Bevacizumab in the 1st line treatment of triple negative metastatic breast cancer patient — case report and review of the literature

Wprowadzenie. Angiogeneza i nadekspresja VEGF (Vascular Endothelial Growth Factor) odgrywają istotną rolę w rozwoju wielu typów nowotworów. Rola bewacyzumabu, humanizowanego przeciwciała anty-VEGF, w leczeniu chorych na rozsianego raka piersi pozostaje niejednoznaczna. Celem pracy jest przedstawienie przypadku chorej na potrójnie ujemnego, rozsianego raka piersi, która odniosła długotrwalą korzyść z immunochemioterapii jako pierwszej linii leczenia. Opis przypadku. U 57-letniej chorej na raka przewodowego piersi prawej, po szerokim wycięciu guza i limfadenektomii pachowej prawostronnej (pT1N0M0) oraz uzupełniającej chemio- i radioterapii, po czterech latach od zakończenia leczenia rozpoznano rozsiew choroby do płuca lewego (dwie zmiany) i węzłów chłonnych śródpiersia. Chora została zakwalifikowana do immunochemioterapii — paklitaksel z bewacyzumabem. W wyniku leczenia uzyskano znamienne zmniejszenie wymiarów zmian przerzutowych. Nie obserwowano poważnych działań niepożądanych terapii, po zakończeniu leczenia paklitakselem kontynuowano podawanie bewacyzumabu w ramach leczenia podtrzymującego. Od października 2009 r. do września 2013 r. chora otrzymała 70 wlewów bewacyzumabu. We wrześniu 2013 r. leczenie zakończono z uwagi na progresję wielkości zmian w płucu lewym, nowych zmian przerzutowych nie obserwowano. Chora została zakwalifikowana do stereotaktycznej radioterapii.Dyskusja. Jak dotąd skuteczność bewacyzumabu w leczeniu pierwszej linii u chorych na rozsianego raka piersi oceniono w trzech randomizowanych badaniach III fazy. We wszystkich tych badaniach stwierdzono znamienne wydłużenie PFS, bez istotnego zysku w zakresie OS. Na podstawie danych z literatury można przypuszczać, że konieczne jest wyodrębnienie podgrupy chorych, które odniosą największą korzyść z leczenia antyangiogennego. Aktualne doniesienia sugerują, ze najpewniej są to chore na potrójnie ujemnego raka piersi, które otrzymują bewacyzumab w skojarzeniu z chemioterapią w pierwszej linii leczenia, podobnie jak opisana przez nas chora.Introduction. Angiogenesis and VEGF (vascular endothelial growth factor) over expression play an important role inthe growth and development of many kinds of cancers. The role of bevacizumab, humanised, anti-VEGF antibody, intreatment of patients with metastatic breast canser (MBC) is still an open question. The aim of this paper is to present a case report of the use of bevacizumab with chemotherapy in the first line treatment of triple negative MBC.Case. We present the case of a 57-year-old woman with infiltrating ductal carcinoma of the right breast (pT1N0M0, TNBC). She underwent wide excision of the tumour with the excision of right axillary lymph nodes, adjuvant chemoterapy and radiotherapy. Four years later metastases in the left lung (two lesions) and mediastinum occured. For this reason the patient started immunochemotherapy — paclitaxel and bevacizumab. She ended paclitaxel after nine cycles, and continued bevacizumab as a maintenance. We observed a marked decrease in size of the metatstatic lesions. No serious adverse events during treatment were noted. From October 2009 to September 2013 the patient received 70 doses of bevacizumab. In September 2013 the treatment was ended due to progression of the size of the lung metastases. No new site of metastases was noted. The patient was considered suitable for stereotactic radiosurgery.Discussion. To date three randomised, multicenter studies, which evaluated effectiveness of adding bevacizumab to chemotherapy were performed. In all trials significant prolongation of progression-free survival (PFS) was observed but with no statistically significant influence on overall survival (OS). The toxicity of the combined treatment was higher. Many experts put a great emphasis on the need to discover a group of patients who will gain a significant benefit from antiangiogenic treatment. Reports in the literature indicate that probably the greatest benefit from adding bevacizumab to the chemotherapy is gained by women with triple-negative breast cancer, who receive bevacizumab as first-line treatment after cancer progression, as our patient described above

Effect of ultrasonic and thermal disintegration of water treatment sludge

This research was conducted to evaluate the effects of thermal and ultrasound disintegration on the disintegration degree (DD) of water treatment sludge from a municipal water treatment plant. A disintegration process was used to (i) improve subsequent coagulation efficiencies and dewatering processes (ii) reduce sludge production, and (iii) obtain both economic and enviromental benefits. The results show that using the disintegration process has an influence on DD values. It is also worth emphasising that the main parameter determining the efficiency of ultrasonic and thermal disintegration was the time of the applied process. Other parameters such as ultrasound intensity and temperature had a reduced impact on DD values

Effect of ultrasonic and thermal disintegration of water treatment sludge

This research was conducted to evaluate the effects of thermal and ultrasound disintegration on the disintegration degree (DD) of water treatment sludge from a municipal water treatment plant. A disintegration process was used to (i) improve subsequent coagulation efficiencies and dewatering processes (ii) reduce sludge production, and (iii) obtain both economic and enviromental benefits. The results show that using the disintegration process has an influence on DD values. It is also worth emphasising that the main parameter determining the efficiency of ultrasonic and thermal disintegration was the time of the applied process. Other parameters such as ultrasound intensity and temperature had a reduced impact on DD values

Impact of Protoporphyrin Lysine Derivatives on the Ability of Nosema ceranae Spores to Infect Honeybees

The effect of two protoporphyrin IX derivatives conjugated with single (PP[Lys(TFA)-OH)]2) or double (PP[Lys(TFA)-Lys(TFA)-OH]2) lysine moieties on the infectious capacity of Nosema ceranae spores was examined, and their efficacies were compared with those of a cationic porphyrin (H2TTMePP). Honeybees were inoculated with spores preincubated with porphyrins or with untreated spores (control). A significantly lower level of infection was observed in the bees infected with the porphyrin-treated spores than in the infected control. Porphyrins 1 and 2 reduced the infectious capability of microsporidia more efficiently than porphyrin 3, with bee mortality declining to almost 50%. Confocal analysis of the midguts of infected bees revealed distinct differences in the number of spores between the control group and the group infected with PP[Lys(TFA)-Lys(TFA)-OH]2-treated spores. Notably, bees with a reduced level of infection consumed less sucrose syrup than the control bees, indicating a reduction in digestive disorders and an improvement in food absorption

Classification of proteins that were differently expressed in DIO1(+) cells when compared with DIO1(-) cells.

<p>The graph shows results of analysis performed using PANTHER (<a href="http://pantherdb.org/" target="_blank">http://pantherdb.org</a>).</p

Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability

Restoration of type 1 iodothyronine deiodinase expression in renal cancer cells downregulates oncoproteins and affects key metabolic pathways as well as anti-oxidative system

<div><p>Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3’,5’-tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3’-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re-expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The ‘downregulated’ group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines.</p></div

Increased T4 concentration in renal cancer cells with re-expressed DIO1.

<p>Intracellular T4 concentration in renal cancer cells with (DIO1+) or without (DIO1-) ectopic DIO1 expression. The plots show mean ± SEM results of three independent biological experiments performed on KIJ265T-DIO1(+) cells and KIJ265-DIO1(-) cells. Statistical analysis was performed using <i>t</i>-test. T3 measurements were below the detection limit. *p<0.05.</p

The network of proteins affected by DIO1 expression.

<p><b>A.</b> Network of expression correlations; the proteomic data of protein expression levels were analyzed using Metscape/Cytoscape application. Blue lines: negative correlations, red lines: positive correlations. Thickness of lines indicates strength of correlations. <b>B.</b> Protein interaction network generated with STRING v. 10.5 accessed on 2017.11.06. with default settings (minimum required interaction score: medium confidence 0.4). Three major clusters are labelled as I (cytoskeleton remodeling and intracellular trafficking), II (cellular adhesion), and III (metabolism).</p

Epigenetic Regulation of Thyroid Hormone Receptor Beta in Renal Cancer

<div><p>Abstract</p><p>Thyroid hormone receptor beta (<i>THRB</i>) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of <i>THRB</i> in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of <i>THRB</i> in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in <i>THRB</i> and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However, <i>THRB</i> CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples. <i>In silico</i> analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting <i>THRB</i> transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3′UTR of <i>THRB,</i> and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous <i>TRHB</i> by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of <i>THRB</i> transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased <i>THRB</i> expression in ccRCC. In contrast, <i>THRB</i> is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of <i>THRB</i> in ccRCC tumors.</p></div