FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICI) are the main therapy currently used in advanced malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Despite the wide variety of uses, the possibility of predicting ICI efficacy in these tumor types is scarce. The aim of our study was to find new predictive biomarkers for ICI treatment. We analyzed, by immunohistochemistry, various cell subsets, including CD3+, CD8+, CD68+, CD20+, and FoxP3+ cells, and molecules such as LAG-3, IDO1, and TGFß. Comprehensive genomic profiles were analyzed. We evaluated 46 patients with advanced MM (31) and NSCLC (15) treated with ICI monotherapy. When analyzing the malignant melanoma group, shorter median progression-free survival (PFS) was found in tumors positive for nuclear FoxP3 in tumor-infiltrating lymphocytes (TILs) (p = 0.048, HR 3.04) and for CD68 expression (p = 0.034, HR 3.2). Longer PFS was achieved in patients with tumors with PD-L1 TPS ≥ 1 (p = 0.005, HR 0.26). In the NSCLC group, only FoxP3 positivity was associated with shorter PFS and OS. We found that FoxP3 negativity was linked with a better response to ICI in both histological groups.

PET/CT-tailored treatment of locally advanced oesophago-gastric junction adenocarcinoma: a report on the feasibility of the multicenter GastroPET study.

BACKGROUND: Perioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients. METHODS: Patients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I - III) stage Ib-IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV)average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data. RESULTS: A total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9-36%) and two non-responders (11%; 95% CI: 2.9-31%), with no statistical difference (p = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2-14%). CONCLUSION: Local and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients.

Effects of Early and Systematic Integration of Specialist Palliative Care in Patients with Advanced Cancer: Randomized Controlled Trial PALINT.

Background: A broad consensus on the optimal structure, intensity, and timing of early specialist palliative care (SPC) intervention is lacking. Objective: To evaluate the benefit of an early and systematic palliative intervention alongside standard oncology care compared with standard oncology care alone in patients with advanced solid tumors. Design: PALINT, a single-center RCT, conducted at the Masaryk Memorial Cancer Institute, the largest comprehensive cancer center in the Czech Republic (CR). Setting/Subjects/Measurements: Patients with newly diagnosed advanced cancer within six weeks from the start of the palliative systemic therapy were randomly assigned to the integration of SPC (intervention; a consultation with a PC physician every six to eight weeks) or to the standard oncology care (control). The primary endpoint was the quality of life (QOL) assessed by EORTC QLQ C30 and Hospital Anxiety and Depression Scale (HADS) at three and six months. Results: From 2015 to 2017, a total of 126 patients were randomly assigned to intervention (60) or to control (66) arm. At baseline, at three and six months, the global QOL scores (mean, 95% CI) in the intervention and control arm were 58.6 (53.9-63.3), 61.9 (56.4-67.4) and 66.7 (60.2-73.2) versus 54.2 (49.4-58.9), 59.0 (53.7-64.3), and 62.8 (56.7-68.9), respectively. The prevalence of anxiety (HADS-A; value >7) was 36.7%, 27.5%, and 18.9% versus 34.8%, 23.5%, and 16.3% and the prevalence of depression (HADS-D; value >7) was 28.3%, 25.4%, and 29.7% versus 28.8%, 29.4%, and 27.9%, respectively. There was no significant difference between the two arms. The overall survival was similar in both arms (347 vs. 310 days; p = 0.203). Conclusions: A model of early integration of SPC consisting of a consultation with a PC physician alone every six to eight weeks did not increase the QOL of patients with advanced cancer compared with routine oncology care in a center with widely available supportive services. These negative results underline the importance of the multidisciplinary patient centered approach in the early SPC.

Effectiveness of Neoadjuvant Therapy with Platinum-Based Agents for Patients with BRCA1 and BRCA2 Germline Mutations - A Retrospective Analysis of Breast Cancer Patients Treated at MMCI Brno.

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are associated with a high risk of developing breast cancer. Tumors arising from this mutation are expected to be more sensitive to platinum-based drugs. The role of platinum-based drugs in systemic neoadjuvant BRCA1/2 breast cancer therapy, and its efficacy in increasing the probability of pathological complete remission (pCR) are discussed repeatedly; however, there are no clear recommendations. PATIENTS AND METHODS: We retrospectively evaluated the contribution of a platinum-based antineoplastic drug to the achievement of pCR in a set of patients with BRCA1/2 mutant breast cancer treated with neoadjuvant chemotherapy from 2010 to 2017. The response to neoadjuvant chemotherapy was evaluated by a pathologist using definitive surgical specimens. A pCR was defined as a condition in which complete invasive breast cancer, and (eventually) positive lymph nodes, had disappeared. RESULTS: Of 76 patients (median age, 39 years; 62% with triple negative breast cancer (TNBC); 70% with BRCA1 positivity), 37 were treated with platinum-based drugs. More patients treated with platinum derivatives achieved pCR (57% vs. 23%, p = 0.005). Patients treated in a neoadjuvant setting with platinum-based antineoplastic drugs had a 4.4× greater chance of achieving pCR than those not treated with platinum, assuming the same tumor phenotype (TNBC or SR+/HER2). CONCLUSION: Neoadjuvant platinum-based chemotherapy for patients with a BRCA1/2 mutation is associated with a higher probability of achieving pCR, which is important for subsequent prognosis. This treatment should be considered particularly for patients with BRCA1 mutation and a TNBC phenotype. This work was supported by grant of the Ministry of Health of the Czech Republic - Conceptual. Development of a Reaserch Organization (MMCI 00209805). This work was supported by grant of the Ministry of Education, Youth and Sport of the Czech Republic (NPU I - LO1413). The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2019 Accepted: 14. 5. 2019.

Oncology Case Report - When Is the Appropriate Time to Integrate Palliative Care?

Many patients with advanced, non-curable cancer experience disease progression to a stage requiring symptomatic care alone. The integration of palliative care into oncology practice is therefore important, with many studies showing the benefits of early introduction of palliative care. In addition to symptom relief, palliative care can include psychological, social, and spiritual support. Although all oncologists provide basic palliative care, recent data indicate that the parallel involvement of a specialist palliative team that addresses the psychological, social, and spiritual needs of patients may be advantageous for both patients and their families. This mode of early integration of palliative care has been found to enhance patient quality of life and to provide more effective use of costly treatments. In Czech hospitals, however, this mode is rarely employed. Palliative care is usually perceived as an end-stage approach, which is initiated only when all other anticancer treatment modalities have been exhausted. This case describes the challenges and missed opportunities when palliative care was initiated late during the dying phase of a young female patient with metastatic colorectal cancer, and it discusses the potential benefits of early integration of palliative care. Supported by Ministry of Health of the Czech Republic, grant No. 15-33590A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 11. 2018 Accepted: 7. 6. 2019.

Afatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with Rare EGFR (in exon 18-T179X) Mutation - a Case Report.

INTRODUCTION: Exon 18-T719X EGFR mutation in non-small cell lung cancer is rare, only 1-5% of all EGFR mutations. The efficacy of EGFR tyrosin kinase inhibitors in tumours with uncommon mutations is still unclear and the prediction of response of such tumours to therapy remains unexplored. CASE: A 71-year-old woman with no previous smoking history with disseminated lung adenocarcinoma with exon 18-T719X EGFR mutation was treated with afatinib. A partial response was achieved in 2 months, progression-free survival was 19 months. The dose of afatinib was reduced to 30mg/day after 3 months due to skin toxicity and stomatitis grade 2. Next reduction to 20mg/day was performed after 10 subsequent months due to leucopenia and neutropenia grade 2. CONCLUSION: With this patient, a partial response which lasted 19 months despite 50% reduction of the afatinib dose was achieved. Key words: afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity This article was supported by Boehringer Ingelheim. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 1. 10. 2018.

Second cancers in Hodgkin's lymphoma long-term survivals: A 60-year single institutional experience with real-life cohort of 871 patients.

BACKGROUND AND PURPOSE: Appropriate surveillance guidelines for patients after successful treatment of Hodgkin's lymphoma (HL) are needed to reduce mortality of iatrogenic secondary cancers (SC). This large single institutional retrospective study analyses the risk of SC in HL patients treated outside of clinical trials over past decades. MATERIAL AND METHODS: Consecutive series of HL patients were analysed with median follow-up 12 years. Standardised incidence ratio (SIR) and absolute excess risk (AER) were calculated for site-specific risk of SC. RESULTS: In total of 871 patients (491 men; median age 34 years), chemotherapy alone, radiotherapy alone, and combined treatment underwent 36%, 40%, and 24% patients. 154 SC were found with significantly increased SIR = 2.9 and AER = 80.8 for all cancers except of nonmelanoma-skin cancer. SC-related death occurred in 71 patients (15% of those who died, 8% of whole cohort). The most common SC were lung (17.5% of all malignancies, SIR = 3.2), breast carcinoma (15.6%, SIR = 4.4), and haematological malignancy (non-Hodgkin's lymphoma SIR = 13.1; leukaemia SIR = 5.8). For SC within radiation field, the highest AER was in breast (AER = 46.9), colorectal (AER = 22.8), and lung cancer (AER = 17). CONCLUSIONS: Patients with HL are generally at great risk of developing SC, which is significantly increased especially by the use of radiotherapy. We suggested special follow-up schema for patients after initial HL treatment suitable for daily real-world clinical practice. The system depends on gender, form of HL treatment and especially the form of radiation therapy in terms of location of radiation fields.

Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer.

Background: The early detection of colon cancer is one of the main prerequisites for successful treatment and mortality reduction. Circulating PIWI-interacting RNAs (piRNA) were recently identified as novel promising biomarkers. The purpose of the study was to assess the profiles of piRNAs in blood serum of colon cancer patients with the aim to identify those with high diagnostic potential.Methods: Blood serum samples from 403 colon cancer patients and 276 healthy donors were included in this 3-phase biomarker study. Large-scale piRNA expression profiling was performed using Illumina small RNA sequencing. The diagnostic potential of selected piRNAs was further validated on independent training and validation sets of samples using RT-qPCR.Results: In total, 31 piRNAs were found to be significantly deregulated in serum of cancer patients compared with healthy donors. Based on the levels of piR-5937 and piR-28876, it was possible to differentiate between cancer patients and healthy donors with high sensitivity and specificity. Moreover, both piRNAs exhibited satisfactory diagnostic performance also in patients with stage I disease and enabled detection of colon cancer with higher sensitivity than currently used biomarkers CEA and CA19-9. Finally, the expression of analyzed piRNAs in blood restored significantly 1 month after the surgical resection.Conclusions: Based on our findings, piRNAs are abundant in human blood serum. Furthermore, their levels in colon cancer have been observed to be significantly deregulated. However, their involvement in carcinogenesis must be further established.Impact: piRNAs could serve as promising noninvasive biomarkers for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1019-28. ©2018 AACR.

Tumor Expression of miR-10b, miR-21, miR-143 and miR-145 Is Related to Clinicopathological Features of Gastric Cancer in a Central European Population.

BACKGROUND/AIM: In Western countries, most patients with gastric cancer (GC) present in advanced stages. Therefore, there is imminent clinical need for novel diagnostic and prognostic biomarkers. Deregulation of microRNAs has been reported as a frequent event in GC development in a number of studies. Our study validated the potential of microRNAs to serve as diagnostic and prognostic biomarkers in patients with GC from the Central European population. MATERIALS AND METHODS: Using quantitative real-time polymerase chain reaction, expression levels of six microRNAs (miR-10b, -21, -93, -107, - 143, and -145) were examined in 67 tumor tissues and 67 paired adjacent gastric tissues, and correlated with clinicopathological features of GC patients. RESULTS: Expression levels of miR-10b, miR-21, miR-93, and miR-107 were significantly higher in GC samples compared to non-tumor tissue. Furthermore, the expression levels of miR-10b, miR-143, and miR-145 positively correlated with advanced stages, and increased expression of miR-10b, miR-21 and miR-145 was significantly associated with worse prognosis of gastric cancer patients. CONCLUSION: Our results indicate that selected tissue microRNAs have the potential to serve as relevant diagnostic and prognostic biomarkers of GC in a central European population.

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9.

Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

Utilization and efficacy of second-line targeted therapy in metastatic renal cell carcinoma: data from a national registry.

BACKGROUND: It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test. RESULTS: The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5-19.5 months), 17.1 months (95% CI 14.5-19.8), and 15.4 months (95% CI 11.0-19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second-line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus. CONCLUSIONS: In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib.

Outcomes of Patients With Long-Term Treatment Response to Vascular Endothelial Growth Factor-Targeted Therapy for Metastatic Renal Cell Cancer.

BACKGROUND: Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long-term response to this treatment. PATIENTS AND METHODS: In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. RESULTS: Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2-93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference). CONCLUSION: There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.

Efficacy of Sunitinib in Elderly Patients with Metastatic Renal Cell Carcinoma: Data from Real-World Clinical Practice.

BACKGROUND: Although a significant proportion of patients with metastatic renal cell carcinoma (mRCC) are elderly, the data on the outcomes of targeted therapies in this population are limited. The aim of the present retrospective registry-based study was to analyse efficacy and toxicity of sunitinib as the first-line targeted therapy of elderly mRCC patients. PATIENTS AND METHODS: The national RENal information system registry of mRCC patients treated with targeted agents in the Czech Republic was used as the data source. Of the 1315 patients treated with sunitinib as first-line targeted therapy, 1016 and 299 patients were aged <70 and ≥70 years, respectively. RESULTS: Elderly patients had a significantly longer interval from diagnosis to the initiation of therapy. Median progression-free survival was 10.8 months (95 % confidence interval 9.8-11.8) and 8.8 months (7.2-10.4) for patients aged <70 and ≥70 years, respectively (p = 0.321). Median overall survival was 31.9 months (27.9-35.9) and 26.3 months (21.3-31.2), respectively (p = 0.044). Significantly more elderly patients started on a reduced dose of sunitinib or discontinued the treatment prior to progression because of adverse events. CONCLUSIONS: The differences in patient profile and dose-reduction rates point to a different approach in the management of older and younger patients in daily clinical practice. The lower dose intensity of sunitinib in the elderly population may have translated into inferior survival.

Epithelial-mesenchymal transition-associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinomas (ccRCCs) are genetically heterogeneous tumors presenting diverse clinical courses. Epithelial-mesenchymal transition (EMT) is a crucial process involved in initiation of metastatic cascade. The aim of our study was to identify an integrated miRNA/mRNA signature associated with metastasis and prognosis in ccRCC through targeted approach based on analysis of miRNAs/mRNAs associated with EMT. A cohort of 230 ccRCC was included in our study and further divided into discovery, training and validation cohorts. EMT markers were evaluated in ccRCC tumor samples, which were grouped accordingly to EMT status. By use of large-scale miRNA/mRNA expression profiling, we identified miRNA/mRNA with significantly different expression in EMT-positive tumors and selected 41 miRNAs/mRNAs for training phase of the study to evaluate their diagnostic and prognostic potential. Fifteen miRNAs/mRNAs were analyzed in the validation phase, where all evaluated miRNA/mRNA candidates were confirmed to be significantly deregulated in tumor tissue. Some of them significantly differed in metastatic tumors, correlated with clinical stage, with Fuhrman grade and with overall survival. Further, we established an EMT-based stage-independent prognostic scoring system enabling identification of ccRCC patients at high-risk of cancer-related death. Finally, we confirmed involvement of miR-429 in EMT regulation in RCC cells in vitro.

Serum-based microRNA signatures in early diagnosis and prognosis prediction of colon cancer.

Early detection of colorectal cancer is the main prerequisite for successful treatment and reduction of mortality. Circulating microRNAs were previously identified as promising diagnostic, prognostic and predictive biomarkers. The purpose of this study was to identify serum microRNAs enabling early diagnosis and prognosis prediction of colon cancer. In total, serum samples from 427 colon cancer patients and 276 healthy donors were included in three-phase biomarker study. Large-scale microRNA expression profiling was performed using Illumina small RNA sequencing. Diagnostic and prognostic potential of identified microRNAs was validated on independent training and validation sets of samples using RT-qPCR. Fifty-four microRNAs were found to be significantly deregulated in serum of colon cancer patients compared to healthy donors (P < 0.01). A diagnostic four-microRNA signature consisting of miR-23a-3p, miR-27a-3p, miR-142-5p and miR-376c-3p was established (AUC = 0.917), distinguishing colon cancer patients from healthy donors with sensitivity of 89% and specificity of 81% (AUC = 0.922). This panel of microRNAs exhibited high diagnostic performance also when analyzed separately in colon cancer patients in early stages of the disease (T1-4N0M0; AUC = 0.877). Further, a prognostic panel based on the expression of miR-23a-3p and miR-376c-3p independent of TNM stage was established (HR 2.30; 95% CI 1.44-3.66; P < 0.0004). In summary, highly sensitive signatures of circulating microRNAs enabling non-invasive early detection and prognosis prediction of colon cancer were identified.

Outcomes for Patients with Metastatic Renal Cell Carcinoma Achieving a Complete Response on Targeted Therapy: A Registry-based Analysis.

BACKGROUND: It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). OBJECTIVE: To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. DESIGN, SETTING, AND PARTICIPANTS: A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcomes were analysed using a log-rank test. RESULTS AND LIMITATIONS: A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis. CONCLUSIONS: Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. PATIENT SUMMARY: According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab.

The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52-10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50-9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.

Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells.

BACKGROUND: Ovarian cancer is the seventh-most common cancer amongst women and the most deadly gynecologic cancer. Cisplatin based drugs are used in first line therapy, but resistance represents a major obstacle for successful treatment. In this study, we investigated the anticancer effects and mechanism of action of three titanocene difluorides, two bearing a pendant carbohydrate moiety (α-D-ribofuranos-5-yl) on their periphery and one without any substitution. RESULTS: The efficacy of these compounds on ovarian cancer cell lines was evaluated in relation to their particular chemical structure and compared with cisplatin as the most common treatment modality for this type of cancer. The typical mechanism of cisplatin action involves DNA damage, activation of p53 protein and induction of cell death, as previously described for titanium ions. Nevertheless, our data indicate that the effect of titanocene difluoride derivatives is mediated via the endoplasmic reticulum stress pathway and autophagy. CONCLUSION: We anticipate that the presence of substituents on cyclopentadienyl ring(s) might play an important role in modulation of the activity of particular compounds. Titanocene difluorides exert comparable cytotoxic activity as cisplatin and are more efficient in cisplatin-resistant cell lines. Our results suggest potential utilization of these compounds especially in the treatment of cisplatin-resistant tumor cells.

miR-155 and miR-484 Are Associated with Time to Progression in Metastatic Renal Cell Carcinoma Treated with Sunitinib.

Background. Sunitinib is a tyrosine kinase inhibitor used in the treatment of metastatic renal cell carcinoma. The main difficulty related to the treatment is the development of drug resistance followed by rapid progression of the disease. We analyzed tumor tissue of sunitinib treated patients in order to find miRNAs associated with therapeutic response. Methods. A total of 79 patients with metastatic renal cell carcinoma were included in our study. miRNA profiling in tumor tissue samples was performed by TaqMan Low Density Arrays and a group of selected miRNAs (miR-155, miR-374-5p, miR-324-3p, miR-484, miR-302c, and miR-888) was further validated by qRT-PCR. Normalized data were subjected to ROC and Kaplan-Meier analysis. Results. We reported decreased tissue levels of miR-155 and miR-484 as significantly associated with increased time to progression (miR-155: median TTP 5.8 versus 12.8 months, miR-484: median TTP 5.8 versus 8.9 months). Conclusion. miR-155 and miR-484 are potentially connected with sunitinib resistance and failure of the therapy. miR-155 is a known oncogene with direct influence on neovascularization. Biological role of miR-484 has to be clarified. Stratification of patients based on miRNA analysis would allow more personalized approach in therapy of metastatic renal cell carcinoma.

Bevacizumab with FOLFIRI or XELIRI in the First-line Therapy of Metastatic Colorectal Carcinoma: Results from Czech Observational Registry.

AIM: To retrospectively compare the efficacy of two irinotecan-based chemotherapy regimens combined with bevacizumab in first-line therapy of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The data of 558 patients with mCRC treated with first-line bevacizumab plus irinotecan-containing regimen were obtained from the national CORECT registry that collects data of all patients with mCRC treated with targeted-agents. The treatment outcomes of patients treated with bevacizumab plus irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) were compared to patients treated with bevacizumab plus irinotecan and capecitabine (XELIRI). RESULTS: Among 4,312 patients with CRC treated with bevacizumab, only 13% (558) received irinotecan-based chemotherapy. No significant differences were observed in terms of progression-free survival and overall survival between FOLFIRI and XELIRI groups. Moreover, the toxicity of both regimens was also comparable. CONCLUSION: This retrospective analysis confirms the comparable activity of FOLFIRI and XELIRI regimens when combined with bevacizumab.