Multiple Faces of the Glioblastoma Microenvironment.

The tumor microenvironment is a highly dynamic accumulation of resident and infiltrating tumor cells, responsible for growth and invasion. The authors focused on the leading-edge concepts regarding the glioblastoma microenvironment. Due to the fact that the modern trend in the research and treatment of glioblastoma is represented by multiple approaches that target not only the primary tumor but also the neighboring tissue, the study of the microenvironment in the peritumoral tissue is an appealing direction for current and future therapies.

Continuous Intravenous Administration of Granulocyte-Colony-Stimulating Factors-A Breakthrough in the Treatment of Cancer Patients with Febrile Neutropenia.

(1) Background: Febrile neutropenia (FN) remains one of the most challenging problems in medical oncology and is a very severe side effect of chemotherapy. Its late consequences, when it is recurrent or of a severe grade, are dose reduction and therapy delays. Current guidelines allow the administration of granulocyte-colony-stimulating factors (G-CSF) for profound FN (except for the case when a pegylated form of G-CSF is administrated with prophylactic intention) in addition to antibiotics and supportive care. (2) Methods: This is a prospective study that included 96 patients with confirmed malignancy, treated with chemotherapy, who developed FN during their oncological therapy, and were hospitalized. They received standard treatment plus a dose of G-CSF of 16 µg/Kg/day IV continuous infusion. (3) Results: The gender distribution was almost symmetrical: Male patients made up 48.96% and 51.04% were female patients, with no significance on recovery from FN (p = 1.00). The patients who received prophylactic G-CSF made up 20.21%, but this was not a predictive or prognostic factor for the recovery time from aplasia (p = 0.34). The median chemotherapy line where patients with FN were included was two and the number of previous chemotherapy cycles before FN was three. The median serological number of neutrophils (PMN) was 450/mm3 and leucocytes (WBC) 1875/mm3 at the time of FN. Ten patients possess PMN less than 100/mm3. The median time to recovery was 25.5 h for 96 included patients, with one failure in which the patient possessed grade 5 FN. Predictive factors for shorter recovery time were lower levels of C reactive protein (p < 0.001) and procalcitonin (p = 0.002) upon hospital admission and higher WBC (p = 0.006) and PMN (p < 0.001) at the time of the provoking cycle of chemotherapy for FN. The best chance for a shorter duration of FN was a short history of chemotherapy regarding the number of cycles) (p < 0.0001). (4) Conclusions: Continuous IV administration of G-CSF could be an alternative salvage treatment for patients with profound febrile neutropenia, with a very fast recovery time for neutrophiles.

Platinum derivatives: a multidisciplinary approach.

Cancer is one of the most difficult diseases to be treated. The particularities regarding the tumors' occurrence mechanism, their evolution under chemotherapy, disease-free interval, but also the increasing number of patients make cancer an intensively studied health domain. Although introduced in therapy since the early 80s, platinum derivatives play an essential role in anticancer therapy. Their use in therapy resulted in improving the patient quality of life and prolonging disease-free interval, which makes them still a benchmark for other anticancer compounds. However, adverse reactions and allergic reactions are a major impediment in therapy with platinum derivatives. This paper summarizes data about platinum derivatives through a multidisciplinary approach, starting from a chemical point of view and on to their mechanism of action, mechanism of cellular resistance, predictive factors for the outcome of chemotherapy such as micro RNAs (miRNAs), tumor suppressor protein p53, and the excision repair cross-complementing 1 protein (ERCC1).

Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of a third-generation chemotherapy regimen in the adjuvant setting to radically operated patients with gastric cancer. This proposed new adjuvant regimen was also compared with a consecutive retrospective cohort of patients treated with the classic McDonald regimen. METHODS: Starting in 2006, a non-randomized prospective phase II study was conducted at the Institute of Oncology of Cluj-Napoca on 40 patients with stage IB-IV radically resected gastric adenocarcinoma. These patients were administered a chemotherapy regimen already considered to be standard treatment in the metastatic setting: ECX (epirubicin, cisplatin, xeloda) and were compared to a retrospective control group consisting of 54 patients, treated between 2001 and 2006 according to McDonald's trial. RESULTS: In a previous paper, we reported toxicities and the possible predictive factors for these toxicities; in the present article, we report on the results concerning predictive factors on overall survival (OS) and disease free survival (DFS). The proposed ECX treatment was not less effective than the standard suggested by McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage was an independent prognostic factor for OS and DFS. N ratio >70% was an independent predictive factor for OS and locoregional disease control. The resection margins were independent prognostic factors for OS and DFS. CONCLUSION: The proposed treatment is not less effective compared with the McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage represented an independent prognostic factor and N ratio >70% was a predictive factor for OS and DFS. The resection margins were proven to be independent prognostic factors for OS and DFS.

Hypersensitivity reactions to platinum derivatives: findings of new predictive markers.

PURPOSE: Platinum derivatives play a very important role in cancer therapy. Despite their outstanding results in the treatment of tumors with different locations, the occurrence of hypersensitivity reactions raises issues when it comes to therapy decision, because the changing of chemotherapy line could influence the tumor's evolution. Over the years the scientific community has paid particular attention to the mechanism by which this occurs and to identification of predictive factors. The purpose of this case-control, retrospective study was to find new predictive markers for the occurrence of allergic reactions to platinum derivatives. METHODS: We identified 59 cases of allergic reactions to platinum derivatives in the Oncology Institute "Prof. Dr. Ion Chiricuta" from Cluj-Napoca city in 2013. Blood tests data were analyzed before the administration of the cycle on which the allergic reaction occurred, along with the mandatory analyses for the patients and we focused on the values of neutrophils, lymphocytes, monocytes, eosinophils and basophils. RESULTS: When these values were compared with the values of the control group (,which was made at a ratio of 1:2 or 1:3, matched for age, tumor location and chemotherapy cycle) we found that each increase of lymphocytes or doses of platinum and each drop in monocytes number increased the risk for allergic reactions to occur. CONCLUSION: These findings are of a great value for the physicians and represent a starting point for more detailed studies.

Dendrimers: Advancements and Potential Applications in Cancer Diagnosis and Treatment-An Overview.

Cancer is a leading cause of death worldwide, and the main treatment methods for this condition are surgery, chemotherapy, and radiotherapy. These treatment methods are invasive and can cause severe adverse reactions among organisms, so nanomaterials are increasingly used as structures for anticancer therapies. Dendrimers are a type of nanomaterial with unique properties, and their production can be controlled to obtain compounds with the desired characteristics. These polymeric molecules are used in cancer diagnosis and treatment through the targeted distribution of some pharmacological substances. Dendrimers have the ability to fulfill several objectives in anticancer therapy simultaneously, such as targeting tumor cells so that healthy tissue is not affected, controlling the release of anticancer agents in the tumor microenvironment, and combining anticancer strategies based on the administration of anticancer molecules to potentiate their effect through photothermal therapy or photodynamic therapy. The purpose of this review is to summarize and highlight the possible uses of dendrimers regarding the diagnosis and treatment of oncological conditions.

Activated Hepatic Stellate Cells (Ito Cells) - Marker of Advanced Fibrosis in Chronic Viral Hepatitis C: A Pilot Study.

BACKGROUND AND AIMS: The aim of this study is to determine whether activated hepatic stellate cells (HSCs) may represent a prognostic marker of progressive liver fibrosis in chronic viral hepatitis C (VHC) before antiviral therapy. The possible correlation between HSCs immunohistochemical features, histopathological aspects and clinical data before therapy were also studied. METHODS: This retrospective pilot study was conducted on 27 liver biopsies from VHC patients before antiviral therapy. HSCs's immunohistochemical analysis used the antibodies alpha-smooth muscle actin (α-SMA), glial fibrillary acidic protein (GFAP) and vinculin. We correlated immunopositive HSCs with HCV load, liver stiffness (LS), fibrosis stage and necro-inflammatory degree before treatment. Also, we assessed the association between liver fibrosis after therapy, the sustained virological response at 12 weeks after therapy (SVR 12) and the type of therapy. RESULTS: HSCs were increased in VHC patients compared to controls, mainly in the intermediate and periportal lobular regions. α-SMA and vinculin HSCs correlated positively with fibrosis stage (p=0.044), (p=0.028). Furthermore, α-SMA and vinculin HSCs were associated with LS (p=0.027), (p=0.002) and viral load (p=0.021), (p=0.006), but not with necro-inflammation degree. GFAP HSCs inversely correlated with fibrosis stage (r= -0.475), LS (r= -0.422) and HCV load (r= -0.517), but positively with necro-inflammation degree (p=0.038). Liver fibrosis post therapy correlated positively with SVR12 (p<0.001) and the type of therapy (p=0.006) and SVR12 correlated positively with treatment's type (p=0.002). CONCLUSIONS: Activated HSCs may represent a marker of increased liver fibrosis in VHC. Different immunohistochemical markers can detect various HSCs subpopulations involved in the evolution of VHC and liver fibrosis.

Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advances in treatment, the prognosis remains poor, highlighting the need for novel therapeutic strategies. The present review explores the potential of targeted epidermal growth factor receptor (EGFR) nanotherapy as an alternative treatment for NSCLC, showing that EGFR-targeted nanoparticles are efficiently taken up by NSCLC cells, leading to a significant reduction in tumor growth in mouse models. Consequently, we suggest that targeted EGFR nanotherapy could be an innovative treatment strategy for NSCLC; however, further studies are needed to optimize the nanoparticles and evaluate their safety and efficacy in clinical settings and human trials.

Short histological kaleidoscope - recent findings in histology. Part III.

The paper provides an overview of the current understanding of different cells' biology (e.g., keratinocytes, Paneth cells, myoepithelial cells, myofibroblasts, chondroclasts, monocytes, atrial cardiomyocytes), including their origin, structure, function, and role in disease pathogenesis, and of the latest findings in the medical literature concerning the brown adipose tissue and the juxtaoral organ of Chievitz.

The Effect of Convalescent Plasma in Patients With Covid-19 in Intensive Care Unit.

BACKGROUND/AIM: Convalescent plasma collected from COVID-19 survivors contains antibodies against receptor binding domains with potent antiviral activity. The use of this therapy for COVID-19 is still under investigation, as the pathophysiological and immunological mechanisms responsible for the evolution of the disease have not been fully identified. PATIENTS AND METHODS: In this retrospective observational study, we included all patients with a confirmed SARS-Cov-2 infection based on positive RT-PCR testing, who received convalescent plasma treatment in addition to standard therapy, between 17.05.2020 and 27.11.2020, following hospitalization in the Anaesthesia and Intensive Care Unit of the Sibiu County Emergency Clinical Hospital, Romania. RESULTS: Convalescent plasma therapy of patients with SARS-Cov-2 infection and severe forms of the disease (requiring only high-flow oxygen therapy or non-invasive ventilation) significantly improved inflammatory markers (CRP, fibrinogen) and ventilatory parameters (SaO2, paO2, paO2/FiO2) reducing the need of supplemental oxygen delivery (p<0.05). Other factors that had a significant influence on the outcome were age and comorbidity. CONCLUSION: Inflammatory markers and ventilatory parameters were significantly improved and the need of supplemental oxygen delivery was reduced in COVID-19 patients treated with convalescent plasma.

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer.

BACKGROUND: Vitamin K-dependent proteins (VKDPs) and the epidermal growth factor receptor (EGFR) are involved in lung cancer progression. Therefore, we aimed to study the serum concentration of Matrix Gla protein (MGP), Growth Arrest-specific 6 (Gas6), and EGFR before and after the first cycle of chemotherapy and to investigate how MGP, Gas6, and EGFR are modified after one cycle of chemotherapy. METHODS: We performed an observational study on twenty patients diagnosed with lung cancer, by assessing the serum concentration of vitaminK1 (VitK1), MGP, Gas6, and EGFR using the ELISA technique before and after three weeks of the first cycle of chemotherapy. Patients were evaluated using RECIST 1.1 criteria. RESULTS: Serum levels of MGP, Gas6, EGFR, and VK1 before and after treatment were not changed significantly. Regarding the pre-treatment correlation of the MGP values, we found a strong positive relationship between MGP and VK1 pre-treatment values (r = 0.821, 95%CI 0.523; 0.954, p < 0.001). Furthermore, there was a moderately negative correlation between VK1 and EGFR pre-treatment values, with the relationship between them being marginally significant (r = -0.430, 95%CI -0.772; 0.001, p = 0.058). Post-treatment, we found a strong positive relationship between MGP and VK1 post-treatment values (r = 0.758, 95%CI 0.436; 0.900, p < 0.001). We also found a moderate positive relationship between Gas6 and EGFR post-treatment values, but the correlation was only marginally significant (r = 0.442, p = 0.051).

Assessment of Specific Tumoral Markers, Inflammatory Status, and Vitamin D Metabolism before and after the First Chemotherapy Cycle in Patients with Lung Cancer.

BACKGROUND: We aimed to investigate the changes of inflammatory status reflected by serum levels of chitotriosidase (CHT) and neopterin, and how specific tumor markers such as neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCCA), as well as vitamin D metabolism assessed by vitamin D receptor (VDR) and 25-hydroxy vitamin D3 (25OHD3), were modified after the first cycle of chemotherapy in patients with lung cancer. METHODS: We performed this first pilot study on twenty patients diagnosed with lung cancer by investigating the serum concentrations of CHT, neopterin, NSE, SCCA, VDR and 25OHD3 before and after the first cycle of chemotherapy. RESULTS: The post-treatment values of NSE were significantly lower compared to the pre-treatment levels (14.37 vs. 17.10 ng/mL, p = 0.031). We noticed a similar trend in neopterin levels, but the difference was only marginally significant (1.44 vs. 1.17 ng/mL, p = 0.069). On the contrary, the variations of circulating SCCA, CHT, neopterin, VDR and 25OHD3, before and after treatment, did not reach statistical significance. CONCLUSION: Only circulating NSE was treatment responsive to the first chemotherapy cycle in patients with lung cancer, while inflammatory markers and vitamin D status were not significantly modified.

Nanocarriers for Drug Delivery: An Overview with Emphasis on Vitamin D and K Transportation.

Mounting evidence shows that supplementation with vitamin D and K or their analogs induces beneficial effects in various diseases, e.g., osteoarticular, cardiovascular, or carcinogenesis. The use of drugs delivery systems via organic and inorganic nanocarriers increases the bioavailability of vitamins and analogs, enhancing their cellular delivery and effects. The nanotechnology-based dietary supplements and drugs produced by the food and pharmaceutical industries overcome the issues associated with vitamin administration, such as stability, absorption or low bioavailability. Consequently, there is a continuous interest in optimizing the carriers' systems in order to make them more efficient and specific for the targeted tissue. In this pioneer review, we try to circumscribe the most relevant aspects related to nanocarriers for drug delivery, compare different types of nanoparticles for vitamin D and K transportation, and critically address their benefits and disadvantages.

Glioblastoma Microenvironment and Cellular Interactions.

The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell-cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.

Assessment of Basal Cell Carcinoma Using Dermoscopy and High Frequency Ultrasound Examination.

Basal cell carcinoma (BCC) is the most common form of cutaneous neoplasia in humans, and dermoscopy may provide valuable information for histopathological classification of BCC, which allows for the choice of non-invasive topical or surgical therapy. Similarly, dermoscopy may allow for the identification of incipient forms of BCC that cannot be detected in clinical examination. The importance of early diagnosis using the dermoscopy of superficial BCC forms is proven by the fact that despite their indolent clinical appearance, they can be included in high-risk BCC forms due to the rate of postoperative recurrence. Nodular pigmentary forms of BCCs present ovoid gray-blue nests or multiple gray-blue dots/globules associated with arborized vessels, sometimes undetectable on clinical examination. The management of BCC depends on this, as pigmentary forms have been shown to have a poor response to photodynamic therapy. High frequency ultrasound examination (HFUS) aids in the diagnosis of BCC with hypoechoic tumour masses, as well as in estimating tumour size (thickness and diameter), presurgical margin delineation, and surgical planning. The examination is also useful for determining the invasion of adjacent structures and for studying local recurrences. The use of dermoscopy in combination with HFUS allows for optimisation of the management of the oncological patient.

Short histological kaleidoscope - recent findings in histology. Part II.

This article focuses on the latest histological knowledge in the field regarding the peripheral lymphoid system [mucosa-associated lymphoid tissue (MALT), bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT)], the thymus stroma, some of the various corpuscles of the human body (Hassall's corpuscles in thymus, arenaceous corpuscles in pineal gland, corpora amylacea in prostate and other locations) and Fañanas glial cells in the cerebellum.

Short histological kaleidoscope - recent findings in histology. Part I.

This article is a review of new advances in histology, concerning either classification or structure of different tissular elements (basement membrane, hemidesmosomes, urothelium, glandular epithelia, adipose tissue, astrocytes), and various organs' constituents (blood-brain barrier, human dental cementum, tubarial salivary glands, hepatic stellate cells, pineal gland, fibroblasts of renal interstitium, Leydig testicular cells, ovarian hilar cells), as well as novel biotechnological techniques (tissue engineering in angiogenesis), recently introduced.

Bone Morphogenetic Protein 7 Expression in Alveolar Bone Addition With Autologous Blood, Lyophilized Bone and Atelocollagen.

BACKGROUND/AIM: The biomaterials used in guided bone regeneration have undergone significant diversification in recent years. This study aimed to evaluate alveolar bone addition and bone morphogenetic protein 7 (BMP7) expression using an improved autologous and xenogeneic biomaterial. MATERIALS AND METHODS: Chronic marginal periodontitis was induced in sheep; the intervention group received bone addition as periodontal therapy, using a composite system with lyophilized bovine bone enriched with atelocollagen type 1, platelet-rich plasma and advanced platelet-rich fibrin (A-PRF). Six weeks after the intervention, the dentoalveolar structures were evaluated using hematoxylin-eosin and immunohistochemical staining, to evaluate bone addition and BMP7 expression. RESULTS: The untreated sheep showed inflammation, periodontal ligament destruction, remnants of calculus and bacterial plaque as well as foreign bodies in the desmodontal space, without sings of repair. In the treated sheep, fibroblasts/fibrosis, cartilage and/or new bone, cellular cementum and desmodontium, along with remnants of biomaterial with various degrees of cellularity were observed. In the untreated group, the presence of BMP7 was found in osteoblasts and osteocytes while in the treated group, it was mainly found in the biomaterial remnants, while immunohistochemical staining was less intense in the newly formed osteo-periodontal tissues. Quantitative analysis using the Mann-Whitney U-test showed highly statistically significant differences between the two groups, demonstrating the efficiency of this composite system. CONCLUSION: The current composite system meets all the necessary conditions for promising guided alveolar bone regeneration.

The pioneer use of a modified PRGF-Endoret® technique for wound healing in a hemodialyzed diabetic patient in a terminal stage of renal disease.

In the literature, this paper is the first to describe the use of plasma rich in growth factors (PRGF)-Endoret® in hemodialyzed diabetic patients, to promote the healing of after amputation wounds. The PRGF-Endoret® was primarily conceived to be used in maxillofacial surgery, oral implantology, etc., the innovation residing in the blood collection technique (quantity, moment of the week, rhythmicity), which was adapted to the specific conditions of the hemodialyzed patient. Moreover, in the initial phases, the two PRGF fractions were innovatively applied as single alternating layers on the wound surface. Only after the surface of the wound decreased, the two PRGF fractions were applied as overlapping layers. Nevertheless, the paper presents the optimal method to assess the clinical evolution of the wound. Histopathological examination of the biopsy performed during wound preparation for PRGF application brought additional, essential data for orienting the therapeutic approach. The exclusion of calciphylaxis, a disease with high mortality risk, encouraged the application of this method, and also demonstrated the microscopic features in hemodialyzed diabetic patients.

Doubling the Dose of Bevacizumab Beyond Progression in Metastatic Colorectal Cancer-the Experience of a Tertiary Cancer Center.

Background: Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities. Methods: We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks-depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome. Results: One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41-71) and 57 years (range 19-75), respectively. The median overall survival in the DDB group was 41 months (range 27-49) compared to 25 months (range 23-29) in the SDB group (p = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (p = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival. Conclusion: Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.