During the past 20 years, targeted therapy based on the understanding of tumor biology has been complementing or even replacing cytotoxic agents that have dominated pharmacotherapy of cancer since the conception of medical oncology. Unfortunately, the fact that targeted therapies with potential to induce cure or at least substantially prolong survival are still not available for many common solid tumors results in skepticism or even nihilism. On the one hand, biomarker research is not keeping pace with the introduction of new agents, while on the other hand, effective drugs are still not available for many potential molecular targets associated with malignant transformation and tumor progression. However, targeted therapies have already transformed the natural history and clinical outcomes not only in patients with rare malignancies like gastrointestinal stromal tumor but also with many common tumors, e.g. breast cancer, malignant melanoma, non-small cell lung cancer or renal cell carcinoma. For further advances, a multidisciplinary effort is indispensible that should, above all, involve the collaboration of medical oncology and laboratory medicine.

In patients with metastatic melanoma the advent of targeted therapy and immune checkpoint inhibitors has transformed the management of advanced and metastatic disease, resulting in improved outcomes. Neopterin is a biomarker of immune activation increased in cancer as well as in other conditions associated with immune activation. We present a case of a patient with advanced metastatic melanoma responding to the combination targeted therapy with dabrafenib and trametinib. The treatment was complicated by a fever that was accompanied by a marked rise in serum and urinary neopterin concentrations. Present case report illustrates not only the efficacy of combined targeted therapy, but also the utilization of neopterin measurements in the diagnosis and monitoring of pyrexia in patients with metastatic malignant melanoma.

Germinální nádory jsou nejčastější malignity diagnostikované u mladých mužů.Poslední roky, stejně jako u řady dalších malignit, jeví incidence stoupající trend, ale zejména díky mezioborové spolupráci urologů s klinickými onkology je léčba těchto pacientů velmi úspěšná.Jedná se o skupinu nádorů s velmi dobrou prognózou a

Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.

Rusarova N, Bartouskova M, Studentova H. Hormonalně senzitivni karcinom prostaty. Karcinom prostaty patři celosvětově mezi druhe nejcastějsi onemocněni postihujici muže a jeho incidence stoupa s věkem. Přestože je u větsiny pacientů onemocněni diagnostikovano a leceno v casných stadiich, přibližně 10 % pacientů stale přichazi již v metastatickem stadiu nemoci a cast pacientů po lokoregionalni terapii dospěje k relapsu. Soucasný výzkum vedl k rozvoji vice lecebných modalit pro muže s pokrocilým hormonalně senzitivnim onemocněnim, zahrnujici kombinaci docetaxelu nebo abirateronu s androgen deprivacni terapii.

Východiska: Primarni intrakranialni sarkomy představuji vzacna onemocněni. S ohledem na chybějici randomizovane studie vychazime v lecebnem algoritmu obvykle z extrapolace dat z extrakranialnich variant těchto sarkomů nebo pouze publikovaných kazuistik, nicmeně prognoza i přes to zůstava neuspokojiva. Připad: V nasi kazuistice prezentujeme 69 letou pacientku, ktera byla dosetřovana pro organický psychosyndrom a parezu leve horni koncetiny. Magneticka rezonance prokazala rozsahlou expanzi mozku frontalně vpravo s kolateralnim edemem. Byla indikovana exstirpace tumoru s histologickým nalezem myxoidniho meningealniho sarkomu. Casna recidiva v mistě původniho tumoru 4 měsice po primarni resekci byla nasledovana reresekci a adjuvantni radioterapii do 50 Gy normofrakcionaci lůžka tumoru stejně jako dalsi recidiva 19 měsiců po předchozi, ktera již vsak byla v jine lokalitě. Systemova lecba zatim nebyla indikovana. V soucasnosti je pacientka bez znamek recidivy a pokracuje v observaci. Zavěr: Myxoidni meningealni sarkom představuje onemocněni s vysokým rizikem lokoregionalni recidivy u něhož v tuto chvili neexistuje jednoznacne doporuceni pro lecebný algoritmus.

We report a patient who presented with synchronous second primary human epidermal growth factor receptor (HER)-2-positive breast cancer and rectal -cancer that both required simultaneous neoadjuvant therapy. A modified regimen combining anti-HER-2 monoclonal antibody trastuzumab with chemotherapy and external beam radiation was selected. An organ-preserving surgical procedure was possible both in the breast and the rectum. Citrulline decreased rapidly after the start of the treatment, and then gradually returned to pre-treatment levels after the completion of chemoradiation. Urinary neopterin concentrations exhibited a fluctuating course. Both serum neopterin and C-reactive protein concentrations were more or less stable during the initial administration of trastuzumab, paclitaxel and carboplatin and then increased steeply during chemoradiation and subsequently declined to pre-treatment levels during the weekly trastuzumab administration. Changes were observed in the serum retinol concentrations. A decline in lymphocyte counts was accompanied by marked changes in peripheral blood cell count-derived ratios. The present case report demonstrates a successful combination of two neoadjuvant regimens in a patient with two synchronous different second primary tumors. Data from this case also illustrate the use of biomarkers for monitoring of intensive therapeutic regimens in medical and radiation oncology.

The aim of the present study was to investigate the association of peripheral-blood cell count (PBC)derived ratios, other biomarkers of inflammation and biomarkers of tumor growth with outcome in a cohort of patients presenting for the next line of therapy after the failure of prior systemic treatment. The data of 51 patients with advanced/metastatic colorectal carcinoma treated with cetuximab in the second or higher line of therapy were retrospectively analyzed. The median duration of cetuximab therapy and the median survival were 5.1 and 12.1 months, respectively. C-reactive protein (CRP), but not urinary neopterin correlated significantly with PBC-derived ratios. Both CRP and urinary neopterin correlated positively with carcinoembryonic antigen (CEA) concentrations and biomarkers of liver dysfunction. Although a number of parameters predicted overall survival in univariate analysis, only hemoglobin, CEA change and serum bilirubin were independent predictors of survival. In conclusion, in patients with metastatic colorectal carcinoma and predominantly liver metastases, the outcome of therapy in the advanced line setting was associated with initial hemoglobin level, a decrease of CEA concentration and initial presence of liver dysfunction. Urinary neopterin did not correlate with PBC-derived ratios, in contrast to CRP, but both urinary neopterin and serum CRP concentrations correlated with laboratory parameters of liver dysfunction.

In the present study, we determined complex indices of inflammatory activity and compared the performance of these indices as prognostic biomarkers in a cohort of breast cancer patients. All proposed composite biomarkers could be evaluated in 418 out of 474 patients in the cohort with complete data on peripheral blood cell count, urinary neopterin, albumin and C-reactive protein. Neutrophil-to-lymphocyte ratio, lymphocyteto-monocyte ratio, platelet-to-lymphocyte ratio, systemic inflammatory index, Glasgow prognostic index, modified Glasgow prognostic index, prognostic nutritional index and C-reactive protein/albumin ratio were calculated and further complex indices were proposed. Although a number of the investigated indices were significantly associated with survival in the univariate analysis, only age and stage, but none of the laboratory biomarkers or composite biomarkers, were significant predictors of survival in the whole group in the multivariate-analysis. In patients evaluated before the start of the treatment, age, stage and urinary neopterin were significant predictors of survival. These results underscore the importance of neopterin as a prognostic biomarker in breast cancer.

With the advent of immunotherapy the topic of biomarkers of immune response is of high interest. Along with the expression of programmed death ligand 1 (PD-L1) or tumor infiltrating lymphocytes (TIL), biomarkers of macrophage activation could be of interest. Neopterin is a biomarker of immune activation increased in different disorders associated with immune activation, including cancer. Neopterin synthesis is induced by interferon-γ that also induces indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing catabolism of tryptophan to kynurenine. Increased urinary or serum concentrations of neopterin have been associated with poor prognosis across a spectrum of malignant disorders of different primary location. Neopterin concentration in peripheral blood as well as in the tumor microenvironment correlates with phenotypic and functional changes of lymphocytes, indicating immune dysfunction. Increased neopterin concentrations are also accompanied by increased rate of conversion of tryptophan to kynurenine. Increasing neopterin concentrations also accompany side effects of anticancer treatment and could predict subsequent complications. Although almost four decades have elapsed since the discovery of increased neopterin concentrations in cancer patients, the full potential of neopterin as a biomarker in this setting has not been so far realized.

Aim: To analyze the prognostic significance of serum and urinary neopterin concentrations in patients with rectal adenocarcinoma treated with (chemo) radiation. Patients and Methods: Urinary and serum neopterin and peripheral blood cell count were determined in 49 patients with rectal carcinoma before the start of (chemo) radiation. Results: Neopterin concentrations exhibited a significant inverse correlation with hemoglobin and positive correlation with leukocyte count, platelet count and platelet-to-lymphocyte ratio. Increased serum neopterin concentration was associated with significantly inferior relapse-free survival (RFS) and overall survival. However, a significant association was observed only in 28 patients treated in the neoadjuvant setting. Although increased urinary neopterin was also associated with inferior RFS and overall survival, this was not statistically significant. The neutrophil-to-lymphocyte ratio was also associated with poor prognosis. Conclusion: The data presented herein indicate a prognostic significance of serum neopterin concentrations in patients with rectal cancer treated with neoadjuvant chemoradiation.

BACKGROUND:Gastrointestinal toxicity is the principal toxicity of chemoradiation in the treatment of rectal carcinoma. The assessment of this toxicity still relies mostly on the symptoms reported by the patient.METHODS:Plasma citrulline, serum neopterin and urinary neopterin were followed weekly in 49 patients with rectal carcinoma during chemoradiation.RESULTS:Citrulline significantly (p<0.05) decreased while serum and urinary neopterin concentrations increased during therapy. Irradiated gut volume correlated significantly inversely with citrulline and positively with urinary neopterin. Statistically significant inverse correlations were also observed between urinary neopterin and plasma citrulline concentrations during the treatment. Urinary neopterin concentrations were significantly higher and citrulline concentrations were lower in patients who experienced grade ≥3 gastrointestinal toxicity.CONCLUSIONS:Citrulline represents a promising biomarker of gastrointestinal toxicity. Moreover, the volume of irradiated gut correlated with urinary neopterin concentrations and an association was observed between gastrointestinal toxicity evidenced by lower citrulline concentrations and systemic immune activation reflected in increased concentrations of urinary neopterin.

Abstract Ovarian cancer is the most frequent cause of gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a poor prognosis. The standard treatment for advanced disease involves maximal cytoreductive surgery and chemotherapy based on platinum compounds and taxanes. Patients presenting at an advanced stage have a higher risk of recurrence. The development of drug resistance currently represents a major obstacle in the systematic treatment and, therefore, the discovery of new anticancer agents and approaches should improve the poor prognosis of these patients. Folate receptor α is overexpressed in epithelial ovarian cancer (EOC), but has limited expression in nonmalignant human tissues. The degree of folate receptor expression corresponds with the stage and grade of the disease. Because of this, folate receptor α seems to be a potential therapeutic target for the treatment of ovarian cancer. Currently, several approaches have been studied to target this protein in ovarian cancer treatment. This review summarizes current knowledge about the potential usage of folate receptors as prognostic and predictive biomarkers as well as their role in the management and targeted therapy of ovarian cancer.

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations are found in 35–45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type ( p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

The presence of wild-type RAS alleles, as determined by genotyping codons 12, 13, 59, 61, 117, and 146, is a prerequisite for personalized anti-EGFR treatment of metastatic colorectal cancer (mCRC) patients. Here we describe analytical validation of in-house developed massively parallel sequencing technology (MPS) in comparison to the in vitro diagnostics (IVD) certified qPCR method. DNA extracted from FFPE samples from CRC patients (n=703) and reference standards (n=33) were tested for KRAS and NRAS mutations in 6 codons of exons 2, 3, and 4 using deep amplicon sequencing (DAS) on a MiSeq benchtop sequencer (Illumina). Two different amplicon lengths and two different library preparation methods (long-RAS and short-RAS) were tested in order to evaluate their impact on DAS performance. In parallel, identical tumor DNA was tested by the following IVD assays: therascreen KRAS RGQ PCR Kit (Qiagen), cobas® KRAS Mutation Test (Roche Diagnostics), and SNaPshot assay (Thermo Fisher Scientific). Both DAS assays detected all the mutations present in reference standards and external quality control samples, except for the artificially generated KRAS codon 146 mutation. The DAS assays performed sufficient analytical specificity and sensitivity (≥0.95). The use of shorter amplicons prolonged the preparation steps but significantly improved the sequencing success rate of FFPE-derived DNA. RAS mutation frequencies in the Czech CRC patients were similar to previous reports, although rare mutations were also detected. DAS with short amplicons is a good strategy for routine assessment of somatic mutations in low-quality FFPE-derived DNA.