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Centrum Onkologii Instytut Im. Marii Sklodowskiej Curie and Cervico Sp. Z O.O. | Date: 2017-02-15

Screening test and process for detecting the presence of oncogenic HPV viruses, in particular based on LNA (locked nucleic acids) technology, as an effective tool in the prevention and early detection of cervical cancer. Probes for use in HPV detection by real time PCR, targeting a conserved region of oncogenic HPV genomes.


Patent
Cervico Sp. Z O.O and Centrum Onkologii Instytut Im. Marii Sklodowskiej Curie | Date: 2015-04-11

The screening test and process for detecting the presence of oncogenic HPV viruses, in particular based on LNA (locked nucleic acids) technology, are effective tools in the prevention and early detection of cervical cancer. Probes for use in HPV detection by real time PCR target a conserved region of oncogenic HPV genomes.


Jagiello-Gruszfeld A.,Nzoz Onko Med | Tjulandin S.,Russian Cancer Research Center | Manikhas A.,St. Petersburg City Oncological Dispensary | Pienkowski T.,Centrum Onkologii Instytut im Marii Sklodowskiej Curie | And 3 more authors.
Oncology | Year: 2010

Introduction: Lapatinib, an orally active tyrosine kinase inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and ErbB2 (HER2), has activity as monotherapy and in combination with chemotherapy in HER2-overexpressing metastatic breast cancer (MBC). Methods: This phase II single-arm trial assessed the safety and efficacy of first-line lapatinib in combination with paclitaxel in previously untreated patients with HER2-overexpressing MBC. The primary endpoint was the overall response rate (ORR). Secondary endpoints were the duration of response (DoR), time to response, time to progression, progression-free survival (PFS), overall survival, and the incidence and severity of adverse events. All endpoints were investigator- and independent review committee (IRC)-assessed. Results: The IRC-assessed ORR was 51% (29/57 patients with complete or partial response) while the investigator-assessed ORR was 77% (44/57). As per the IRC, the median DoR was 39.7 weeks, and the median PFS was 47.9 weeks. The most common toxicities were diarrhea (56%), neutropenia (44%), rash (40%), fatigue (25%), and peripheral sensory neuropathy (25%). Conclusions: First-line lapatinib plus paclitaxel for HER2-overexpressing MBC produced an encouraging ORR with manageable toxicities. This combination may be useful in first-line treatment for patients with HER2-overexpressing MBC and supports the ongoing evaluation of this combination as first-line therapy in HER2-overexpressing MBC. Copyright © 2010 S. Karger AG, Basel.


Petrylak D.P.,Yale Cancer Center | Vogelzang N.J.,Us Oncology Research | Vogelzang N.J.,Comprehensive Cancer Centers of Nevada | Budnik N.,Russian Railways | And 20 more authors.
The Lancet Oncology | Year: 2015

Background: Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m2) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208. Findings: 1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group. Interpretation: Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted. © 2015 Elsevier Ltd.


PubMed | Celgene, Russian Railways, San Camillo and Forlanini Hospitals, Yale Cancer Center and 12 more.
Type: Journal Article | Journal: JAMA oncology | Year: 2016

The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles.To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial.The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors.Total number of docetaxel cycles delivered as an independent factor for OS.Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P<.001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P=.41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P<.001).These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.


Brahmer J.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Reckamp K.L.,City of Hope Comprehensive Cancer Center | Baas P.,Netherlands Cancer Institute | Crino L.,University of Perugia | And 21 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. Copyright © 2015 Massachusetts Medical Society.


PubMed | Netherlands Cancer Institute, Dana-Farber Cancer Institute, Rocky Research, Yale Cancer Center and 10 more.
Type: Journal Article | Journal: European urology | Year: 2016

Elevated circulating tumor cell (CTC) blood levels (5 cells/7.5ml) convey a negative prognosis in metastatic castration-resistant prostate cancer but their prognostic significance in patients receiving chemotherapy is uncertain. The association between CTC counts (at baseline or after treatment), overall survival (OS), and response to docetaxel with lenalidomide was evaluated in a 208-patient subset from the MAINSAIL trial, which compared docetaxel-prednisone-lenalidomide and docetaxel-prednisone-placebo in metastatic castration-resistant prostate cancer patients. Baseline CTCs were <5 cells/7.5ml blood in 87 (42%) patients and 5 cells/7.5ml in 121 (58%) patients. Neither tumor response nor prostate-specific antigen response correlated with baseline CTCs. However, CTC count 5 cells/7.5ml was significantly associated with lower OS (hazard ratio: 3.23, p = 0.0028). Increases in CTCs from <5 cells/7.5ml to 5 cells/7.5ml after three cycles were associated with significantly shorter OS (hazard ratio: 5.24, p=0.025), whereas CTC reductions from 5 cells/7.5ml to <5 cells/7.5ml were associated with the best prognosis (p=0.003).Our study in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy, with or without lenalidomide, showed that patient survival was best predicted by circulating tumor cell count at the start of treatment. A rising circulating tumor cell count after three cycles of therapy predicted poor survival, while a decline predicted good survival.


PubMed | Bayer AG, Bordeaux University Hospital Center, Royal Marsden Hospital, IRCCS Policlinico San Matteo and 5 more.
Type: | Journal: BJU international | Year: 2016

To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC).Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-nave patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with 6 months of treatment including 4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety.In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months (ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%).Sorafenib demonstrated clinical benefit in treatment-nave patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-nave mRCC. Alternative protocols for sorafenib dose escalation could be explored.


Szala S.,Centrum Onkologii Instytut im. Marii Sklodowskiej Curie
Postpy higieny i medycyny doświadczalnej (Online) | Year: 2011

Growth of tumors usually depends on the development of the tumor's own vasculature. Small avascular tumors (1-2 mm3) cannot continue growth provided an equilibrium between pro-angiogenic and anti-angiogenic factors is maintained within the tumor environment. Angiogenesis is not the only factor responsible for tumor blood vessels forming, as vasculogenic mimicry plays an equally substantial role in this process. Vessel-like structures formed during this process are made up from cancer cells, macrophages and mast cells. Certain neoplasms are capable of growing without developing their own vasculature; instead they secure growth via normal blood vessels of the host. Slowed-down blood flow through an abnormally built tumor vascular network is the main reason for cancer cells' underoxygenation (hypoxia). Defective blood vessels, with hypoxia resulting, play a major role in tumor progression. Underoxygenation induces formation of novel vessels and these new defective vessels are in turn the principal reason for hypoxia. The latter increases cancer cells' malignancy and invasiveness. A particular process, called transdifferentiation, takes place in tumor vasculature when hypoxia is present and involves neoplastic cells transforming into endothelial cells. Since growth of a tumor is dependent on its own blood supply, inhibition of such vascular network growth and/or damage to this network should exert a strong impact on tumor growth. Long-term administration of anti-angiogenic drugs, however, encounters unexpected problems. Anti-angiogenic drug resistance, together with paradoxical stimulation of invasiveness and metastasis by these drugs, has lately become a dominant issue in anticancer therapy.


Opielka W.,NZOZ Vito Med. Sp. z o.o | Miszczyk L.,Centrum Onkologii Instytut im. Marii Sklodowskiej Curie
Onkologia i Radioterapia | Year: 2015

Introduction. Early diagnosis and modern radiotherapy have helped to significantly improve the prognosis in breast cancer, decrease mortality and increase the frequency of vascular complications connected with the treatment. The increase in the risk of vascular complications may be caused by inflammatory and atheromatous changes in the coronary and carotid arteries provoked by ionizing radiation. It has been proved that the risk of stroke in a long-term observation of patients who have completed the treatment (average observation time 4.5 years) is significantly higher than in non-treated patients. On the basis of the above information, one can suppose that the factor responsible for acute brain incident, such as stroke, in patients after radiotherapy due to breast cancer, as in patients irradiated because of head and neck cancers, is hemodynamically significant radiation-induced narrowing of the vessels. Objectives. Ultrasound assessment of vessel walls and Doppler measurement of blood flow parameters in the radiated arteries in the supraclavicular area (the first part of the common carotid artery, vertebral artery) as well as determination of a difference in the assessed parameters of the wall morphology and blood flow waveform between the side treated with radiotherapy and the non-treated side. The third aim was the assessment of the dynamics of atheromatous changes over time after finishing radiotherapy. Material and method. A group of 41 patients treated at the Institute of Oncology in Gliwice, Poland were observed from the year 2003 to 2014. The average age of the patients was 60. The dose in the supraclavicular area was identical for all patients and amounted to 50.0 Gy. The average time after the treatment ended was 54 months. The assessment of vessels concerned both common carotid arteries (CCA), the division of the common carotid arteries, the initial internal carotid arteries (ICA) including the measurement of the internal and medial membrane (Intima-Media Thickness – IMT) in the proximal segment of the CCA and the vertebral arteries with particular regard to their proximal segment. Results. The average IMT on the radiated side was 0.68 +/- 0.11 mm, and on the opposite side – 0.62 +/- 0.09 mm. On the basis of the statistical analysis of the differences between average IMT on the radiated side (IMT-RT) and IMT of the non-radiated side (IMT NRT), it has been confirmed that it is statistically significant (p = (0,044) for the assumed relevance level of p = 0.05. When analyzing the change of IMT over the time that passed from the conclusion of treatment, it was found that it had no important influence on the increase in the internal membrane thickness. In the second stage of the research, it was attempted to assess the proximal segment of the vertebral artery and indirectly the subclavian artery using B-duplex ultrasonography. The results show that narrowing is more common on the radiated side. In one case, narrowing of the vertebral artery and its thickening throughout all the observed segment from V0 to V2 were observed, which suggests inflammatory lesions caused by radiation in all three arterial walls. Conclusions. Radiotherapy of patients with breast cancer involving the supraclavicular arteries causes an increase in internal membrane thickness in the common carotid arteries. Radiation of this area increases the frequency of vertebral artery narrowing in the proximal segment. © ONKOLOGIA I RADIOTERAPIA 2015.

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