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.

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.

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.

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.

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.

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.

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.

Post-Finasteride Adverse Effects in Male Androgenic Alopecia: A Case Report of Vitiligo.

Finasteride has proved to be relatively safe and effective in the therapeutic management of male androgenic alopecia. However, literature data report several endocrine imbalances inducing various adverse effects, which often persist after treatment cessation in the form of post-finasteride syndrome. Here we present the case of a 52-year-old man receiving finasteride (1 mg/day) who developed an uncommon adverse effect represented by generalized vitiligo 2 months after finasteride discontinuation. Associated adverse effects encountered were represented by mild sexual dysfunction (as determined by the International Index of Erectile Function, IIEF) and moderate depressive symptoms (according to DSM-V criteria), all of these manifestations aggregating within/as a possible post-finasteride syndrome. Further studies should develop and compare several therapeutic approaches, taking into account not only compounds that decrease the circulating dihydrotestosterone level but also those that could block the dihydrotestosterone receptors (if possible, compounds with selective tropism towards the skin). In addition, the possibility of predicting adverse effects of finasteride (according to hand preference and sexual orientation) should be taken into account.

Are hand preference and sexual orientation possible predicting factors for finasteride adverse effects in male androgenic alopecia?

Sexual side effects of finasteride seem to be redoubtable, being encountered not only during therapy but also after treatment cessation. Consequently, any possible clinical/paraclinical elements that might predict these adverse effects would be useful in the selection of a therapeutic strategy for male androgenic alopecia. Previous published studies show that some compounds that interfere with sexual hormones can decrease sexual activation and response, according to hand preference (as reported for finasteride and tamoxifen) and according to sexual orientation (as noted for bicalutamide). Our preliminary published data and the arguments presented here suggest that these two individual parameters might be used by dermatologists in the therapeutic approach of male androgenic alopecia, so as to alert specific subsets of men, prior to treatment, of the potential increased risk for developing adverse effects to finasteride.

A Pilot Study on Tamoxifen Sexual Side Effects and Hand Preference in Male Breast Cancer.

Recent clinical and imaging studies suggest that sex hormones modulate sexuality according to a psychophysiologic process of lateralization of the brain, with androgens playing a greater role in sexual functioning of left hemibrain/right handedness and estrogens possibly for right hemibrain/left handedness. Based on this perspective, the current study attempted to specify the relationship between hand preference, estrogens, and sexual function in subjects with male breast cancer, taking into account the sexual side effects of tamoxifen as the agent for inhibiting estrogen action. Twenty-eight Romanian men-17 right-handed and 11 left-handed-undergoing treatment with tamoxifen for male breast cancer participated in this study. These men were assessed both prior to and during tamoxifen treatment using the International Index of Erectile Function, a standardized instrument used for the evaluation of various aspects of sexual functioning, including erectile function (EF), orgasmic function (OF), sexual desire (SD), and overall functioning (OF). A main effect for handedness was found on EF, OF, SD, and OS scales, with right-handed men showing higher functioning than left-handed men. Regarding interaction effects, the left-handed group of men showed greater decreased sexual functioning during tamoxifen (on three subscales: OF, SD, OS) compared to right-handed men. Further research should be conducted in order to support and refine this potential lateralized process of sexual neuromodulation within the brain.

The ventral-hypothalamic input route: a common neural network for abstract cognition and sexuality.

Classically, external receptors of the body transmit information from the environment to the cerebral cortex via the thalamus. This review explains and argues that only concrete external information is transmitted from peripheral receptors to the cortex via a thalamic route, while abstract and sexual external information are actually transmitted from peripheral receptors to the cortex through a cognitive hypothalamic route. Sexual function typically implies participation of two distinct partners, ensuring reproduction in many species including humans. Human sexual response involves participation of multiple (environmental, biological, psychological) kinds of stimuli and processing, so the understanding of sexual control and response supposes integration between the classical physiological mechanisms with the more complex processes of our 'mind'. Cognition and sexuality are two relational functions, which are dependent on concrete (colours, sounds, etc.) and/or abstract (gestures, facial expression, how you move, the way you say something seemingly trivial, etc.) environmental cues. Abstract cues are encoded independent of the specific object features of the stimuli, suggesting that such cues should be transmitted and interpreted within the brain through a system different than the classical thalamo-cortical network that operates on concrete (material) information. Indeed, data show that the cerebral cortex is capable of interpreting two distinct (concrete and abstract) formats of information via distinct and non-compatible brain areas. We expand upon this abstract-concrete dichotomy of the brain, positing that the two distinct cortical networks should be uploaded with distinct information from the environment via two distinct informational input routes. These two routes would be represented by the two distinct routes of the ascending reticular activating system (ARAS), namely the classical/dorsal thalamic input route for concrete information and the ventral hypothalamic input route for abstract cognition and sexuality. Physiologically, the hypothalamic (dual-autonomic) route of the ARAS that processes abstract and sexual information is incompatible with the thalamic (somatic) route of the ARAS that processes concrete information, such that the two distinct routes would be needed to support the mind processes (awareness, consciousness, sexuality) through their own informational inputs from the environment. Informationally, the concrete external data are differentiated from abstract and sexual external data, so that they should be transmitted to cortex through distinct input routes. Pathologically, the hardware and/or software impairments of the hypothalamic default-mode network generate disturbed messages within the brain (related to information transmitted on this route), laying at the basis of mental and sexual disorders. The novel conceptualisations presented in the present paper help address issues surrounding the mind-brain dichotomy and, in doing so, suggest new possible avenues for exploration in the treatment and interventions for cognitive and sexual problems.

A pilot study on the sexual side effects of finasteride as related to hand preference for men undergoing treatment of male pattern baldness.

OBJECTIVE: To investigate the relationships between pharmacologically induced deprivation of dihydrotestosterone, sexual arousal, libido and hand preference, by comparing the self-reported sexual response prior to and during reception of the anti-androgen finasteride in men undergoing treatment for male pattern baldness. PATIENTS AND METHOD: In total, 33 sexually healthy Romanian men participated in this study. Patients prospectively provided information regarding their sexual functioning (over 4 weeks), as measured by the International Index of Erectile Function (IIEF) prior to and after commencing treatment with 1 mg finasteride for male pattern baldness. RESULTS: Overall IIEF scores as well as the erectile function, orgasmic function, sexual desire and overall satisfaction subscales showed group, treatment and group by treatment effects. The intercourse satisfaction subscale showed group and group by treatment effects. On most subscales, right-handed men showed no effect or lower sexual function whereas left-handed men reported no effect or improved sexual function, primarily. CONCLUSIONS: These results suggest that the sexual effects of dihydrotestosterone deprivation may depend on handedness--a proxy variable that may represent cognitive style--which lends further support to the idea of two distinct neuroendocrine psychosexual axes. They further suggest that detection of such sexual effects may be enhanced by using research methodologies and communication strategies that increase patients' sensitization to such effects.

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.

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.

A dual physiological character for cerebral mechanisms of sexuality and cognition: common somatic peripheral afferents.

The dual theory of sexuality is a work in progress that tries to put together all the significant physiological aspects described on this subject, the most recent published article discussing about the hormonal and pheromonal neuromodulation of somatic peripheral afferents. But sexuality and cognition shares common somatic peripheral afferents, so that a good understanding of sexual mechanisms supposes also a good knowledge of the essential psychological mechanisms/neuromodulators. Current psychological approaches could be limited to two general tendencies. Some authors consider that cerebral neuronal connexions generate a unitary network substrate that - increasing in its complexity - becomes compatible with our complex mental function. Others suggest that such a complex cerebral function correspond actually to a system based on subsystems, represented by distinct neuronal units (not necessarily complexes) that interact each other. Starting from basic somatic/sexual neurophysiological elements and general accepted psychological aspects, the discussion gave sense to the last point of view, namely that genesis of a new function is the result of cooperation between distinct structural and functional units. Contrary to the classical concepts, this paper sows the fact that mental perception corresponds actually (in term of touch/tangibility) to the internal representation of an external object while sensations realize an internal representation of the external characteristics of environmental object. As a conclusion, sexuality and cognition are two distinct autonomic/dual functions, interrelated at both cerebral and peripheral level. Peripheral interference implies intervention of some specific (mental and sexual) neuromodulators, making external information act as internal mental or internal sexual stimuli. Central cerebral interferences are also clinically and pharmacologically documented, specific neuromodulators being taken into account. Supplementary studies would be necessary to complete psychosexual dualism, presenting the association between image and perception for the genesis of visual perception or between image and sensation for the genesis of visual sensations, complex (mental or sexual) stimuli that suppose a synergic action between distinct neuromodulators. This central synergism supposes a peripheral synergism between left visual field and right nostril, aspects that will be discussed largely in a future article.

Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal.

OBJECTIVE: • Not only has a precise characterization of libido and sexual arousal in men as a central neural process been lacking, but the interactive role of gonadal hormones and sexual orientation in such processes has never been investigated. We investigate the relationships among sexual hormones, sexual arousal, and sexual orientation in men by comparing the self-reported sexual response of heterosexual and homosexual men with locally advanced prostate neoplasm, receiving the non-steroidal anti-androgen bicalutamide as monotherapy. PATIENTS AND METHODS: • 29 Romanian men participated in this study: 17 heterosexual and 12 homosexual. Patients were undergoing treatment for prostate cancer consisting of a standard daily dose of 50 mg bicalutamide, a fast acting non-steroidal anti-androgen with action comparable to other anti-androgen drugs but with reportedly fewer sexual side effects. • Patients retrospectively provided information regarding their sexual functioning measured by the IIEF prior to commencing bicalutamide treatment. • Then, about five weeks later, patients were asked to prospectively provide information regarding their current sexual functioning while undergoing bicalutamide treatment. RESULTS: • Overall IIEF scores as well as the Erectile Function, Orgasmic Function, Sexual Desire, and Overall Satisfaction subscales showed group, treatment, and group by treatment effects. • The Intercourse Satisfaction subscale showed group and group by treatment effects. • On most subscales, homosexual men showed lower functioning than heterosexual men, primarily in response to treatment with bicalutamide. CONCLUSIONS: • Treatment with an anti-androgen in a clinical population of men undergoing therapy for prostate cancer affected homosexual men more than heterosexual men, although not all heterosexual men were unaffected. • These results are discussed in the context of dual sexual natures, a concept recently developed in the sexual literature. • Furthermore, these findings reiterate the importance of incorporating such variables as sexual orientation into studies investigating medical treatments on sexual response.