A Retrospective Analysis of the First 41 mCRPC Patients with Bone Pain Treated with Radium-223 at the National Institute of Oncology in Hungary.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical which significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. This was a retrospective analysis of the efficacy and safety of Radium-223 in the first 41 patients treated at a single center in Hungary. Radium-223 was given at a dose of 50 kBq/kg intravenously every 4 weeks for up to 6 cycles. Between 23rd July 2014 and 23rd February 2016, 41 patients were treated. Patient demographics, laboratory values, treatment outcomes and adverse events were collected from medical records. The mean age was 72.2 years (SD: 7.1). 24 patients received Radium-223 as first-line treatment (58%), 7 patients as second (17%), 3 as third (7.3%), 6 as (14.6%), and 1 as fifth-line therapy (2.4%). The mean number of cycles administered was 5.5 (SD: 1.1). The most common side effects were anemia (32% grade 1-3), nausea (28%, grade 1), diarrhea (4%, grade 2), thrombocytopenia (4%, grade 3). The mean baseline PSA level was 307.2 ng/ml (SD: 525.7), which increased to a mean value of 728.5 ng/ml (SD: 1277) by the end of treatment. The baseline mean ALP of 521.1 U/L (SD: 728) decreased to 245.1 U/L (SD: 283.5). The majority of patients experienced a decrease (37%) or complete cessation (43%) of bone pain intensity. In our symptomatic prostate cancer patient population, Radium-223 proved to be efficient in terms of pain relief, with moderate side effects. No PSA response was detected, while alkaline phosphatase levels significantly decreased.

Comparison of immunophenotypes of primary breast carcinomas and multiple corresponding distant metastases: an autopsy study of 25 patients.

Phenotypical change in metastatic breast carcinoma has widely been accepted as an inherent biological feature rather than technical fault. We analyzed the immunohistochemical phenotype and histopathological features of 25 primary breast carcinomas and 90 corresponding distant metastases in 23 organs retrospectively. Histological slides were reviewed for prognostic and predictive factors. Overall, metastases were more similar to each other and often differed from the primary tumor. We created a 3-step grouping system based on the localization of metastases. Regions: tumors metastasizing to the abdominal region were likely to lose ER (p = 0.002); we detected loss of PR in metastases to the thorax (p = 0.039) and abdomen (p < 0.001). Organ systems: loss of ER and PR was observed in metastases to the gastrointestinal system (p = 0.026 and p = 0.001, respectively), in the respiratory system only the loss of PR was significant (p = 0.05). Individual organs: the primaries were likely to lose the hormone receptors in liver metastases (ER p = 0.026; PR p = 0.004). In lung metastases only loss of PR was apparent (p = 0.049). We did not observe significant change in HER2 status, regarding Ki67 change occurred only in bone metastases compared to the primary (p = 0.048). 7/25 patients' distant metastases had heterogeneous immunoprofiles. The later the metastasis was discovered the more likely it had a differing IHC profile compared to the primary tumor, patients who had longer OS had a higher chance to develop a discordant metastasis. Immunoprofile of metastases may differ from primary breast cancer and from each other, probably resulting in different response to therapy.

Association between Dictyocaulus viviparus status and milk production parameters in Dutch dairy herds.

The objective of this study was to estimate the association between Dictyocaulus viviparus bulk tank milk (BTM) test results and milk production and milk composition parameters in adult Dutch dairy cattle herds. Bulk tank milk samples were collected in August and November 2013, and ELISA tests were performed. Two hundred BTM positive (BTM+) and 200 BTM negative (BTM-) herds were selected based on their BTM test result of November 2013, obtained from a list of farms that participated in the Dutch GD Animal Health voluntary monitoring program for controlling nematode infections. The relationship between D. viviparus BTM status and 3 production parameters (milk production, milk fat %, and milk protein %) in summer (June to August 2013) and autumn (September and October 2013) was investigated using generalized linear mixed models. Production data were available for 126 BTM- herds and 109 BTM+ herds. Results showed that a positive D. viviparus status was associated with decreased milk production (June: -1.01, July: -1.19, August: -1.68, September and October: -1.33kg/cow per d). Milk fat percentage was 0.14% and 0.08% lower during summer and autumn, respectively, in BTM+ herds. No significant association was demonstrated between a positive BTM test result and milk protein percentage. Because a strong correlation was present between the BTM status for D. viviparus and that for Ostertagia ostertagi, these losses cannot be attributed to one of the two parasites. However, it is clear that these parasite infections have a considerable effect on production.

Vitamin D-neutralizing CYP24A1 expression, oncogenic mutation states and histological findings of human papillary thyroid cancer.

OBJECTIVE: The aims of the present study were to examine gene and protein expression of the vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human papillary thyroid cancer (PTC), furthermore, to investigate the association between CYP24A1 expression and numerous clinical, histological parameters and somatic oncogene mutation status of thyroid tumor tissues. MATERIALS AND METHODS: Gene expression analysis was carried out in 100 Hungarian thyroid samples, both normal and papillary tumor tissue sections of the same patient. The specific mRNA to the selected genes was analyzed by TaqMan probe-based quantitative real-time RT-PCR. The somatic oncogene mutation states of BRAF, NRAS, HRAS and KRAS were also tested. RESULTS: CYP24A1 mRNA expression was markedly increased in 52 cases (52%) of the examined papillary cancers compared with that of normal thyroid tissue. There was a tendency toward difference in the distribution of high-level CYP24A1 in the PTC accompanied with somatic oncogene mutation. Positive correlation was seen between increased CYP24A1 expression rate and a group of variables reflecting tumor malignity (mainly vascular invasion, lymph node metastasis, tumor size, hypothyreosis) by principal components analysis. No significant alteration was seen in CYP27B1 gene expression between neoplastic and normal tissues. CONCLUSIONS: A definite alteration was seen in vitamin D3-inactivating CYP24A1 gene activity in PTC compared to their normal tissues on a relatively large patient population. Our findings raise the possibility that CYP24A1 may also directly be involved in thyroid carcinogenesis.

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study.

BACKGROUND: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Atypical myopathy: a review and description of the outbreak in the Netherlands during autumn 2009 and spring 2010.

This article reviews the literature on equine atypical myopathy (AM), an acute, severe rhabdomyolysis that occurs in horses at pasture. The prevalence, mortality, clinical signs, pathology, potential aetiology, typical aspects, diagnosis, treatment, and prognosis are described. Horse management, characteristic weather conditions, and possible preventive measures are also discussed. In addition, the characteristics of 54 highly probable or confirmed cases of equine AM occurring between autumn 2009 (27 cases) and spring 2010 (27 cases) in the Netherlands are described. Of the 54 affected horses, nineteen were mares, eleven geldings, and eight stallions; the sex of the other sixteen horses was not recorded. The mortality rate (74.5%) was in the same range as that reported in earlier studies. Many cases were reported at about the same time. Thirty-five horses had been pastured near maple trees, and in fifteen cases the maple trees were known to be infected with the fungus Rhytisma acerinum.

Primary systemic therapy in breast cancer--an update for gynecologic oncologists.

Primary systemic - or neoadjuvant - chemotherapy (PST) is the standard of care in locally advanced breast cancer and it has also become an option in primary operable disease for patients who are candidates for adjuvant systemic chemotherapy. There are several advantages of administering PST: tumor downstaging--improving the chance of breast conserving surgery; in vivo assessment of tumor sensitivity to the chosen therapeutic regimen; and, early control of micrometastatic disease. On the other hand, the rate of tumor response can be used as a surrogate prognostic marker and for rapid screening of efficiency of new drugs. PST initially referred to systemic chemotherapy, but in recent years endocrine--and now multiple targeted therapies--are available in most of the countries within the confines of clinical trials.

Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: We aimed to establish the superiority (or noninferiority if superiority was not achieved) in terms of time to progression (TTP) of irinotecan/5-fluorouracil (IF) over cisplatin/5-fluorouracil (CF) in chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction. PATIENTS AND METHODS: Patients received either IF: i.v. irinotecan 80 mg/m(2) 30 min, folinic acid 500 mg/m(2) 2 h, 5-fluorouracil (5-FU) 2000 mg/m(2) 22 h, for 6/7 weeks or CF: cisplatin 100 mg/m(2) 1-3 h, with 5-FU 1000 mg/m(2)/day 24 h, days 1-5, every 4 weeks. RESULTS: In all, 333 patients were randomized and treated (IF 170, CF 163). Patient characteristics were balanced except more IF patients had Karnofsky performance status 100%. TTP for IF was 5.0 months [95% confidence interval (CI) 3.8-5.8] and 4.2 months (95% CI 3.7-5.5) for CF (P = 0.088). Overall survival (OS) was 9.0 versus 8.7 months, response rate 31.8% versus 25.8%, time to treatment failure (TTF) 4.0 versus 3.4 months for IF and CF, respectively. The difference in TTF was statistically significant (P = 0.018). IF was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10.0% versus 21.5%), severe neutropenia, thrombocytopenia and stomatitis, but not diarrhea. CONCLUSION: IF did not yield a significant TTP or OS superiority over CF, and the results of noninferiority of IF were borderline. However, IF may provide a viable, platinum-free front-line treatment alternative for metastatic gastric cancer.

Primary systemic therapy (PST) of locally advanced breast cancer using Doxorubicin/Docetaxel combination.

BACKGROUND: PST of locally advanced breast carcinomas causes tumour shrinkage and down-staging, therefore, optimal circumstances for surgery. PATIENTS AND METHODS: We treated 25 stage IIIA-IIIB breast cancer patients with PST (Doxorubicin/Docetaxel). Histological diagnosis (core biopsy) was available in each case. Tumour regression and cardiac function were recorded regularly. RESULTS: Five patients showed complete pathological remission. Instead of 19 mastectomies, only nine were performed and 16 patients underwent breast-conserving therapy. CONCLUSION: Using PST breast conservation rate is improved.

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

[Tumorus anorexia/cachexia syndrome] / A tumoros anorexia-cachexia szindróma.

The clinical importance of tumor-induced cachexia is indicated by the fact that two thirds of the cancer patients suffer from it and it plays an outstanding role in mortality of the disease. The onset of the tumorous anorexia/cachexia syndrome does not depend on tumor burden or the stage of the disease. The syndrome is very complex in nature and cannot be reversed by "over-feeding" of the patient. The appropriate supply of calories, carbohydrates, proteins and lipids is impossible, therefore administration of nutrients which do not cause volume-load for the patient is justified. Enteral feeding must be the primary aim in cancer patients till the gastrointestinal tract is functioning. To improve appetite and increase body weight specific pharmacological intervention may also be necessary. Understanding the molecular mechanisms of the development of tumorous anorexia/cachexia syndrome opens new ways of treatment.

[Management of cancer pain] / Fájdalomcsillapítás a daganatos betegek kezelésében.

The morphin-analogue, Durogesic, has robust analgetic effect without repeated side-effects and is suitable for special applications providing it as the first choice for therapy of cancer pain and as an acceptable alternative for CR morphin. Clinical studies not only provided evidences for the pharmacological effectivity of Durogesic but suggested that the quality of life of cancer patients improved significantly as well.

[Human recombinant anti-HER2 monoclonal antibody--a new targeted treatment in breast cancer]. / Rekombináns humán anti-HER2 monoklonális antitest--egy új célzott terápia az emlórák kezelésében.

The HER2 protein is encoded by the HER2/neu gene and it is homologous to the epidermal growth factor receptor. Overexpression of HER2, usually in association with gene amplification, occurs in approximately 25-30% of breast cancers. There are currently several different methods available to evaluate HER2 status, e.g. immunohistochemical (IHC), and fluorescence in situ hybridization (FISH) assays. The HER2 protein is a viable therapeutic target. The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) has demonstrated activity in clinical trials in women with metastatic breast cancer overexpressing HER2. The mechanisms of the action of this antibody involve disruption of DNA repair and induction of antibody-dependent cellular cytotoxicity. Response rates to the antibody given as a single agents in the treatment of HER2 overexpressing metastatic breast cancer have ranged from 12 to 27%. Patients who received trastuzumab in combination with chemotherapy had a significantly longer time to progression, higher overall survival compared with patients who had received chemotherapy alone. In the treatment of women with HER2 overexpressing tumors an overall response rate of 57% for combination trastuzumab plus paclitaxel compared with 25% for paclitaxel alone was found. Trastuzumab has an important role in the treatment of HER2 overexpressing metastatic breast cancer. Its place in adjuvant treatment has not been proved up to now. The optimal use of trastuzumab in the treatment of HER2 positive advanced breast cancer is under active investigation. Due to the high rate of clinical activity and low incidence of severe toxicity trastuzumab is a very promising drug in the treatment of breast cancer. The author's purpose was to summarize the results of the trials using trastuzumab treatment, and discuss the methods used to determine the HER2 status.

Increased interleukin-6 levels, interleukin-6 receptor and gp130 expression in peripheral lymphocytes of patients with inflammatory bowel disease.

Interleukin-6 is one of the most well-characterized cytokines with pleiotropic properties. Besides its B-lymphocyte activation role in hematopoiesis, interleukin-6 plays a central role in regulation of systemic inflammation. Interleukin-6 binds to receptors on target cells (such as hepatocytes and lymphocytes), consisting of an 80 kDa binding chain and gp130, a polypeptide responsible for signal transduction. In addition to the detection of elevated amounts of interleukin-6 in the blood, gene expression (mRNA) of subunits of the interleukin-6 receptor complex have also been studied by examining the reverse transcriptase polymerase chain reaction on peripheral lymphocytes from patients with characteristic radiological symptoms suffering from Crohn's disease. Our data show significantly elevated gene expression both of the 80 kDa interleukin-6 binding chain and gp130. These results suggest that enhancement of the expression of the constituents of interleukin-6 and the interleukin-6 receptor system plays a relevant role in systemic inflammation in inflammatory bowel disease.

[Chronic gastritis and the presence of Helicobacter pylori in patients with non-ulcerative dyspepsia]. / Krónikus gastritis és Helicobacter pylori elöfordulása non ulcer dyspepsiás beteganyagban.

After definition in the group of the non ulcer dyspepsia (NUD) can be counted all those patients at whom beside the dyspeptical complaints, the radiological and endoscopical examinations didn't show ulcerative changes. The authors made biopsy 550 times on the occasion of 1390 gastroscopical examination (39.5% of the cases). The histological examination showed chronic gastritis in 372 cases (26.7% of all the examinations, 67.6% of the histological examinations). At this group of patients the dyspeptical complaints gave the principal indication of gastroscopical examination. Also it was examined the presence of dysplasia and intestinal metaplasia beside the different severity grade of chronic gastritis. The presence of Helicobacter pylori (Hp) was examined by histological methods. Hp positivity was noticed in 16.4% in the upper group. The authors made Hydrogen-breath examinations in 34 cases between patients with NUD. The results of Hydrogen-breath examinations also raise the multifactorial nature of the NUD. On the basis of examinations chronic gastritis and CP infection can form subdivisions in the heterogenic group of patients with NUD. For exacter judgement of Hp pathogenicity are needed further and wide-spread examinations. The authors would like to call the attention to the indispensability of the biopsy during the gastroscopical examination.

[Diffuse intestinal malignant lymphoma]. / Diffuz intestinalis malignus lymphoma.

The authors describe a patient with malignant lymphoma presenting with clinically severe malabsorption due to diffuse involvement of the small intestine and with intestinal obstruction. The histologic diagnosis was based on the association of (1) diffuse involvement of the small intestine showing lymphoid tissue expansion and (2) a non-classified form of highly malignant lymphoma. After surgical resection of a stenotic part of the small intestine, abdominal irradiation therapy was done, and the patient improved.