Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

Introduction: The 21-gene analysis (OncotypeDX) is validated test for pT1-3, pN0-1 with hormone receptor (HR) positive and normal expression of human epidermal growth factor receptor-2 (HER2) breast cancer (BC) to determine the aggressiveness of the disease based on the calculation of Recurrence Score (RS). Methods: In this retrospective study the authors correlated pathological characteristics and Recurrence Score (RS) by traditional statistical methods and Observed Oriented Modeling (OOM) in a realistic cohort of BC patients. Results: OncotypeDX tests were performed in 94 tumour specimens of 90 BC patients. >83% of node-negative (pN0) and >72% of node-positive (pN1) cases could avoid chemotherapy. For pN0 cases, non-parametric correlation and tests demonstrated significant association in eight types of characteristics [progesterone receptor (PR) expression, Ki-67 value, Ki-67 group, PR group, grade, estrogen receptor (ER) expression, Nottingham Prognostic Index (NPI) and Clinical Risk]. For pN1 cases, parametric correlation and tests showed significant association in six characteristic types (number of positive nodes, ER and PR expression, PR group, Ki-67 group and NPI). Based on OOM for pN0 cases, significant associations were established in three characteristics (Ki-67 group, grade and NPI group). For pN1 cases OOM found significant associations in seven characteristics (PR group, PNI, LVI, Ki-67 group, grade, NPI group and number of positive nodes). Conclusion: First in oncology, OOM was applied, which found some other significant characteristics associated with RS than traditional statistical methods. There were few patients, where no clinical associations were found between characteristics and RS contrary to statistically significant differences. Therefore, the results of these statistical analyses can be neither applied for individual cases nor able to provide the bases for screening patients, i.e., whether they need for OncotypeDX testing or not. OncotypeDX still provides a personalised approach in BC.

The Role of Cell-Free DNA in Cancer Treatment Decision Making.

The aim of this review is to evaluate the present status of the use of cell-free DNA and its fraction of circulating tumor DNA (ctDNA) because this year July 2022, an ESMO guideline was published regarding the application of ctDNA in patient care. This review is for clinical oncologists to explain the concept, the terms used, the pros and cons of ctDNA; thus, the technical aspects of the different platforms are not reviewed in detail, but we try to help in navigating the current knowledge in liquid biopsy. Since the validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, ctDNA may be used for this soon in routine clinical practice and in other different areas as well. The cfDNA fragments can be obtained by liquid biopsy and can be used for diagnosis, prognosis, and selecting among treatment options in cancer patients. A great proportion of cfDNA comes from normal cells of the body or from food uptake. Only a small part (<1%) of it is related to tumors, originating from primary tumors, metastatic sites, or circulating tumor cells (CTCs). Soon the data obtained from ctDNA may routinely be used for finding minimal residual disease, detecting relapse, and determining the sites of metastases. It might also be used for deciding appropriate therapy, and/or emerging resistance to the therapy and the data analysis of ctDNA may be combined with imaging or other markers. However, to achieve this goal, further clinical validations are inevitable. As a result, clinicians should be aware of the limitations of the assays. Of course, several open questions are still under research and because of it cfDNA and ctDNA testing are not part of routine care yet.

Corrigendum: Overall Survival Prediction of Advanced Cancer Patients by Selection of the Most Significant Baseline Serum Biomarker Combination.

[This corrects the article DOI: 10.3389/pore.2022.1610004.].

Overall Survival Prediction of Advanced Cancer Patients by Selection of the Most Significant Baseline Serum Biomarker Combination.

Introduction: Consistent association between elevated baseline serum values and C-reactive protein (CRP), cross-linked fibrin degradation products (D-dimer), lactate dehydrogenase (LDH), decreased baseline serum albumin, absolute lymphocyte count to absolute monocyte count ratio (LMR), elevated absolute neutrophil count to absolute lymphocyte count ratio (NLR), elevated platelet count to absolute lymphocyte count ratio (PLR), and between some combinations of these biomarkers and the short overall survival of patients with malignant diseases has already been reported. These biomarkers are independent prognostic factors for cancer. Here, the most significant biomarker combination of these values was searched and studied in real-life advanced cancer patients of a single center. Methods: The authors retrospectively analyzed the association of the aforementioned biomarkers and their combination and OS of 75 consecutive cancer patients with locally advanced, recurrent, or metastatic diseases. Validated cut-off determination was used. Results: CRP, albumin, and PLR showed marked association with OS. Cut-off values for significant shorter OS were 30.65 mg/L (p < 0.001), 44.35 g/L (p < 0.001), and 168.20 (p < 0.001), respectively. Based on assessed biomarker cut-offs, four patient groups were created to determine whether biomarker values were out of range (ORV) compared to cut-off: 1) No ORV biomarkers (n = 24; OS = 26.07 months); 2) one ORV biomarker (n = 21; OS = 13.50 months); 3) two ORV biomarkers (n = 20; OS = 7.97 months), and 4) three ORV biomarkers (n = 10; OS = 3.91 months). Significant differences in OS were detected between the groups: For 1. vs. 2. hazard ratio (HR) = 3.0 (95% CI: 1.5-6.2), p = 0.003; for 1. vs. 3. HR = 4.1 (95% CI: 2.0-8.3), p < 0.001; and for 1. vs. 4. HR = 10.2 (95% CI: 4.2-24.6), p < 0.001. Conclusion: Based on our analysis, we can confirm that the complex monitoring of CRP, albumin, and PLR would provide a good estimation of OS. Large scale prospective studies are warranted to explore this and other useful combinations of prognostic biomarkers and their relationship to the well-established prognostic systems in real-life.

Site-specific N-glycosylation of HeLa cell glycoproteins.

We have characterized site-specific N-glycosylation of the HeLa cell line glycoproteins, using a complex workflow based on high and low energy tandem mass spectrometry of glycopeptides. The objective was to obtain highly reliable data on common glycoforms, so rigorous data evaluation was performed. The analysis revealed the presence of a high amount of bovine serum contaminants originating from the cell culture media - nearly 50% of all glycans were of bovine origin. Unaccounted, the presence of bovine serum components causes major bias in the human cellular glycosylation pattern; as is shown when literature results using released glycan analysis are compared. We have reliably identified 43 (human) glycoproteins, 69 N-glycosylation sites, and 178 glycoforms. HeLa glycoproteins were found to be highly (68.7%) fucosylated. A medium degree of sialylation was observed, on average 46.8% of possible sialylation sites were occupied. High-mannose sugars were expressed in large amounts, as expected in the case of a cancer cell line. Glycosylation in HeLa cells is highly variable. It is markedly different not only on various proteins but also at the different glycosylation sites of the same protein. Our method enabled the detailed characterization of site-specific N-glycosylation of several glycoproteins expressed in HeLa cell line.

[Principles of pharmacotherapy in the elderly]. / Az idoskori gyógyszerterápia alapjai.

The proportion of elderly patients is getting increased in the developed countries as a consequence of which pharmacotherapy takes a more and more important place in the healthcare system. Important biological alterations are characteristic for the elderly subjects, which have effect on the pharmacokinetics and pharmacodynamics of the pharmaceuticals. Gradually decreased kidney function may demand the modification of the administration of the pharmaceuticals. Certain pharmaceuticals and drug-interactions are potentially dangerous for this population. Therefore several factors have to be taken into account in conjunction with the therapy of elderly patients including co-morbidities, cognitive function and the social state. At the same time, the risk-benefit ratio of the pharmaceuticals is the worst among elderly patients with pharmaceutical therapy including polypragmasy. Thus, it is inevitable for the development of geriatric pharmacotherapy that the physiologic alteration of elderly has to be taken into account not only in the daily practice but also during the development and formulation of a pharmaceutical. The present paper gives an overview of the most important factors influencing the pharmacotherapy of the elderly. Orv Hetil. 2019; 160(23): 896-907.

Technologies for circulating tumor cell separation from whole blood.

The importance of early cancer diagnosis and improved cancer therapy has been clear for years and has initiated worldwide research towards new possibilities in the care strategy of patients with cancer using technological innovations. One of the key research fields involves the separation and detection of circulating tumor cells (CTC) because of their suggested important role in early cancer diagnosis and prognosis, namely, providing easy access by a liquid biopsy from blood to identify metastatic cells before clinically detectable metastasis occurs and to study the molecular and genetic profile of these metastatic cells. Provided the opportunity to further progress the development of technology for treating cancer, several CTC technologies have been proposed in recent years by various research groups and companies. Despite their potential role in cancer healthcare, CTC methods are currently mainly used for research purposes, and only a few methods have been accepted for clinical application because of the difficulties caused by CTC heterogeneity, CTC separation from the blood, and a lack of thorough clinical validation. Therefore, the standardization and clinical application of various developed CTC technologies remain important subsequent necessary steps. Because of their suggested future clinical benefits, we focus on describing technologies using whole blood samples without any pretreatment and discuss their advantages, use, and significance. Technologies using whole blood samples utilize size-based, immunoaffinity-based, and density-based methods or combinations of these methods as well as positive and negative enrichment during separation. Although current CTC technologies have not been truly implemented yet, they possess high potential as future clinical diagnostic techniques for the individualized therapy of patients with cancer. Thus, a detailed discussion of the clinical suitability of these new advanced technologies could help prepare clinicians for the future and can be a foundation for technologies that would be used to eliminate CTCs in vivo.

High sensitivity proteomics of prostate cancer tissue microarrays to discriminate between healthy and cancerous tissue.

Biopsies, in the form of tissue microarrays (TMAs) were studied to identify anomalies indicative of prostate cancer at the proteome level. TMAs offer a valuable source of well-characterized biological material. However, because of the small tissue sample size method development was essential to provide the sensitivity and reliability necessary for the analysis. Surface digestion of TMA cores was followed by peptide extraction and shotgun proteomics analysis. About 5 times better sensitivity was achieved by the optimized surface digestion compared to bulk digestion of the same TMA spot and it allowed the identification of over 500 proteins from individual prostate TMA cores. Label-free quantitation showed that biological variability among all samples was about 3 times larger than the technical reproducibility. We have identified 189 proteins which showed statistically significant changes (t-test p-value <.05) in abundance between healthy and cancerous tissue samples. The proteomic profile changed according to cancer grade, but did not show a correlation with cancer stage. Results of this pilot study were further evaluated using bioinformatics tools, identifying various protein pathways affected by prostate cancer progression indicating the usefulness of studying TMA cores to identify quantitative changes in tissue proteomics. SIGNIFICANCE: Detailed proteomics analysis of TMAs presents a good alternative for tissue analysis. Here we present a novel method, based on tissue surface digestion and nano-LC-MS measurements, which is capable of identifying and quantifying over 500 proteins from a 1.5 mm diameter tissue section. We compared healthy and cancerous prostate tissue samples, and tissues with various grades and stages of cancer. Tissue proteomics clearly distinguished healthy and cancerous samples, furthermore the results correlated well with cancer grade, but not with cancer stage. Over 100 proteins showed statistically significant abundance changes (t-test p-value <.05) between various groups. This was sufficient for a meaningful bioinformatics evaluation; showing e.g. increased abundance of proteins in cancer in the KEGG ribosome pathway, GO mRNA splicing via spliceosome, and chromatin assembly biological processes. The results highlight the feasibility of the developed method for future large-scale tissue proteomics studies using commercially available TMAs.

[Effectivity of bevacizumab rechallenge treatment in liver metastasis of colon cancer]. / Bevacizumab rechallenge kezelés hatékonysága vastagbéldaganat májáttétje esetén.

Since the therapeutic options for colon cancer are limited, the reinduction of treatments (rechallenge) is part of the therapeutic strategy. Our case is an example for that. A 65-year-old female patient was operated on stenotizing sigmoid cancer. Resectio was performed. Surgically incurable multiple hepatic metastases were proven. The histology revealed adenocarcinoma (grade II, pT3pN1cM1). In the first line, 13 cycles of bevacizumab (BEV) + FOLFOX followed by 2 cycles of BEV + capecitabine and 11 cycles of BEV + 5FU/LV were administered. In the second line, 28 cycles of cetuximab (CET) + FOLFIRI were given. In the third line, due to liver limited disease and based on the preference of the patient, two cycles of transarterial chemoembolisation (doxorubicin + lipiodol) were administered. In the fourth line, four cycles of trifluridine/tipiracil were given. In the fifth line, 13 cycles of BEV + FOLFIRI were given, as a rechallenge, which improved the overall survival by 6,5 months. Orv Hetil. 2018; 159(31): 1284-1290.

[Prognostic importance of albumin in oncology]. / Az albumin prognosztikai jelentosége az onkológiában.

Diminished serum albumin level can be observed in inflammatory processes. Serum albumin level also reduces - irrespective of the presence of malnutrition - in locally advanced or metastatic malignancies. Low serum albumin level may have an influence also on the results of anticancer therapy (e.g., drug pharmacokinetics, adverse drug reactions). Extensive data of the literature and empirical experience prove the better prognosis of patients involved in nutritional therapy. Based on the most relevent data of the literature, the authors summarize the studies which have revealed the close correlation between the baseline serum albumin level and the prognosis of malignant diseases. Orv Hetil. 2018; 159(3): 96-106.

[Prognostic importance of cross-linked fibrin degradation products (D-dimer) in oncology]. / A keresztkötött fibrindegradációs termékek (D-dimer) prognosztikai jelentõsége az onkológiában.

Cross-linked fibrin degradation products (D-dimer) are formed in two ways: on the one hand through coagulation cascade and on the other hand through fibrinolytic cascade. In the former case, plasmin cleaves the soluble cross-linked fibrin, and in the latter it cleaves the non-soluble cross-linked fibrin. In patients with malignant diseases, several factors influence the clinical evaluation of the result of D-dimer assay. First, D-dimer level can be elevated in cancer patients without thrombosis, which can be explained by procoagulant factors produced by malignant cells. Second, none of the algorithms used for diagnosing venous thromboembolism have been validated on patients with malignant diseases. Furthermore, the negative predictive value of D-dimer on thrombosis or thromboembolism is lower in cancer patients comparing to those who are not suffering from malignant disease. In patients with malignant disease, where venous thrombosis has not been proven, higher D-dimer level correlates with shorter survival. Based on the available data of the literature, the authors summarize some important studies which revealed the relationship between baseline D-dimer level and prognosis in cancer patients.

[Prognostic importance of lactate dehydrogenase (LDH) in oncology]. / A laktátdehidrogenáz (LDH) prognosztikai jelentosége az onkológiában.

Glycolysis is increased in most of the malignant cells, providing the largest proportion of energy needed for cell proliferation. Lactate dehydrogenase (LDH) catalyses the reversible process of pyruvate to lactate in anaerobic condition. LDHA isoenzyme expressed mainly by malignant cells, significantly increases lactate formation. Lactate induces the proliferation of oxygenated malignant cells, angiogenesis, and inhibits the innate and adaptive immune responses. Baseline serum LDH elevation correlates with shorter survival. The authors review the relevant studies exploring the correlation between LDH elevation and the prognosis of malignant diseases. Orv Hetil. 2017; 158(50): 1977-1988.

[Approaching new pharmacotherapy options in pain treatment]. / A gyógyszeres fájdalomcsillapítás közelgõ új lehetõségei.

The evolution of medicine is noticeable in most therapeutic areas, the worse the current therapeutic result, the more quick the improvement. This is especially true in such areas that require substantial social resources, namely oncology, diabetology and CNS diseases. Pain is not a disease, it is a symptom. Pain is one of the most important components of human suffering thus it deserves special attention. In recent years new formulations of old medicines were introduced rather than new medicines. Maybe ziconitide is the last pain killer with new mechanism of action which was approved by FDA in 2004. However, the new information and techniques are also appearing in the field of analgesia. Nowadays one can talk about genetic/epigenetic targets, RNA therapies, voltage-gated calcium channels, new pain receptors (TRPV1, TRPV4, NMDA, Nav receptors) regarding pain treatment, indicating that the practice of the pharmacotherapy of pain will change fundamentally in the immediate future. This paper is intended to give a short summary of these new options.

[Prognostic importance of plasma C-reactive protein (CRP) in oncology]. / A C-reaktív protein (CRP) plazmaszintjének prognosztikai jelentosége az onkológiában.

Chronic inflammation has a key role in the pathogenesis of malignancy. C-reactive protein (CRP) is produced due to the induction of inflammatory cytokines primarily in hepatocytes. In case of malignant diseases CRP might be elevated without any other condition of inflammation. Thus in the literature the authors searched for correlation between CRP levels and the course of malignant diseases. Normal CRP level measured at baseline correlates with longer overall survival in early staged malignancies. Lower CRP level at baseline predicts better prognosis in locally advanced or metastatic stages. Based on the available data, baseline CRP might be a prognostic factor in oncological diseases. Further prospective studies are warranted in various locally advanced and metastatic malignancies to clarify a possible prognostic and predictive role of CRP. Orv. Hetil., 2017, 158(7), 243-256.

[Chemotherapeutic treatment of metastatic ovarian cancer for 8 years. Case report]. / Metasztatikus ovariumcarcinoma kemoterápiás kezelése nyolc éven át.

The authors present the history of a 48-year-old woman, who developed pleural effusion, abdominal pain and ascites due to an advanced ovarian cancer. She underwent hysterectomy and bilateral adnexectomy in 2006, and histology revealed FIGO IIIB papillary adenocarcinoma. After surgery the patient recieved the standard, 6 cycle taxol-carboplatin therapy. Taxol-carboplatin therapy was reinitiated because of retroperitoneal lymph node metastases in 2008, but soon the therapy had to be changed because of progression. Thereafter the patient recieved 6 different types of chemo- and biological therapy including the off-label FOLFOX-4 treatment at seventh line. Significant regression in response to FOLFOX-4 therapy was confirmed with a progression free survival of about 9 months. The general condition of the patient was satisfying during the whole chemotherapy, and the side effects were tolerable. The overall survival was 98 months. This case history is a good example for the success of individualized, long term chemotherapy even if ovarian tumor diagnosed at advanced stage as it happened in this case. Orv. Hetil., 2016, 157(44), 1769-1773.

[Ramucirumab - a new anticancer agent]. / Ramucirumab ­ egy új gyógyszer az onkológiában.

Ramucirumab is a humanized monoclonal antibody against vascular endothelial growth factor receptor-2, which inhibits the binding of vascular endothelial growth factor-A, -C and -D ligands. Furthermore it blocks the ligand stimulated activation of p44/p42 mitogen activated protein kinases, thus neutralizing the ligand induced proliferation and migration of human endothelial cells. Based on the results of the REGARD (Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) and the RAINBOW (Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma) studies ramucirumab was approved for 2nd line treatment as monotherapy and in combination with paclitaxel for patients with local relapse and unresectable or metastatic gastric cancer (including gastro-esophegal junction adenocarcinoma). Based on the results, in advanced solid malignancies, ramucirumab may prolong progression free survival and overall survival, although it may increase the risk of all adverse events (fatigue, neutropenia, haemorrhage, nausea, stomatitis). The authors review the clinical studies of ramucirumab. Orv. Hetil., 2016, 157(40), 1587-1594.

[Close follow-up of oncologic patients with imaging - advantage or disadvantage?] / Onkológiai betegek szoros képalkotó követése - elony vagy hátrány?

The International Commission on Radiological Protection estimates, that 100 mSv exposure of radiation increases cancer risk by 0.5%. The central hypothesis of the Linear No Threshold model is that low dose ionizing radiation can induce carcinogenesis through the so called "one hit action", that is one or more deoxyribonucleic acid strands can be broken by the hit of only one electron particule. Regardless of the radiation dose, radiation exposure increases cancer risk. In the United States of America, one-third of computed tomographic scans are carried with no clear clinical indication, i.e. non radiating imaging can be applied with equal sensitivity and specificity. Furthermore, computed tomographic scans are repeated unnecessarily. Although technical improvements have reduced the concern of the potential danger of radiation exposure, the cumulative aspects and cancer risk should always be considered. Cancer risk, accompanied by ionizing radiation, should be minimized during the follow up of oncologic patients. It is mandatory, that all diagnostic tools which are not using ionizing radiation should be made widely accessable (eg. whole body diffusion weighted magnetic resonance imaging, positron emission tomography/magnetic resonance imaging). Orv. Hetil., 2016, 157(39), 1538-1545.

[Oncologic aspects of Clostridium difficile]. / A Clostridium difficile onkológiai vonatkozásai.

Clostridium difficile infection is one of the most frequent among cancer patients. Its diagnosis is complicated by the fact that the symptoms of the infection and the side effects of the anticancer treatments could be similar. Chemotherapy itself might facilitate Clostridium difficile infection. Several risk factors are known but Clostridium difficile infection can develop in the absence of these. Neutreopenia is a risk factor for fatal Clostridium difficile infection and also the side effect of chemotherapy. Therefore, if symptoms of the potential infection develop (eg. diarrhoea more than three times a day, fever above 38.5 °C, colitis, rapid increase of serum creatinin) Clostridium difficile infection should be excluded. If the infection is confirmed it should be managed in the most efficient way. Orv. Hetil., 2016, 157(28), 1110-1116.

[Synovial sarcoma. Case report]. / Sarcoma synoviale.

In 2013 there were 94,770 new cancer patients reported in Hungary. Synovial sarcoma accounts for 0.05-0.1% of all cancers and, therefore its incidence is predicted to be 47-94 patients/year in Hungary. The authors report the history of a 18-year-old man who was operated on a right upper abdominal wall tumor with R1 resection. During the next 5 months the tumor grew up to 8 cm in largest diameter. Histology revealed monophasic synovial sarcoma. Immunohistochemistry showed bcl2, focal CD99 and high molecular weight cytokeratin positivity, while smooth muscle actin, S100 and CD34 immunostainings were negative. Becose of this reoperation was not possible, curative six cycles of doxorubicine and ifosfamide with granulocyte colony stimulating factor support and 60 Gy radiotherapy was given to the tumor bed. After these treatments computed tomography scan was negative and the patient attended regular imaging every 3 months. At the age of 20 years the patient developed two neoplastic lesions in the surgical scar measuring 10 mm and 45 × 10 mm in size. R0 resection, partial rib resection and abdominal wall reconstruction were performed. Histology confirmed residual monophasic synovial sarcoma. Radiotherapy was not given because of a risk of intestinal wall perforation. Staging positron emission tomography-computed tomography proved to be negative. At the age of 22 years magnetic resonance imaging scans indicated no tumor recurrence, but after one month a rapidly growing tumorous lesion was found on ultrasound in the surgical scar measuring 20 × 20 × 12 mm in size. Cytology confirmed local recurrence and fluorescence in situ hibridization indicated t(x;18). R0 exstirpation and partial mesh resection were performed and histology showed the same monophasic synovial sarcoma. Because of the presence of vascular invasion and a close resection margin (1 mm) the patient underwent 3 cycles of adjuvant chemotherapy (doxorubicine and ifosfamide) with granulocyte colony stimulating factor support and 3 cycles of ifosfamide. After 2 years follow up at the age of 24 years, imaging studies did not reveal any local or distant recurrence.

Simple correction improving long-term reproducibility of HPLC-MS.

Chromatographic peak areas in long series of high-performance liquid chromatography-MS experiments often vary, which decrease reproducibility and may cause bias in the results. It was found that the sensitivity of various components change differently; in our case, variability is in the order of 20-40%, and it is most likely due to changing conditions in electrospray ionization (ESI). The most often used peak area correction methods do not take this effect into account. The change in peak areas can be well described by a polynomial function; we found that a fourth-order polynomial is most often suitable. We suggest a simple correction algorithm based on polynomial fitting. When the experiments were inherently well reproducible, this correction improved reproducibility from 12% to 3% (on average for various components). When random errors were larger, this improvement was less significant (15% to 12% in nano-ESI) but nevertheless essential in order to avoid possible bias in the results.