Noncortical coding of biological motion in newborn chicks' brain.

Biological motion, the typical movement of vertebrates, is perceptually salient for many animal species. Newly hatched domestic chicks and human newborns show a spontaneous preference for simple biological motion stimuli (point-light displays) at birth prior to any visual learning. Despite evidence of such preference at birth, neural studies performed so far have focused on a specialized neural network involving primarily cortical areas. Here, we presented newly hatched visually naïve domestic chicks to either biological or rigid motion stimuli and measured for the first time their brain activation. Immediate Early Gene (c-Fos) expression revealed selective activation in the preoptic area of the hypothalamus and the nucleus taeniae of the amygdala. These results suggest that subpallial/subcortical regions play a crucial role in biological motion perception at hatching, paving the way for future studies on adult animals, including humans.

Naïve chicks do not prefer objects with stable body orientation, though they may prefer behavioural variability.

Domestic chicks (Gallus gallus domesticus) have been widely used as a model to study the motion cues that allow visually naïve organisms to detect animate agents shortly after hatching/birth. Our previous work has shown that chicks prefer to approach agents whose main body axis and motion direction are aligned (a feature typical of creatures whose motion is constrained by a bilaterally symmetric body plan). However, it has never been investigated whether chicks are also sensitive to the fact that an agent maintains a stable front-back body orientation in motion (i.e. consistency in which end is leading and which trailing). This is another feature typical of bilateria, which is also associated with the detection of animate agents in humans. The aim of the present study was to fill this gap. Contrary to our initial expectations, after testing 300 chicks across 3 experimental conditions, we found a recurrent preference for the agent which did not maintain a stable front-back body orientation. Since this preference was limited to female chicks, the results are discussed also in relation to sex differences in the social behaviour of this model. Overall, we show for the first time that chicks can discriminate agents based on the stability of their front-back orientation. The unexpected direction of the effect could reflect a preference for agents' whose behaviour is less predictable. Chicks may prefer agents with greater behavioural variability, a trait which has been associated with animate agents, or have a tendency to explore agents performing "odd behaviours".

Spontaneous preference for unpredictability in the temporal contingencies between agents' motion in naive domestic chicks.

The ability to recognize animate agents based on their motion has been investigated in humans and animals alike. When the movements of multiple objects are interdependent, humans perceive the presence of social interactions and goal-directed behaviours. Here, we investigated how visually naive domestic chicks respond to agents whose motion was reciprocally contingent in space and time (i.e. the time and direction of motion of one object can be predicted from the time and direction of motion of another object). We presented a 'social aggregation' stimulus, in which three smaller discs repeatedly converged towards a bigger disc, moving in a manner resembling a mother hen and chicks (versus a control stimulus lacking such interactions). Remarkably, chicks preferred stimuli in which the timing of the motion of one object could not be predicted by that of other objects. This is the first demonstration of a sensitivity to the temporal relationships between the motion of different objects in naive animals, a trait that could be at the basis of the development of the perception of social interaction and goal-directed behaviours.

Quality of life of adult cancer survivors enrolled in Humanitas Research Hospital's survivorship care model.

INTRODUCTION: Clinicians should address the different health needs of cancer survivors (CS). We investigated concerns about physical/psychosocial symptoms and quality of life (QoL) of CS enrolled in our survivorship program. Our primary aim is to describe the CS population and their quality of life, considering both physical and psychosocial issues, with the intent to identify some possible association with the most frequently observed variables. METHODS: Adult patients, after ≥ 5 years from achieving complete hematologic or solid tumor remission, were included. The self-administered questionnaire used in the survey was based on the "Cancer Survivors Survey of Needs" (Mayo Clinic). RESULTS: We analyzed data from 191 CS. The median age was 63 years (53 years at diagnosis), and 70% of patients were females. A total of 93 patients (49%) reported a quality of life (QoL) score > 2. The most common psychosocial symptom concerns were fear of relapse (53%), genetic counseling (43%), living with uncertainty (35%), defining a new sense of normal (31%), and managing stress (28%). Females are more at risk to develop the following concerns compared with males: pain (40% vs 21%), sleep disturbance (54% vs 30%), weight gain (42% vs 21%), osteoporosis (41% vs 11%), body changes (45% vs 13%), hair or skincare issues (42% vs 16%), hot flashes (40% vs 11%), fear of recurrence (74% vs 54%), and living with a sense of uncertainty (53% vs 29%). Younger patients reported a higher score (> 2) for physical and psychological concerns compared with older patients. CONCLUSION: In this study, differences in physical and psychological symptoms/stressors among women and younger patients were identified. Female and younger patients appear to report physical and psychosocial concerns more frequently than other subgroups of patients. These observations should be validated and deepened in larger, prospective studies and considered during the long-term follow-up of these subgroups of patients.

Prognostic relevance of temporal muscle thickness as a marker of sarcopenia in patients with glioblastoma at diagnosis.

OBJECTIVES: Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia, correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. We evaluated the prognostic relevance of TMT measured on brain MRIs acquired at diagnosis in patients affected by glioblastoma. METHODS: We retrospectively enrolled 51 patients in our Institution affected by methylated MGMT promoter, IDH1-2 wild-type glioblastoma, who underwent complete surgical resection and subsequent radiotherapy with concomitant and maintenance temozolomide, from January 1, 2015, to April 30, 2017. The last clinical/radiological follow-up date was set to September 3, 2019. TMT was measured bilaterally on reformatted post-contrast 3D MPRAGE images, acquired on our 3-T scanner no more than 2 days before surgery. The median, 25th, and 75th percentile TMT values were identified and population was subdivided accordingly; afterwards, statistical analyses were performed to verify the association among overall survival (OS) and TMT, sex, age, and ECOG performance status. RESULTS: In our cohort, the median OS was 20 months (range 3-51). Patients with a TMT ≥ 8.4 mm (median value) did not show a statistically significant increase in OS (Cox regression model: HR 1.34, 95% CI 0.68-2.63, p = 0.403). Similarly, patients with a TMT ≥ 9.85 mm (fourth quartile) did not differ in OS compared to those with TMT ≤ 7 mm (first quartile). The statistical analyses confirmed a significant association among TMT and sex (p = 0.0186), but none for age (p = 0.642) and performance status (p = 0.3982). CONCLUSIONS: In our homogeneous cohort of patients with glioblastoma at diagnosis, TMT was not associated with prognosis, age, or ECOG performance status. KEY POINTS: • Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia and has been correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. • We appraised the correlation among TMT and survival, sex, age at surgery, and performance status, measured on brain MRIs of patients affected by glioblastoma at diagnosis. • TMT did not show any significant correlation with prognosis, age at surgery, or performance status, and its usefulness might be restricted only to patients with brain metastases and recurrent or treated glioblastoma.

Anatomical asymmetries in the tectofugal pathway of dark-incubated domestic chicks: Rightwards lateralization of parvalbumin neurons in the entopallium.

The discovery of the role of light exposure for the development of lateralization in domestic chick embryos revolutionized this research field. However, two main issues remain unresolved: (i) while in chicks anatomical light-dependent lateralization is mostly confined to the thalamofugal visual pathway, in pigeons only the tectofugal pathway is lateralized after light exposure. However, no study in either species ever investigated anatomical lateralization in the entopallium, the forebrain station of the tectofugal pathway. (ii) It is now known that lateralization can be observed also in dark-incubated chicks, both at the behavioural and at the Immediate Early Gene-expression level. We hypothesized that lateralization of the tectofugal system may underlie these light-independent effects. To investigate structural lateralization in the tectofugal pathway of dark-incubated chicks, we used parvalbumin (PV) as a marker of a sub population of entopallial neurons, quantifying PV-ir cell densities in the left and right entopallium. We found higher density in the right hemisphere, revealing for the first time anatomical lateralization in entopallium and confirming its potential role in supporting lateralized brain processing in dark-incubated birds. Results are discussed in relation to the possible functional role of PV-ir cells in inhibitory neural functions.

Quantitative analyses at baseline and interim PET evaluation for response assessment and outcome definition in patients with malignant pleural mesothelioma.

PURPOSE: Quantitative analyses on FDG PET for response assessment are increasingly used in clinical studies, particularly with respect to tumours in which radiological assessment is challenging and complete metabolic response is rarely achieved after treatment. A typical example is malignant pleural mesothelioma (MPM), an aggressive tumour originating from mesothelial cells of the pleura. We present our results concerning the use of semiquantitative and quantitative parameters, evaluated at the baseline and interim PET examinations, for the prediction of treatment response and disease outcome in patients with MPM. METHODS: We retrospectively analysed data derived from 131 patients (88 men, 43 women; mean age 66 years) with MPM who were referred to our institution for treatment between May 2004 and July 2013. Patients were investigated using FDG PET at baseline and after two cycles of pemetrexed-based chemotherapy. Responses were determined using modified RECIST criteria based on the best CT response after treatment. Disease control rate, progression-free survival (PFS) and overall survival (OS) were calculated for the whole population and were correlated with semiquantitative and quantitative parameters evaluated at the baseline and interim PET examinations; these included SUVmax, total lesion glycolysis (TLG), percentage change in SUVmax (ΔSUVmax) and percentage change in TLG (ΔTLG). RESULTS: Disease control was achieved in 84.7 % of the patients, and median PFS and OS for the entire cohort were 7.2 and 14.3 months, respectively. The log-rank test showed a statistically significant difference in PFS between patients with radiological progression and those with partial response (PR) or stable disease (SD) (1.8 vs. 8.6 months, p < 0.001). Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (p < 0.001). In the entire population, both ΔSUVmax and ΔTLG were correlated with disease control based on best CT response (p < 0.001). ΔSUVmax was significantly correlated with PFS in the entire population (p = 0.02) and with both PFS and OS in patients not undergoing talc pleurodesis (n = 65; p < 0.01 for PFS, p = 0.03 for OS), and in patients without pleurodesis presenting a SD and/or PR at CT after two cycles. CONCLUSION: These results confirm the role of FDG PET in the assessment of disease prognosis and treatment efficacy in MPM patients receiving first-line pemetrexed-based chemotherapy. In particular, metabolic response evaluated using ΔSUVmax can be used to predict outcome in MPM patients not undergoing talc pleurodesis who achieve SD and/or PR at the interim CT evaluation.

Targeted therapy for thymic epithelial tumors: a new horizon? Review of the literature and two cases reports.

Surgical resection remains the cornerstone of therapy for early-stage thymic epithelial tumors (TETs), while in advanced or recurrent forms, a multimodality approach incorporating radiation and chemotherapy is required. Given the absence of effective treatment options for metastatic/refractory TETs and the poor related prognosis, there is a compelling need to identify promising 'drugable' molecular targets. Initial reports of activity from targeted agents in TETs derived from anecdotal cases have been often associated with specific activating mutations. Only in recent years, several agents have been formally investigated into prospective clinical trials, with varying success rates. We reviewed the literature on targeted therapy in TETs along with two cases of thymoma achieving striking responses to sorafenib in combination with lapatinib.

Retreatment with Immune Checkpoint Inhibitors in the New Scenario of Immunotherapy in Non-Small Cell Lung Cancer.

The advent of immunotherapy has transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC). In the past few years, several studies have investigated the potential role of immune checkpoint inhibitors (ICIs) in resectable and unresectable locally advanced disease, achieving remarkable results that led to their approval in clinical practice. However, there is limited evidence on immunotherapy rechallenge after recurrence, with the majority of available knowledge coming from retrospective studies which involve heavily pretreated patients with advanced NSCLC. The recent introduction in the curative setting and the potential regulatory restrictions raise questions about the optimal choice of first-line and subsequent therapies for patients with systemic relapse. The role of immunotherapy readministration in this new scenario needs to be clarified, as well as the identification of patients for whom it is more appropriate, including clinical characteristics, duration of response, switching to other ICIs, reasons for discontinuation and immune-related toxicity. Here, we review literature on rechallenge with immunotherapy, including efficacy, safety profile and potential predictive factors of response.

Functional MRI of imprinting memory: a new avenue for neurobiology of early learning.

Filial imprinting, a crucial ethological paradigm, provides insights into the neurobiology of early learning and its long-term impact on behaviour. To date, only invasive techniques, such as autoradiography or lesion, have been employed to understand this behaviour. The primary limitation of these methods lies in their constrained access to the entire brain, impeding the exploration of brain networks crucial at various stages of this paradigm. Recently, advances in functional magnetic resonance imaging (fMRI) in the avian brain have opened new windows to explore bird's brain function at the network level. Here, we developed a ground-breaking non-invasive functional MRI technique for awake, newly hatched chicks that record whole-brain BOLD signal changes throughout imprinting experiments. While the initial phases of memory acquisition imprinting behaviour have been unravelled, the long-term storage and retrieval components of imprinting memories are still unknown. Our findings identified potential long-term storage of imprinting memories across a neural network, including the hippocampal formation, the medial striatum, the arcopallium, and the prefrontal-like nidopallium caudolaterale. This platform opens up new avenues for exploring the broader landscape of learning and memory processes in neonatal vertebrates, contributing to a more comprehensive understanding of the intricate interplay between behaviour and brain networks.

Refining patient selection for next-generation immunotherapeutic early-phase clinical trials with a novel and externally validated prognostic nomogram.

Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.

Manganese-enhanced magnetic resonance imaging reveals light-induced brain asymmetry in embryo.

The idea that sensory stimulation to the embryo (in utero or in ovo) may be crucial for brain development is widespread. Unfortunately, up to now evidence was only indirect because mapping of embryonic brain activity in vivo is challenging. Here, we applied for the first time manganese enhanced magnetic resonance imaging (MEMRI), a functional imaging method, to the eggs of domestic chicks. We revealed light-induced brain asymmetry by comparing embryonic brain activity in vivo of eggs that were stimulated by light or maintained in the darkness. Our protocol paves the way to investigation of the effects of a variety of sensory stimulations on brain activity in embryo.

Endoscopic Treatment for Nonhypertrophic Idiopathic Pyloric Stenosis in an Adolescent Patient.

Nonhypertrophic idiopathic pyloric stenosis (NHIPS) is a rare occurrence in children. It could be related to peptic ulcers, but a definitive cause is yet to be found. Treatment is a matter of debate, ranging from medical to surgical. We report the case of a 15-year-old boy suffering postprandial vomiting and weight loss in the previous 3 months. NHIPS was diagnosed and successfully treated with several sessions of endoscopic pyloric dilation and jejunal feeding. In association with a multidisciplinary approach, endoscopic dilation should be considered as a first-line treatment to avoid surgery.

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations.

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest "driver" genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply "precision oncology" in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma.

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.

Numerosities and Other Magnitudes in the Brains: A Comparative View.

The ability to represent, discriminate, and perform arithmetic operations on discrete quantities (numerosities) has been documented in a variety of species of different taxonomic groups, both vertebrates and invertebrates. We do not know, however, to what extent similarity in behavioral data corresponds to basic similarity in underlying neural mechanisms. Here, we review evidence for magnitude representation, both discrete (countable) and continuous, following the sensory input path from primary sensory systems to associative pallial territories in the vertebrate brains. We also speculate on possible underlying mechanisms in invertebrate brains and on the role played by modeling with artificial neural networks. This may provide a general overview on the nervous system involvement in approximating quantity in different animal species, and a general theoretical framework to future comparative studies on the neurobiology of number cognition.

Risks of molecular targeted therapies to fertility and safety during pregnancy: a review of current knowledge and future needs.

INTRODUCTION: As the population of young cancer survivors is increasing and a trend toward postponing pregnancy later in life is reported, more efforts are focused toward understanding treatment-induced sequelae, in particular, the effects of cancer and/or treatment on fertility. AREA COVERED: Whereas the fertility risk of cytotoxic agents for both men and women is well recognized, the impact of molecular-targeted therapy (MTT) on fertility parameters, their teratogenic potential and pregnancy outcome/management in case of an accidental exposure are not established. We update available clinical data on the impact of new MTTs on fertility in both sexes, their potential teratogenic effects and the outcome of pregnancy during accidental exposure. Agents are categorized by class and the potential relevance of their target signaling pathways to gonadal maturation. EXPERT OPINION: The majority of MTTs have worrying preclinical data discouraging their use during pregnancy and reinforcing the idea that they can induce impairment in gonadal function. However, it does not mean that all MTTs result in permanent infertility and that they should be completely avoided during pregnancy. The current review provides a critical evaluation on the most commonly used MTTs, offering a possible guide for clinicians.

Resurgence of an Inborn Attraction for Animate Objects via Thyroid Hormone T3.

For inexperienced brains, some stimuli are more attractive than others. Human neonates and newly hatched chicks preferentially orient towards face-like stimuli, biological motion, and objects changing speed. In chicks, this enhances exposure to social partners, and subsequent attachment trough filial imprinting. Early preferences are not steady. For instance, preference for stimuli changing speed fades away after 2 days in chicks. To understand the physiological mechanisms underlying these transient responses, we tested whether early preferences for objects changing speed can be promoted by thyroid hormone 3,5,3'-triiodothyronine (T3). This hormone determines the start of imprinting's sensitive period. We found that the preference for objects changing speed can be re-established in female chicks treated with T3. Moreover, day-1 chicks treated with an inhibitor of endogenous T3 did not show any preference. These results suggest that the time windows of early predispositions and of sensitive period for imprinting are controlled by the same molecular mechanisms.

COVID-19 lung injury as a primer for immune checkpoint inhibitors (ICIs)-related pneumonia in a patient affected by squamous head and neck carcinoma treated with PD-L1 blockade: a case report.

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65-year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.

Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.