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.

Prognostic role of neutrophil-to-lymphocyte ratio determined by complete blood count in malignant diseases / A vérképbol meghatározott neutrophil-lymphocyta arány prognosztikai értéke daganatos betegségekben

Introduction: Chronic low grade and intensity inflammation is considered to be a predisposing factor in the development and progression of malignancies. White blood cells play a key role in the process of inflammation. Based on numerous data of the literature, the author demonstrates some results of important meta-analyses and validation studies, which revealed the association between baseline elevated neutrophil-to-lymphocyte ratio (NLR) and the poor prognosis of the malignant diseases. Method and results: The author demonstrates the results of his observations of advanced cancer patients (n = 75) treated at his institution. NLR cut-off value, hazard ratio, confidence interval and p-value were determined by validated procedure (fitting Cox-model to NLR, survival and cenzored values, and point with the most significant split was defined by log-rank test). Hedges' g value was used for the determination of the effect of magnitude. Discussion: Based on the data of the literature, NLR above cut-off value correlates with poor survival. Based on the author's own results, in the case of NLR>4.34, survival of the patients above the cut-off value (n = 22) was also significantly shorter compared to the patients below the cut-off value (n = 53) (HR 2.3; 95% CI 1.37-3.85; p = 0.0012). The effect of magnitude was large (0.8). Conclusion: Poor prognostic importance of elevated NLR is supported by the author's results in accordance with the literary data. Based on NLR values, modification of the therapeutic intensity can also be considered.

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.

[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.

[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 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.

[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 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.

[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.

[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.

[Individualized therapy of synchronous ovarian and colon cancers with lymph]. / Személyre szabott kezelés szinkrón, nyirokcsomó-pozitív petefészek- és vastagbéldaganatban.

A 71-year-old female patient underwent urgent laparotomy due to severe right lower quadrant abdominal pain and fever. Macroscopically duplex coecal and transverse colon cancer as well as a sigmoid or left ovarian cancer were suspected. Pathological findings revealed synchronous left ovarian and transverse colonic neoplasms. Both primaries metastatized to their regional lymph nodes. Furthermore, the ovarian cancer infiltrating the sigmoid colon gave distant metastasis in the coecum, too. Ovarian cancer histology showed papillary adenocarcinoma, and transverse colon cancer was a tubular adenocarcinoma. The affected lymph nodes were clearly distinguished by immunohistochemistry staining: ovarian metastases were CK7 positive, and colonic metastases were CK20 and CEA positive. The patient was treated with combinated chemotherapy: FOLFOX-4 two weekly and paclitaxel monotherapy every other week. The patient tolerated this combined treatment well. The authors conclude that multiple synchronous neoplasms can be treated with individualized chemotherapeutic protocol with good efficacy and few adverse reactions.

[Therapeutic options for synovial sarcoma]. / A sarcoma synoviale kezelési lehetoségei.

Synovial sarcomas account for approximately 5 to 10% of soft tissue sarcomas and 0.05 to 0.1% of all malignant neoplasms. They predominantly affect the extremities but can occur in any part of the body. More than 50% of the patients are expected to develop metastatic disease within 3-5 years. In some patients disease recurrence may develop after 20 years. The 5-year overall survival rate is 10% for patients with metastatic disease and 76% for patients with localized one. Age, tumour size, histological subtype, and adjuvant radiotherapy influence prognosis. The role of adjuvant chemotherapy has not been proven yet. There are several ongoing clinical trials to determine the efficacy of active agents used for therapy of locally advanced, relapsed/refractory or metastatic disease. Better understanding of the biological behaviour of synovial sarcomas would provide the future way for the targeted therapy in combination with conventional treatments.

[Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure, mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case]. / TTP-HUS klinikai képét utánzó és heveny veseelégtelenséggel szövodo krónikus DIC hátterében álló metasztatikus prosztatarák: patomechanizmus, differenciáldiagnózis és kezelés egy eset kapcsán.

Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (>5 µg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case.

[Maximal initial dose of simvastatin causing acute renal failure through rhabdomyolysis: risk factors, pathomechanism and therapy related to a case]. / Maximális kezdo dózissal indított és heveny veseelégtelenséggel szövodött, simvastatin indukálta rhabdomyolysis: rizikófaktorok, patomechanizmus és kezelés egy eset kapcsán.

UNLABELLED: Rhabdomyolysis (RML) is a rare and severe adverse effect of simvastatin (SIM). Several risk factors have been described which play a role in its pathogenesis, namely age >65, diabetes mellitus, renal disease, high-dose statin therapy, chemicals metabolized by cytochrome P450 3A4 or idiosyncrasy. CASE SUMMARY: A 66-year-old man with diabetes, ischaemic heart disease and hypertension, on medication of CYP3A4 substrates amlodipine and alprazolam, maximal daily dose of SIM has been started for unknown cholesterol level. On the second day dark-brown urine, paraparesis, bile-like vomiting, on his fourth day of treatment total tetraparesis and oliguria characterized RML with acute renal failure. During his hospitalization of one-hundred-six days he underwent fourty-nine dialysis treatments. Sixteen months follow-up after discharge from hospital, his walking improved up to using one stick now. His cholesterol level is in physiological range with no statin therapy. CONCLUSIONS: On account of risk factors listed above this case should have been administered to low initial dose of SIM. Developing myalgia or weakness in muscles, treatment must be stopped. In a case of predisposition to RML statin therapy and dosage can only be performed under continuous supervision.