[Analysis of the work of the Immunohistochemical Quality Control Center of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia in 2023]. / Analiz raboty Tsentra kontrolya kachestva immunogistokhimicheskikh issledovanii FGBOU DPO «RMANPO¼ Minzdrava Rossii v 2023 godu.

The article demonstrates a detailed analysis of the results of the rounds of quality control of immunohistochemical studies conducted by the Central Committee of the Immunohistochemical Quality Control Center of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia in 2023. Typical shortcomings and errors in the immunohistochemical examination of various tumors have been identified and ways to eliminate them are given. Particular attention is paid to defining a panel of standard breast cancer markers and eliminating the shortcomings of immunohistochemical examination of markers of accompanying diagnosis.

[Epidemiology and diagnosis of mutations in the ALK gene in patients with non-small cell lung cancer in the Moscow region]. / Epidemiologiya i diagnostika mutatsii v gene ALK u patsientov s nemelkokletochnym rakom legkogo v Moskovskoi oblasti.

AIM OF STUDY: To determine a diagnostic algorithm for detecting translocation of the ALK gene and its frequency in the Moscow region. MATERIALS AND METHODS: During the priod between 2014 and 2018 (inclusive), 488 patients without activating mutations in the EGFR gene in the Moscow region were tested. To detect translocation of the ALK gene, fluorescence in situ hybridization (FISH) methods, an immunohistochemical method, and, in some cases, a polymerase chain reaction were used. RESULTS: Revealed ALK gene rearrangement in a population of patients with lung adenocarcinoma amounted to an average of 7.6% of cases. With this, the main method that we used was immunohistochemical method, applicable in more than 80% of cases. The use of other methods for verification of abnormalities in the ALK gene was found necessary in rare cases (3.3%). CONCLUSIONS: Using the algorithm presented in the article, it was possible to detect ALK gene rearrangement in a population of patients with lung adenocarcinoma in the Moscow region in an average of 7.6% of cases.

[Role of clustered HER2/neu amplification as a marker for a special sensitivity to neoadjuvant anti-HER2 therapy with trastuzumab in patients with stage II-III breast cancer]. / Rol' klasternoi amplifikatsii gena HER2/neu kak markera 'osoboi' chuvstvitel'nosti k neoad''iuvantnoi anti-HER2-terapii trastuzumabom pri rake molochnoi zhelezy II­III stadii.

OBJECTIVE: To evaluate the influence of clinical and morphological factors and HER2 copy numbers on pathologic complete response (pCR) rates in patients with HER2-positive stage II-III breast cancer (BC). MATERIAL AND METHODS: Treatment results were studied in 73 patients with HER2-positive Stage II-III BC, who received treatment at the N.N. Blokhin National Medical Research Center of Oncology in 2015 to 2018. Treatment included neoadjuvant chemotherapy (NACT) with HER2-blockade and radical surgery followed by the evaluation of a pathologic response in the primary tumor and regional lymph nodes. The patients` age varied from 29 to 71; its median was 51.5; 45.2% of patients had primary operable stages (T1-3N0-1) and 54.8% had locally advanced tumors. All the patients had grade 2-3 anaplasia; luminal HER2-positive BC was diagnosed in 41.4% of patients; hormone-negative tumors were seen in 58.9%; 91.5% of patients had Ki-67 ≥20% in 75.3% of patients, preoperative systemic therapy included anthracycline-containing regimens (4AC + 4 x paclitaxel 175 mg/m2/12 × weekly administrations of paclitaxel 80 mg/m2; trastuzumab therapy was simultaneously performed with the administration of taxanes in the standard regimen) and anthracycline-free regimen TCH ± Pertuzumab regimen in 24.7% of cases. After NACT patients underwent surgery (radical mastectomy in 78.1%, breast-sparing treatment in 21.9%) with the assessment of morphological findings. Biopsy specimens obtained before the treatment was restudied; HER2 amplification was detected using a Dako HER2 IQFISH pharmDx kit according to its instruction and the 2018 ASCO/CAP guidelines. In 87.1% of cases, the HER2-positive status corresponded to the first category of the 2018 ASCO/CAP criteria for HER2-positive BC; clustered HER2 amplification was found in 30.1% of cases. The authors analyzed the frequency of bpCR and tpCR attainment by various clinical and morphological factors, as well as the impact of a HER2 amplification level on pCR rates. RESULTS: A breast pCR (bpCR) was achieved in 57.4% patients; bpCR and lymph node CR (lnCR) were noted in 48.9% patients. The rates of bpCR significantly depended on female age, chemotherapy regimen, addition of Pertuzumab, and HER2 copy number. That of bpCR in women less than 35 years of age, in those aged 36-50 years, and in those aged older than 50 years was 22.2, 57.7 and 71.9%, respectively (p=0.026). The maximum bpCR rate observed with the TCH±P regimen was 80.0%, that with anthracycline-containing regimes was 52.8% (p=0.045), and the addition of Pertuzumab increased complete response rates up to 88.9% (that with Trastuzumab was 54.2% (p=0.049). The relationship of bpCR rates to the detection of cluster amplification turned out to be highly significant (81% in its detection and 48.9% in its absence (p=0.013). In addition, clustered HER2 amplification was the only significant predictive factor for complete regression in the primary tumor and lymph nodes: in its presence, the tpCR rate reached 68.8% versus 38.7%. CONCLUSION: Clustered amplification of the HER2 gene is the most significant factor of sensitivity to anti-HER2 therapy for Stage II-III BC, and is associated with the maximum rate of both bpCR and total pCR. Further study of this factor may assist in optimizing the treatment algorithm for HER2 + BC.

Comparison of the results of PCR analysis of gene expression in breast cancer tissue specimens stabilized in formalin and RNAlater.

We compared the results of real-time PCR analysis of gene expression in paired specimens breast cancer tissue fixed in RNAlater (Qiagen) stabilization reagent (FF samples) and in formalin (FFPE samples). A clear-cut linear relationship (correlation coefficient 0.76 ± 0.07) was detected between the gene expression logarithm values in FF and FFPE samples. This fact suggests that collections of paraffin blocks with formalin-fixed tissue specimens from patients with a many-year disease history can be effectively used in modern studies.

Expression profile of inflammatory breast cancer.

Inflammatory breast cancer is characterized by high malignancy, early and rapid lymphogenic and hematogenic metastasizing, and high mortality. The diagnosis of this form of cancer is based fully on the clinical criteria. Whole transcriptome analysis of tumor tissue specimens from patients with inflammatory breast cancer detected 137 differentially expressed mRNA (17 genes with low expression and 120 with high expression). Genes involved in the organization of inflammatory process, chemotaxis, and transcription regulation were active in the process of pathogenesis of inflammatory breast cancer.

Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non-small-cell lung cancer: The global, multicenter EXPRESS study.

OBJECTIVES: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC. MATERIALS AND METHODS: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). RESULTS: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 [6%]). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%. CONCLUSIONS: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.

[Surgery for mesenchymal tumours of the mediastinum].

Results of treatment of 52 patients with mesenchymal tumours of the mediastinum. Clinical finding is various and nonspecific. Computer tomography and MRT are the most informative diagnostic techniques. Among 52 patients with mesenchymal tumours of the mediastinum, 40 patients were treated surgically and 12 patients got conservative treatment. Chemotherapy and radiotherapy were carried out in 7 patients in pre- and postoperative periods. Radical surgical treatment was carried out in 21 patients with benign tumors. Among 19 patients with malignant tumors, 42% of patients got radical surgical treatment, and 58 % of patients got palliative therapy in combination with chemotherapy. Benign tumors have a favorable prognosis after surgical treatment. Major factors of the prognosis of surgical treatment are dissemination and the histologic form of a tumor as well as type of surgical intervention. Re-operation is necessary in case of relapse.

Immunophenotypic profile of biomarkers related to anti-apoptotic and neural development pathways in the Ewing's family of tumors (EFT) and their therapeutic implications.

BACKGROUND: Ewing's family of tumors (EFT) comprises a broad spectrum of tumors composed of primitive committed cells with neuroectodermal capacity. The degree of neural differentiation within EFT, as measured with morphological features and expression of neural markers, delimits two members: Ewing's sarcoma (ES) and peripheral primitive neuroectodermal tumor (pPNET). Molecules such as c-kit and its ligand (Stem cell factor, SCF), CD95 (FAS), CD95L (FASL), IGF-IR, protect EFT cells from apoptosis, whereas c-erb-B2, erythropoietin (EPO) and its receptor (EPO-R) participate in the maturation of primitive committed neuroectodermal cells and in the normal embryonal brain development. The aim of the present study was to analyse the expression of these molecules in paraffin-embedded material from a series of EFT. MATERIALS AND METHODS: Forty-five cases of EFT (23 typical ES, 4 atypical and 18 pPNET) were analysed following the immunohistochemical LSAB method, with antigen retrieval heating using an autoclave, citrate buffer pH 6.0 and the following primary antibodies: FAS (APO-CD 95), FAS-L, c-kit, SCF, IGF-IR and c-erbB2. The expression was evaluated independently by three of the authors and the final score (0 to 3+) was based on the intensity and percentage of positively stained cells. In a second cooperative analysis, tissues from 30 cases of EFT (15 typical, 3 atypical and 12 PNET) were immunostained with EPO and EPO-R. RESULTS: High expression of c-kit/SCF (2+, 3+) was detected in 28/45 cases of EFT (62.2%), whereas FAS-FAS-L and IGF-IR were observed in 16/45 (37.7%) and 9/45 (20%), respectively. Regarding the neuroectodermal pathway, membranous and cytoplasmic expression of c-erb-B2 was observed in 9/45 (20%) EFT, regardless of the morphological and immunohistochemical expression of conventional neural markers. High expression of EPO and EPO-R was observed in 20/30 EFT (66.6%). CONCLUSION: C-kit/SCF and EPO/EPO-R seem to participate in the pathway of anti-apoptotic and proliferative advantage, while c-erb-B2 does not play an important role in the neuroectodermal differentiation pathway in EFT cells.

[Chronic heart failure: structural and microbiological changes in the colon].

AIM: To study microbiocenosis of the parietal layer of the colon and feces, concentrations of endotoxin and proinflammatory cytokines in patients with chronic heart failure (CHF) of different functional classes vs. healthy subjects of the same age. MATERIAL AND METHODS: The trial includes 37 patients with ischemic CHF and 13 healthy volunteers. The examination comprised 6-min walking test, echocardiographic evaluation of the left ventricular ejection fraction, clinical state by a special scale, assay for C-reactive protein, endotoxin, fecal seeding, colonoscopy with biopsy and seeding. RESULTS: Gram-negative flora in the colon and parietal layer occurred in high concentrations correlating with severity of CHF. The examinees with CHF of functional class III-IV had elevated levels of circulating endotoxin and serum C-reactive protein.

[Immunohistochemical diagnosis of metastases of small round cell carcinomas with undetected primary focus].

17 small round cell tumors of unkown primary site were studied. The main location was lymph nodes and brain. Immunohistochemical study was performed. One of the following diagnosis was obtained in 14 cases (82.4%): small cell carcinoma, Merkel cell carcinoma, melanoma, Ewing sarcoma family tumor. In other three cases (17.6%) tumor histogenesis was not determined definitively.

[Female genital tract polyneoplasia: primary multiple neoplasms or metastases?].

The analysis of 49 cases of synchronous and metachronous malignant mucinous tumors of the colon (rectum) and ovaries in the patients treated in 1990 to 2004 again has confirmed the data that metastatic ovarian cancer occurs from a primary focus in the colorectal region. Immunohistochemical studies (using cytokeratin 7 and cytokeratin 20) may be used in the differential diagnosis of ovarian mucinous ovarian carcinoma from metastatic colonic mucinous tumors.

[Infiltrating lobular breast cancer: histological and immunohistochemical characteristics].

Lobular carcinoma ranks second among most frequent tumors of the breast. Metastases to the lymph nodes and distant organs are one of the most important prognostic factors. 60% regional lymph node metastases were morphologically diagnosed during surgical removal of the tumor. Distant metastases rate was 1% at the beginning of the treatment and reached 10% within 5-year follow-up. Cases of secondary uterus and epiploon lobular carcinoma are rare and tumor location in the breast should be proved.

[Askenazi (Hurtle) cell tumors of the thyroid].

Oncocytic adenomas have primarily follicular structure; trabeculas, solid areas, necrosis are rare. They may possess malignant potential as their malignant transformation occurs in 35% cases against 5% in adenomas of follicular cells. Oncocytic follicular carcinomas can be hardly distinguished from oncocytic adenomas. Tumors larger than 4-5 cm in diameter are considered to be malignant. Main difference with adenomas is invasion into the capsule surrounding thyroid or into the vessels. They can be well or poorly differentiated or anaplastic. Oncocytic papillary carcinoma and oncocytic medullary carcinoma are rare. The clinical course of oncocytic tumors is more aggressive than that of tumors from follicular cells. Of key importance in differential diagnosis is electron microscopy (EM) and immunohistochemistry with antimitochondrial antibodies. EM may be also useful in determination of the degree of oncocytic tumors maturation.

[Insullar cancer. Diagnosis and place in the structure of thyroid carcinoma].

15 cases of thyroid insullar carcinoma in patients aged from 10 to 65 years are described. It is shown that the tumor has aggressive histological signs and represents a prognostically important form of thyroid carcinoma.

[Angiomyolipoma of the kidneys].

59 angiomyolipomas were studied: immunohistochemistry (IHC) was used in 24 cases, electron microscopy (EM) in 6 cases. 57 tumors had a typical structure, 2 did not contain fat component. Premelanosomes were found by EM in one tumor. Smooth muscle actin was found in all tumor cells. Involvement of lymph nodes was observed in 2 patients. Histogenesis of this tumor is discussed.

[Papilloma virus infection in pretumor and tumor masses of the larynx]. / Papillomavirusnaia infektsiia v predopukholevykh i opukholevykh obrazovaniiakh gortani.

There has been recent evidence suggesting that papilloma virus infection is of no small importance in the pathogenesis of tumors of the head and neck. This study has involved a screening of the mucosa having laryngeal pretumors and tumors for papilloma virus infection by polymerase chain reaction and immunohistochemistry. Specimens were studied in 130 patients. All the patients with laryngeal papillomatosis were found to have human papilloma virus (HPV) types 6 and 11. HPV-18 was detected in 6 (13%) of 48 cases of laryngeal cancer and in 4 (9%) of 46 cases of laryngeal mucosal precancer. Mixed HPV infection of 2-3 different types was revealed in 6 (20%) of 30 HPV-positive patients. Such a wide survey of laryngeal pretumors and tumors in the Russian population for virus infection has been conducted for the first time.

[The hierarchical relationships between the organs of the hypothalamo-hypophyseal-adrenal system (HHAS) in inflammation]. / Ierarkhicheskie vzaimootnosheniia mezhdu organami gipotalamo-gipofizarno-adrenalovoi sistemy (GGAS) pri vospalenii.

The HPA axis is the major system of adaptation to the action of different stressors, including inflammatory agents. The glucocorticoids, the end product of HPA axis prevent the extension of inflammation. In this article we discuss the classic direct and feedback loops in the HPA axis during acute bacterial inflammation. On the basis of literary and own findings we put forward a speculation that different systemic cytokines released one by one during inflammation induce the appearance of new functional relations between the organs of HPA axis. Because of cytokines are involved in the modulation of hormonal sensitivity in the HPA axis the serious modification of direct as well as feedback relations is postulated. On the other hand cytokines and immune cells induce autocrine and paracrine production of cytokines in the HPA axis, that result in autonomization of pituitary and adrenals functions. So, the acute inflammation factors could be seen as "short-time" functional dominants of HPA axis functioning.

[Vasopressin and inflammation]. / Vasopressin i vospalenie.

At least three vasopressinergic brain systems are involved in inflammatory reaction. The first one is VP neurons of the bed nucleus of stria terminalis, projecting to antipyretic center in the preoptic forebrain region. The second system is neurons of the parvocellular subnucleus of the hypothalmic paraventricular nucleus. VP from these neurons reaches portal blood through the external zone of the median eminence. VP potentiates the effect of corticotropin releasing hormone on ACTH cells in the anterior pituitary. Synergetic modulation of pituitary-adrenal axis by these neurohormones maintains synthesis and release of glucocorticosteroids. The latter plays crucial role as endogenous immunosuppresants. The third VP system is magnocellular hypothalamic neurons that release vasopressin into general circulation. Systemic VP is capable of compensating the water lost caused by symptoms of inflammation. The review is devoted to analysis of current information concerning physiology and interactions between these systems during acute and chronic inflammation. The special reference has been made on the magnocellular neurons and the role of circulating vasopressin in the renal function regulation.

[Histiocytic sarcoma from phagocyting histiocytes]. / Gistiotsitarnaia sarkoma iz fagotsitiruiushchikh gistiotsitov.

Histiocytic sarcoma consisting of phagocyting histiocytes is a rare variant of histiocytic sarcoma. It is hard to detect because of its similarity with large cell lymphomas, in particular with anaplastic large cell lymphoma. Histological and immunohistochemical findings are presented. Differential diagnosis with tumours of hematopoietic and non-hematopoietic nature is described.