Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy.

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO2 = 1%) vs. normoxia (pO2 = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC.

Hypoxia-Mediated Decrease of Ovarian Cancer Cells Reaction to Treatment: Significance for Chemo- and Immunotherapies.

Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen ability to diffuse into surrounding tissues. Thus, the vasculature state modulates the microenvironment of the tumor cells. Cells sense and react to small variations in oxygen tension, which explains the lack of tumor cells' unicity in their reaction to drugs. Ovarian cancers are highly hypoxia-dependent, ascites worsening the access to oxygen, in their reactions to both chemotherapy and new immunotherapy. Consequently, hypoxia affects the results of immunotherapy, and is thus, crucial for the design of treatments. Controlling key immunosuppressive factors and receptors, as well as immune checkpoint molecule expression on tumor, immune and stromal cells, hypoxia induces immunosuppression. Consequently, new approaches to alleviate hypoxia in the tumor microenvironment bring promises for ovarian cancer immunotherapeutic strategies. This review focuses on the effects of hypoxia in the microenvironment and its consequences on tumor treatments. This opens the way to innovative combined treatments to the advantage of immunotherapy outcome in ovarian cancers.

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.

BACKGROUND: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance.

Cancer stem-like cells (CSLCs) are defined as cancer cells with stem cell characteristics. Although CSLCs constitute no more than a few percent of the tumor mass, they play important roles in cancer chemo-resistance, metastasis and disease recurrence. Ovarian cancer (OC) is considered the most aggressive gynecological malignancy in which the role of CSLCs is of major significance, although it remains to be specified. The studies describing ovarian CSLC phenotype vary in the definition of the molecular pattern of expression of the main markers such as CD133, CD44, CD117, and CD24. Stem-like features of OC have been shown to correlate with the clinical course of the disease and permit diagnosis, prognosis and treatment outcome to be improved. Identification of CSLC markers could provide hallmarks which, related to the chemo-resistance of the disease, will facilitate treatment selection. This review describes recent advances in research on stem-like cell status in OC, mainly focusing on surface markers of CSLCs and their clinical relevance.

Role of WNT/ß-Catenin Pathway as Potential Prognostic and Predictive Factors in Renal Cell Cancer Patients Treated With Everolimus in the Second and Subsequent Lines.

BACKGROUND: The aim of the present study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of the WNT/ß-catenin pathway. PATIENTS AND METHODS: In a prospective, single-arm, phase II study, patients with mRCC received everolimus (10 mg/d) in a 30-day cycle. We performed a prospectively planned evaluation of the potential biomarkers of the WNT/ß-catenin pathway. RESULTS: The serum level of soluble E-cadherin (sE-cadherin) in patients with RCC was significantly greater than that in the controls (71.62 ± 22.28 pg/mL vs. 54.26 ± 10.317 pg/mL; P = .0069). After 2 cycles of everolimus therapy, we observed a significance increase in sE-cadherin (from 71.81 ± 21.18 pg/mL to 77.50 ± 28.212 pg/mL; P = .0151). The Dickkopf-1 protein levels in the study and control groups were not significantly different (P = .2135). The favorable independent predictors for everolimus therapy were normal lactate dehydrogenase level before treatment (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.98; P = .0443) and low sE-cadherin level (HR, 0.54; 95% CI, 0.29-0.98; P = .0422). On multivariate analysis, we observed that worse overall survival was seen in patients with a lower regression coefficient of sE-cadherin after 2 cycles of treatment (HR, 2.60; 95% CI, 1.23-5.52; P = .0128), an increased corrected calcium level (HR, 3.09; 95% CI, 1.21-7.88; P = .0180), and an increased lactate dehydrogenase level before treatment (HR, 1.98; 95% CI, 1.02-3.83; P = .0426). CONCLUSION: WNT/ß-catenin component expression in patients with mRCC had no effect on progression-free survival or overall survival. However, we found that the sE-cadherin level might interact with response to everolimus therapy, although confirmation in future studies is needed.

Acute Phase Proteins for Monitoring Hematopoietic Recovery After Early Engrafting of CD34+ Peripheral-Blood-Stem-Cells for Autografting or Allografting in Patients with Malignant Diseases.

BACKGROUND Neutropenic fever (NF) is associated with delayed engraftment after peripheral blood stem cell transplantation (PBSCT). MATERIAL AND METHODS We followed the levels of acute-phase proteins (APPs) serially in 60 patients after peripheral blood stem-cell autograft (n=39) or peripheral blood stem-cell allograft (n=21) for hematologic malignancies and germinal tumors; we then examined the correlation of those levels with the presence of fever and with markers of engraftment. RESULTS Fever (present in 60% of patients) was associated with a highly statistically significant delay in reaching conventional engraftment targets (ANC >500/µL [0.5×10^9/L]; platelets >20,000/µL [20×10^9/L]; reticulocytes >20,000/µL [20×10^9/L]) (for all associations, p<0.001). Every 4th day for 24 days, we measured the APPs levels and the number of neutrophils (ANC), platelets (PL), and reticulocytes (RET) to reach the reference values of >0.5 G/L or >1.0 G/L for ANC, >20 G/L or >50 G/L for PL, and >20 G/L for RET, respectively. The presence of NF resulted in longer time to engraft hematopoietic stem cells with ANC, PL, and PET counts statistically significant (range 0.001-0.004). The median day range for NF patients was 21.22-26.89 versus 13.88-19.13 for no NF patients. CONCLUSIONS Our results provide additional information for monitoring hematopoietic engraftment in patients following PBSCT; the presence of NF can be tracked by serial measurements in serum of three investigated APPs throughout an early phase of hematopoietic recovery.

Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients.

BACKGROUND: The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors. METHODS: Between 2002 - 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC [exon 20], 4153delA [exon 11.17], and 300 T > G [exon 5]. PFS (progression free survival) and OS (overall survival) were determined by Kaplan-Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model. RESULTS: Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age ≥70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012). CONCLUSION: In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian cancer.

[The role of the Fanconi anemia pathway in the pathophysiology of ovarian cancer]. / Udzial bialek szlaku niedokrwistosci Fanconiego w patofizjologii raka jajnika.

We reviewed the literature on the relationship between the Fanconi anemia pathway (FA) and response to chemotherapy in patients with ovarian cancer. Despite continuous developments in medicine, ovarian cancer remains a challenge for both, physicians and researchers seeking ways to achieve better results of chemotherapy combined with other targeted therapies. Clinically relevant resistance to chemotherapy is a major problem in treating ovarian cancer. Researchers continue to investigate mechanisms responsible for drug resistance in order to develop better therapeutic methods against ovarian cancer. Among the resistance mechanisms, defects in DNA repair, including the FA pathway may be important in increasing the sensitivity of ovarian cancer cells to chemotherapy agents at the clinical level. A growing number of data has shown that disruption of the FA genes may be a useful predictor of OC sensitivity to chemotherapy agents whose activity is based on DNA crosslinking mechanisms.

[Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers]. / Badania przesiewowe w kierunku raka jajnika u nosicielek mutacji genów BRCA1/BRCA2.

Worldwide screening for early detection of ovarian cancer in both, the general population and the group of women at high risk for ovarian cancer including BRCA genes mutations carriers, has proven to be ineffective. The recommended screening methods, including a pelvic examination, transvaginal ultrasound, and CA125 performed biannually continue to fail due to their relatively low sensitivity specificity and positive predictive value tests, as well as the fact that cancer is still detected in advanced stages (FIGO III/IV). However proteomic techniques and the ongoing search for more sensitive and specific biomarkers to increase effectiveness of screening tests for ovarian cancer bring new hope. We reviewed the current literature on screening for ovarian cancer in BRCA genes mutations carriers.

[Surgical treatment in ovarian cancer prevention in carriers of the BRCA1/BRCA2 mutation]. / Postepowanie chirurgiczne w profilaktyce raka jajnika u nosicielek mutacji genów BRCA1/BRCA2.

Ovarian cancer remains to be a real challenge in spite of considerable progress in many areas of modern medicine. The use of genetic testing for detecting mutations of the BRCA genes has been offering clinical scrutiny between mutated versions of the BRCA genes and higher risk of both breast and ovarian cancer A population survey is a method of choice to find out more efficient screening management in order to identify cancer patients who further will be treated effectively early A review of literature on surgical PBSO (prophylactic bilateral salpingooophorectomy) in the BRCA genes mutations carriers with focus on preventive results against morbidity of ovarian cancer has been presented in the article.

Cystatin C as a parameter of glomerular filtration rate in patients with ovarian cancer.

AIMS: To evaluate the potential role of serum cystatin C as a marker of renal function in patients with ovarian cancer. METHODS: Treatment of consecutive ovarian cancer patients who were eligible for chemotherapy with paclitaxel (135 mg/m²/24 h) and cisplatin (75 mg/m²) every 3 weeks in 6 cycles. Glomerular filtration rate (GFR) markers, i.e. serum levels of creatinine and cystatin C, estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease formulas, were recorded before each cycle and 3 weeks after the 6th course. RESULTS: The median age of 34 patients was 54 years. In the initial stage of treatment, we did not observe any correlation between cystatin C and other GFR markers. We noted a significant association between cystatin C and tumor extent on spiral CT scans (diameter: >1 cm) performed at baseline (p = 0.004), and after the 1st (p = 0.03) and 2nd cycle (p = 0.026). We observed a correlation between cystatin C and CA-125 level before chemotherapy (R = 0.4; p = 0.02) and after the 1st cycle (R = 0.43; p = 0.04). CONCLUSION: The results of our study suggest that cystatin C is not a reliable marker of the GFR in ovarian cancer patients, probably due to its nature as a cysteine protease inhibitor.

The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells From clinic to bench - a critical review.

Recombinant human erythropoietin (rhEPO) has been used clinically to alleviate cancer- and chemotherapy-related anemia. However, recent clinical trials have reported that rhEPO also may adversely impact disease progression and survival. The expression of functional EPO receptors (EPOR) has been demonstrated in many human cancer cells where, at least in vitro, rhEPO can stimulate cell growth and survival and may induce resistance to selected therapies. Responses to rhEPO measured by alterations in tumor cell growth or survival, activation of signaling pathways or modulation of sensitivity to anticancer agents are variable. Both methodological and inherent biological issues underlie the differential cell responses, including reported difficulties in EPOR protein detection, potential involvement of EPOR isoforms or of cytoplasmic EPOR, possible differential structure and/or binding affinities of hematopoietic versus non-hematopoietic cell EPOR, possible aberrant regulation of EPOR activity, and a functional EPO/EPOR autocrine/paracrine loop. The modulation by rhEPO of tumor cell response to anticancer agents is coincident with modulation of multiple signaling pathways, BCL-2 family proteins, caspases and NFkB. The molecular interplay of pro-survival and pro-death signals, triggered by EPO and/or by anticancer agents, is multifactorial and tightly coordinated. Expression microarray analysis may prove critical for deciphering this potentially novel network and its broad spectrum of genes and proteins.

Serous peritoneal psammocarcinoma with an aggressive course: a case and review of the literature.

BACKGROUND: Primary serous peritoneal psammocarcinoma (PSPP) is a rare variant of serous carcinoma characterized by massive psammoma body formation and low-grade cytological features. Patients with serous psammocarcinoma have a protracted clinical course and relatively favourable prognosis, although a more aggressive course of PSPP may occur. CASE PRESENTATION: A 52-year-old woman suffering from abdominal pain with ascites and serum CA-125 level substantially elevated underwent an exploratory laparoscopy which revealed bulk disease. The pathology report detected PPSP at the FIGO stage IIIC. The patient received neoadjuvant chemotherapy (3 courses of paclitaxel/pegylated liposomal doxorubicin/carboplatin). Optimal interval debulking surgery was performed as the next step, followed by three courses of adjuvant chemotherapy (paclitaxel/carboplatin). Due to the fact that the patient had residual disease, at the second-look surgery she received consolidation therapy with intraperitoneal and intravenous chemotherapy carboplatin. Eight months after the completion of treatment the patient developed disease recurrence in the peritoneum. Palliative surgery (enterostomy) was performed. Furthermore, the patient received two lines of chemotherapy consisting of cyclophosphamide/cisplatin and then gemcitabine. After twenty five months she developed brain metastases, treated with palliative radiotherapy. The patient died twenty-eight months since her primary presentation of PSPP. CONCLUSION: PSPP is an infrequent variant of epithelial cancer with favourable prognosis. The disease may however, take a more aggressive course. Thus, an aggressive therapy is required to postpone the progression.

Salvage therapy with topotecan in heavily pretreated ovarian cancer patients.

BACKGROUND: We showed feasibility and efficacy of topotecan in third or a higher line of chemotherapy in heavily pretreated ovarian cancer (HPOC) patients. METHODS: Between January 2004 and June 2007, 25 cases of HPOC were treated with topotecan as 30-min infusion at the dose of 1.5 mg/m2 through 5 consecutive days every 21 days. We assessed toxicity profile using NCI CTC and the response was measured according to RECIST and CA-125 criteria described by Rustin. RESULTS: Heavily pretreated ovarian cancer received at least two cycles of topotecan (median 6, range 2-6) with prior chemotherapy lines (median 3, range 3-7). In 20 HPOC who met RECIST criteria results were as follows: PR, 6/20 (30%); NC, 7/20 (35%); PD, 7/20 (35%). Biochemical response was noted in 20 patients having ?15% (3/20) of 75% and 20% (4/20) of 50% decline of CA-125. Time to progression was median 6 months (95% CI: 4.06-6.18) and overall survival was median 9 months (95% CI: 8.69-16.27). In multivariate analysis, primary optimal debulking and response to primary chemotherapy (HR = 0.24, 95% CI: 0.08-0.69, P = 0.0084; HR = 0.38, 95% CI: 0.14-0.98, P = 0.0448, respectively) were independent prognostic factors when assessed in relation to salvage therapy with topotecan. We did not observe difference in side effects after topotecan treatment among patients in relation to the higher number of previously used chemotherapy line (3 vs. >3). CONCLUSIONS: We state that topotecan is able to offer a control of ovarian cancer, despite previous treatment, but reliable management is needed to alleviate hematologic toxicity.

Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study.

BACKGROUND: The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5 g) was administered before each course of standard chemotherapy with paclitaxel (135 mg/m(2)/24 h) plus cisplatin (75 mg/m(2)) every 3 weeks in patients with EOC. Magnesium subcarbonate (500 mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft-Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course. RESULTS: 41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p=0.0069), ClCG (p=0.0077) and MDRD (p=0.032) formulae compared with the magnesium supplemented group. CONCLUSIONS: These results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.

[Cystatin C as a marker of glomerular filtration rate in patients with ovarian cancer]. / Cystatyna C jako wskaznik filtracji klebuszkowej nerek u kobiet chorych na raka jajnika.

UNLABELLED: Cystatin C, a cysteine protease inhibitor, has been recommended as a new marker of glomerular filtration rate (GFR). THE AIM OF STUDY We investigated significance of cystatin C in assessment of GFR and its influence on overall survival (OS) in patients with ovarian cancer (OC). MATERIAL AND METHODS: We prospectively included consecutive patients with OC, who after surgery were qualified to first line chemotherapy according to the following protocol: cisplatin 75 mg/m2 and 24-hour infusion of paclitaxel 135 mg/m2 every three weeks. We assessed: serum levels of creatinine (Cr), cystatin C (Cys C), creatinine clearance (ClCr) calculated from 24-hour urine collection, GFR estimated according to Cocroft-Gault (CG) and Modification Diet of Renal Disease (MDRD) formulas. RESULTS: Age median of 37 patients enrolled into this study was 54 years (range from 28 to 68). We noted correlation between cystatin C and CrCl (R Spearman= -0.36; p = 0.03). We did not state any correlation between Cys C and another markers of GFR as: serum creatinine, CG, MDRD. However, we observed correlation between Cys C and measured tumor mass seeing in spiral CT-scan (diameter more than 1 cm) after surgery (R Spearman = 0.4; p = 0.01) and serum level of marker CA 125 (R Spearman= 0.4; p = 0.03). We didn't find any statistical correlation between values of serum Cys C (using median's as cutoff values) in overall survival of our patients (log-rank test, p = 0.9). CONCLUSIONS: Serum cystatin C level in patient with ovarian cancer is both the poor marker of GFR and has not prognostic value in the course of cancer after surgery with further primary chemotherapy. The explanation of this phenomenon could rely on the presence of residual ovarian cancer.

[CA 125 regression after two cycles of neoadjuvant chemotherapy as prognostic factor in patients with advanced ovarian cancer and primary peritoneal serous cancer who underwent interval surgical cytoreduction]. / Regresja markera CA 125 po dwóch kursach neoadjuwantowej chemioterapii jako czynnik prognostyczny u chorych na raka jajnika i pierwotnego surowiczego raka otrzewnej poddawanych interwalowej operacji cytoredukcyjnej.

OBJECTIVES: The aim of our study was to assess the prognostic role of CA 125 regression during neoadjuvant chemotherapy (NAC) in patients with ovarian cancer (OC) or primary peritoneal serous carcinoma (PPSC) that underwent interval debulking surgery (IOC). MATERIAL AND METHODS: Thirty one patients with advanced OC or PPSC (FIGO stage IIIC and IV) who underwent initial exploratory surgery, followed by NAC containing platinum analogs, have been analyzed, retrospectively. We have used a regression coefficient (RCA 125), which was calculated as following: log10 (CA 125 level measured after two cycles of NAC/baseline CA 125) for statistical analysis. The median value of RCA 125 reached -0.788 and has been used to dichotomize. Optimal IOC has been performed in 67.74% (21/31) patients, suboptimal in 25.81% (8/31) patients and 6.45% (2/31) of patients did not undergo IOC due to the progression of the disease. RESULTS: We have noted significant correspondence between time to progression and RCA 125 in univariate analysis, which we have also confirmed in multivariate analysis (HR 0.27; 95% CI, 0.15-0.96; p = 0.0178). Similarly, we have observed significant relationship between overall survival, RCA 125 and extension IOC in univariate analysis. Multivariate analysis confirmed that RCA 125 was independent prognostic factor, HR-0.18 (95% CI, 0.07-0.56; p = 0.004). In case of patients with high RCA 125, a greater rate of optimal debulking cytoreduction (p = 0.0278, U = 50.0) has been observed. CONCLUSIONS: RCA 125 after two courses of NAC appears to be an important prognostic factor in patients with OC or PPSC, who underwent IOC High RCA 125 during NAC seems to be a good predictive factor in order to achieve optimal IOC.

Molecular underpinnings of the targeted therapy for cancer.

Cancer is a real challenge for modern medicine. Biologically, it is of a host origin and therefore its eradication appears not so easy as one could expect to do it. Cancer presents itself with many faces as if it would be Janus the deity. The basic knowledge on tumorigenesis at the level of evolutionary science is weak. Additionally, accumulating molecular data are still focused on experimental systems, but more important fact is to determine the molecular pathobiology that could have impact on improvement of control of malignant disease. Poland is among the countries with high cancer morbidity and mortality. Multidisciplinary approach to detect, control, and treat cancer diseases is the only way to get improved clinical results. Moreover, it is worth pointing out that individual considerations of every patient would offer clinical benefits. Biology of human tumors with the modem armament of molecular and chemical methods would be a help-hand to construct novel drugs. Making a list of crucial pathways worth blocking with their translation into clinical benefits appears to be a great step forward. Chemistry is a real partner to modem medicine due to a technical possibility to have impact on molecules (xenobiotics) that will finally become approved drugs. Combinatorial chemistry offers automated methods for pipeline organic synthesis a large number of chemicals that are further capable of undertaking investigation at a bed. Many chemicals have been used for more than ten years upon treating various cancer patients. New drugs have various origin , i.e., monoclonal antibodies (Herceptin, Erbitux, Avastin) or small molecules (Glivec, Tarceva, Sutent, Nexavar). We do hope that in the future many new drugs will be available for treatment of particular disease in relation to genetic characterization of individual patient's tumor. At the same time, we realize the great need for changes in the financial facets of modem individual treatment, and hoping not to hamper the development of new drugs due to the lack of financial solution how to make new and expensive drugs available to many patients.

Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature.

OBJECTIVE: There has been only one report available that focuses on the treatment with imatinib mesylate of two individual persons with aggressive fibromatosis. The authors concluded that after long-term treatment, for 9 and 11 months, with imatinib mesylate, both patients demonstrated radiographic and clinical responses. The novel therapy should be considered as salvage in patients with aggressive fibromatosis expressed platelet-derived growth factor receptor-alfa, beta (PDGFR-alfa, PDGFR-beta), and/or c-kit, whose tumors are uncontrollable by the standard management. On the other hand, the number of kinases blocked by imatinib mesylate is notching up, for instance the tyrosine kinase, which is associated with macrophage-colony stimulating factor receptor (M-CSFR). METHODS: The patient was suffering from aggressive fibromatosis after prior therapy including surgery (R2), radiotherapy, and systemic treatment with combination of tamoxifen and sulindac. The tumor specimen was immunostained for PDGFR-beta and c-kit (CD117), and PDGFR-alfa and cytokines platelet-derived growth factor-alfa and beta were not assessed. The tests for both assessed molecules revealed negative results. In spite of this, the patient underwent a unique treatment with imatinib mesylate at the dose of 400 mg orally once daily for 3 years and 2 months. RESULTS: After three months of the therapy, radiographic (met criteria of SD but small decrease of the tumor was noted) and clinical responses were recorded for the first time. The same was seen after 6 and 13 months of therapy continuation with imatinib mesylate. Currently, the patient is treated with imatinib mesylate (400 mg orally once daily) without any toxicity effects. The last MRI revealed readily a smaller tumor (35 x 20 mm) after such a therapy lasted more than 3 years. CONCLUSIONS: Treatment with imatinib mesylate has been a well-accepted therapy for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). There have been established four kinases (p210(bcr/abl), c-kit, PDGFR-alfa, PDGFR-beta) suggested as the target for imatinib mesylate. Other potential targets will be discovered as it has lately been determined that M-CSFR kinase activity was blocked by imatinib mesylate. The salvage therapy for aggressive fibromatosis with imatinib mesylate seems to be an attractive opportunity for patients with the advanced disease, whose prior therapy failed.

[The role of proteasome in pathophysiology of cancer cachexia]. / Udzial proteasomu w patofizjologii zespolu wyniszczenia nowotworowego.

Cancer cachexia is a serious and life-treating syndrome that appears in most solid tumor patients. The syndrome is associated with anorexia, loss of protein mass, wasting of lipids, and disturbances of carbohydrate metabolism. Moreover, psychological distress and lower quality of life are often seen in patients with cancer cachexia. The latter is a multimodality process in which cytokine interactions, action of enzymes playing a key role in lipid metabolism, and activity of proteolytic proteinases are the complex net that are responsible for destruction of an organism suffering from cancer cachexia. Recently, it has been shown a growing role of ubiquitin-proteasome pathway in cachexia. Biochemical interactions are crucial for further study, mainly, when a novel target therapy appears to treat cancer in different modalities. In case of proteasome, PS-341 (bortezomib, Velcade) an inhibitor of proteasome is under investigation in clinical trials phase I.