues in breast cancer patients with skin involvement are not systematized. In some cases when the tumor is small and skin involvement symptoms are minimal ("local" skin edema), should this category of patients be considered as patients with non-inflammatory skin involvement breast cancer? Current research confirms the presence of skin involvement has much less prognostic value than, for example, tumor size or lymph node metastases, and the surgical term "unresectable" may not always be adequate. In addition, clinical data often do not correspond to pathological data, which also complicates the staging and leads to "overtreatment" of such patients. Thus, further research is needed to identify categories of breast cancer (patients with skin involvement similar in prognosis, as well as to individualize approaches to local and systemic treatment.

V-shaped radial forearm free flap is a new way to reduce the morbidity of the donor area

Background. Radial forearm free flap is one of the most frequently used in the head and neck reconstruction. A significant disadvantage is the appearance of the donor site. We have developed and introduced into clinical practice a V-shaped fabrication skin of the flap, which allows direct closure of the donor site and reduces morbidity. Aim. To assess the possibility of direct closure of the donor site and to reduce the morbidity of the donor site when performing the V-shaped fabrication of the skin area of the flap. Materials and methods. During the period from 2014 to 2020, the radial free flap was used in 43 cases. In 15 (35%) cases, a V-shaped fabrication of the skin area was used during flap harvest, which made it possible to carry out a direct closure of the donor site. The length of the skin area stretched from the top of the wrist, not reaching 34 cm to the elbow bend and varied from 715 cm, on average 12 cm. The width of the flap was determined by the elasticity of the forearm skin, was maximum in the middle third and varied from 2 up to 4 cm, averaging 3.3 cm. If necessary, the upper and lower edges of the skin area can be sutured together, as well as the entire medial edge of the flap. This technique increases the flap width by almost 2 times. This arrangement was applied in 8 cases. Results. When comparing the results of using the two techniques, the following data were obtained: "V-shaped" fabrication of the skin was used mainly in women (11/15 73%) for reconstruction limited defects in the retromolar region (5/15), soft (4/15) or hard palate (6/15). Most of the patients had localized T1-T2 (10/15) stage. None of the patients had any problems with the healing of the donor area. An excellent aesthetic result was obtained in all patients. In the group of standard harvest, the predominance of males was noted (17/28). Defects had a varied localization, most patients was with relapses after chemo-radiation treatment (10/28) or primary locally advanced T3-T4 stage process (6/28) 16, with a localized T1-T2 stage (11/28) 11, in one case, delayed reconstruction was performed. In all cases, the plastic of the donor site was performed with a split skin autograft. Partial necrosis of the donor site flap was observed in 9 patients (32%), in 4 cases with exposure of the flexor muscle tendon. Conclusion. As a result of the comparative analysis of the two methods, we concluded that the use of V-shaped fabrication of the skin area of the radial forearm flap allows to obtain better aesthetic results of the donor site, however, the use of this technique leads to a significant reduction in the length of the vascular pedicle and a decrease in the width of the flap.

The relationship of GITR, Lag-3 and PD-1 expression with the main indicators of systemic and local immunity in patients with breast cancer

Background. To enhance the antitumor immune response, new promising methods of immunotherapy are being developed. They consist in the blockade and activation of immune check-point molecules, in particular, the blockade of the Lag‐3 molecule (lymphocyte-activation gene 3) and the activation of the GITR receptor (Glucocorticoid induced TNF receptor). In the studies of combined use with PD-1 blockers, encouraging results were obtained, which makes the assessment of the expression of Lag-3 and GITR on immunocompetent cells of peripheral blood (PB) and tumor tissue necessary for the personalization of such treatment and understanding of the mechanisms of the antitumor immune response. Materials and methods. The study included peripheral blood samples and surgical material from 39 breast cancer patients being treated at the Blokhin National Medical Research Center of Oncology. The subpopulation composition and expression of PD-1, Lag-3, and GITR molecules were evaluated by flow cytometry. Results. The analysis of the main populations of PB lymphocytes showed that in patients with breast cancer, the content of NKT-lymphocytes was increased, and the proportions of lymphocytes expressing CD11b and CD25 markers were increased compared to the donor group. It was revealed that the tumor tissue is dominated by T-cells, an increase in the proportion of which occurs due to a reduced content of NK-lymphocytes and B-lymphocytes. The structure of Tumor-infiltrating lymphocytes (TILs) is dominated by subpopulations with immunosuppressive activity, which is indicated by a decrease in the content of CD11b+, CD25+ and perforin-positive cells, increased expression of Lag-3 and PD-1. For PB and tumor tissue, the average degree of dependence of Lag-3 expression on the content of PD-1+ lymphocytes was shown. There is an increase in the content of immunosuppressive subpopulations with high PD-1 values in PB and TILs. The direct dependence of the number of perforin-containing lymphocytes and CD11b expression on the GITR content in the PB was established, but it is not typical for breast cancer tissue. Conclusion. Since the blockade of the Lag-3 molecule by monoclonal antibodies can enhance the effect of anti-PD-1 therapy in cancer patients, it is necessary to evaluate the expression and co-expression of these two markers. A high content of GITR-positive lymphocytes in the tumor tissue, on the one hand, and a decrease in the proportion of effector subpopulations of lymphocytes, on the other, indicates the influence of the tumor microenvironment on the functioning of GITR-mediated activation of the immune response. Further investigation of GITR expression and functional activity is required to understand the nature of this contradiction.

Malignant neoplasms associated with HIV infection. Problems and solutions (problem outline)

HIV infection refers to socially significant diseases. As a result of the wide coverage of effective antiretroviral therapy for people living with HIV, the rates of AIDS-related mortality have significantly decreased. At the same time, there was a noticeable increase in morbidity and mortality from other non-AIDS-related diseases, not the last place in this list is occupied by malignant neoplasms. A decrease in the frequency of AIDS-associated tumors and an increase in the proportion of AIDS-unassociated tumors are significant changes in the structure of malignant neoplasms. There is a complex relationship between HIV-induced immune suppression, chronic antigenic stimulation and concomitant oncogenic viral infections, which increases the risk of developing malignant tumors in these patients. People living with HIV have higher rates of cancer mortality associated with both the lack of adequate antitumor therapy, complications of treatment, and the existence of a direct relationship between immunosuppression and tumor progression. This article analyzes the problems that arise in the treatment of oncological HIV-infected patients, and offers specific practical steps to solve complex interdisciplinary problems.

Extrapulmonary small cell carcinoma. Literature review

The review shows the features of rare tumors extrapulmonary small cell carcinomas (EPSCC). The possible approaches for the treatment of this unfavorable group of tumors are discussed. EPSCC can occur in every organ. The clinical course and morphology of EPSCC are similar to small lung cell carcinoma (SCLC). EPSCC belongs to the group of low-grade neuroendocrine tumors with high proliferative activity. There are a small number of publications in the literature concerning EPSCC. Basically, these publications concerning the various clinical cases with comments. Most often, EPSCC occurs in the female genital tract, gastrointestinal tract, genitourinary SCC and known cases of SCC of the head and neck. The cases concerning SCC in other organs are also described. For the treatment of EPSCC are usually applied guidelines developed for SCLC, and several publications on the use of immunotherapy in the treatment of EPSCC have already appeared. The analysis of the available literature let us suggest EPSCC is a big problem that requires a more in-depth study and consensus guidelines adoption for the management of these patients.

Clinical and morphological case of lung cancer with generalized metastases to the internal organs

Lung cancer has occupied a leading position in the structure of cancer morbidity and mortality throughout the world for many years. Lifetime diagnosis is often difficult due to the absence of any defining signs of cancer, and it is quite difficult to track the first signs of lung cancer. This is justified by the fact that the lungs are completely devoid of nerve endings and the presence of 26% of healthy lung tissue is sufficient to provide the body with the required amount of oxygen. Prolonged absence of clinical manifestations leads to late seeking medical help, which is often fatal. Description of the case. A 65-year-old patient who died at home was referred for a postmortem examination. The sectional study revealed signs of peripheral cancer of the right lung with multiple metastases in all fields of the lungs, in the liver, spleen, pancreas, with no metastases in the lymph nodes. Histological examination revealed extensive areas of tumor tissue, consisting of solid structures with glandular differentiation of tumor tissue of various sizes and shapes, with round and oval atypical nuclei. There was a pronounced polymorphism of cells, with a large number of pathological mitoses. Thrombi were detected in the lumen of the segmental and small branches of the pulmonary artery. Thus, the presented case is of particular interest for practicing physicians due to the fact that with adenocarcinoma of the lung, there were no characteristic metastases to the lymph nodes. Hematogenous metastasis occurred with the development of generalized metastases to the internal organs.

Antiangiogenic therapy in pretreated patients with lung adenocarcinoma without activating mutations: new features

The possibilities of treatment of patients with metastatic non-small cell lung cancer have significantly expanded in the recent years. Several combined regimens of chemoimmunotherapy are currently being proposed as the first line, some patients with PD-L1 overexpression may be prescribed pembrolizumab or atezolizumab in monotherapy. Standard platinum-containing chemotherapy (PCT) has lost its position and is relevant only for contraindications to immuno-oncological (IO) drugs. The change in the standart of the first line inevitably led to the search for new optimal modes of the second line. The strategy of "angio-immunogenic switching" is promising after progression on the regimens with IO, anti-angiogenic drugs are used. Nintedanib a multikinase angiogenesis inhibitor in combination with docetaxel is a standard second-line therapy option in patients with lung adenocarcinoma after progression on PCT. The effectiveness of this regimen is being studied in a prospective non-interventional VARGADO study. The patients were divided into 3 cohorts, depending on which regimen was used earlier one line of PCT or PCT, followed by IO or chemoimmunotherapy. The results showed that the combination of docetaxel + nintedanib was effective both as a third line (after PCT and IO), and in the second after chemoimmunotherapy. The research is ongoing.