The Association of Death Receptors and TGF-ß1 Expression in Urothelial Bladder Cancer and Their Prognostic Significance.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-ß1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-ß1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-ß1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-ß1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-ß1 and indicates independent prognostic significance of high FAS and TGF-ß1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

Prognostic Value of Lactate Dehydrogenase in Patients with Melanoma Treated with Pembrolizumab.

INTRODUCTION: Elevated LDH levels have been extensively reported as a biomarker of poorer outcome in patients with melanoma during the chemotherapeutic era. The role of LDH level as a prognostic factor for treatment outcomes in patients with metastatic melanoma treated with immunooncological therapy has also been reported but requires further analysis. OBJECTIVES: In this study, we aimed to evaluate the prognostic value of lactate dehydrogenase (LDH) among patients with metastatic and unresectable melanoma treated with pembrolizumab in terms of progression-free survival (PFS). METHODS: The study included 59 patients with unresectable and metastatic melanoma treated with pembrolizumab. A comparison was performed between patients with normal and elevated levels of LDH in terms of PFS, with subgroup analysis. RESULTS: There was a significant reduction in PFS among patients with elevated levels of LDH compared with patients with normal levels of LDH (NR vs. 5 months; P=0.02). Patients with elevated LDH levels were older (P=0.01), with liver metastasis (P=0.004), and with less frequent CNS deposits (P=0.028). CONCLUSION: Although novel agents improved outcomes in patients with melanoma, high levels of LDH persist as an independent prognostic biomarker of poor prognosis.

Survival of patients with liver metastases from colorectal cancer treated with bevacizumab and FOLFOX4.

Purpose: In patients with colorectal liver metastases (CLM) a long term survival and a probability of cure might be achieved with the surgical treatment of metastatic sites after prior application of systemic treatment. The purpose of this study was to assess the survival of patients with unresectable CLM treated with bevacizumab (bev) and FOLFOX4 (FOLFOX-bev) and to compare survival according to patient, disease and treatment characteristics. Methods: This research included 110 patients with unresectable CLM treated with FOLFOX-bev. Treatment response and resectability were estimated every 3 months. If resectability was achieved, patients were operated on and followed. Patient, disease and treatment characteristics in patients with and without hepatectomy were compared. Survival was estimated according to Kaplan-Meier method. Comparison of survival according to patient, disease and treatment characteristics was performed using log-rank test. Results: In patients with hepatectomy, treatment response was significantly more frequent (63, 63% vs 16, 66%, p<0.001). One- and three-year survival rate for the whole group was 87, 3% and 36, 1%, respectively; median overall survival (OS) was 23 months (95%CI 19, 63-28, 26). One- and three-year survival for patients with hepatectomy was 98, 48%, and 54, 76%, respectively; median OS was 35 months (95%CI 28, 83-41, 17). Three-year survival was significantly better in patients with hepatectomy (HR=3.775; 95%CI 2.150-6.627, p<0.001), older than 60 years (p=0.033), those without extrahepatic metastases (p=0.008) and those with treatment response (p=0.05). Conclusion: Significantly better survival had patients with hepatectomy, treatment response, older than 60 years and without extrahepatic metastases. FOLFOX4-bev is effective treatment for molecularly unselected patients.

Current and future targets and therapies in metastatic colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-related deaths worldwide. Despite early diagnosis and treatment improvement, the majority of patients will still suffer from metastatic disease (mCRC), which has a poor prognosis. Molecular diversity of CRC requires personalized targeted approach for improving patient outcomes. Antiangiogenic agents proved to be beneficial in the continuum of mCRC treatment. For efficient epidermal growth factor receptor (EGFR) directed therapy, subtle molecular selection and better strategies to overcome resistance are needed. BRAF mutant and HER-2 positive mCRC will soon be provided with approved targeted treatments and check-point inhibitors demonstrated effectiveness in microsatellite instability (MSI) - high mCRC. Moreover, numeorous promising agents are entering clinical trial arena. This review summarizes actual and possible targets and current and promising agents for mCRC treatment. With broader accessibility of liquid biopsy we could track molecular evolution of CRC and target genetic alterations as they emerge.

Prognostic Impact of Canonical TGF-ß Signaling in Urothelial Bladder Cancer.

Background and objectives: Dysregulation of TGF-ß signaling plays multiple roles in cancer development and progression. In the canonical TGF-ß pathway, TGF-ß regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-ß1, Smad2, and Smad4, the key components of canonical TGFß pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients' outcome. Materials and Methods: Immunohistochemical analysis of TGF-ß1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results: High expression of TGF-ß1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-ß1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage (p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade (p = 0,003, p = 0.048, respectively), and low tumor stage (p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014). High TGF-ß1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression (p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-ß1 manifested as an independent predictor of poor outcome. Conclusions: Unraveling the complex roles and significance of TGF-ß signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-ß pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-ß signaling cascade.

Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma. METHODS: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals. RESULTS: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. INTERPRETATION: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680.

Checking the potential shift to perceived usefulness-The analysis of users' response to the updated electronic health record core features.

OBJECTIVE: The primary objective of this paper is to identify the main factors which have an impact on the users' attitude towards the functionalities representing the perceived ease of use and to those representing the perceived usefulness. Another objective is to examine whether there occurred a shift towards the perceived usefulness of users' behavior over a period of time. To support these objectives, two different cases are examined - the case in which users are simultaneously offered basic and updated functionalities, and the one in which users are offered a completely new set of features. The results of this study are expected to exert a significant impact on a further development of new software components, as well as the updates of the existing ones. MATERIAL AND METHODS: As the starting point, there were employed the user behavior indicators defined in similar researches and conducted in the countries with a similar cultural background or with a comparatively similar national healthcare system. What ensued was an updated set of functionalities offered within the electronic health record based medical information system. Instead of the survey being posted, the effects of implanted updates were measured through the analysis of the collected data. The data collected in the Nis Primary and Ambulatory Care Center during a four-year period represented the material used in the research. The obtained records indicating the usage of the initial and updated visit registration form, as well as the usage of the new types of visits, were examined in relation to the technology acceptance model and integrated behavior model. RESULTS: The response to the initial functionalities, perceived as easy to use, was high as expected since they kept the users in their "comfort zone". As regards the updated features, the ones corresponding to the perceived usefulness, the initial overall acceptance rate was 60%, while the overall increase of their acceptance was around 20%. The overall usage of the newly introduced features was doubled in some cases throughout the four-year period, while some of them were not accepted as expected. DISCUSSION: Carefully designed additional functionalities, aimed to improve the most common daily activities, have a significant potential to be accepted by the medical professionals. The shift from the perceived ease of use to the perceived usefulness is not uniform, nor is its use in different departments or by the users of the same department. A higher acceptance rate was observed in the departments with more complex administrative procedures, as well as among the users having contacts with more patients and using the system for a longer period. CONCLUSION: When accepting new features, medical professionals will initially choose the simpler ones with obvious benefits. If the usage of a feature triggers indirect benefits, the number of examined patients is of a crucial importance for the acceptance of that feature. In the event of the advanced functionality with an extended set of options competing with the simple functionality covering basic requirements, the latter will be used. A feature design, together with a proper training, system stability and ensuring utilization, represent a key point for increasing the positive impact that the information system can have in many application areas, including the healthcare.

Is it possible to improve prognostic value of NCCN-IPI in patients with diffuse large B cell lymphoma? The prognostic significance of comorbidities.

The prognostic value of the International Prognostic Index (IPI) has been re-evaluated in the rituximab-treated diffuse large B cell lymphoma (DLBCL) patients. Accordingly, National Comprehensive Cancer Network-IPI (NCCN-IPI) has been introduced to estimate prognosis of DLBCL patients. However, comorbidities that frequently affect elderly DLBCL patients were not analyzed. The aim of this study was to evaluate the prognostic significance of comorbidities using Charlson Comorbidity Index (CCI) in 962 DLBCL patients. According to CCI, majority of patients (73.6%) did not have any comorbidity, while high CCI (≥ 2) was observed in 71/962 (7.4%) patients, and in 55/426 (12.9%) of the elderly patients aged ≥ 60 years. When the CCI was analyzed in a multivariate model along with the NCCN-IPI parameters, it stood out as a threefold independent risk factor of a lethal outcome. Also, we have developed a novel comorbidity-NCCN-IPI (cNCCN-IPI) by adding additional 3 points if the patient had a CCI ≥ 2. Four risk groups emerged with the following patient distribution in low, low-intermediate, high-intermediate, and high group: 3.4, 34.3, 49.4, and 12.5%, respectively. The prognostic value of the new cNCCN-IPI was 2.1% improved compared to that of the IPI, and 1.3% improved compared to that of the NCCN-IPI (p < 0.05). This difference was more pronounced in elderly patients, in whom the cNCCN-IPI showed a 5.1% better discriminative power compared to that of the IPI, and 3.6% better compared to the NCCN-IPI. The NCCN-IPI enhanced by the CCI and combined with redistributed risk groups is better for differentiating risk categories in unselected DLBCL patients, especially in the elderly.

Two-Year Complete Remission of Diffuse Large B-Cell Lymphoma in an Immunological Nonresponder HIV-Infected Patient: Case Report.

INTRODUCTION: HIV-infected patients are affected significantly more frequently by all types of lymphoma, with diffuse large B-cell lymphoma (DLBCL) as the most prevalent histological type. Since the introduction of combination antiretroviral therapy (cART) morbidity and mortality of DLBCL has been markedly reduced, which is primarily interpreted as a result of the drug-mediated immune reconstitution. CASE REPORT: We present a previously healthy, 44-year-old HIV-infected man with DLBCL of the oral cavity, treated with immunochemotherapy and cART. During HIV-directed treatment, despite the successful virologic response, a satisfactory immunological response was not achieved. However, the patient had a 2-year complete remission after first-line treatment of DLBCL. CONCLUSION: Response to cART strongly predicts outcome in patients with DLBCL. Close monitoring of HIV-directed therapy efficacy, especially as to achievement of successful virologic response, independently associated with prolonged survival, is essential for estimating future DLBCL treatment strategies.

FCG (FLIPI, Charlson comorbidity index, and histological grade) score is superior to FLIPI in advanced follicular lymphoma.

The Follicular Lymphoma International Prognostic Index (FLIPI) is widely used in the identification of risk groups among follicular lymphoma (FL) patients. The aim of the present study was to evaluate the prognostic value of FLIPI combined with the Charlson comorbidity index (CCI) and histological grade of lymphoma. 224 newly diagnosed FL patients (median age 56 years) treated with immunochemotherapy were retrospectively analysed. Low FLIPI had 21.0 % of patients, intermediate 28.1 % and high 46.9 %. 50.9 % of patients had no comorbidities. Only 7.1 % of patients had a high CCI score (≥2), while 25.9 % of patients were histological grade 3. Parameters that influenced overall survival were evaluated using Cox regression analysis, in which CCI, FLIPI and histological grade (p < 0.05) retained prognostic significance. By combining these parameters, we have developed the FCG score, which incorporates FLIPI, CCI, and histological grade. This score defines three risk categories (low: 41.5 %; intermediate: 37.5 %; high: 13.4 %), associated with significantly different survival (p < 0.0001); this consequently improves discriminative power by 9.1 % compared to FLIPI. FCG score represents a possible new prognostic index, highlighting the role of the patient's clinical state and the histological characteristics of disease, as indicated by comorbidity index and histological grade of lymphoma.

Synchronous mantle cell lymphoma and prostate adenocarcinoma-is it just a coincidence?

Introduction: Synchronous occurrence of lymphomas and other cancers, mostly carcinomas are well established. The most of cases describe chronic lymphocytic leukemia as the leading lymphoproliferative disease with the tendency towards secondary malignancies development. Mantle cell lymphoma (MCL) has been described in only 2 cases to co-occur with prostate adenocarcinoma (PAC). There are scarce data about the connection between MCL and urology cancers. We presented the first case of synchronous occurrence of MCL and PAC in the same patient in Serbia. Case report: A 64-year-old male initially presented with fatigue, splenomegaly, and bicytopenia. The bone marrow biopsy specimen revealed extensive infiltration with MCL. During lymphoma staging procedure prostate enlargement (57 mm) was accidentally found by multislice- computed tomography (MSCT). The serum prostate specific antigen (PSA) was elevated (52 ng/mL; normal values ≤ 4 ng/mL). Transrectal ultrasound biopsy revealed PAC. High Gleason score determined high-risk locally advanced PAC. The patient underwent treatment with chemotherapy and hormone therapy due to the existence of double malignancies. Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) was applied for MCL, and luteinizing hormonereleasing hormone (LHRH) agonist, triptorelin, for PAC. Partial response was obtained for MCL, and stable disease for PAC. In a 1.5-year observation period the patient was still disease progression free for both of malignancies. Conclusion: This case points aut that elderly males are in need for careful observation during the staging procedure for lymphoma. The literature data suggest that MCL patients are in increased risk for urologic malignancies development. However, the etiologic connection between these two entities, except male gender and older age, remains unclear.

Current trends in the treatment of primary mediastinal large B-cell lymphoma - an overview.

Primary mediastinal large B-cell lymphoma has been recognised as a distinct entity with unique clinical, pathologic, and genetic features. According to WHO 2008 classification it is marked as a variant of diffuse large B-cell lymphoma but shares characteristics with classic Hodgkin lymphoma. Genetic analysis has shown that amplification of the 9p24.1 region is the disease's specific structural alteration. Aggressive behaviour and a tendency to invade surrounding tissues of the thoracic cavity, often causing superior vena cava syndrome, or pleural or pericardial effusions, are the clinical hallmarks of this disease. For a long period of time it has been considered as a disease with poor prognosis, which responds poorly to the conventional treatment created for diffuse large B-cell lymphoma. An elective treatment has not yet been established, but recently the situation has became much more favourable. After the introduction of rituximab the cure rates have risen to over 80%, and the most recent results have demonstrated a new insight with dose-adjusted intensified continuous treatments, in which the cure rates have exceeded 90%. Current trends have led to the introduction of dose-adjusted intensified protocols becoming a standard of care, whereas the use of radiotherapy remains controversial because of the questionable predictive value of post-treatment PET/CT validity. The relapse rate is very low after two years of sustained complete remission. If the disease relapses or is resistant the outcome is very poor regardless of the applied treatment modality.

Mantle cell lymphoma-current literature overview.

Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma identified as a particular entity in the early 1990s. The prognosis of MCL is generally poor, and is considered one of the worst among all B-cell lymphomas. In general, conventional chemotherapy is only palliative and the median duration of remissions is only 1-2 years. With the exception of allogeneic hematopoietic stem cell transplantation (allo-SCT), current treatment approaches are not curative and the corresponding survival curve is characterized by a relatively steep and continuous decline, with a median survival of about 4 years and <15% long-term survivors. Only a small proportion of patients may be exempted from this disappointing picture, because they have an indolent course of the disease and could be handled with watch and wait strategy. Optimal first-line therapy in MCL is not established yet. Very intensive regimens, including autologous (auto-SCT) and allo-SCT, seem to be required to improve the outcome. Allogeneic stem cell transplantation is the only therapy that can achieve a plateau in the survival curve, but, however, it is not applicable in most of the cases due to the patients' older age when the disease mostly occurs. Molecular knowledge of MCL has progressed and therefore a large number of molecular targeted therapies have been introduced in relapsed and refractory disease.

Clinical benefit of cetuximab and prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer: a single institution analysis.

PURPOSE: To evaluate the clinical benefits of cetuximab (CTX) and the prognostic value of CTX-related skin toxicity in metastatic colorectal cancer (mCRC) patients. METHODS: Sixty patients were tested for KRAS mutation at the Department of Oncology, Clinical Centre Nis. We assessed 34 wild-type KRAS mCRC patients treated with CTX. All of them were refractory to prior fluoropyrimidine, oxaliplatin and irinotecan-based regimens. The maximum grade skin toxicity according to treatment cycle was analyzed. Skin toxicity was grouped into clinically non-relevant skin toxicity (grade 0-1: Group 1) and clinically relevant skin toxicity (grade 2-4: Group 2). RESULTS: Ten out of 33 patients (30.30%) achieved partial response (PR). Eight additional patients (24.24%) showed stable disease (SD), whereas 15 (45.45%) had disease progression (PD). No patient achieved complete response (CR). Overall response rate (ORR) was 30.30%, whereas the disease control rate (DCR) was 54.54%.The median progression free survival (PFS) was 14 weeks. Some degree of skin toxicity was observed in 79.41% (27/34) of the patients. Clinically non-relevant skin toxicity was observed in 50% (17/34), and clinically relevant in 50 % (17/34) of the patients. Grade 4 skin toxicity was documented in 1 patient. The mean PFS in Group 1 was 12.65±5.59 weeks and in Group 2 22.82±12.16 (p<0.05). The results showed that grade 2-4 skin toxicity was associated with significantly better response to treatment than skin toxicity grade 0-1, with regard to ORR (80.00 vs 20.00%; p<0.05) and DCR ( 66.66 vs 33.33%; p<0.05). CONCLUSION: Cetuximab has clinical benefit when given alone or in combination with irinotecan in patients with irinotecan-refractory CRC. Skin toxicity was one of the predictors of response and it was in line with what was expected.

Are we a step forward with targeted agents in resolving the enigma of mantle cell lymphoma?

Mantle cell lymphoma has been recognized as a distinct entity from the other non-Hodgkin lymphomas in middle 1990's. It carries a worst prognosis among all mature B-cell malignancies. Cyclin D1 and recently SOX11 are the hallmarks for this disease. Even if it is highly responsive to induction treatment, it remains incurable, since it inevitably relapses. Highly aggressive approaches with stem cell transplantation can shift the survival curve for a bit, but even so the overall survival is not significantly improved in most of the cases. Small portion of patients with this heterogeneous disease have an indolent course with long-term survival. Conventional immunochemotherapy has reached its maximal possibilities, so novel target agents are absolutely warranted. The large number of ongoing early phase trials demonstrated promising results, especially emphasizing agents that target B-cell receptor. They are mostly investigated in relapsed/refractory disease, while front-line approaches with those agents need to be explored in future times.

[Significance of serum tumor markers monitoring metastases in carcinomas of unknown primary site].

BACKGROUND/AIM: Unknown primary tumors represent a heterogeneous group of malignancies that are indicative of ominous prognosis. Cancer of unknown primary site (CUP) is defined as the lack of any detectable primary site after full evaluation, and accounts for approximately 3-5% of all newly diagnosed patients with malignancies. The aim of this report was to present the prognostic and predictive value of 8 serum tumor markers in this group of patients. METHODS: The study involved 63 patients. On histological examination, all the patients were presented with metastatic tumors whose primary site (origin) could not be detected with noninvasive diagnostic techniques. Following the routine light microscopy, all histological findings were classified into one of the following three groups: plano-cellular carcinoma--8 patients; adenocarcinoma--33 patients; unclassifiable (undifferentiated) carcinoma--22 patients. In all the cases we evaluated 8 serum tumor markers: alpha-fetoproteins (AFP), chronic gonadotrophin beta submit, human (beta-HCG), neuron specific enolase (NSE), marker of malignant ovarian tumors (CA 125), prostate-specific antigene (PSA), marker of malignant brest tumor (CA 15-3), marker of malignant pancreas tumor and gastrointestinal tumor (Ca 19-9), carcinoembryonic antigen (CEA) at the time of diagnosis. The patients on chemotherapy had the markers determined after the third and sixth chemocycle, i.e. at the time of illness progression observation, if present. The patients responding to chemotherapy with complete response (CR), partial response (PR) or stable disease (SD) had the markers determined after three-month periods until the time of relapse or progression. Chemotherapy was applied in 32 patients (20 females and 12 males), aged 29-70 years, who met the inclusion criteria. The following chemotherapy regimen was used: doxorubicin 50 mg/m2 (day 1), cisplatin 60 mg/m2 (day 1), and etoposide 120 mg/m2 (days 1-3). The period between two chemotherapy cycles was three weeks, and maximum five weeks in the case of prolonged hematological toxicity. RESULTS: Most commonly elevated were NSE values (82.54%), while AFP values were least commonly elevated (11.11%). Average survival time was 17.89 months (95% CI 12.96; 22.83). The probability of 24 months' survival was 0.228. The group of 32 patients treated with chemotherapy had 12 (37.5%) fatal outcomes in the observed period (72 months). Average survival time was 26.6 months (95% CI 19.5; 33.7). Average tumor marker values before and after the chemotherapy were significantly lower for NSE and CA 125. Survival was significantly better in cases of NSE and CA 125 decrease of more than 20%. CONCLUSION: Increased values of serum tumor markers are very often in CUP. The tumors show nonspecific overexpression of tumor markers. The NSE and CA 125 levels show good correlation with response to the given chemotherapy. However, a routine evaluation of commonly used serum tumor markers has not been proven of any prognostic and predictive assistance.