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Patients with advanced high-grade serous ovarian cancer (HGSOC) are usually treated with paclitaxel and carboplatin; however, predictive markers for this drug combination are unknown. Tumor samples from 71 consecutive HGSOC patients, who received neoadjuvant chemotherapy with paclitaxel and carboplatin, were subjected to molecular analysis. BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 months vs. 3.8 months; P = 0.007). Fifty-one HGSOCs had sufficient quality of tumor DNA for the next-generation sequencing (NGS) analysis by the SeqCap EZ CNV/LOH Backbone Design panel. All 13 tumors obtained from BRCA1/2 germline mutation carriers and 12 sporadic HGSOCs showed a high number of evenly spread chromosomal breaks, which was defined as a BRCAness phenotype; median TFI for this combined group approached 9.5 months. The remaining 26 HGSOCs had similarly high global LOH score (above 20%); however, in contrast to BRCAness tumors, LOH involved large chromosomal segments; these patients had significantly lower TFI (3.7 months; P = 0.006). All patients with CCNE1 amplification (n = 7), TP53 R175H substitution (n = 6), and RB1 mutation (n = 4) had poor response to paclitaxel plus carboplatin. This study describes a cost-efficient method of detecting the BRCAness phenotype, which is compatible with the laboratory-scale NGS equipment. Some molecular predictors allow the identification of potential non-responders to paclitaxel plus carboplatin, who may need to be considered for other treatment options.

Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.26–7.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC.

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514–522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5–11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8–2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.

Colorectal carcinomas (CRCs) caused by hereditary biallelic MUTYH gene mutations are characterized by elevated mutation load and high lymphocyte infiltration. Given that these tumor features are associated with the response to immune checkpoint inhibitors, we administered nivolumab to a CRC patient who carried two inactive MUTYH alleles (p.Y179C and p.G396D) and previously experienced failure of chemotherapy. This experimental treatment resulted in a pronounced tumor response. We further compared tumor lymphocyte infiltration in MUTYH-associated (n = 3), high-level microsatellite instability (MSI-H, n = 8) and microsatellite stable (MSS, n = 6) CRCs. Both MUTYH-driven and MSI-H CRCs showed noticeably higher lymphocyte densities than those of microsatellite stable tumors; this difference reached the level of statistical significance for the comparison of central areas of the tumors (p = 0.02 and 0.03, respectively) but not for the invasive tumor margins. Although MUTYH-associated tumors are exceptionally rare among unselected CRC cases, their share in CRC patients with somatic KRAS p.G12C substitution approaches 5-25%. These observations provide a rationale for further evaluation of the efficacy of the immune checkpoint blockade in MUTYH-driven CRC.

Background Cisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs). Methods Ten HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme). Results None of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1). Conclusions The attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.

Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. Nineteen patients were prospectively included in the study. Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6–15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

We report a patient with a metastatic relapse of clear cell sarcoma, whose tumor harbored BRAF V600E mutation. Standard chemotherapy with doxorubicin and ifosfamide failed to slow the disease progression. Subsequent administration of vemurafenib (960 mg twice a day) resulted in complete tumor response after 8 weeks of treatment. Literature data on the use of vemurafenib and dabrafenib in non-melanoma BRAF-mutated tumors are reviewed.

Vemurafenib, a specific inhibitor of mutated BRAF kinase, may activate wild-type BRAF and therefore induce squamous cell skin carcinomas in patients treated for melanoma. All vemurafenib clinical trials excluded patients with multiple primary malignant tumors; therefore, the action of this drug on concurrent BRAF wild-type malignancies remains insufficiently studied. We observed a patient, who was administered vemurafenib for BRAF mutation-containing melanoma, but experienced immediate relapse of previously controlled breast cancer disease. Interestingly, breast cancer lesions underwent regression soon after vemurafenib discontinuation. Therefore, caution must be taken while considering vemurafenib treatment for patients with multiple tumors.

Development of malignancies in BRCA1 germ-line mutation carriers usually involves somatic inactivation of the remaining BRCA1 allele. This feature leads to a tumor-specific deficiency of double-strand DNA break repair and underlies pronounced sensitivity of BRCA1-driven cancers to cisplatin. BRCA1-specific activity of cisplatin has been repeatedly demonstrated in cell culture and animal experiments; however, corresponding clinical evidence remains limited. We applied neoadjuvant monotherapy by cisplatin (75-100 mg/m(2), 4-6 cycles) to six breast cancer patients carrying BRCA1 5382insC mutation. Pronounced reduction in tumor size was observed in all treated women. Three patients (T2N0M0, T4N2M0 and T4N2M0) showed pathologic complete response, two women (T4N0M0 and T2N1M0) had partial pathologic response, and one woman (T3N2M0) declined surgery. This study and available literature data suggest that cisplatin is a preferable option for systemic treatment of BRCA1-related hereditary breast cancer.

The effect of a traveling sonic wave on a convective flow in a horizontal layer with a fixed linear temperature distribution on the boundaries is investigated. Convective rolls with axes parallel to the basic flow (lengthwise rolls) are considered. On the basis of a weakly nonlinear analysis, it is shown that the lengthwise rolls appear smoothly and the regular flows are stable near the stability threshold. A direct numerical simulation is performed. Secondary near-critical flow regimes and regimes corresponding to finite supercriticalities are investigated.

Somatic inactivation of the remaining allele is a characteristic feature of cancers arising in BRCA1 and BRCA2 mutation carriers, which determines their unprecedented sensitivity to some DNA-damaging agents. Data on tumor-specific status of the involved gene in novel varieties of hereditary breast cancer (BC) remain incomplete. We analyzed 32 tumors obtained from 30 patients with non-BRCA1/2 BC-associated germ-line mutations: 25 women were single mutation carriers (7 BLM, 15 CHEK2 and 3 NBN/NBS1) and 5 were double mutation carriers (2 BLM/BRCA1, 1 CHEK2/BLM, 1 CHEK2/BRCA1 and 1 NBN/BLM). Losses of heterozygosity affecting the wild-type allele were detected in none of the tumors from BLM mutation carriers, 3/18 (17 %) CHEK2-associated BC and 1/4 (25 %) NBN/NBS1-driven tumors. The remaining 28 BC were subjected to the sequence analysis of entire coding region of the involved gene; no somatic mutations were identified. We conclude that the tumor-specific loss of the wild-type allele is not characteristic for BC arising in CHEK2, NBN/NBS1 and BLM mutation carriers. Rarity of "second-hit" inactivation of the involved gene in CHEK2-, NBN/NBS1- and BLM-associated BC demonstrates their substantial biological difference from BRCA1/2-driven cancers and makes them poorly suitable for the clinical trials with cisplatin and PARP inhibitors.

One hundred and ninety-five consecutive surgically treated Russian colorectal cancer (CRC) patients were retrospectively analyzed for the presence of mutations in KRAS, NRAS, BRAF and PIK3CA genes as well as for the microsatellite instability status. Comparison between high-resolution melting analysis, co-amplification at lower denaturation temperature PCR, DNA sequencing and allele-specific PCR for the detection of KRAS codon 12/13 mutations revealed that none of these methods alone provided satisfactory results in 100 % of the analyzed cases; this experience supports the use of more than one mutation-detecting technique at least in some circumstances. KRAS codon 12/13 substitutions were detected in 70 (35.9 %) CRC cases. Other mutations in the RAS/RAF genes occurred in 22 (11.3 %) cases and included rare KRAS (n = 6), NRAS (n = 8) and BRAF (n = 8) alterations. 5 BRAF mutations affected codon 600, while the remaining 3 potentially functional substitutions were located in the position 594. Twenty-four (12.3 %) CRC cases carried mutations in the PIK3CA, and 18 of these tumors also contained activating alteration in the RAS/RAF genes (p = 0.007). Only 3 (1.5 %) CRC cases showed high-level microsatellite instability (MSI-H) as determined by a panel of mononucleotide markers. Overall, the distribution of potentially predictive mutations in Russian CRC cases is similar to the one observed in other patient series of European descent. Noticeable occurrence of D594G mutation in BRAF oncogene and low frequency of MSI-H may deserve specific attention.