A global phase II randomized trial comparing oral taxane ModraDoc006/r to intravenous docetaxel in metastatic castration resistant prostate cancer.

STUDY AIM: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. METHODS: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/200-100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20-20/200-100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS. RESULTS: There was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20-20/200-100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively. CONCLUSIONS: ModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted.

Beyond a decade: a comparative study of 15-year survival rates in screen-detected vs. symptomatic breast cancer patients in Hungary.

BACKGROUND: Breast cancer is the leading cancer in women globally. Despite decreasing mortality rates, largely due to early detection and modern treatment, the effectiveness of screening on long-term survival outcomes remains unclear. AIMS: This study evaluates the 15-year survival outcomes of a national breast cancer screening program initiated in Hungary in 2002. METHODS: Using a prospectively maintained patient database, the study included individuals from the first 6 years of the program who underwent surgery for histologically confirmed breast cancer and had available follow-up information. Patients were categorized based on the method of breast cancer detection into two groups: those diagnosed during or 2 years after the population-based screening exam (Group A), and those who self-detected or sought medical attention for symptoms (Group B). RESULTS: Of the 309 patients who underwent breast cancer surgery, 208 were screen-detected (Group A) and 101 were symptomatic (Group B). The 15-year overall survival was 75.0% for Group A and 76.2% for Group B (p = 0.927). The 15-year disease-specific survival was 85.6% and 81.2% (p = 0.249), respectively. A statistically not significant positive trend in disease-free survival was observed in Group A (81.7% vs. 75.2%; p = 0.144). CONCLUSIONS: The study underscores the importance of extended follow-up periods in evaluating the outcomes of breast cancer screening programs. While the screening program may not significantly enhance overall survival rates, it has demonstrated a reduction in the mastectomy rate and could potentially extend periods of disease-free survival. These findings contribute to the ongoing discourse about the long-term benefits of breast cancer screening programs.

Immune-related adverse events of anti-PD-1 immune checkpoint inhibitors: a single center experience.

Objectives: Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center. Patients and methods: Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors. Results: At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab. Conclusion: ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

A new perspective on the proper timing of radiotherapy during CDK4/6 inhibitor therapy in patients with "bone-only" metastatic breast cancer.

The vast majority of hormone positive and HER2 negative advanced breast cancers can be controlled well by endocrine therapy combined with the groundbreaking use of CDK4/6 inhibitors in the metastatic first-line setting. Approximately 50%-60% of these patients have "bone-only" metastatic disease. In oligometastatic cases or if a certain number of uncontrolled lesions develop during the aforementioned therapy, ablative radiotherapy can be delivered or, in symptomatic cases, urgent irradiation is needed with palliative intent. To achieve the most effective results, parallel with good quality of life, the timing of radiotherapy must be determined precisely, taking into account that different cell cycles are involved during different treatment modalities; therefore, optimization of treatment schedules ensures longer and safer post-progression overall survival. The key question is whether the two treatment modalities are safe concurrently or whether they should be administered separately, and if so, what is the optimal sequence and why? This manuscript aims to answer this important question, with a focus on quality of life. Existing publications focus on safety and toxicity profiles, and efficacy is detailed only tangentially and minimally.

In Vivo Assessments of Mesoblastic Nephroma (Ne/De) and Myelomonoblastic Leukaemia (My1/De) Tumour Development in Hypercholesterolemia Rat Models.

Given the rising prevalence of lipid metabolic disorders and malignant diseases, we aimed to establish an in vivo hypercholesterinaemic tumour-bearing rat model for the induction and assessment of these conditions. A normal standard CRLT/N, 2 (baseline),- or 4 (2 + 2, pretreated)-week-long butter and cholesterol rich (BCR) diet was applied to mesoblastic nephroma (Ne/De) and myelomonoblastic leukaemia (My1/De) tumour-bearing and healthy control Long­Evans and Fischer 344 rats. The beginning of chow administration started in parallel with tumour induction and the 2 weeks of pre-transplantation in the baseline and pretreated groups, respectively. Fourteen days post-inoculation, the measurement of lipid parameters and [18F]F-FDG PET/MRI examinations was executed. The comparable lipid status of baseline healthy and tumorous rats proves that regardless of tumour presence, BCR-based hypercholesterolemia was achieved. A higher tumour mass among pretreated tumorous animals was found when compared to the control groups (p < 0.05, p < 0.01). Further, a visually greater [18F]F-FDG accumulation was observed in pretreated BCR tumorous animals; however, the quantitative data (SUVmean: 9.86 ± 0.98, 9.68 ± 1.24; SUVmax: 19.63 ± 1.20; 17.56 ± 3.21 for Ne/De and My1/De, respectively) were not statistically significantly different from those of the CRLT/N tumorous rats (SUVmean: 8.40 ± 1.42, 7.22 ± 1.06 and SUVmax: 15.99 ± 2.22, 12.46 ± 1.96 for control Ne/De and My1/De, respectively). Our model seems to be appropriate for simultaneously investigating hypercholesterolemia and cancer in the same rat.

Hazai tapasztalatok metasztatikus kolorektális karcinóma bevacizumabbal kiegészített indukciós kemoterápiás kezelésével (AVACONT vizsgálat).

The primary aim of AVACONT was to collect data in the course of routine oncological care from patients with metastatic colorectal cancer (mCRC) treated with bevacizumab supplemented fluoropyrimidine-based chemotherapy doublet in an open, multicentre, observational study in Hungary. Primary endpoint of the study was to determine progression-free survival (PFS). The Full Analysis Set (FAS) comprised 280 patients. Median PFS calculated from enrolment was 270 days in the FAS population. The metastatic involvement of the liver or more than one organ significantly decreased (250 and 245 days), while a clinical response achieved significantly increased (partial response: 404, complete response: 623 days) the mPFS calculated from enrolment. PFS calculated from the start of the first-line treatment was significantly decreased by the presence of mutant RAS gene (481 vs. 395 days). The results confirm the efficacy, known prognostic factors and safety profile of bevacizumab in combination with chemotherapy dosed during standard oncology care in Hungarian centres.

Standardized data on the incidence and mortality of female and male breast cancers in Hungary between 2000 and 2016. / A noi és a férfiemlorák standardizált incidencia- és mortalitásadatai Magyarországon 2000 és 2016 között.

Összefoglaló. Bevezetés: A rákbetegségek incidencia- (gyakorisági) értékei világszerte, így Magyarországon is folyamatosan növekednek. Az emlorákok elofordulása és kórlefolyása a két nemben azonban sajátosan különbözik. Célkituzés: Célul tuztük ki, hogy megvizsgáljuk és értékeljük a noi és a férfiemlorák incidencia- és mortalitási (halálozási) adatait Magyarországon 2000 és 2016 között. Módszer: A Központi Statisztikai Hivatalból és a Nemzeti Rákregiszterbol származó adatok standardizált, 100 000 fore számított feldolgozása. Eredmények: Magyarországon a vizsgált idoszakban az emlorákok gyakoriságának növekedése megközelítoleg ugyanolyan mértéku (39%) volt, mint az összes ráké (34%). Az emelkedés jelentos: a 2016-ban 8,7% részarányú noi emlorák esetében 39%, a 0,22%-os részarányú férfiráknál 60%. Ezzel szemben a halálozási adatok jelentos mértéku csökkenéseket mutatnak mind az összes daganat, mind a noi emlorák vonatkozásában, míg a férfiemlorák esetében a csökkenés nagyobb mértéku. A rosszindulatú daganatok incidenciája és a 2-es típusú diabetes mellitus (2DM) prevalenciája egyaránt magasan szignifikáns korrelációt mutatott az egy fore jutó bruttó nemzeti össztermék (GDP) értékének növekedésével. Új megfigyelés, hogy a 2DM-növekedés idoben megelozte a daganatok incidenciájának növekedését. Következtetés: A vizsgált idoszakban a noi és a férfiemlorákok magyarországi gyakorisági és halálozási adatai a nemzetköziekhez hasonló tendenciákat mutatnak. A férfiemlorákok sokkal ritkábbak, de kezelésük kevésbé hatékony. Új szempont, hogy a rosszindulatú daganatok gyakoribb megjelenésében a klinikailag kedvezotlenebb 2DM százalékos arányának (prevalenciájának) emelkedése is jelentos tényezo lehet az elhízáshoz kapcsolódva. A GDP növekedése kedvezoen hathatott a halálozások csökkenésében a kedvezobb gyógyítási és megelozési feltételek megteremtésével. Ugyanakkor ennek a növekedésnek szerepe lehet az elhízással összefüggo 2DM prevalenciájának emelkedésében is. Orv Hetil. 2022; 163(5): 181-186. INTRODUCTION: The incidence of malignant cancers is continuously growing. In breast cancers, the incidence and clinical course are greatly different in the two genders. OBJECTIVE: We aimed to investigate the incidence and mortality of breast cancers in females and males in Hungary between 2000 and 2016. METHODS: The data derived from the Hungarian Central Statistical Office and the National Cancer Registry were evaluated and standardized for 100 000 inhabitants. RESULTS: In Hungary, the elevation of breast cancer incidence (39%) showed a similar extent as that of total tumours (34%). In female breast cancers representing a much greater percent (8.7% in 2016) than that in males (0.22%), the increase was significant (39%) as in males (60 %). On the other hand, mortality was significantly lower for both of them regarding total malignant and female breast tumours, whereas the decrease was greater in the male breast cancers. The increase of GDP per capita showed highly significant correlation with the incidence of malignant tumours and prevalence of diabetes mellitus type 2 (2DM). It was a new finding that the increase in the prevalence of 2DM precedes the elevation of the incidence of cancer. CONCLUSION: In Hungary, the data of incidence and mortality of female and male breast cancers showed similar tendencies as the international ones. The breast cancers of males were rarer but their treatment was less effective. However, it was a new aspect that in the increased incidence of malignant tumours also the greater prevalence of 2DM could be an important factor related to obesity. Orv Hetil. 2022; 163(5): 181-186.

[The role of low grade glioma prognostic factors in therapeutic choices - summary of international literature and recommendations with conclusions]. / Az alacsony grádusú gliómák prognosztikai faktorainak szerepe a terápia megválasztásában ­ a nemzetközi irodalom és ajánlások összefoglalása konklúziókkal.

Our knowledge on low grade gliomas has grown extensively recently. Both molecular alterations and clinical trials unraveling their clinical significance are difficult to get familiar with. Thus, efforts made to reach any consensus are of upmost importance, so that multidisciplinary teams involved in patient management can make up-to-date, individually-tailored therapeutic plans. Our aims were to synthesize all the molecular and clinical investigations, recommendations and guidelines related to low grade gliomas in Hungarian language, and to define low and high risk prognostic groups with different therapeutic strategies. The roles of 21 molecular pathological markers and their significance levels in low grade gliomas are summarized in this paper. Data from relevant literature, as well as recommendations of neuro-oncological organizations were included. This summary could help to integrate diverse therapeutic plans of the past decades in low grade gliomas. Moreover, this paper may serve as a source for future revisions when updating low and high risk groups in low grade gliomas.

[Prognostic significance of invasion in glioblastoma]. / Az inváziós spektrum prognosztikai jelentôsége glioblastomában.

BACKGROUND AND PURPOSE: Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness - mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. METHODS: Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. RESULTS: Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin ß2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. CONCLUSION: The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.

Analysis of Low Cancer Mortality Rates in the Wine Regions of Tokaj and Balaton in Hungary.

The age-adjusted death rates (AADRs) due to cancers were investigated in two historical regions of white wines (Tokaj and Balaton) and in Hódmezovásárhely (HMV) as a control territory in Hungary between 2000 and 2010 evaluating 111,910 persons. The results of AADRs due to the eight most frequent types/gastrointestinal cancers were as follows: Tokaj 2120/664, Balaton: 2417/824, HMV: 2770/821, nationwide: 2773/887. The values found in Tokaj and Balaton regions were significantly less than those of HMV and nationwide. However, the least values were found in Tokaj. This Tokaj-related strong difference was not found among the regions in the case of young populations with hematological diseases but only in the older people who have been consuming their wines for decades. Supposedly, this wine-specific anti-cancer phenomenon could be related to the chemical differences existing in the two types of white wines, namely, to the pro-oxidant molecules of Tokaj wines derived from Botrytis cinerea. The roles of red meat consumption, hardness of drinking water, mineral content of soil, and socioeconomic status were negligible. It should be stressed that these data are valid only for these populations, for this period. Noteworthily, the different types of wines may have different effects on mortality rates during long-lasting consumptions.

Eight pillars of oncorheumatology: Crossroads between malignancies and musculoskeletal diseases.

ONCORHEUMATOLOGY: RELATIONSHIP BETWEEN MALIGNANCIES AND MUSCULOSKELETAL DISEASES: Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.

Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress.

Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome's capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.

Oncorheumatology: relationship between malignancies and musculoskeletal diseases / Onkoreumatológia: a daganatos és mozgásszervi kórképek összefüggései

Oncorheumatology is the meeting point of tumour formation and rheumatic diseases. Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. In the first group, secondary malignancies associated with rheumatic diseases, role of tumour-associated antigens in rheumatology, the possible carcinogenicity of conventional and targeted antirheumatic drugs and physical therapy of rheumatic patients with recent or current cancer will be discussed. The second large topic includes paraneoplastic syndromes, autoimmune-rheumatic side effects of oncotherapies (chemotherapy and immunotherapy), effects of hormone-deprivation therapies on bone and primary and secondary malignancies of the musculoskeletal system. Orv Hetil. 2020; 161(28): 1151-1165.

Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma is one of the most lethal cancers in both men and women, with a median five-year survival of around 5%. Therefore, pancreatic adenocarcinoma represents an unmet medical need. Neoplastic diseases, such as pancreatic adenocarcinoma, often are associated with microbiome dysbiosis, termed oncobiosis. In pancreatic adenocarcinoma, the oral, duodenal, ductal, and fecal microbiome become dysbiotic. Furthermore, the pancreas frequently becomes colonized (by Helicobacter pylori and Malassezia, among others). The oncobiomes from long- and short-term survivors of pancreatic adenocarcinoma are different and transplantation of the microbiome from long-term survivors into animal models of pancreatic adenocarcinoma prolongs survival. The oncobiome in pancreatic adenocarcinoma modulates the inflammatory processes that drive carcinogenesis. In this review, we point out that bacterial metabolites (short chain fatty acids, secondary bile acids, polyamines, indole-derivatives, etc.) also have a role in the microbiome-driven pathogenesis of pancreatic adenocarcinoma. Finally, we show that bacterial metabolism and the bacterial metabolome is largely dysregulated in pancreatic adenocarcinoma. The pathogenic role of additional metabolites and metabolic pathways will be identified in the near future, widening the scope of this therapeutically and diagnostically exploitable pathogenic pathway in pancreatic adenocarcinoma.

Prognosis and Treatment Outcomes of Patients Undergoing Resection of Brain Metastases from Breast Cancer.

BACKGROUND: Brain metastases from breast cancer have poor prognosis and are a challenge to treat. Multiple treatment options are available. Descriptive and prognostic data on breast cancer brain metastases is limited. PATIENTS AND METHODS: This study analyzed clinical data of patients who underwent surgical resection of one or more brain metastases. Histological and clinical characteristics, as well as treatment modalities, were analyzed. RESULTS: Initial tumor stage or grade was found not to correlate with the median time to developing brain metastases or survival. Human epidermal growth factor receptor 2 (HER2)-positive status was not associated with shorter median time to developing brain metastases. No correlation was found between the number of brain metastases and patient outcome. Results confirm the survival benefit of surgical resection with or without irradiation. CONCLUSION: Data showed that patients with HER2-positive and those with triple-negative breast cancer develop brain metastases at lower stages but not earlier after diagnosis, and survival is mostly dependent on treatment modality rather than histological subtype.

Significance of liquid biopsy in glioblastoma - A review.

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor with a 16-24 -months overall survival time (OS). Effective management is hindered by intratumoral heterogeneity, a characteristic trait of GBM which results in subpopulations of cells with altered therapeutic responsiveness, different invasiveness and growth potential. Correct initial molecular profiling of the tumor, as well as following its molecular biological changes are further impeded by the intracranial location of the tumors, hence the risks of surgical interventions. Radiological examination, the sole non-invasive method of obtaining information about the tumors, also has limitations. This review article aims to summarize the currently available information about the promising applicability of liquid biopsy, extracellular vesicles (EVs), and circulating cell-free nucleic acids (cf-NAs) in GBM patients. Liquid biopsy is a quick and inexpensive way of obtaining exceptionally relevant information about tumors, and can be performed multiple times during the clinical course of the disease. Furthermore, integrating analyses of EVs and related cf-NAs in clinical practice might also help to establish diagnosis in a non-invasive manner, and complex oncotherapy could be indicated in the future without high-risk neurosurgical interventions.

Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors.

Recent studies showed that changes to the gut microbiome alters the microbiome-derived metabolome, potentially promoting carcinogenesis in organs that are distal to the gut. In this study, we assessed the relationship between breast cancer and cadaverine biosynthesis. Cadaverine treatment of Balb/c female mice (500 nmol/kg p.o. q.d.) grafted with 4T1 breast cancer cells ameliorated the disease (lower mass and infiltration of the primary tumor, fewer metastases, and lower grade tumors). Cadaverine treatment of breast cancer cell lines corresponding to its serum reference range (100-800 nM) reverted endothelial-to-mesenchymal transition, inhibited cellular movement and invasion, moreover, rendered cells less stem cell-like through reducing mitochondrial oxidation. Trace amino acid receptors (TAARs), namely, TAAR1, TAAR8 and TAAR9 were instrumental in provoking the cadaverine-evoked effects. Early stage breast cancer patients, versus control women, had reduced abundance of the CadA and LdcC genes in fecal DNA, both responsible for bacterial cadaverine production. Moreover, we found low protein expression of E. coli LdcC in the feces of stage 1 breast cancer patients. In addition, higher expression of lysine decarboxylase resulted in a prolonged survival among early-stage breast cancer patients. Taken together, cadaverine production seems to be a regulator of early breast cancer.

Hemodynamic consequences of intravenously given E. coli suspension: observations in a fulminant sepsis model in pigs, a descriptive case-control study.

BACKGROUND: The aim of the present work was to assess systemic hemodynamic changes using PiCCo monitoring in a porcine model of E. coli-induced fulminant sepsis. METHODS: Thirty-one healthy female Hungahib pigs were randomly assigned into control (n = 15) or septic groups (n = 16). In the sepsis group Escherichia coli culture was intravenously administrated in a continuously increasing manner according to the following protocol: 2 ml of bacterial culture suspended in physiological saline was injected in the first 30 min, then 4 ml of bacterial culture was administered within 30 min, followed by infusion of 32 ml bacterial culture for 2 h. Control animals received identical amount of saline infusion. Systemic hemodynamic parameters were assessed by PiCCo monitoring in both groups. RESULTS: Resting hemodynamic parameters were identical in the two groups. In control animals, systemic hemodynamic variables were relatively stable during the entire procedure. In septic animals shock developed in 165 (IQR: 60-255) min after starting the injection of E. coli solution. Blood pressure values gradually decreased, whereas pulse rate increased. A decrease in cardiac index, an increased systemic vascular resistance, and a decreased stroke volume variation were observed. CONCLUSIONS: These results may serve as additional pathophysiological information of hemodynamic changes occurring during hypodynamic sepsis and may contribute to a better understanding of the pathomechanism of septic multiple organ failure.

Short- and Long-Term (10-year) Results of an Organized, Population-Based Breast Cancer Screening Program: Comparative, Observational Study from Hungary.

BACKGROUND: A nationwide breast cancer screening program was introduced in Hungary in the year 2002 for women aged 45-65 years to be performed biannually. METHODS: To investigate and report the short-term and 10-year follow-up results, we analyzed our Breast Unit's prospectively led database of screened (Group A) and age-matched symptomatic (Group B) patients from 2002 to 2007. We compared the clinicopathologic features of tumors and the impact of screening on surgical treatment, as well as the overall (OS), disease-specific (DSS) and disease-free survival (DFS) of different groups. RESULTS: Data from 208 screen-detected and 101 symptomatic patients between 45 and 65 years of age were examined. Screen-detected women were younger (54 vs. 58.5 years; p = 0.001) had significantly smaller tumors (15.5 vs. 17 mm; p = 0.044), and more breast-conserving surgery (68.8 vs. 59.4%; p = 0.032). Survival statistics were not statistically different at the median follow-up of 123 months; however, there was a trend toward improved DFS in Group A (82.7 vs. 74.3%; p = 0.074). CONCLUSIONS: Our study showed a significant reduction in rates of mastectomy in the screen-detected group in the short term, which does not translate into better survival rates based on initial long-term data. In order to realize the real advantage of this newly enstated screening program, a longer period of investigation is needed.

Comparison of different lymph node staging systems in prognosis of gastric cancer: a bi-institutional study from Hungary.

OBJECTIVE: The Union for International Cancer Control (UICC) Node (N) classification is the most common used staging method for the prognosis of gastric cancer. It demands adequate, at least 16 lymph nodes (LNs) to be dissected; therefore different staging systems were invented. METHODS: Between March 2005 and March 2010, 164 patients were evaluated at the Department of General Surgery in the Kenézy Gyula Hospital and at the Department of General, Thoracic and Vascular Surgery in the Kaposi Mór Hospital. The 6th, 7th and 8th UICC N-staging systems, the number of examined LNs, the number of harvested negative LNs, the metastatic lymph node ratio (MLR) and the log odds of positive LNs (LODDS) were determined to measure their 5-year survival rates and to compare them to each other. RESULTS: The overall 5-year survival rate for all patients was 55.5% with a median overall survival time of 102 months. The tumor stage, gender, UICC N-stages, MLR and the LODDS were significant prognostic factors for the 5-year survival with univariate analysis. The 6th UICC N-stage did not follow the adequate risk in comparing N2 vs. N0 and N3 vs. N0 with multivariate investigation. Comparison of performances of the residual N classifications proved that the LODDS system was first in the prediction of prognosis during the evaluation of all patients and in cases with less than 16 harvested LNs. The MLR gave the best prognostic prediction when adequate (more than or equal to 16) lymphadenectomy was performed. CONCLUSIONS: We suggest the application of LODDS system routinely in western patients and the usage of MLR classification in cases with extended lymphadenectomy.