Mismatch repair status predicts survival after adjuvant treatment in stage II colon cancer patients.

BACKGROUND AND OBJECTIVES: Stage II colon cancer is primarily a surgical disease. Only a still not well-defined subset of patients may benefit from postoperative adjuvant chemotherapy. The relationship between adjuvant chemotherapy and survival after relapse is furthermore still not definitely explored in this group of patients. A number of reports suggest some association between defective mismatch repair (dMMR) and colorectal cancer stage II prognosis, but due to contradictory results from existing studies, the exact predictive role is still not fully understood. METHODS: Retrospective multicenter study including 451 stage II colon cancer patients. The proficiency or deficiency of mismatch repair was tested using immunohistochemistry and analyzed in relationship to two survival outcomes: overall survival (OS) and postrelapse survival. RESULTS: Patients with dMMR (20.4%) derived no OS benefit from adjuvant chemotherapy (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.47-2.38; P = .897). Patients with proficient mismatch repair (pMMR) tumors receiving adjuvant chemotherapy had the significantly better OS in comparison to those not receiving chemotherapy (HR, 0.54; 95% CI, 0.35-0.82; P = .004). This relationship remained significant in multivariable analysis (HR, 0.42; 95% CI, 0.22-0.78; P = .007). Patients with pMMR relapsing after adjuvant treatment lived significantly longer than those relapsing without previous adjuvant treatment (HR, 0.55; 95% CI, 0.32-0.96; P = .033) and this result remained significant in the multivariable model (HR, 0.49; 95% CI, 0.26-0.93; P = .030). CONCLUSION: In stage II CC patients, adjuvant chemotherapy improves therapeutic outcomes only in patients with pMMR tumors. Survival after relapse in patients having received adjuvant chemotherapy is significantly longer for patients with pMMR. No survival benefit from adjuvant chemotherapy was seen among patients with dMMR tumors.

[Current Possibilities for Predicting Responses to EGFR Blockade in Metastatic Colorectal Cancer]. / Soucasné moznosti predikce odpovedi na cílenou anti-EGFR lécbu metastatického kolorektálního karcinomu.

BACKGROUND: The combination of modern systemic chemotherapy and anti-EGFR monoclonal antibodies improves overall survival and quality of life for patients with metastatic colorecal cancer. By contrast, the addition of anti-EGFR therapy to the treatment regime of resistant patients may lead to worse progression-free survival and overall survival. Therefore, identifying sensitive and resistant patients prior to targeted therapy of metastatic colorecal cancer is a key point during the initial decision making process. Previous research shows that primary resistance to EGFR blockade is in most cases caused by constitutive activation of signaling pathways downstream of EGFR. Of all relevant factors (mutation of KRAS, NRAS, BRAF, and PIK3CA oncogenes, inactivation of tumor suppressors PTEN and TP53, amplification of EGFR and HER2, and expression of epiregulin and amphiregulin, mikroRNA miR-31-3p, and miR-31-5p), only evaluation of KRAS and NRAS mutations has entered routine clinical practice. The role of the other markers still needs to be validated. The ongoing benefit of anti-EGFR therapy could be indicated by specific clinical parameters measured after the initiation of targeted therapy, including early tumor shrinkage, the deepness of the response, or hypomagnesemia. The accuracy of predictive dia-gnostic tools could be also increased by examining a combination of predictive markers using next generation sequencing methods. However, unjustified investigation of many molecular markers should be resisted as this may complicate interpretation of the results, particularly in terms of their specific clinical relevance. AIM: The aim of this review is to describe current possibilities with respect to predicting responses to EGFR blockade in the context of the EGFR pathway, and the utilization of such results in routine clinical practice.

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

Impact of two extubation techniques on the intra-abdominal pressure: a preliminary study.

PURPOSE: High pressure peaks might be a risk factor for the development of abdominal hernia. The course of abdominal pressure during extubation remains unclear. This preliminary study assessed the impact of two established extubation techniques. METHODS: Twenty-four consecutive patients suffering from abdominal wall hernia with the indication for surgical treatment were included. Twelve patients were extubated directly after the intravenous anaesthesia was stopped, before they had spontaneous breathing (deep extubation). The other 12 were extubated after they had spontaneous breathing (awake extubation). Intra-abdominal pressure (IAP) was measured via bladder catheter continuously. RESULTS: The highest value during extubation as well as the main increase in IAP was significantly lower in patients who underwent deep extubation (p < 0.001). CONCLUSIONS: Therefore, this extubation technique might improve the outcome of hernia repair.

[The role of chemotherapy and targeted antiVEGF- and antiEGFR-therapy in metastatic colorectal cancer: a case report of long-term and intensive response]. / Pouzití chemoterapie v kombinaci s cílenou biologickou lécbou u diseminovaného kolorektálního karcinomu: kazuistika dlouhodobé a výrazné klinické odpovedi.

BACKGROUNDS: Colorectal cancer (CRC) is the second most frequent malignancy in the Czech Republic. Treatment of a metastatic disease is based on application of palliative chemotherapy (fluorouracil, leucovorin, irinotecan, oxaliplatin). When combined with targeted agents against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), it can result in significant and long-term response. CASE: We present a case of a 34-years old man with adenocarcinoma of sigmoid colon (Dukes C) with 5 years disease-free survival (DFS) after primary surgery (in 2002) and adjuvant chemotherapy with FOLFIRI (12 cycles). A solitary relapse in retroperitoneal lymph nodes in November 2007 was treated with retroperiotoneal dissection followed by adjuvant chemotherapy with FOLFOX 4 (12 cycles) and targeted radiotherapy of retroperitoneal area (completed in May 2008). An early relapse occurred one month later (June 2008--infraclavicular area, thoracic wall and retroperitoneal lymph nodes), patient underwent first line palliative chemotherapy with XELIRI + bevacizumab leading to partial remission (PR) after 3 months and complete remission (CR) after 6 months of treatment. Bevacizumab monotherapy was continued for the next 8 months up to March 2010, when a progression in the lung occurred. After wild-type status was confirmed, KRAS treatment was changed to the second line combination of irinotecan and cetuximab that resulted in nearly complete remission after 6 months and preservation of this remission after the next 6 months of cetuximab monotherapy. All treatments were well tolerated with good quality of life. CONCLUSION: Our case demonstrates the current options in the treatment of metastatic CRC. There is a trend to gradually use all the above listed cytostatics in combination with anti-VEGF and anti-EGFR monoclonal antibodies. When administered early, it may provide a significant and long-term treatment response.

[EGFR tyrosine kinase inhibitors as a targeted therapy for bronchioloalveolar carcinoma of the lung: a case report of a clinically prompt and intensive response and literature review]. / Cílená lécba bronchioloalveolárního plicního adenokarcinomu inhibitory tyrozinkinázové aktivity EGFR: kazuistika klinicky promptní a výrazné odpovedi a prehled literatury.

INTRODUCTION: Bronchioloalveolar carcinoma (BAC) is an adenocarcinoma belonging to non-small cell lung carcinomas (NSCLC) that, in addition to its morphology and endobronchial spread, presents with certain specific clinical characteristics: greater incidence in women, non-smokers and younger patients, presence of malignant bronchorrhea and lower susceptibility to conventional cytostatic therapies in comparison to other subtypes of NSCLC. On the other hand, nonmucinous type of BAC may show better therapeutic response to targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) erlotinib or gefitinib, as it is 5 times more frequently a carrier of EGFR gene mutations compared to conventional lung adenocarcinomas. CASE DESCRIPTION: We present a case of a 41 years old man, non-smoker for the last 5 years, who was diagnosed with a pneumonic form of nonmucinous bronchioloalveolar carcinoma. Metastases to regional and distant lymph nodes and massive involvement of skeleton with infiltrations in the bone marrow were present at the diagnosis. During the first line palliative chemotherapy with combination regimen of carboplatin and paclitaxel, the disease progressed significantly and the patient's condition deteriorated (performance status (PS) 3, severe dyspnoea at rest, malignant bronchorrhea). Subsequently, administration of erlotinib was initiated based on a series of case studies describing good response of BAC to treatment with EGFR TKI. An evident improvement of the patient's condition was observed as early as 4 days of administration, together with regression of peripheral lymphadenopathy. Nearly complete disappearance of pulmonary infiltrates was observed after 30 days of therapy, with the patient becoming asymptomatic, PS 0. Molecular genetics confirmed the tumour phenotype to be highly responsive to EGFR TKI therapy. The tumour contained EGFR mutation in exon 19 (in-frame L747-753insS deletion) and wild-type K-ras. Disease relapse in the liver occurred 6 months later confirming disease progression. Further treatment remained ineffective despite brief stabilisations of liver enzyme progression following repeated administration of pemetrexed and gefitinib. The patient died 12 months after the diagnosis. CONCLUSIONS: Our case confirms the importance of targeted therapy when treating tumours of an appropriate phenotype. Such treatment may have prompt and intensive effect that may reverse the course of the disease even in patients with poor overall health status.

[Profiles of low-molecular proteome spectrum obtained through SELDI-TOF mass spectrometry in the sera of patients with metastatic malignant melanoma: pilot study]. / Profily nízkomolekulárniho proteomového spektra získané pomocí hmotnostní spektrometrie SELDI-TOF v sérech pacientus diseminovaným maligním melanomem: pilotní studie.

BACKGROUNDS: Recently, research at genetic and molecular levels has extensively accelerated due to advances in new technologies. Since the mid-90s, a relatively new discipline--clinical proteomics, has evolved, which focuses on studying gene products--proteins. The evaluation of protein profiles may contribute to the more accurate stratification of patients in the future, in terms of both prediction of treatment results and prognosis. In pursuing this objective, proteomic approaches are currently used for the identification of new biomarkers. This is also the case with malignant melanoma, a disease without typical serum marker possessing high sensitivity and high specificity. METHODS: We analyzed human blood serum samples from 25 patients with metastatic malignant melanoma treated with palliative chemotherapy at the Masaryk Memorial Cancer Institute, Brno, in 2004-2006. The analysis was performed by Surface Enhanced Laser Desorption/lonisation Time of Flight Mass Spectrometry (SELDI-TOF-MS). Our patients were divided into two subgroups: a group relatively resistant to chemotherapy--14 patients--and a group with certain clinical benefit from the treatment (complete and partial remission, stabilized disease)--11 patients. We were searching for a new biomarker or typical protein profile in the selected two subgroups. Then, we recategorized our patients into three groups according to the similarity of their protein profiles regardless of sensitivity to chemotherapy. Finally, we evaluated differences in laboratory and clinical parameters, between both the groups of chemo-resistant and chemo-sensitive patients, and newly defined subgroups with similar protein profiles. CONCLUSION: We did not identify any significant differences in protein profiles or laboratory parameters in the predefined chemo-sensitive or chemo-resistant groups of patients. However, with regard to the new groups with similar protein profiles, we identified a subgroup of patients with different laboratory and clinical parameters. The results are very interesting and merit further research.

[Bevacizumab in combination with capecitabine and irinotecan (XELIRI) in treatment of metastatic colorectal cancer]. / Bevacizumab v kombinaci s kapecitabinem a irinotekanem (XELIRI) v lécbe metastatického kolorektálního karcinomu.

BACKGROUND: Incidence and mortality rates of colorectal malignancies in the Czech Republic are one of the highest in the world since over 7,500 patients are diagnosed yearly. About 25% of patients are diagnosed in clinical stage IV and in average more than 50% of patients who are diagnosed initially with resectable disease will relapse sooner or later. Management of palliative treatment of colorectal cancer therefore is becoming of a great importance. OBSERVATION: We designed a study protocol in 2005 and 16 patients with metastatic colorectal cancer were treated accordingly in the first line setting with XELIRI regimen (capecitabin, irinotecan) + bevacizumab. The regimen has proven high antitumor effectiveness (78% responses to treatment, median TTP: 12 months, 1-year survival reached 100% of patients) and excellent tolerance. No serious grade G3 or G4 toxicity was observed. Increase of blood pressure was observed sporadically within the group. We present below the case of 55 year old patient who underwent treatment of 4 cycles of XELIRI + bevacizumab and reached complete remission of the disease which lasted over the next 9 months (TTP 13 months). CONCLUSION: Successful choice of a regimen of the first line treatment determines the next course of a disease including duration of patient's overall survival. We have confirmed within our pivotal population that combination treatment XELIRI + bevacizumab is a very effective and well tolerated regimen moreover suitable for administration at outpatient setting.

[Adjuvant treatment for stage I of testicular germ cell tumours]. / Adjuvantní lecba u i. stádia germinálních nádoru varlat.

BACKGROUND: Testicular germ cell tumors (TGCT) are the most frequent malignancy seen in young men. More than 95% of patients diagnosed with early stage TGCT are cured. In management of stage I seminoma there are several treatment options, including adjuvant radiotherapy, adjuvant chemotherapy with one cycle of carboplatin or surveillance. Patients with stage I nonseminoma are treated with adjuvant chemotherapy, with nerve sparing retroperitoneal lymph node dissection or surveillance being considered another treatment alternatives for stage I disease. METHODS AND RESULTS: Fifty five patients with stage I TGCT were diagnosed and treated in Masaryk Memorial Cancer Institute between January 2000 to December 2004. In a retrospective analysis, we reviewed treatment outcome and treatment strategy used in these patients. Patients characteristics also included histological subtype, risk status, age at the time of diagnosis, relapse rate, delayed toxicity, etc. Despite the small number of patients included in the analysis (55), there was observed a clear preference toward adjuvant radiotherapy in seminoma patients (95%) and adjuvant chemotherapy in nonseminoma patients (97%). During median follow up (5,6 years in seminoma group, 5,7 years in nonseminoma group) only two patients experienced relapse of disease in the seminoma group and none in the nonseminoma group. One patient died of metastatic colorectal cancer. Acute toxicity was acceptable, with no treatment related death. The long- term side effects were not significant (no grade 3 or 4 toxicity). CONCLUSION: The achieved cure rates were high, with acceptable toxicity. The role of adjuvant chemotherapy with carboplatin in stage I seminoma remains controversial. Further management of TGCT should be guided by complete and correct assessment of known risk factors to ensure the potential for cure.

[Cardiotoxicity of drugs used in oncology]. / Kardiotoxicita léku pouzívaných v onkologii.

Administration of cytotoxic drugs is accompanied by many serious side effects, with cardiac toxicity as one of the most dangerous. In clinical practice anthracyclines are the best known chemotherapeutic agents linked to cardiotoxicity, however there are a number of other anti-cancer drugs (cyclophosphamide, taxans, trastuzumab, 5-fluorouracil, imunomodulators etc) that may cause cardiac toxicity as well. Basic mechanism through which anthracylines cause cardiac damage is recognized, though many pathogenetic ways of their toxicity still remain to be elucidated. Administration of trastuzumab is also clearly associated with cardiotoxicity, however, depression of left ventricular ejection fraction (LVEF) caused by this agent (unlike anthacyclines) seems to be fully reversible. For monitoring cardiotoxicity we use several methods--biochemical examination, use of X-ray, radionuclides or ultrasound. The most commonly used method to identify patients with heart damage is echocardiography with clinical examination. When a cardiac damage (mostly congestive heart failure with low LVEF) occures, following treatment depends on clinical symptoms and LVEF. These patients are then treated according to common internal medecine recommendations. Several cardioprotective agents have been tested, among these dexarazoxane seems do show significant cardioprotective activity. Also liposomal encapsulation of anthacyclines may reduce heart damage, especially early cardiotoxicity. Cardiotoxicity of cytostatic agents is a very serious side effect of anti-cancer therapy, which may affect survival more than the malignancy itself. Therefore a concentrated effort should be expended to prevent cardiac damage or at least to its early identification and prompt treatment.

The study of exposure to cadmium in the general population. II. Morbidity studies.

An epidemiological study was performed to assess whether environmental pollution by cadmium as found in cadmium polluted areas of CSFR (Pribram and Frýdek-Mistek) is associated with changes in biological indicators of renal dysfunction in non-occupationally exposed population groups. Polluted areas were chosen on the basis of existing sources of Cd emission. The city of Prague was selected as a control area. Environmental monitoring (Cd in air, dust fall and soil) did not confirm significant contamination of selected areas. It was found that Cd levels in urine (Cd-U) of inhabitants living in areas chosen as Cd-contaminated were significantly higher than in the control area. Differences in concentrations of Cd in blood (Cd-B) levels between individual areas were not significant. No significant differences between the study populations were noted in the urinary excretion of low molecular weight proteins (beta 2-microglobulin, retinol binding protein) and albuminuria. However, total proteinuria and aminoaciduria in persons living in Pribram area was significantly higher. This area suffers from combined contamination by cadmium and lead. In smokers of both sexes the Cd-B levels were significantly higher in all areas, no significant differences were found in Cd-U levels. However, it was found that in smokers there is higher percentage of persons excreting more than 0.9 micrograms Cd.g-1 creatinine in urine. Consumption of home-grown vegetable and fruit in Cd-polluted areas led to significantly higher levels of Cd-B and Cd-U and total proteinuria. The results of the study show that smoking and food seem to be the most important sources of Cd intake in non-occupationally exposed populations. In spite of the fact that environmental monitoring does not reveal a significant contamination of selected areas by Cd, Cd-U levels confirmed that population living in these areas is really exposed to Cd.

The study of exposure to cadmium in the general population. I. Autopsy studies.

From 1982 to 1986 samples of materials (liver tissue, kidney cortex) were collected from 438 autopsies in Prague. The age of persons was over 50 years and residence time in the area was at least 10 years Concentrations of Cd and Zn were determined in the kidney cortex and the liver tissue using the AAS method. On the basis of the Questionnaire for Relatives, data on smoking habits, and occupational history of the investigated persons were obtained. The results of the study confirmed that the concentration of Cd in analyzed tissues did not exceed values reported in the literature for people of similar age living in Cd uncontaminated areas. In smokers significant increase of Cd in the kidney cortex was found in all age and sex groups. The body burden of Cd in smokers is significantly higher.

Phenotypic alterations of 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea induced rat mammary tumors during repeated transplantations.

New transplantable rat mammary tumor lines derived from 7,12-dimethylbenz(a)anthracence (DMBA)- and N-methyl-N-nitrosourea (MNU)-induced carcinogenesis were established and characterized for biological and morphological criteria in the course of multiple tumor generations growing in female or male Wistar rats. DMBA-derived tumors RMT-1, RMT-2 and RMT-3 converted from adenocarcinoma to fibrosarcoma in the early passages. Conversion proceeded earlier in tumors with a well differentiated epithelial component compared to less differentiated ones, providing evidence for clonal spindle cell selection as the most probable mechanism responsible. On the other hand, MNU-derived tumor lines--RMT-4 and RMT-5--maintained histological patterns of parent tumors for a long time, exceeding 20 passages. Analysis of stromal cell tumor component and its interference with developmental sequences of transplantable tumor progression contributes to the explanation of some recent divergent findings (1, 2, 3, 4, 5).