Connexin 43 Expression in Primary Colorectal Carcinomas in Patients with Stage III and IV Disease.

BACKGROUND/AIM: Protein connexin 43 (Cx43), a part of intercellular gap junctions, is frequently down-regulated in tumors. The aim of the study was to compare Cx43 expression in primary colorectal tumors of patients with stage III and IV disease. PATIENTS AND METHODS: Immunohistochemical expression of Cx43 was analyzed in 50 colorectal adenocarcinomas from surgically-treated patients of stage pT3N1-2 without metastases (M0) and 50 specimens of the same pTN stage from patients with synchronous liver metastases (M1). Association of Cx43 expression with clinicopathological factors and tumor site was also analyzed. RESULTS: There was no significant difference in Cx43 expression between M0 and M1 tumor specimens (p=0.817), as well as in Cx43 expression between colonic and rectal tumors (p=0.116), respectively. Stromal expression of Cx43 was higher in M1 than in M0 tumors (p=0.004). CONCLUSION: Stromal Cx43 expression is possible indicator of metastatic potential of colorectal adenocarcinoma.

Results of National Colorectal Cancer Screening Program in Croatia (2007-2011).

AIM: To study the epidemiologic indicators of uptake and characteristic colonoscopic findings in the Croatian National Colorectal Cancer Screening Program. METHODS: Colorectal cancer (CRC) was the second leading cause of cancer mortality in men (n = 1063, 49.77/100,000), as well as women (n = 803, 34.89/100,000) in Croatia in 2009. The Croatian National CRC Screening Program was established by the Ministry of Health and Social Welfare, and its implementation started in September, 2007. The coordinators were recruited in each county institute of public health with an obligation to provide fecal occult blood testing (FOBT) to the participants, followed by colonoscopy in all positive cases. The FOBT was performed by hypersensitive guaiac-based Hemognost card test (Biognost, Zagreb). The test and short questionnaire were delivered to the home addresses of all citizens aged 50-74 years consecutively during a 3-year period. Each participant was required to complete the questionnaire and send it together with the stool specimen on three test cards back to the institute for further analysis. About 4% FOBT positive cases are expected in normal risk populations. A descriptive analysis was performed. RESULTS: A total of 1,056,694 individuals (born between 1933-1945 and 1952-1957) were invited to screening by the end of September 2011. In total, 210,239 (19.9%) persons returned the envelope with a completed questionnaire, and 181,102 of them returned it with a correctly placed stool specimen on FOBT cards. Until now, 12,477 (6.9%), FOBT-positive patients have been found, which is at the upper limit of the expected values in European Guidelines for Quality Assurance in CRC Screening and Diagnosis [European Union (EU) Guidelines]. Colonoscopy was performed in 8541 cases (uptake 66%). Screening has identified CRC in 472 patients (5.5% of colonoscopied, 3.8% of FOBT-positive, and 0.26% of all screened individuals). This is also in the expected range according to EU Guidelines. Polyps were found and removed in 3329 (39% of colonoscopied) patients. The largest number of polyps were found in the left half of the colon: 64% (19%, 37% and 8% in the rectum, sigma, and descendens, respectively). The other 36% were detected in the proximal part (17% in the transverse colon and 19% in ceco-ascending colon). Small polyps in the rectum (5-10 mm in diameter), sigmoid and descending colon were histologically found to be tubular adenomas in 60% of cases, with a low degree of dysplasia, and 40% were classified as hyperplastic. Polyps of this size in the transverse or ceco-ascending colon in almost 20% had a histologically villous component, but still had a low degree of dysplasia. Polyps sized 10-20 mm in diameter were in 43% cases tubulovillous, and among them, 32% had areas with a high degree of dysplasia, especially those polyps in the ceco-ascending or transverse part. The characteristics of the Croatian CRC Screening National Program in the first 3 years were as follows: relatively low percentage of returned FOBT, higher number of FOBT-positive persons but still in the range for population-based programs, and higher number of pathologic findings (polyps and cancers). CONCLUSION: These results suggest a need for intervention strategies that include organizational changes and educational activities to improve awareness of CRC screening usefulness and increase participation rates.

One year efficacy and safety of oral sildenafil treatment in severe pulmonary hypertension.

Severe pulmonary hypertension is a progressive disease which leads to limitations of functional status and poor survival. We evaluated efficacy and safety of a short (3 months) and a long term (12 months) sildenafil treatment in patients with severe pulmonary hypertension. We treated 12 patients with pulmonary hypertension with oral sildenafil. Patients were followed at three time points, at baseline, and after 3 and 12 months of treatment. Primary end point was improvement in functional exercise capacity assesed by 6-minute walk test, and secondary end points were changes in right ventricle hemodynamics. We found significant improvement in 6-minute walk test distance from 357 +/- 193 m at baseline to 431 +/- 179 m after three months and further improvement to 501 +/- 159 m after 12 months (p < 0.01); decrease in right ventricule pressure from 107 +/- 42 mmHg at baseline to 87 +/- 32 mmHg after 12 months (p < 0.01); and, decrease in right ventricule diameter from 3.2 +/- 1.1 cm to 2.76 +/- 0.86 cm after twelve months (p < 0.01). Drug-related adverse events were mild and transient in our group of patients. Long-term (12 months) sildenafil treatment is effective and safe in our patients with idiopathic and chronic thrombo-embolic pulmonary hypertension.

Efficacy and safety of budesonide/formeterol combination therapy in asthma patients.

Budesonide/formoterol as single inhaler was developed for treating asthma patients who are not adequately controlled on glucocorticoides alone. The aim of this study was to evaluate efficacy, safety and patient/physician satisfaction of budesonide/formoterol therapy.Total of 268 asthma patients (120 men, mean age 38.8 +/- 37.2 years, and 148 women, mean age 42.2 +/- 32 years) were included in the study. All patients received budesonide/formoterol bid (640 mcg of budesonide and 18 mcg of formoterol daily) during run-in period for three weeks. Patients were followed during 14 weeks at 5 visits. At each visit lung function (FEV1 and PEF) was measured,presence of side affects was recorded and questionnaire was given to patients and physicians to estimate the level of satisfaction with budesonide/formoterol therapy (1 very unsatisfied to 5 very satisfied). Significant improvement was noticed in FEV1, from 76.25% of predicted value to 86.94% (p < 0.01); and in PEF from 380.84 L/min to 442.29 L/min (p < 0.01) in all patients. At the end of the study patients' satisfaction with budesonide/formeterol therapy was significantly improved comparing with satisfaction with previously taken therapy, in average grade, from 2.94 to 4.56 (p < 0.01), and similar results were noticed with physicians' satisfaction, from 2.60 to 4.41 (p < 0.01). Budesonide/formoterol in single inhaler, significantly improved lung function in patients with asthma.

Religiosity and quality of life in breast cancer patients.

Our aim was to assess relations between the quality of life and religiosity in breast cancer patients. The participants were 115 consecutively admitted female in-patients with breast cancer in the radiotherapy unit in the course of six months. The measures used were Santa Clara Strength of Religious Faith Questionnaire (SCSORF), World Health Organisation Well-Being Index Five (WHO-WBI 5) and International Breast Cancer Study Group Quality of Life (IBCSG-QL) Questionnaire. The participants responded on three statements relating to religious coping with cancer. Moderate religiosity was associated with perception of worse physical health. The statement "the illness decreased my faith" was associated with worse quality of life (QOL) domains: less well-being, more pain, poor physical health, more effort to cope, worse fatigue and less general satisfaction. The statement "the faith helps me in illness" was associated with higher social support.

Efforts in fighting against cancer in Croatia have to be focused on the primary health care.

This manuscript is a comprehensive review of the long-lasting tradition and the state-of-the-art in the prevention and early detection of cancer in Croatia. Compared with other European countries, Croatia holds a high and unfavourable position in cancer morbidity and mortality. Global experience in implementation of national programmes for the early detection of cancer clearly shows that such approach is the most successful and in the long-term the least expensive method for fighting against cancer. In Croatia, numerous separate actions in cancer care have been taken, but never systematically, nor included in a health care policy. The National Programme for the Prevention and Early Detection of Cancer of the common localizations for which effective screening tests are available (breast, uterine cervix, colon and prostate) has recently been launched. Local long-standing experience of the Osijek-Baranja County in implementation of programmes of cancer care contributed significantly to these initiatives. In this review, draft National Programme and the early results of its implementation were presented. In addition, preparations for the research project "Model of early cancer detection integrated in a practice of family physician", recently set up by the Department of Family Medicine of the School of Medicine, University of Osijek, were described. In this project, the programme of the early detection of cancer in which family physicians take responsibility for the programme implementation is suggested. Possible advantages of this model, compared with the model proposed by the National Programme, centrally directed and mostly supplied by the public services, are pointed out.

Immunohystochemical expression of cancer/testis antigens (MAGE-A3/4, NY-ESO-1) in non-small cell lung cancer: the relationship with clinical-pathological features.

The aim of this study was to explore the expression of cancer/testis tumor associated antigens (C/T TAAs) MAGE-A 3/4 and NY-ESO-1 in lung squamous cell carcinoma and adenocarcinoma, and to evaluate their association with the standard clinical-pathological features of surgically treated lung cancer patients. The study included 80 patients with non-small cell lung cancer (40 adenocarcinomas, 40 squamous cell carcinomas) who had undergone surgery in the period between 2002 and 2005. The MAGE-A3/4 and NY-ESO-1 antigen expression was analyzed immunohistochemically (IHC). The results showed MAGE-A3/4 and NY-ESO-1 positive staining in 65.1% and 23.3% of squamous cell carcinomas and 18.9% and 10.8% of adenocarcinomas, respectively. A statistically higher MAGE-A3/4 expression was observed in planocellular bronchial carcinoma (p < 0.001), while no difference was found in the expression of NY-ESO-1 in adenocarcinoma and planocellular carcinoma (p = 0.144). A significant association was found between the MAGE-A3/4 expression and presence of tumor necrosis in squamous cell cancer specimens (p = 0.001), but not in adenocarcinoma (p = 0.033). A statistically significant association was noted between the NY-ESO-1 expression and positive hilar and mediastinal lymph nodes in adenocarcinoma (p = 0.025) whereas it was not the case in squamous cell carcinoma. Non-small cell lung cancer frequently expresses cancer/testis tumor associated antigens. Our results demonstrate that the MAGE-A3/4 and NY-ESO-1 expression was significant associated with prognostic factors of poor outcome of disease (presence of tumor necrosis and lymph node metastasis). As C/T antigens are important for inducing a specific immune reaction in lung cancer patients, there is an intention to form a subgroup of patients in the future, whose treatment would be enhanced by specific immunotherapy based on the observed scientific results.

Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain.

Strong opioids are recommended for treating severe cancer pain in the advanced stages of the disease. Few data are available concerning the efficacy of buprenorphine in cancer pain. We compared transdermal buprenorphine 70 microg/h (BUP TDS) to placebo in an enriched design study. Opioid-tolerant patients with cancer pain requiring strong opioids in the dose range of 90-150 mg/d oral morphine equivalents entered a two-week run-in phase, during which they were converted to BUP TDS. Patients who could be stabilized on BUP TDS were randomized to BUP TDS or placebo patch for a two-week maintenance phase. Rescue medication (buprenorphine sublingual tablets 0.2mg) was allowed as required. Response was defined as a mean pain intensity of <5 (0-10 scale) and a mean daily buprenorphine sublingual tablet intake of < or =2 tablets during the maintenance phase. Of 289 patients who entered the run-in phase, 100 discontinued treatment due to lack of efficacy or adverse events; 189 patients continued treatment in the maintenance phase (94 BUP TDS, 95 placebo), of whom 31 discontinued treatment (7 BUP TDS, 24 placebo). A significant difference in the number of treatment responders was observed: 70 BUP TDS (74.5%, 65.7-83.3) vs. 47 placebo (50%, 39.9-60.1) (P=0.0003). This result was supported by a lower daily pain intensity, lower intake of buprenorphine sublingual tablets and fewer dropouts in the BUP TDS group. The incidence of adverse events was slightly higher for BUP TDS. In conclusion, BUP TDS 70 microg/h is an efficacious and safe treatment for patients with severe cancer pain.

Detection of disseminated melanoma cells by reverse-transcription - polymerase chain reaction.

Detection of circulating melanoma cells by reverse transcriptase - polymerase chain reaction (RT-PCR) is a molecular diagnostic procedure which is used to predict prognosis in melanoma patients. The most widely used specific marker for detection of circulating melanoma cells by RT-PCR is expression of tyrosinase gene. This procedure has shown high specificity and low threshold for detection of melanoma cells. Most of the studies have shown that prognosis is worse in patients in which circulating melanoma cells were detected. Detection of circulating melanoma cells has been studied also as a marker for predicting response to therapy. The clinical value of this procedure is limited by the proportion of patients with clinically confirmed distant metastases being tyrosinase negative in almost all the studies. Studies have shown that analysis of additional markers to tyrosinase enables detection of circulating melanoma cells in a higher percentage of melanoma patients. RT-PCR has shown a lower threshold for detection than other methods (immunohistochemistry) in detection of melanoma metastases in lymph nodes.

[Croatian guidelines for use of eicosapentaenoic acid and megestrol acetate in cancer cachexia syndrome]. / Hrvatske smjernice za primjenu eikozapentaenske kiseline I megestrol-acetata u sindromu tumorske kaheksije.

Among many oncological patients we can notice a substantial loss of body weight, fat and proteins with significant proinflammatory activity at the time of diagnosis. This wasting condition is well known as cancer cachexia syndrome. Anorexia is important part of this syndrome. Because cancer cachexia reduces tumor response to treatment and it is an indicator of poor prognosis, we need to start correcting these nutritional deficits at once. In the presence of cancer cachexia it is extremely difficult to achieve protein anabolism and stop the body wasting by standard nutritional formulas only. During the last few years, the use of eicosapentaenoic acid (EPA) and megestrol acetate (MA) as anticahectic agents has been tested. These guidelines are intended to give evidence-based recommendations for the use of eicosapentaenoic acid and megestrol acetate in cancer cachexia syndrome. These guidelines have been developed by interdisciplinary expert group of Croatian clinicians. Based on relevant literature, we have concluded that the use of metabolic modulators such as eicosapentaenoic acid and megestrol acetate for 8 weeks may help to improve nutritional status in cachectic patients.

Combined action of virus injection and local tumor irradiation on tumor growth in mice.

The dynamics of SCCVII transplantable tumor growth in C3H/H mice was determined after local tumor irradiation and/or virus (NDV LaSota) i.p. injection. The virus applied alone significantly suppressed tumor growth, particularly until the 19th day after tumor transplantation. Local irradiation with 30 Gy resulted in tumor disappearance followed with its regrowth about 15 days later. However, if the virus was injected after the irradiation, there was no tumor growth until the end of the 31 day observation period. It should be noted that virus application prior to local irradiation did not have any additional influence on tumor growth. Thus, the pronounced efficacy of virus applied after tumor irradiation deserves attention. It is possible that the virus injected after irradiation induced a chain of cytokine production joining the action of tumor destruction induced by irradiation. This should be further studied in clarifying the approaches to combined tumor therapy with possible cell-free vaccine production.

Expression and possible prognostic role of MAGE-A4, NY-ESO-1, and HER-2 antigens in women with relapsing invasive ductal breast cancer: retrospective immunohistochemical study.

AIM: To evaluate the possible prognostic role of the expression of MAGE-A4 and NY-ESO-1 cancer/testis antigens in women diagnosed with invasive ductal breast cancer and determine the expression of HER-2 antigen. METHODS: The expression of MAGE-A4, NY-ESO-1, and HER-2 antigens was evaluated immunohistochemically on archival paraffin-embedded samples of breast cancer tissue from 81 patients. All patients had T1 to T3, N0 to N1, M0 tumors and underwent postoperative radiotherapy and, if indicated, systemic therapy (chemotherapy and hormonal therapy). The antigen expression in women who were disease-free for 5 years of follow up (n=23) was compared with that in women with either locoregional relapse (n=30) or bone metastases (n=28). Patient survival after 10 years of follow up was assessed. RESULTS: The three groups of women were comparable in terms of age, type of operation, tumor size, tumor grade, number of metastatically involved axillary lymph nodes, Nottingham prognostic index (NPI), progesterone receptor (PR) status, and adjuvant hormonal therapy. Estrogen receptors (ER) were positive in 13 women in the 5-year relapse-free group vs 8 in locoregional relapse and 7 in bone metastases group (P=0.032). There were significantly fewer women who received adjuvant chemotherapy in the 5-year relapse-free group than in other two groups (7 vs 23 with locoregional relapse and 25 with bone metastases; P<0.001). This group also had a significantly better 10-year survival (14 women vs 1 with locoregional relapse and 1 with bone metastases; P<0.001). The three groups did not differ in the NY-ESO-1 or HER-2 expression, but the number of patients expressing MAGE-A4 antigen was significantly lower in the group with locoregional relapse (P=0.014). In all groups, MAGE-A4 antigen expression was associated with the NY-ESO-1 antigen expression (P=0.006), but not with tumor size and grade, number of metastatically involved axillary lymph nodes, or the ER and PR status. MAGE-A4-positive patients had a significantly longer survival than the MAGE-A4-negative patients (P=0.046). This was not observed with NY-ESO-1 and HER-2 antigens. CONCLUSION: Our results suggest that the MAGE-A4 antigen may be used as a tumor marker of potential prognostic relevance.

Present state and possibilities for improvement of cancer prevention and early detection in the Osijek-Baranya county.

Cancer morbidity and mortality are on a steady increase in Croatia. Technologic possibilities for appropriate management are available for four cancer sites, i.e. cancer of the breast, cervix uteri, colorectum and prostate, and include cancer prevention and early detection in individuals yet free from manifest signs of the disease. The magnitude of the problem, the experience acquired to date, health care personnel available, and additional resources required to launch a systematic program of early detection of the disease are presented. The program should be initially launched in a county with greatest experience in early detection of cancer, where health care service is ready to immediately start its implementation. The role of family physician, gynecologic service at primary health care level, and polyclinic-consultation hospital service in program implementation is described. The following three possible options for early detection of cancer are analyzed and proposed: minimal program (early detection every 3 years), medium program (the same individuals examined every 2 years), and optimal program proposed by the American Cancer Society and other national and international organizations.

Religiosity, depression and pain in patients with breast cancer.

There is a growing body of evidence that religiosity can buffer depression and support the healing process. Our objective was to assess the relationship between religiosity, depression and pain in patients with breast cancer. Participants in our study were 115 breast cancer female patients recruited from a radiotherapy unit of a cancer teaching hospital, surveyed during the course of 6 months. The assessment used the Santa Clara Strength of Religious Faith Questionnaire as the measure of religiosity, and the subjects were categorized into low-, moderate- and high-religiosity groups according to its score. Depression was measured with the Center for Epidemiologic Studies Depression Scale, a 20-item self-report scale. The score of >or=16 indicated clinically relevant depression. A visual analogue scale was used for the assessment of pain. High religiosity was associated with a significantly lower prevalence of depression (chi(2)=6.635; df=2; P=.036), but religiosity was not related to the intensity of pain perception. Higher religiosity was associated with older age, lower education, unemployment and more children. Depression was associated with a higher pain level (U=1027.5; P=.004). The type of operation and tumor stage were not associated with categories of depression or religiosity, but mastectomized patients who belonged to the high-religiosity group were significantly less depressed (chi(2)=9.552; df=2; P=.008).

Gemcitabine in the first and second-line chemotherapy of advanced non-small cell lung cancer.

Aim of this study was to estimate efficacy of gemcitabine in first and the second-line chemotherapy for patients with advanced non-small cell lung cancer (stage III and IV). In first-line chemotherapy, 120 patients were treated with different chemotherapy regimens. Fifty-nine patients were treated with gemcitabine / cisplatin (PG), 41 with cisplatin / etoposide (PE) and 20 with mitomycin / ifosfamide / cisplatin (MIC). Forty patients, unsuccessfully treated with PE and MIC in first-line therapy were treated with PG (24 pts) and with best supportive care (BSC) (16 pts). In first-line therapy PG was superior to PE and MIC protocol (mean survival (MS) 10 vs. 7 vs. 8.5 months). Response rate (RR) for PG in first-line therapy was 46% and 21% in second-line. We showed also significantly better survival in patients treated with PG in second-line chemotherapy comparing to best supportive care (MS 9 vs. 5.5 months). Toxic side effects for combination PG was acceptable. This study confirmed that PG combination is safe and effective as first and second-line chemotherapy for patients with advanced non-small cell lung cancer.

Radiotherapy of stage IEA primary breast lymphoma: case report.

A 47-year-old woman was referred for the treatment to our Hospital because of a palpable nodule in the upper medial quadrant of her right breast. After tumor excision, pathohistological examination showed a follicular center cell lymphoma grade 2, B-cell type (CD20+, bc16+, CD10+, bcl2+). The final diagnosis was stage IEA primary extranodal non-Hodgkin s breast lymphoma. The involved breast was irradiated isocentrically with two opposite 6-megavolt (MeV) photon beams delivered from the linear accelerator (tangential fields) using asymmetric collimator opening. Radiation volume, inclinations of the medial and lateral field, and the part of the underlying chest wall and lung parenchyma were determined during the radiotherapy simulation process. The total irradiation dose was 44 Gy delivered in single daily doses of 2 Grays (Gy). After breast photon irradiation, a boost to the tumor bed was performed by a direct 12 MeV electron beam, with a total dose of 6 Gy delivered over three days. Since primary non-Hodgkin lymphoma of the breast is rather rare, there has been no uniform approach to its treatment. The advantage of applying the asymmetric collimator jaw opening in breast radiotherapy is the instant reduction of the dose at margin fields, resulting in both the protection of neighboring lung parenchyma and the good coverage of planned target volume.