Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report

Background Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC. Case presentation Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30–32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis. Conclusions High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.

MOLECULAR-GENETIC CRITERIA AND PROSPECTIVE BIOMARKERS OF SERRATED ADENOMAS OF COLORECTAL LOCALIZATION

A retrospective analysis of the database of patients with histologically verified serrated adenomas of the colon was carried out as part of an observational study. Inclusion criteria: patients with serrated colon adenomas who underwent a molecular genetic study to detect mutations and further sequencing 16 sRNAs of intestinal microbiota from January 2021 to October 2021. The exclusion criteria: patients with a primary tumor of the colon who had previously received complex treatment, who had accompanying pathologies of the other organs and systems, which did not allow for the planned examination. According to the results of the study, BRAF mutations are diagnosed in half of the cases in serrated adenomas and in one-third of cases - KRAS mutations. As a result of a comparative analysis of the intestinal microbiome of young patients with serrated colon adenomas with summary statistical data on the presence of bacteria in the intestines of people from the Russian population; promising markers were found for the development of effective approaches for the early diagnosis of colorectal cancer.

Solid Thyroid Follicular Nodules With Longitudinal Nuclear Grooves: Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 18 Cases

Context.— Follicular thyroid nodules can be a source of diagnostic difficulties, particularly when they display atypical features commonly associated with malignancy, such as nuclear grooves. Objective.— To differentiate lesions with atypical features from similar-appearing benign and malignant lesions. Design.— Eighteen cases of atypical follicular thyroid nodules characterized by a solid growth pattern and prominent longitudinal nuclear grooves were studied and examined for clinicopathologic characteristics. Results.— The lesions occurred in 16 women and 2 men aged 36 to 88 years and measured from 0.2 to 1.5 cm. The tumors were well circumscribed and noninvasive, and histologically characterized by a predominantly solid growth pattern with rare scattered follicles or a combination of solid growth pattern with minor follicular areas. A striking feature seen in all cases was the occurrence of longitudinal nuclear grooves. Immunohistochemical stains showed negativity for cytokeratin 19 (CK19) and HBME-1 in 8 cases; in the other 10, there was focal positivity for HBME-1 in 4 cases and diffuse positivity in 6. All cases were negative for galectin-3 and for CK19, with the exception of 1 case, which was CK19+/HBME-1−. Next-generation sequencing of 16 cases with a 161-gene panel detected 14 single nucleotide variants in 12 cases, predominantly NRAS and HRAS mutations. Clinical follow-up ranging from 18 to 72 months (median, 43.7 months) did not disclose any evidence of recurrence or metastases. Conclusions.— We interpret these lesions as low-grade, indolent follicular proliferations that need to be distinguished from papillary thyroid carcinoma, follicular adenoma, and noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Two species of Leymus (Poaceae) are artificial as inferred from the molecular-genetic data

The results of studying taxonomic relationships between five species of the aggregate Leymus secalinus (Georgi) Tzvel. of the genus Leymus Hochst. are presented. The research is based on the study of the ITS1-5.8S-ITS2 region obtained by sequencing the nuclear ribosomal DNA internal transcribed spacers, and on the anatomical and morphological data. A molecular-genetic study of the L. secalinus aggregate has revealed that the two species L. ovatus and L. jenisseiensis are artificial.

Successful treatment of pulmonary tuberculosis in a child with acute promyelocytic leukemia, on the background of intensive chemotherapy

The predisposition of patients with acute leukemia (АL) to various infectious complications is a well-known fact. The reason is a decrease in immunity due to the underlying disease and due to the use of immunosuppressive cytostatic and radiotherapy. Tuberculosis infections (TIs) are serious and life-threatening complications in patients with malignant hematological disorders and recipients after hematopoietic stem cell transplantation. Verification of tuberculosis (TB) is often delayed among patients with hematooncological diseases due to low suspicion and due to the search for other infectious complications. Those with the involvement of the respiratory system are the most common complications in immunologically compromised patients. In acute leukemia, the TB process may have been underestimated, due to negative tests for mycobacterium tuberculosis (MBT), and patients with neoplasia are often prescribed antibacterial agents such as amikacin and ftorchinolones, which are also effective against TI. We describe a 10-year-old boy who was diagnosed with pulmonary tuberculosis, a disseminated form complicated by hydrothorax, during induction chemotherapy for acute promyelocytic leukemia (APL). For diagnostic purposes, repeated punctures of the pleural cavity with drainage of pathological effusion and diagnostic and remedial bronchoscopy were performed, bacterial pneumonia and systemic mycosis were suspected. The diagnosis of TB was verified on the basis of positive PCR test for TB, molecular genetic study of sputum, bronchial lavage for the presence of genome of MBT without resistance to rifampicin, sputum microscopy, while sputum culture and pleural fluid were negative for MBT. TB treatment was coEadministered with AML-BFM 2004 intensive cytostatic therapy without dose reduction of cytostatics. The child was prescribed intensive tuberculostatic therapy with 4 drugs (rifampicin + isoniazid + pyrazinamide + inbutol) for 3 months and subsequent maintenance antituberculous chemotherapy with two drugs for 4 months (rifampicin + isonimazide). With this analysis, we advocate the need for early suspicion of TB in patients receiving treatment for AL. The results of our study suggest that antitumor chemotherapy is not an obstacle to effective TB-treatment. The described patient is in remission of AML and TB for 21 months. The research was carried out in accordance with the principles of the Helsinki declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: acute promyelocytic leukemia, tuberculosis, cytostatic therapy, children.

Genomic imbalance in a patient with two balanced translocations and abnormal phenotype

Представлены клинические и молекулярно-генетические результаты обследования пациента с задержкой психомоторного развития, аномалиями фенотипа и множественными врожденными пороками систем и органов. При стандартном цитогенетическом исследовании определены две реципрокные транслокации между хромосомами 2 и 6 и хромосомами 7 и 11, подтвержденные FISH-методом. Хромосомный микроматричный анализ позволил выявить делецию 6q14.1 в точке разрыва на длинном плече хромосомы 6. Делеция включает несколько десятков генов, в том числе гены PHIP, FILIP1, MYO6, HTR1B, IMPG1, EVOLV4, TENT5A, которые вероятнее всего ассоциированы с клиническими проявлениями у пациента. The results of clinical and molecular genetic study of the patient with psychomotor delay, phenotype abnormalities and multiple congenital malformations of systems and organs are presented. A standard cytogenetic study determined a double translocation between chromosomes 2 and 6 and chromosomes 7 and 11, confirmed by the FISH method. Chromosomal microarray analysis revealed a deletion of 6q14.1 region at the break point on the long arm of chromosome 6. The deletion involves several dozen genes, including PHIP, FILIP1, MYO6, HTR1B, IMPG1, EVOLV4, TENT5A genes, which are most likely associated with clinical symptoms in the patient.

Molecular genetic study of Trollius L. species using ISSR, ITS, rbcL and matK markers

Trollius L. – plant genus of Ranunculaceae Juss. family that has decorative and practical applications. Onthe territory of Siberia, the greatest diversity of representatives is noted. During the study, a population genetic analysis for7 populations of T. asiaticus, 2 populations of T. vitalii and 1 population of T. sibiricus was carried out. Revealed 114 loci,the total polymorphism of which is 98.25 %. The number of amplified fragments is related to the primer and range from27 (17899A) to 32 (ISSR-17 and HB14). GST is 0,5186, therefore, the studied populations have a high degree of differentiation according to the classification of Wright’s classification and are divided into separate species. On the dendrogram of population similarity, 2 clusters are distinguished, one of which is formed by populations belonging to the speciesT. sibiricus. The second cluster includes populations of T. asiaticus and T. vitalii. A separate group that, probably, belongsto T. austrosibiricus Erst et Luferov is formed by the Baikal and Idzhim populations. When constructing a tree for individual representatives, a clear division of populations into separate groups is observed. Phylogenetic analysis of the nucleotidesequences of the ITS regions, chloroplast genes matK and rbcL revealed the absence of significant differences between thespecies T. asiaticus, T. vitalii, T. kolonok, T. europaeus L., T. altaicus, and T. sibiricus. SNPs were noted in the matK sequences in T. europaeus, T. altaicus, and T. kolonok.

Association of ITGB3 gene polymorphisms with the risk of developing fetal growth restriction syndrome

The article presents a molecular genetic study of the ITGB3 gene polymorphism in pregnant women with fetal growth restriction syndrome. Purpose: Assessment of the detectability of the association of the ITGB3 gene polymorphism in women with physiological pregnancy and fetal growth restriction syndrome in the uzbek population of the Bukhara region. Materials and methods: 80 pregnant women were examined during gestation from 8-36 weeks: 40 pregnant women with fetal growth restriction syndrome and 40 women with physiological pregnancy, hospitalized in the department of pathology of pregnant women in the Bukhara city maternity hospital in the city of Bukhara. Conclusion: The study showed that the functionally unfavorable allele C and the association of the T / C genotype polymorphism of the ITGB3 gene polymorphism can be a determinant of an increased risk of developing FGRS in Uzbekistan (χ2 <0.47; P> 0.05).

Modern strategy for treatment of metastatic colorectal cancer as key to increasing life expectancy of patients with metastatic colorectal cancer without mutations in RAS genes

The review is devoted to the place of cetuximab in the treatment of metastatic colorectal cancer (mCRC) without mutations in the RAS (RAS wt) and BRAF (BRAF wt) genes, depending on the goals of therapy, as well as to the analysis of the inflence of various factors, including the localization of the primary tumor, on the effectiveness of treatment. Randomized clinical trials and meta-analyses conducted on their basis allow us to conclude that cetuximab in combination with an infusion doublet or triplet provides the maximum frequency of deep and early objective responses, regardless of the location of the primary tumor. The drug is superior in this parameter to both a single chemotherapy (CT) and a combination of CT with bevacizumab which is important in terms of achieving resectability in patients with potentially resectable metastases. For patients with left-sided localization of the primary tumor and RAS wt, cetuximab, prescribed in the 1st line, provides a reliable and clinically signifiant increase in life expectancy. Postponing the start of its use until 2–4 cycles of CT (until the result of a molecular genetic study is obtained) does not negatively affect the effectiveness of the 1st line of therapy for mCRC RAS wt, and with left-sided localization of the primary tumor, CT with delayed cetuximab exceeds the usage of CT with bevacizumab from the fist cycle for ORR, OS and PFS. The optimal duration of induction chemo-targeted therapy is 3–4 months (6–8 courses), after which it is advisable to switch to maintenance treatment with one cetuximab. The new mode of administration of cetuximab once every 2 weeks at a dosage of 500 mg/m 2 IV provides maximum convenience of its use.

Comparative Study of the Genetic Diversity of Local Steppe Cattle Breeds from Russia, Kazakhstan and Kyrgyzstan by Microsatellite Analysis of Museum and Modern Samples

The comparative molecular genetic study of museum and modern representatives of cattle breeds can help to elucidate the origin and maintenance of historical genetic components in modern populations. We generated the consensus genotypes for 11 microsatellite loci for 24 museum samples of Kalmyk, Kyrgyz, and Kazakh cattle, dated from the first quarter of the 20th century, and compared them with those of modern Kalmyk, Kyrgyz, and Kazakh white-headed breeds. The level of genetic diversity of the modern Kalmyk and Kyrgyz cattle (uHe = 0.771–0.778) was similar to those observed in the museum samples (uHe = 0.772–0.776), while a visible decrease in genetic variability in the modern Kazakh white-headed breed compared to museum Kazakh cattle was detected (uHe = 0.726 and 0.767, respectively). The PCA plot, FST- and Jost’s D-based networks, and STRUCTURE clustering provided strong evidence of the maintenance of the historical genetic background in modern populations of Kalmyk and Kyrgyz cattle. In spite of the allele pool of Kazakh white-headed cattle having undergone great changes compared to the museum Kazakh cattle, several animals still carry the visible aspect of the historical genetic components. Our results can be used for the selection of individuals for the creation of gene banks and may significantly improve the efficiency of conservation programs aimed at preserving genetic diversity in the national genetic resources of cattle.