Synergies Radiotherapy-Immunotherapy in Head and Neck Cancers. A New Concept for Radiotherapy Target Volumes-"Immunological Dose Painting".

The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy-immunotherapy (RT-IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system through already known mechanisms, it is necessary to identify biomarkers that direct the "nonresponders" of immunotherapy towards a synergistic RT-IT stimulation strategy. Stimulation of the immune system by irradiation can convert "nonresponder" to "responder". With the development of modern techniques, re-irradiation is becoming an increasingly common option for patients who have previously been treated with higher doses of radiation. In this context, radiotherapy in combination with immunotherapy, both in the advanced local stage and in recurrent/metastatic of HNC radiotherapy, could evolve from the "first level" of knowledge (i.e., ballistic precision, dose conformity and homogeneity) to "level two" of "biological dose painting" (in which the concept of tumor heterogeneity and radio-resistance supports the need for doses escalation based on biological criteria), and finally to the "third level" ofthe new concept of "immunological dose painting". The peculiarity of this concept is that the radiotherapy target volumes and tumoricidal dose can be completely reevaluated, taking into account the immune-modulatory effect of irradiation. In this case, the tumor target volume can include even the tumor microenvironment or a partial volume of the primary tumor or metastasis, not all the gross and microscopic disease. Tumoricidal biologically equivalent dose (BED) may be completely different from the currently estimated values, radiotherapy treating the tumor in this case indirectly by boosting the immune response. Thus, the clinical target volume (CTV) can be replaced with a new immunological-clinical target volume (ICTV) for patients who benefit from the RT-IT association (Image 1).

Anticipatory Grief in the Families of Patients with Palliative Requiring Metastatic Cancer.

BACKGROUND/AIM: When dealing with metastatic cancer patients, family distortions, such as anticipatory mourning, psychiatric and psychosocial disorders may occur. In the case of anticipatory mourning, there exists the risk of the patient being "given up" as if he is already gone, which will only make the patient feel lonely, with numerous problems occurring in the subsequent period of familial mourning. Currently, the importance of identifying the type of mourning affecting families of cancer patients has become more and more clear, as this allows not only for greater therapeutic success, but also avoids a high number of risks and complications that appear during the critical care period. Our paper aims to identify and assess these risk factors in order to contribute to the optimization and success of palliative therapy. MATERIAL AND METHOD: We performed this study on a group of 78 subjects with metastatic cancer. We developed a questionnaire in order to assess the patient-family relationship, family profile and the patient's unique psychological traits, in order to identify potential risk factors. Data processing was performed using Microsoft Excel; the XLSTAT package was used to perform complex statistical tests (χ2 test, Spearman correlation coefficient). RESULTS AND CONCLUSIONS: Women are more prone to fears related to developing cancer themselves. No risk factors leading to the development of significant pathological mourning were identified in our study group. However, the clinician who deals with the treatment of the terminally ill cancer patient will have to include the following objectives related to the relatives in the therapeutic plan: to motivate their involvement, but with the maintenance of a separation in order to maintain the individuality; to keep their realism and to distinguish between normal/pathological mourning.

Subtle Immunoreactivity Differences in the Fractal Patterns of Membrane E-Cadherin in Gastric Adenocarcinoma.

Gastric cancer continues to be a significant malignancy worldwide, accounting for approximately one million new cases in 2020. Scientists are focusing on the cancerous cells' plasma membrane (PM) as a potential therapeutic target in cancer because it functions as the cell's interface with its environment through a variety of mechanisms. The capacity of membrane shape and its structures to influence biological processes frequently occurs through the regulation of enzymes or preferential protein binding to membranes via membrane shape changes. We aimed here to assess the morphological irregularities of the cellular membranes in gastric adenocarcinoma tumors, and to find any putative differences from normal gastric mucosae epithelial cells. We analyzed the pattern of E-cadherin at the level of the cell membrane using the fractal dimension (FD) analysis on fluorescence immunohistochemistry samples labeled with E-cadherin in gastric well/moderate and solid gastric adenocarcinoma from patients without any associated chemotherapeutic treatment or radiotherapy. Images were binarized based on a fixed threshold of the E-cadherin fluorescence channel, and then the FD of the binarized image outlines has been calculated in order to assess the ruggedness of the cellular membranes. Overall assessment of the FD revealed that the subtle membrane variations were evident enough to deem a statistically significant difference and the complexity of the membrane roughness was clearly higher for adenocarcinoma cases. We intended to evaluate if separating adenocarcinoma cases as low grade (G1 and G2) and high grade (G3 and solid), FD analysis could still differentiate membrane patterns and check if the available clinical parameters like age, gender, tumor location, lymph ganglia involved might correlate with FD values for adenocarcinoma patients. Altogether, the morphological analysis of a simple marker for the cell membrane can identify and distinguish tumor cells. Although there was a limited correlation between this analysis and the main clinical and pathological indicators of the disease, it will be very useful in the future for automatic computer-assisted diagnosis on slides, as well as for evaluating cellular adhesion and inter-cellular trafficking in cancer cells.

Maternal and Fetal Metabolites in Gestational Diabetes Mellitus: A Narrative Review.

Gestational diabetes mellitus (GDM) is a major public health issue of our century due to its increasing prevalence, affecting 5% to 20% of all pregnancies. The pathogenesis of GDM has not been completely elucidated to date. Increasing evidence suggests the association of environmental factors with genetic and epigenetic factors in the development of GDM. So far, several metabolomics studies have investigated metabolic disruptions associated with GDM. The aim of this review is to highlight the usefulness of maternal metabolites as diagnosis markers of GDM as well as the importance of both maternal and fetal metabolites as prognosis biomarkers for GDM and GDM's transition to type 2 diabetes mellitus T2DM.

Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects.

INTRODUCTION: Non-alcoholic steatohepatitis (NASH) is a progressive form of liver steatosis that involves a risk of progression towards fibrosis, cirrhosis, and end-stage liver disease. Low-grade inflammation is recognized to be involved in non-alcoholic fatty liver disease (NAFLD) pathogeny. Additionally, adipose tissue dysfunction plays an important role in the development of metabolic diseases. PATIENTS, MATERIALS AND METHODS: We conducted a study on 68 patients with liver steatosis confirmed through liver biopsy during the surgery. In all the patients, we recorded anthropometric parameters and we performed blood tests for systemic inflammation [high-sensitivity C-reactive protein (hs-CRP), fibrinogen] and serum adipokines related to adipose tissue inflammation (leptin, adiponectin). Additional to histopathological examination, we also performed the immunohistochemical study of inflammatory mononuclear cells. RESULTS: The 68 patients had a mean age of 56.57±4.94 years old, had a mean value of hs-CRP of 2.30±0.91 mg∕L, a mean value of leptin of 14.02±17.02 ng∕mL and a mean value of adiponectin of 7.54±0.38 mg∕L. In all the cases studied by liver biopsy, the steatosis exceeded 5% of hepatocytes, but the frequency of NASH was 26.47%. Cluster of differentiation (CD)45-positive, CD4-positive, and CD8-positive T-lymphocytes predominated in the studied cases. We obtained a statistically significant high association between definite NASH and the values of hs-CRP, serum adiponectin and leptin∕adiponectin ratio (p<0.0001). CONCLUSIONS: Systemic and adipose tissue inflammation was statistically significant associated with histological lesions of steatosis and NASH, suggesting that the determination of hs-CRP and serum adipokines in dynamics in patients with NAFLD is predictive for the progression of the disease.

Immunoexpression of E-cadherin, P-cadherin and fibronectin in gastric carcinomas.

One of the mechanisms involved in gastric carcinomas progression is represented by epithelial-mesenchymal transition (EMT), a complex process during which tumor cells acquire an invasive and migratory mesenchymal phenotype. In this study, we analyzed the immunoexpression of E-cadherin, P-cadherin and fibronectin in 50 gastric carcinomas, in relation with the tumoral type, differentiation grade and lesions stage. The reactions presented variable patterns related to lesions stage. Membrane and cytoplasmic reactions were present in 62% of cases for E-cadherin and in 56% of cases for P-cadherin, being present only cytoplasmic in 34% of cases for fibronectin. The immunoexpression for E-cadherin and P-cadherin was superior in tubular gastric carcinomas, of low grade and early stage, while fibronectin expression was superior in discohesive or mixed gastric carcinomas, of high grade and in advanced stages. Negative E-∕P-cadherin and positive fibronectin immunophenotype may be associated with aggressive gastric carcinomas and supports the EMT involvement in gastric carcinogenesis.

Immunoexpression of Snail, Twist1 and Slug in clear cell renal cell carcinoma.

Clear cell renal cell carcinomas (ccRCC) represent about 80% of the malignant neoplasia with this localization. Snail, Twist1 and Slug are transcription factors and play a central role in the epithelial-mesenchymal transition (EMT), which is involved in the progression of renal cell carcinoma (RCC). In this study, we analyzed the immunoexpression of these transcription factors in 50 cases of ccRCC, in relation to histopathological aggressiveness parameters of the lesions. The results indicated the association of Snail and Twist1 expression with high Fuhrman grade, as well as the association of Slug expression with low Fuhrman grade. The immunoexpression of Snail and Twist1 was significantly superior for advanced stages and Slug was overexpressed in early stages of ccRCC. Our study supports the usefulness of the Snail, Twist1 and Slug expression for the appreciation of aggressiveness in ccRCC, the panel being attractive for targeted therapy.

Study of the diagnosis and treatment of cancer located in the head and neck and correlation with expression of prognostic markers.

A prospective study made by authors was initiated in 2000 in order to analyze differences in terms of response rate, overall survival and progression free survival for patients with advanced head and neck carcinoma treated with radiotherapy vs. radiochemotherapy, respectively and to analyze the role of modern molecular biomarkers in the prognosis of these patients (p53, EGFR and Ki67). It was detected one significant difference appeared between the two groups for response rate (p<0.0001) and median overall survival [18.8 months in Group A and 17.2 months in Group B, with a hazard ratio for survival of 0.88 (95% CI, 0.75-1.12, p<0.0001]. Progression free survival was not significant different between these two groups [6.9 months for Group A and 7.2 months for Group B, p=0.3179]. Multivariate analysis by sex, age, TNM stage, site of disease, revealed TNM stage and site of disease as clinical phenotypes with predictive value. Also, the molecular biomarkers p53, EGFR and Ki67 have a prognostic significance in head and neck cancer in addition to the established clinical prognostic factors such as the stage, site of the tumor and the type of treatment. Because of material reasons, we decided to carry out the immunohistochemical marking in the group of patients who were radiochemotherapy-treated and the results of multivariate analysis reached statistical significance threshold in terms of response rate to treatment, overall survival and disease-free interval. Furthermore, immunohistochemical examination was not performed for patients with rhinopharyngeal carcinoma with marked radiochemosensibility and reduced tumor aggressiveness reflected in significantly better therapeutic outcomes by treatment response rate, overall survival and disease free interval. In the present study of the 93 cases that underwent immunohistochemical staining for EGFR, the majority (66 cases) showed a positive reaction for this marker, in 36 cases are highly immunohistochemical staining, and in 30 cases were weakly positive. In addition, cell proliferation was intense in 26 cases in which Ki67 index was greater than 45%, p53 protein expression was positive in 18 cases, but the majority (22) of cases showed a positive reaction for this marker; index was greater than 55%, and in the most (22) cases p53 protein was not expressed. Radio/chemoradiotherapy regimen associated with molecular anti-EGFR target therapy is standard therapy in advanced squamous head and neck carcinoma.

Vertebral bone metastasis in breast cancer: a case report.

BACKGROUND: We report here a case of a 66-year-old woman with a very aggressive form of breast carcinoma, having both liver and bone dissemination points. CASE DESCRIPTION: The patient was admitted for a rapid onset disk-herniation-like syndrome, but which on further investigation proved to be in fact a metastatic case of breast cancer. We found evidence of disseminations at least in the lumbar vertebral bodies and the liver. Pathological analysis of the available vertebral metastasis revealed a HER2+ molecular pattern, accordingly to the newly evolving molecular typing of breast cancers. Despite a rapid treatment instauration, the patient reacted poorly to taxanes and octeoclast inhibitors, and died after less than 11 months from admitting to the hospital. CONCLUSIONS: This is a rare case of an aggressive breast carcinoma identified initially after the vertebral metastases themselves that induced a non-specific symptomatology.

Recent data about the role of human papillomavirus (HPV) in oncogenesis of head and neck cancer.

Human papillomavirus (HPV) is a small circular DNA-virus and the high-risk types 16, 18 is implicated in oncogenesis of head and neck cancer--especially oropharynx (tonsil and base of tongue), poorly differentiated (the basaloid type), locoregional advanced stage, poorly differentiated, at the younger male, non-smokers, non-drinkers, sexual behaviors. The prognostic is favorable of human papillomavirus tumor status for patients with oropharynx squamous cell carcinoma treated with radiotherapy (accelerated fractionation without total dose reduction). The impact of HPV-vaccination (ACIP 2007) decreasing the incidence of oropharyngeal cancer, but that patients HPV-positive, have good prognostic in generally (two-year overall survival: 95%, two-year progression-free survival: 88%), therefore HPV-vaccination in routine practice it is controversy.