The Significance of Preoperative Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Systemic Inflammatory Index (SII) in Predicting Severity and Adverse Outcomes in Acute Calculous Cholecystitis.

The prediction of severity in acute calculous cholecystitis (AC) is important in therapeutic management to ensure an early recovery and prevent adverse postoperative events. We analyzed the value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammatory index (SII) to predict advanced inflammation, the risk for conversion, and postoperative complications in AC. Advanced AC was considered the cases with empyema, gangrene, perforation of the gallbladder, abscesses, or difficulties in achieving the critical view of safety. A 3-year retrospective was performed on 235 patients admitted in emergency care for AC. The NLR was superior to the PLR and SII in predicting advanced inflammation and risk for conversion. The best predictive value was found to be at an NLR "cut-off" value of >4.19, with a sensitivity of 85.5% and a specificity of 66.9% (AUC = 0.824). The NLR, SII, and TG 13/18 correlate well with postoperative complications of Clavien-Dindo grade IV (p < 0.001 for all variables) and sepsis. For predicting early postoperative sepsis, TG 13/18 grading >2 and NLR > 8.54 show the best predicting power (AUC = 0.931; AUC = 0.888, respectively), although not significantly higher than that of the PLR and SII. The NLR is a useful biomarker in assessing the severity of inflammation in AC. The SII and PLR may be useful in the prediction of systemic inflammatory response.

When Not to Operate on Acute Cases-A Surgeon's Perspective on Rapid Assessment of Emergency Abdominopelvic Computed Tomography.

Clinical problem solving evolves in parallel with advances in technology and discoveries in the medical field. However, it always reverts to basic cognitive processes involved in critical thinking, such as hypothetical-deductive reasoning, pattern recognition, and compilation models. When dealing with cases of acute abdominal pain, clinicians should employ all available tools that allow them to rapidly refine their analysis for a definitive diagnosis. Therefore, we propose a standardized method for the quick assessment of abdominopelvic computed tomography as a supplement to the traditional clinical reasoning process. This narrative review explores the cognitive basis of errors in reading imaging. It explains the practical use of attenuation values, contrast phases, and windowing for non-radiologists and details a multistep protocol for finding radiological cues during CT reading and interpretation. This systematic approach describes the salient features and technical tools needed to ascertain the causality between clinical patterns and abdominopelvic changes visible on CT scans from a surgeon's perspective. It comprises 16 sections that should be read successively and that cover the entire abdominopelvic region. Each section details specific radiological signs and provides clear explanations for targeted searches, as well as anatomical and technical hints. Reliance on imaging in clinical problem solving does not make a decision dichotomous nor does it guarantee success in diagnostic endeavors. However, it contributes exact information for supporting the clinical assessments even in the most subtle and intricate conditions.

When Critical View of Safety Fails: A Practical Perspective on Difficult Laparoscopic Cholecystectomy.

The incidence of common bile duct injuries following laparoscopic cholecystectomy (LC) remains three times higher than that following open surgery despite numerous attempts to decrease intraoperative incidents by employing better training, superior surgical instruments, imaging techniques, or strategic concepts. This paper is a narrative review which discusses from a contextual point of view the need to standardise the surgical approach in difficult laparoscopic cholecystectomies, the main strategic operative concepts and techniques, complementary visualisation aids for the delineation of anatomical landmarks, and the importance of cognitive maps and algorithms in performing safer LC. Extensive research was carried out in the PubMed, Web of Science, and Elsevier databases using the terms "difficult cholecystectomy", "bile duct injuries", "safe cholecystectomy", and "laparoscopy in acute cholecystitis". The key content and findings of this research suggest there is high intersocietal variation in approaching and performing LC, in the use of visualisation aids, and in the application of safety concepts. Limited papers offer guidelines based on robust data and a timid recognition of the human factors and ergonomic concepts in improving the outcomes associated with difficult cholecystectomies. This paper highlights the most relevant recommendations for dealing with difficult laparoscopic cholecystectomies.

Characteristics of men who report symptoms of delayed ejaculation: providing support for empirically derived diagnostic criteria.

BACKGROUND: Little is known regarding the demographic, sexual, and relationship characteristics of men with symptoms of delayed ejaculation (DE). AIM: To identify differences between men with and without DE symptomology to validate face-valid diagnostic criteria and to identify various functional correlates of DE. METHODS: A total of 2679 men meeting inclusion criteria were partitioned into groups with and without DE symptomology on the basis of their self-reported "difficulty reaching ejaculation/orgasm during partnered sex." Men were then compared on a broad array of demographic and relationship variables, as well as sexual response variables assessed during partnered sex and masturbation. OUTCOMES: Outcomes included the identified differences between men with and without DE symptomology. RESULTS: Men with DE-whether having comorbid erectile dysfunction or not-differed from men without DE on 5 face-valid variables related to previously proposed diagnostic criteria for DE, including ones related to ejaculation latency (P < .001); self-efficacy related to reaching ejaculation, as assessed by the percentage of episodes reaching ejaculation during partnered sex (P < .001); and negative consequences of the impairment, including "bother/distress" and (lack of) "orgasmic pleasure/sexual satisfaction" (P < .001). All such differences were associated with medium to large effect sizes. In addition, men showed differences on a number of functional correlates of DE, including anxiety, relationship satisfaction, frequency of partnered sex and masturbation, and level of symptomology during partnered sex vs masturbation (P < .001). CLINICAL IMPLICATIONS: Face-valid criteria for the diagnosis of DE were statistically verified, and functional correlates of DE relevant to guiding and focusing treatment were identified. STRENGTHS AND LIMITATIONS: In this first comprehensive analysis of its kind, we have demonstrated widespread differences on sexual and relationship variables relevant to the diagnosis of DE and to its functional correlates between men with and without DE symptomology during partnered sex. Limitations include participant recruitment through social media, which likely biased the sample; the use of estimated rather than clocked ejaculation latencies; and the fact that differences between men with acquired and lifelong DE were not investigated. CONCLUSION: This well-powered multinational study provides strong empirical support for several face-valid measures for the diagnosis of DE, with a number of explanatory and control covariates that may help shed light on the lived experiences of men with DE and suggest focus areas for treatment. Whether or not the DE men had comorbid erectile dysfunction had little impact on the differences with men having normal ejaculatory functioning.

Severe Forms of Acalculous Acute Pancreatitis in Young Female Patients. A Preliminary Study.

BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) is a severe disease that usually involves hospitalization and a customized therapy. To date, remarkable progress has been made in establishing the etiology, diagnosis and therapy of this condition. For example, it is well documented that the AP course consists of two distinct pathophysiological phases. The first phase lasts about 1-2 weeks, involving only local inflammatory changes and possibly a transient SIRS syndrome, which require conservative therapy. The second phase is represented either by disease remission in patients with mild forms of AP, or by the persistence of SIRS syndrome and the occurrence of local complications in patients with moderate forms. Local complications therefore often occur in the second phase, when therapy must be customized according to the complications of the pancreatic area, as well as to provide adequate systemic support. Methods/ Results: Severe forms are less common and generally associate MSOF, which can develop at any time in the evolution of AP. MSOF worsens preexisting SIRS syndrome and local complications, making treatment more difficult and significantly increasing morbidity and mortality. This study presents the evolution of a group of patients with acalculous AP, who did not present in the first phase any systemic determinant of SIRS syndrome. Consequently, our initial prognosis was favorable, but the evolution of some patients was unexpectedly severe. Conclusions: Such surprising cases in terms of the evolution may suggest that increased caution is required in all AP patients, even if preliminary data suggest a mild form of the disease. Additional studies are necessary in the near future on this topic, both to improve therapy and to establish a better prognostic score by using new diagnostic tools.

Biology of cancer; from cellular and molecular mechanisms to developmental processes and adaptation.

Cancer research has been largely focused on the cellular and molecular levels of investigation. Recent data show that not only the cell but also the extracellular matrix plays a major role in the progression of malignancy. In this way, the cells and the extracellular matrix create a specific local microenvironment that supports malignant development. At the same time, cancer implies a systemic evolution which is closely related to developmental processes and adaptation. Consequently, there is currently a real gap between the local investigation of cancer at the microenvironmental level, and the pathophysiological approach to cancer as a systemic disease. In fact, the cells and the matrix are not only complementary structures but also interdependent components that act synergistically. Such relationships lead to cell-matrix integration, a supracellular form of biological organization that supports tissue development. The emergence of this supracellular level of organization, as a structure, leads to the emergence of the supracellular control of proliferation, as a supracellular function. In humans, proliferation is generally involved in developmental processes and adaptation. These processes suppose a specific configuration at the systemic level, which generates high-order guidance for local supracellular control of proliferation. In conclusion, the supracellular control of proliferation act as an interface between the downstream level of cell division and differentiation, and upstream level of developmental processes and adaptation. Understanding these processes and their disorders is useful not only to complete the big picture of malignancy as a systemic disease, but also to open new treatment perspectives in the form of etiopathogenic (supracellular or informational) therapies.

Contemporary clinical trials in pancreatic cancer immunotherapy targeting PD-1 and PD-L1.

Pancreatic cancer (PC) is a major gastrointestinal cancer in terms of worldwide incidence and mortality. Despite advances in diagnostic and treatment modalities, the mortality of PC is still a serious concern in both sexes. Immune therapy using inhibitors of immune checkpoints, especially inhibitors of programmed cell death protein 1/programmed cell death ligand-1(PD-1/PD-L1), offer huge benefits to cancer patients. This review describes an up-to-date information on the role of PD-1 and PD-L1 in the development of immune tolerance in PC alongside the current clinical trials and the known outcomes citing the available literature. We also included the details on PD-1/PD-L1-mediated signalling in maintenance of PC stem cells and metastasis. We reviewed the critical information on safety, tolerance, and efficacy of clinically important regimens of PD-1/PD-L1 blocking agents and targeted therapeutics. This review elucidates the underlying mechanisms of PD-1/PD-L1 alliance in tolerance of the immune system, maintenance of stem cells, and metastasis promotion as well as design regimens with high safety and excellent tolerability and efficacy for management of PC in advanced stages.

Nobel Prize for immune checkpoint inhibitors, understanding the immunological switching between immunosuppression and autoimmunity.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a revolutionary form of immunotherapy in cancer. However, the percentage of patients responding to therapy is relatively low, while adverse effects occur in a large number of patients. In addition, the therapeutic mechanisms of ICIs are not yet completely described. AREAS COVERED: The initial view (articles published in PubMed, Scopus, Web of Science, etc.) was that ICIs increase tumor-specific immunity. Recent data (collected from the same databases) suggest that the ICIs pharmacotherapy actually extends beyond the topic of immune reactivity, including additional immune pathways, such as disrupting immunosuppression and increasing tumor-specific autoimmunity. Unfortunately, there is no clear delimitation between these specific autoimmune reactions that are therapeutically beneficial, and nonspecific autoimmune reactions/toxicity that can be extremely severe side effects. EXPERT OPINION: Immune checkpoint mechanisms perform a non-selective immune regulation, maintaining a dynamic balance between immunosuppression and autoimmunity. By blocking these mechanisms, ICIs actually perform an immunological reset, decreasing immunosuppression and increasing tumor-specific immunity and predisposition to autoimmunity. The predisposition to autoimmunity induces both side effects and beneficial autoimmunity. Consequently, further studies are necessary to maximize the beneficial tumor-specific autoimmunity, while reducing the counterproductive effect of associated autoimmune toxicity.

The Role of Suppression and the Maintenance of Euthymia in Clinical Settings.

Background: Defense mechanisms serve as mediators referred to the subjects' attempt to manage stressors capable of threatening their integrity. Mature defense mechanisms represent the high adaptive group, including suppression, which allows the subject to distance disturbing contents from consciousness. In line with general defensive intents, suppression would preserve stable mood states, as in the case of euthymia. Clinical issues usually disturb homeorhesis, so that the study of subjects' suppressive tendencies would suggest possible existing relations among defense mechanisms, mood states, and clinical issues. The study highlighted the significant existing relations among factors such as suppression, euthymia, mood states, and clinical psychological phenomena. Methods: The observation group was composed of 150 participants, 51 males (34%) and 99 females (66%), aged from 25 to 30 years old, with a mean age of 26.63 years old (SD = 1.51). The study was conducted through the use of measures related to subjects' characteristics, euthymia, psychological flexibility and psychological well-being (Euthymia Scale), suppression (Suppression Mental Questionnaire), well-being (Who-5), and compassion (ProQol-5). Results: The performed analyses consisted of descriptive statistics, correlations, differences, and regressions among the considered variables. Starting from the first hypothesis, SMQ factors appeared to be significantly and positively correlated with Euthymia factors, rather than Regression in the Ego service (-). In line with the previous result, significant and positive correlations emerged among SMQ and Well-being (WHO-5) variables, maintaining an inverse relation with Regression in the Ego service. Significant differences emerged between male and female groups concerning SMQ total score and rationalization, with higher male group scores. Finally, significant dependencies emerged among the selected predictors (SMQ variables) and Compassion satisfaction. Conclusion: The emerged results highlighted significant relations among the considered variables so that it was possible to highlight the common directions assumed by suppression variables, well-being, and euthymia. Moreover, suppression appeared as a significant predictor with a causal role in clinical satisfaction. The results that have emerged allow us to consider defenses through an empirical perspective, useful to suggest an extension to other groups, phenomena, and conditions.

Clinical and therapeutic features of acute cholecystitis in diabetic patients.

The present study aimed to compare the clinical, paraclinical, intraoperative findings, and postoperative complications in acute cholecystitis in diabetic patients vs. non-diabetic patients. A 2-year retrospective study was performed on the patients who underwent emergency cholecystectomy for acute cholecystitis between 2017 and 2019 at the 4th Department of Surgery, Emergency University Hospital Bucharest. The diabetic subgroup numbered 46 eligible patients and the non-diabetic one 287 patients. Demographics, the severity of the clinical forms, biological variables (including white cell count, urea, creatinine, coagulation and liver function tests) comorbidity status, surgical approach, postoperative complications, and hospital stay were analyzed. Statistical analyses were performed to assess comparative results between the aforementioned data (SPSS V 13.0). The CCI and ASA risk classes were increased in the diabetic group, with 34.78% of patients having 3 or more associated comorbidities. No statistically significant associations were demonstrated between diabetes and the severity of the cholecystitis and risk for conversion. Postoperatively both minor complications such as surgical site infections and major cardiovascular events were more common in the diabetic subgroup (P=0.0254), well associated with the preoperative status and baseline cardiovascular comorbidities. Laparoscopic cholecystectomy is a safe procedure for diabetic patients, which can provide the best outcomes, by decreasing the risks of surgical wounds. Attentive perioperative care and good glycemic control must be provided to minimize the risk of complications.

Cardiovascular risk estimation in young patients with ankylosing spondylitis: A new model based on a prospective study in Constanta County, Romania.

Cardiovascular (CV) risk assessment charts are useful in establishing a patient therapeutic plan, but the most commonly used charts have essential limitations when applied to special populations. Our aim was to determine whether the Systematic Coronary Risk Evaluation (SCORE) chart underestimates the CV risk in young patients with ankylosing spondylitis (AS) and to promote the necessity of new risk assessment models. We conducted a prospective study in Constanta County, Romania including 70 consecutive patients ≤50 years of age, previously diagnosed with AS, without a history of established CV disease, diabetes mellitus and chronic kidney disease. We estimated the CV risk using SCORE based on total cholesterol, applied for a high-risk population, such as the Romanian population. Estimation of CV risk was also conducted with the relative risk (RR) chart, considering the following variables: Smoking, systolic blood pressure and total cholesterol. The majority of patients (n=46, 65.71%) had low risk according to the SCORE chart and only 24 (34.28%) were found to have moderate CV risk; none of them with high or very high CV risk. Ten patients (21.74%) of the 46 who were considered to have a low risk based on the SCORE system presented with carotid plaques. Twelve patients (50%) of the remaining 24 with moderate CV risk were found to have carotid plaques. According to 2016 'European Society of Cardiology' (ESC) guidelines, 22 of all 70 patients were at high/very high CV risk due to the presence of carotid plaques. Comparing the RR chart with carotid plaque detection, only 4 out of 30 (13.3%) patients with RR=1 had carotid plaques; the frequency was higher in those with RR>1. Our results attested that the SCORE system underestimates the risk in patients with carotid plaques. Carotid ultrasound provided a more heightened sensitivity of the RR chart. C-reactive protein (CRP) >3 mg/dl is associated with RR>1, making this chart a better CV risk predictive system in this particular category of patients.

Clinical Psychological Figures in Healthcare Professionals: Resilience and Maladjustment as the "Cost of Care".

Background: The health professionals are involved in the paths of care for patients with different medical conditions. Their life is frequently characterized by psychopathological outcomes so that it is possible to identify consistent burdens. Besides the possibility to develop pathological outcomes, some protective factors such as resilience play a fundamental role in facilitating the adaptation process and the management of maladaptive patterns. Personal characteristics and specific indexes such as burdens and resilience are essential variables useful to study in-depth ongoing conditions and possible interventions. The study was aimed at highlighting the presence and the relations among factors as personal variables, burdens, and resilience, to understand health professionals' specific structure and functions. Methods: The observation group was composed of 210 participants, 55 males (26.2%), and 155 females (73.8%), aged from 18 to 30 years old with a mean age of 25.92 years old (SD = 3.33). The study considered personal characteristics of the subjects, such as age, gender, years of study, days of work per week, hours of work per week, and years of work. Our study had been conducted with the use of measures related to burdens (Caregivers Burden Inventory) and resilience (Resilience Scale for Adults). Results: The performed analyses consisted of descriptive statistics, correlations, and regressions among the considered variables. Several significant correlations emerged among personal characteristics, CBI, and RSA variables. Specifically, age and work commitment indexes appeared to be significantly related to the development of burdens, differently from the years of study. Significant correlations emerged among personal and RSA variables, indicating precise directions for both domains. Age and gender were identified as predictors to perform multivariate regression analyses concerning CBI factors. Significant dependence relations emerged with reference to all CBI variables. Conclusion: Pathological outcomes and resilience factors represent two sides of the health professionals' experiences, also known as "invisible patients." Greater knowledge about present conditions and future possibilities is a well-known need in literature so that the current analyses considered fundamental factors. In line with state of the art, future studies are needed in order to deepen elusive phenomena underlying maladjustment.

Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review.

Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms "distal symmetrical polyneuropathy", "neuropathic pain treatment", "diabetic neuropathy", "diabetes complications", "glycaemic control", "antidepressants", "opioids", and "anticonvulsants". Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.

Finasteride and androgenic alopecia; from therapeutic options to medical implications.

Androgenic alopecia (AGA) is an esthetic condition with varying psycho-social implications, easily accepted by some patients and tolerated only with difficulty by others. Modern therapeutic options such as 5α-reductase inhibitors have significant outcomes, but also exert significant side effects in a subset of patients. The literature describes three distinct situations regarding finasteride administration, a compound largely used for AGA. Some studies show finasteride to be very safe with minimal or no side effects. Other studies take a more cautious approach, recognizing such side effects but, at the same time, considering the putative relationship between finasteride and adverse effects to be disputable, given that placebo administration in AGA is associated with relatively similar or even more severe side effects. Finally, some authors/studies are concerned that, when compared to placebo, finasteride administration may result in side effects with greater frequency and severity, and sometimes that persist even after treatment cessation in the form of post-finasteride syndrome. Several factors presented in this paper appear to explain finasteride inconsistency regarding its therapeutic and side effects. Such factors should be further investigated and used to categorize subjects into distinct subgroups, either predisposed to adverse reactions or more tolerant of the finasteride administration.

Heart failure and chronic obstructive pulmonary disease: a review.

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are important causes of morbidity and mortality worldwide. The association between the two conditions have significant systemic effects and a chronic, progressive evolution, affecting exercise tolerance and quality of life. The diseases share common risk factors, such as smoking, advanced age, and low-grade systemic inflammation. The majority of symptoms and physical signs, such as dyspnoea, orthopnea, nocturnal cough, exercise intolerance, muscle weakness may coexist in both pathologies. Thus, the differential clinical diagnosis between exacerbation of COPD and HF decompensation may be difficult. Natriuretic peptides are sensitive biomarkers of HF, used mostly to exclude HF if their values are less than 100 pg/mL for Brain Natriuretic Peptide (BNP), respectively less than 300 pg/mL for N-terminal-pro Brain Natriuretic Peptide (NT-proBNP). Natriuretic peptides are very useful in emergency, for the differential diagnosis of acute dyspnoea. Echocardiography is the standard imaging technique of HF diagnosis and should be performed in all patients with potential HF. Treatment of patients with both HF and COPD should include drugs that prolong survival in HF, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, cardioselective beta1-blockers, aldosterone antagonists, and long-acting bronchodilators (an antimuscarinic rather than a beta2-agonist). The prognosis of patients with both diseases is worse than in patients with only one of the two conditions. These patients represent a continuous challenge of diagnosis and treatment for the clinicians and require a close monitoring of cardiopulmonary function.

Malignant Melanoma: Autoimmunity and Supracellular Messaging as New Therapeutic Approaches.

OPINION STATEMENT: Melanoma is one of the most aggressive forms of cancer, with a high mortality rate in the absence of a safe and curable therapy. As a consequence, several procedures have been tested over time, with the most recent (immunological and targeted) therapies proving to be effective in some patients. Unfortunately, these new treatment options continue to generate debate related to the therapeutic strategy (intended to maximize the long-term results of patients with melanoma), not only about the monotherapy configuration but also regarding association/succession between distinct therapeutic procedures. As an example, targeted therapy with BRAF inhibitors proved to be effective in advanced BRAF-mutant melanoma. However, such treatments with BRAF inhibitors lead to therapy resistance in half of patients after approximately 6 months. Even if most benign nevi incorporate oncogenic BRAF mutations, they rarely become melanoma; therefore, targeted therapy with BRAF inhibitors should be viewed as an incomplete or perfectible therapy. Another example is related to the administration of immune checkpoint inhibitors/ICIs (anti-CTLA-4 antibodies, anti-PD-1/PD-L1 antibodies), which are successfully used in metastatic melanoma. It is currently believed that CTLA-4 and PD-1 blockade would favor a strong immune response against cancer cells. The main side effects of ICIs are represented by the development of immune-related adverse events, which in some cases can be lethal. These ICI side effects would thus be not only therapeutically counterproductive but also potentially dangerous. Surprisingly, a subset of immune-related adverse events (especially autoimmune toxicity) seems to be clearly correlated with better therapeutic results, perhaps due to an additional therapeutic effect (currently insufficiently studied/exploited). Contrary to the classical approach of cancer (considered until now an uncontrolled division of cells), a very recent and comprehensive theory describes malignancy as a supracellular disease. Cancerous disease would therefore be a disturbed supracellular process (embryogenesis, growth, development, regeneration, etc.), which imposes/coordinates an increased rhythm of cell division, angiogenesis, immunosuppression, etc. Melanoma is presented from such a supracellular perspective to be able to explain the beneficial role of autoimmunity in cancer (autoimmune abortion/rejection of the melanoma-embryo phenotype) and to create premises to better optimize the newly emerging therapeutic options. Finally, it is suggested that the supracellular evolution of malignancy implies complex supracellular messaging (between the cells and host organism), which would be interfaced especially by the extracellular matrix and noncoding RNA. Therefore, understanding and manipulating supracellular messaging in cancer could open new treatment perspectives in the form of digitized (supracellular) therapy.

The Current Surgical Managemnt of the Parietal Deffects in Patients with Liver Cirrhosis - Options and Limits. Our Experience and Review of Literature.

Introduction: The abdominal wall hernias in patients with liver cirrhosis have a significant higher prevalence than those in non- cirrhotic patients. The best surgical treatment option and the optimal operative time still represent a subject of debate. Material and method: We have retrospectively analyzed the cases of abdominal wall hernias in patients with liver cirrhosis admitted in the Surgical Department of the Sfantul Pantelimon Clinical Emergency Hospital from Bucharest, undergoing surgical treatment between January 2012 and December 2016. Data regarding the laboratory results (the serum albumin and bilirubin levels, the Prothrombin Time) and the clinical aspects (the presence of ascites or encephalopathy) that helped establish the grade of the disease according to Child classification system, and, also, the information regarding the type of hernia, the character of the surgical indication (emergency or elective), the surgical technique and the postoperative evolution have been collected from the medical documents of the patients included in the present study. The statistical analysis has been made using the chi- square test. Results: 32 cases out of the total 65 patients included in the study, that underwent surgical intervention for the treatment of the abdominal wall defects, had umbilical hernia (49,23%), 18 cases presented with inguinal hernia (27.69%), 11 with incisional hernia (16.92%) and 4 with epigastric hernia (6.15%). 29 patients were subjected to elective surgery (44.6%) and 36 to emergency surgery (55,4%). Regarding the Child classification system used in the present study, 24 patients presented with Child A grade of cirrhosis (36.92%), 30 with Child B (46.15%) and 11 with Child C (16.92%). The postoperative morbidity rate was 45,83% in Child A group, 56,66% in Child B group and 81,8% in Child C group. The mortality rate was 4,16% in the Child A group (one death), 13.33% in the Child B group (4 deaths) and 72.72% in Child C group (8 cases). The highest mortality rates have been registered in patients that underwent emergency surgical intervention. Conclusions: The parietal defects in patients with liver cirrhosis can be surgically treated with satisfactory outcomes. The best results have been registered in patients with compensated form of the cirrhosis or in cases undergoing elective surgery. The methods used for the surgical treatment of the abdominal wall defects vary from herniorrhaphy to alloplastic techniques. For patients with ascites, a good control of this complication represents an important factor for the favourable postoperative evolution. The emergency surgical interventions are associated with greater risks of morbidity and mortality.

Melanoma and autoimmunity: spontaneous regressions as a possible model for new therapeutic approaches.

Until now, malignancy has been considered a cellular problem represented by the perturbed (uncontrolled) division of the cells associated with invasion and metastasis. Contrary to this classical approach, a new perspective suggests that cancerous disease is, in fact, a supracellular problem represented by inadequate evolution of complex supracellular processes (embryogenesis, development, regeneration, etc.). Such complex processes would be disconnected from the real needs of the body, inducing unnecessary or even dangerous events such as an exacerbated rate of the cell division, angiogenesis, immunosuppression (specific to embryogenesis and melanoma), invasion (mediated by trophoblastic/placental factors in melanoma), and migration (specific to neural crest cells, which generate melanocytes - the most common origin for melanoma). As a result, a correct and comprehensive interpretation of cancer (causes, evolution, therapy, and prevention) should be conducted from a supracellular perspective. After presenting the supracellular perspective, this article further investigates the favorable evolution of malignant melanoma in two distinct situations: in patients receiving no therapy and in patients treated with immune-checkpoint inhibitors. In patients receiving no therapy, spontaneous regressions of melanoma could be the result of several autoimmune reactions (inducing not only melanoma regression but also vitiligo, an autoimmune event frequently associated with melanoma). Patients treated with immune-checkpoint inhibitors develop similar autoimmune reactions, which are clearly correlated with better therapeutic results. The best example is vitiligo, which is considered a positive prognostic factor for patients receiving immune-checkpoint inhibitors. This finding indicates that immune-checkpoint inhibitors induce distinct types of autoimmune events, some corresponding to specific favorable autoimmune mechanisms (favoring tumor regression) and others to common unfavorable adverse reactions (which should be avoided or minimized). In conclusion, the spectrum of autoimmune reactions induced by immune-checkpoint inhibitors should be restricted in the near future to only these specific favorable autoimmune mechanisms. In this way, the unnecessary autoimmune reactions/autoaggressions could be avoided (a better quality of life), and treatment specificity and efficiency should increase (a higher response rate for melanoma therapy).

Biology of Cancer; From Cellular Cancerogenesis to Supracellular Evolution of Malignant Phenotype.

Until now cancerogenesis has been studied in close relation with the corresponding malignant phenotype. Such unified approach defines cancer as uncontrolled cellular multiplication, associating invasion and metastasis. Contrary to the classical approach, this paper presents cancerous disease from two distinct perspectives: cancerogenesis as the cause (investigated especially to cellular or molecular level), and malignant phenotype as the resulting effect (with supracellular evolution). It is advanced the perspective that exacerbated cell division in cancer would be actually a very responsive event to supracellular signals, which are received from extracellular matrix and supracellular programs of the body.