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Living in complexity and being part of it, becoming self-aware, recognizing the other’s right to existence, embodying nature in oneself as a natural, obvious and everyday fact depends, as Edgar Morin said, on our educational system. To do this, we need to activate a process that focuses on direct experience with what surrounds us, and in particular with nature, remembering that education is the kindling of a flame, not the filling of a vessel.Starting from some contemporary principle, especially from the Edgar Morin’s ‘reliance’ and the Gilles Clément’s ‘planetary garden’ and ‘terrestrial citizenship’, the research goes back in time and attempts a reinterpretation of some of the founding principles of Maria Montessori’s thought. This sees the garden as a privileged place for experimenting with an educational system capable of developing in human beings a greater awareness of themselves and their surroundings. In ‘our garden’, Montessori’s ideal place for a cosmic education, “The great law that regulates life in cosmos is that of collaboration between all beings” (Montessori, 2004).

Questo numero di Ri-Vista nasce nell’Aprile del 2020, in pieno lockdown, con l’esigenza di raccogliere alcune delle riflessioni espresse durante il periodo della pandemia prodotta dal COVID-19, nel dibattito sulla qualità dei luoghi che abitiamo, su come questi dovrebbero essere e su come gli esseri umani dovrebbero abitare il pianeta. Un tentativo di compilare una sorta di diario di bordo, o se vogliamo una serie di appunti, utili a ricordare cosa non dovremmo dimenticare di questa esperienza e cosa dovremmo portare all’interno del progetto di paesaggio per migliorare la qualità della vita di tutti gli esseri viventi del pianeta.

Background: HRQoL is generally conceptualized as a broad multidimensional construct that refers to patients' perceptions of the impact of disease and its treatment on their physical, psychological, and social functioning and well-being. Little is known in patients with onco-hematological cancer in comparison with the general population and other chronic diseases. Objective: We assessed HRQoL in patients diagnosed with haematological cancers in comparison with the general population and other chronic diseases. Methods: The questionnaire Short Form (SF)-12 was administered to 62 patients with onco-hematological disease and results were compared with 702 controls (184 healthy people, 37 Major Depression, 201 Multiple Sclerosis; 23 Wilson disease; 46 Carotidal Atherosclerosis; 60 Celiac disease; 151 solid tumours). Results: HRQoL in patients diagnosed with a haematological cancer was significantly worse in comparison with the general population (F= 43.853, p Conclusion: This study confirmed that haematological cancers negatively affects overall HRQoL. The results showed an impact of haematological cancers on HRQoL that is similar to what found in patients with solid tumors, Major Depression and Carotid Atherosclerosis. Current successful therapeutic strategy achieved in the treatment of haematological cancers not only positively impact on survival rate but also could improve the overall HRQoL.

Background Overweight and obese patients with solid tumors receiving anti-programmed cell death-1 (PD-1)/PD-ligand-1(PD-L1) immune checkpoint inhibitors exhibit improved survival and higher risk of immune-related adverse events (irAEs) than those with a normal body mass index (BMI). In classic Hodgkin lymphoma (cHL), the impact of BMI on survival and immune-related toxicity is unknown. We evaluated for the first time associations of BMI with survival and irAEs in patients with relapsed/refractory (RR)-cHL undergoing PD-1 blockade. Methods Data from a multicenter study on 133 patients treated with the anti-PD1 antibody nivolumab (July 2015–December 2016) were retrieved from a prospective database. Progression-free (PFS), overall survival (OS), incidence and severity of irAEs according to BMI categories were estimated by Kaplan–Meier method, landmark-analyses and Cox regressions. Results Patients, mostly males (63%, n = 84) with a median age of 35 years (range, 15–82), advanced stage (75%), B symptoms (63%), bulky disease (24%), a median of 4 previous treatments (range, 1–9), received a median of 18 nivolumab doses (range, 1–57). No statistically significant differences across BMI subgroups emerged as to PFS, with 1-year rates of 67.1% for both normal weight (n = 66; 49.6%) and overweight (n = 31; 23.3%) patients. Underweight (n = 12; 9%) and obese (n = 24; 18%) patients had a 1-year PFS of 54.5% and 49%, respectively. In survival analyses, BMI either as a continuous (P = 0.5) or categorical (P for trend = 0.63) variable failed to associate with PFS. Response rates and time-to-response did not cluster in any BMI subset. No BMI-related differences in OS emerged across normal, overweight and obese patients but underweight patients had the worst survival. Occurrence of irAEs of whatever severity did not statistically associate with BMI. Conclusions In patients with RR-cHL receiving nivolumab, no statistically significant differences emerged in response rates, PFS and OS across BMI categories of normal weight, overweight and obese. Overweight/obese patients did not display an increased risk of irAEs. The exquisite sensitivity to anti-PD-1 antibodies, the unique cytokine milieu and effector pathways triggered by nivolumab in cHL, may represent biologic ‘equalizers’ counteracting the immunoregulatory effects of adiposity. Differently from solid tumors, BMI is not associated with treatment efficacy and immune-related toxicity and does not represent a predictive tool for PD-1-targeted immunotherapies in cHL.

My intention in this research is to focus on the idea of spiritual crisis in human rights arena. The topic I shall be discussing concerns a basic set of issues dealing with the purpose of human rights, their moral foundation and their ultimate metaphysical ground. Simply put I shall be asking whether there is something special in human beings which entitles them to rights. Some arguments such as human agency, dignity and natural law tend to be quite abstract. It could therefore be tempting to assume that the issue, being of not much practical importance, is not relevant. But this would be a rush assumption because determining the foundation of human rights means determining the very legitimacy of human rights themselves in the international arena. I will consider Ignatieff’s pragmatic point of view that can be summed up with a catch phrase: “without the Holocaust no Declaration, because of the Holocaust, no unconditional faith in the Declaration either” and Stackhouse’s religious one developed in Religion and Human Rights: a Theological Apologetic. My purpose is to analyse both Ignatieff’s view, that avoids contentious religious ground for human rights and offers a secular ground designed with the idea of human agency, and Max Stackhouse who, instead, defends the idea of a theological ethic as religious ground for human rights. First of all, through this analysis I aim at pointing out that while on the one hand the respect for our fellow human beings needs a reverential attitude and our commitment to protect our species needs to be sustained by some faith; on the other hand grounding human rights in religion is extremely dangerous and may imply violent clashes between different religious faiths. Secondly, I also aim at criticizing Ignatieff’s view because a defence of human rights as pragmatic instruments on pragmatic grounds seems to be too weak and human rights regime needs moral and metaphysical foundations to be universally recognized and implemented. Thirdly and ultimately, using Rawls’s concept of overlapping consensus I aim at showing the unecessity to agree upon a “single foundation”. A single foundation risks to be authoritative, whereas, what a human rights regime relies on is a plural foundations. If we arrive at respecting human rights on a plurality of grounds, then we are making them more broadly acceptable to people. If we publicly defend human rights for a plurality of reasons, we are rightly proving that there is no “proper” metaphysical foundation. A good reason why we do not need to ground human rights in any particular metaphysics can be that they are already grounded in many metaphysics and can already derive sustenance from many sources. Hence, it would be worthwhile and wise to welcome a plurality of nonexclusive claims concerning the ways in which human rights can legitimately be grounded. Human agency, human dignity, equal creation are, for instance, some examples of different foundations that are not mutually exclusive. هدف من در این تحقیق تمرکز بر ایدة بحران معنوی در عرصه حقوق بشر است. موضوعی که من آن را مورد بحث قرار می­دهم به مجموعه­ای اساسی از مسائلی مرتبط می­شود که به هدف حقوق بشر، پایه اخلاقی آن­ها و زمینه متافیزیکی غایی آن­ها مربوط می­شود. به شکل ساده تر این پرسش را مطرح می­کنم که آیا در افراد نوع بشر چیز خاصی وجود دارد که آن­ها را مستحق داشتن حق می­کند؟ برخی از استدلال­ها مانند عامل انسان، کرامت و قانون طبیعی کاملا انتزاعی هستند. بنابراین می­توان چنین فرض کرد که چون مسئله اهمیت کاربردی زیادی ندارد، این استدلالات مرتبط نیستند. اما این فرض کمی عجولانه است، زیرا تعیین پایه و اساس حقوق بشر به معنی تعیین مشروعیت خودِ حقوق بشر در عرصة بین­المللی است. من دیدگاه عملگرا ایگناتیف را که می­توان به صورت یک جمله کلیدی خلاصه کرد در نظر می­گیرم: «بدون هولوکاست اعلامیه حقوق بشر وجود نداشت. به خاطر هولوکاست، هیچ اعتقاد بی قید و شرطی در این اعلامیه وجود ندارد.» و دین داری استاک هاوس در دین و حقوق بشر توسعه یافته است: متکلمان دینی. هدف من این است که هر دو دیدگاه را بررسی کنم. هم دیدگاه ایگناتیف که از پرداختن به زمینه­های مذهبیِ حقوق بشر دوری می­کند و یک دیدگاه با پایه­های سکولار با ایده عاملیت انسان ارائه می­دهد و هم دیدگاه مکس استاک هاوس که بر خلاف ایگناتیف از اخلاقی دینی به عنوان پایه­های حقوق بشر دفاع می­کند. اول از همه از طریق این تجزیه و تحلیل، قصد دارم اشاره کنم در حالی که از یک سو احترام به هم نوعان ما نیازمند یک رویکرد محبت آمیز است و تعهد ما به حفظ نوع بشر نیازمند تقویت توسط ایمان دارد؛ از سوی دیگر پایه گذاری حقوق بشر در دین بسیار خطرناک است و ممکن است درگیری­های خشونت آمیز میان مذاهب مختلف به وجود آورد. دوماً به انتقاد از دیدگاه ایگناتیف می­پردازم، چرا که دفاع از حقوق بشر به عنوان ابزار عملگرایانه، در زمینه­های عملی بسیار ضعیف است و نظام حقوق بشر نیازمند مبانی اخلاقی و متافیزیکی است که به طور جهانی شناخته شده باشد و به اجرا درآمده باشند. سوماً و در نهایت با استفاده از مفهوم رالز در خصوص همپوشانی اجماع، قصد من نشان دادن عدم نیاز به توافق بر سر «بنیان­های واحد» می­باشد. در نظر گرفتن یک بنیان واحد توانا و معتبر برای حقوق بشر، ریسک پذیر است. در حالی که یک رژیم حقوق بشری بر بنیان­های چندگانه استوار است. پذیرش حقوق بشر با بنیان­های چندگانه توسط ما به پذیرش وسیع تر آن توسط مردم کمک می­نماید. اگر به علت گوناگونی به طور عمومی از حقوق بشر دفاع کنیم، به درستی ثابت می­کنیم که هیچ پایه متافیزیکی مناسبی وجود ندارد. دلیل خوبی برای آنکه که چرا ما نیازمند زمینه­های حقوق بشری در هر متافیزیک خاص نیستیم می­تواند این باشد که آن­ها هم اکنون نیز به بسیاری از متافیزیک­ها متکی هستند و در حال حاضر می­توانند از منابع بیشتری بهره ببرند. از این رو ارزشمند و عاقلانه است که از ادعاهای غیر انحصاری متکثر مرتبط با راه­هایی که حقوق بشر [به واسطة آن­­ها] به طور قانونی پایه گذاری می­شود، استقبال کرد. برای مثال عاملیت انسان، کرامت انسانی، ایجاد برابری، نمونه­هایی از مبانی مختلفی هستند که منحصر به فرد و ناسازگار با دیگری نیستند.

Introduction: An effective communication is an integral part of the patient-physician relationship. Lack of a healthy patient-physician relationship leads to a lower level of patient satisfaction, scarce understanding of interventions and poor adherence to treatment regimes. Patients need to be involved in the therapeutic process and the assessment of risks and perspectives of the illness in order to better evaluate their options. Physicians, in turn, must convey and communicate information clearly in order to avoid misunderstandings and consequently poor medical care. The patient-physician relationship in cancer care is extremely delicate due to the complexity of the disease. In cancer diagnosis, the physician must adopt a communicative approach that considers the psychosocial factors, needs and patient’s preferences for information,which in turn all contribute to affect clinical outcomes. Search Strategy and Methods : This review was conducted using the Preferred Reporting Items for Systematic and Meta-analyses (PRISMA) statement. We included studies on the importance of physician-patient communication in Acute Myeloid Leukaemia and Myelodysplastic Syndrome care. We searched PubMed, Web of Sciences, Scopus, Google scholar for studies published from December 1 st , 2020 up to March 1 st , 2021. Using MeSH headings, we search for the terms “Physician and patient communication AND Acute Myeloid leukemia” or “Myelodysplastic syndrome” or “Doctor” or “Clinician”, as well as variations thereof . Purpose of the Review : This review examines the progress in communication research between patient and physician and focuses on the impact of communication styles on patient-physician relationshipin hematologic cancers, including Acute Myeloid Leukaemia and Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and blood cytopenia with a variable risk of progression to acute myeloid leukemia. The main goal of therapy for the large majority of patients is to improve health-related quality of life (HRQoL). Its rigorous assessment is now recommended in international MDS guidelines. Our review provides an overview of HRQoL results from randomized controlled trials (RCTs) in MDS patients. The literature search undertaken in PubMed identified 10 RCTs with HRQoL endpoints (all secondary) published between August 2008 and September 2020. These RCTs have helped to better understand the impact of therapies from the patient perspective and have generated valuable information that can be used to further support clinical decisions. However, the number of RCTs in MDS patients, including HRQoL endpoints, is still low. Given the importance of symptom relief and HRQoL improvement in the treatment of MDS patients, the assessment of the patient perspective in future RCTs is highly recommended to keep expanding the knowledge of the impact of new MDS therapies.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, small vessel, necrotizing vasculitis. The disease is mainly characterized by hypereosinophilia and asthma with frequent sinonasal involvement, although multiple organs can be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. IL-5 production is pathogenetically central for the development of the disease by promoting proliferation, transvascular migration and functional activation of eosinophils. The degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis and eosinophil depletion represents a promising treatment approach for EGPA. We prospectively evaluated the efficacy and safety of a low dose (100 mg q4w), 12-month course of mepolizumab, an anti-IL-5 monoclonal antibody, in eight patients with severe asthma and active EGPA. Patients were recruited by the tertiary care center of Clinical Immunology and Allergy, University of Naples Federico II. The following outcomes were assessed before (T0), and after 6 (T6) and 12 months (T12) of mepolizumab treatment: Birmingham Vasculitis Activity Score (BVAS), prednisone intake, Sino-Nasal Outcome Test (SNOT-22), Total Endoscopic Polyp Score (TENPS), Asthma Control Test (ACT), Forced Expiratory Volume one second (FEV1)%, blood eosinophilia. BVAS score significantly decreased showing a sharp reduction in disease activity score. Clinical improvements in terms of sinonasal scores and asthma symptoms were observed, in parallel with a drastic drop in eosinophil blood count. Prednisone intake was significantly reduced. In two patients, asthma exacerbations led to discontinuation in mepolizumab therapy after 6 and 12 months despite BVAS reduction. Mepolizumab treatment was well tolerated, and no severe adverse drug effects were registered. In conclusion, our 12-month real-life study suggests that mepolizumab may be beneficial and safe in active EGPA patients by improving disease activity score, sinonasal and asthma outcomes while reducing the burden of prednisone intake.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

Differentiation syndrome (DS), previously known as retinoic acid syndrome or ATRA (all-trans retinoic acid) or ATO (arsenic trioxide) syndrome, is a life-threatening complication of the therapy with differentiating agents in patients with acute promyelocytic leukemia (APL). The latter is a rare subtype of acute myeloid leukemia and represents a hematological emergency. The clinical manifestations of DS, after induction therapy with differentiating agents, include unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure and acute renal failure. The therapy is based on early intravenous administration of high-dose dexamethasone, in order to counteract the cytokine storm responsible for the DS. Among the supportive measures for the management of DS, furosemide (in 87% of patients) and dialysis (12% of patients) are used to manage acute renal failure, peripheral and pulmonary edema. We describe a case of acute renal failure, treated with haemodialysis, in a young patient with APL and an early and severe DS after induction therapy. This is a rare condition, not well known among nephrologists, where early recognition and treatment are crucial for the prognosis.

Objective: Aims of the present study were to investigate the association between awareness of own illness condition and psychological outcome in end-of-life phase and to test the association between the spirituality and the awareness of own illness condition. Methods: Three hundred and ninety-nine terminally ill patients with cancer were enrolled in a hospice in central Italy. One hundred patients satisfied the inclusion criteria. The Systems of Belief Inventory, the Hospital Anxiety and Depression Scale, and a psychological interview to determine the level of awareness of the illness diagnosis (aware; partially aware; and not aware) were administered to terminally ill patients. Results: The main finding was that the awareness of one’s own illness condition was positively associated with the extrinsic spirituality and negatively associated with intrinsic spirituality (regression model R = .26; R2 = .07; adjusted R2 = .05; F2, 97 = 3.45; P = .036). The aware group showed lower anxiety and depression ( F2, 97 = 1.9; P = . 075; F2, 97 = 2.6; P = .04) scores than partially aware and not aware groups. The psychological outcome was not associated with the spirituality level. Conclusion: In terminally ill patients with cancer, the levels of depression and anxiety were lower in patients aware of their own illness state. Moreover, higher levels of extrinsic and lower levels of intrinsic spirituality predicted the awareness of one’s own illness state.

No robust biomarkers have been yet validated to identify the recurrence of disease in classical Hodgkin Lymphoma (cHL) patients upon induction treatment. The relevance of the inflammatory microenvironment in cHL prompted us to investigate the key immunomodulator myeloid dendritic cells type-1 (mDC1), type-2 (mDC2) and plasmacytoid dendritic cells (pDC). Blood DC levels were assessed in 52 newly diagnosed patients through multiparametric flow-cytometry. All but two patients received ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The median counts of all DC subsets were lower in cHL patients than in healthy controls (P < 0·001). Median mDC counts were inferior for the advanced vs early stage patients for both mDC1s and mDC2s (P = 0·008; P = 0·0007 respectively). Also, median mDC2 counts were reduced in case of bulky (P = 0·0004) and extra-nodal (P = 0·046) disease. Patients with B symptoms had lower levels for mDC1s (P = 0·046), mDC2s (P = 0·009) and pDCs (P = 0·040). All the DC subtypes increased at the end of treatment in 26 patients (P < 0·001): 4·6-fold for mDC1, 2·4-fold for mDC2, 4·5-fold for pDC and aligned DCs subsets with the reference frequencies and the interquartile ranges of the controls. In conclusion, DCs may contribute to the disturbed immunological interplay typical of cHL, prompting a further evaluation of their value as a potential new biomarker.

We have analyzed the effects of environmental enrichment (EE) in a seizure-prone mouse model in which the genetic disruption of the presynaptic protein Bassoon leads to structural and functional alterations in the hippocampus and causes early spontaneous seizures mimicking human neurodevelopmental disorders. One-month EE starting at P21 reduced seizure severity, preserved long-term potentiation (LTP) and paired-pulse synaptic responses in the hippocampal CA1 neuronal population and prevented the reduction of spine density and dendrite branching of pyramidal neurons. These data demonstrate that EE exerts its therapeutic effect by normalizing multiple aspects of hippocampal function and provide experimental support for its use in the optimization of existent treatments.

Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2–P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2–P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors.

The aim of the study was to test whether high levels of caregiver burden, as other confirmed predictors, are associated with the risk of prolonged grief disorder in caregivers of terminally ill patients. A predictive study was carried out in order to test the hypothesis. A demographic schedule, the Prolonged Grief 12 (PG-12), the Toronto Alexithymia Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Caregiver Burden Inventory were administered to 60 caregivers of 51 patients who were admitted in Hospice. In the regression analysis, difficulty in recognizing emotions, total burden, depression, and developmental burden dimension were significant predictors of PG-12 levels. Findings showed that feeling of deprivation of existential expectations represents the greater risk factor for the prolonged grief disorder, among the burden dimensions.

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.

Specific trials on adult Burkitt lymphoma (BL) and 'unclassifiable' lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60years) with BL (n=15) and BL/DLBCL (n=15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60years as compared to younger ones (49%vs 93%, P=0·03; median, 36months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.

Non-Hodgkin lymphomas arising from mature post-thymic T cells (T-NHL) encompass biologically heterogeneous malignancies with a dismal prognosis (1, 2). Patients with histotypes such as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL), angioimmunoblastic T-cell lymphoma, and Sezary syndrome (SS) experience early disease recurrence with 5-yr overall survival rates rarely exceeding 40%, also because of the lack of effective salvage strategies (1–3). While the biologic basis of T-NHL aggressiveness is under extensive research, investigation into novel active agents remains a critical need, especially in the setting of stem cell transplantation ineligibility/failure and end-stage disease (2, 4). Fotemustine is a third-generation chloroethylnitrosourea displaying a significant clinical efficacy in highly chemoresistant cancers such as disseminated melanoma and primary or metastatic brain tumors (5–9). While second-generation nitrosoureas have been incorporated into standard and high-dose salvage regimens for NHL, including T-cell subtypes (10–13), the activity of fotemustine in lymphoma has been poorly explored, despite its lower hepatic and renal toxicity, as compared to congener agents, and several more favorable pharmacodynamic properties (14, 15). First, the presence of a phosphoalanine carrier group renders fotemustine more lipophilic because its octanol/water partition coefficient results within the optimal lipophilicity interval, differently from both carmustine and lomustine (16, 17). Second, preclinical studies on rat and human tissues have shown that intracellular penetration of fotemustine is superior to that of carmustine (18, 19). Third, studies have documented that fotemustine is cleared 2–5 times more slowly than carmustine from tumor tissues (17–19). The higher lipophilic properties, the more efficient tissue distribution, and slower elimination of fotemustine from tumor tissues, as compared to other nitrosoureas, might provide a preclinical rationale for testing this drug in chemorefractory lymphomas. Because normal and malignant T cells express a low level of O6-alkylguanine-DNA alkyltransferase (AGT) and of O6-methylguanine-DNA methyltransferase (MGMT) (20, 21), two DNA repair enzymes implicated in cellular resistance to nitrosureas, and specifically to fotemustine (22–25), we speculated that alkylator-refractory T-NHL could represent a proper setting to explore the potential clinical activity of this newer nitrosourea derivative. Here, we report the first evidence ever that fotemustine is able to induce substantial clinical responses in patients with post-thymic T-cell malignancies.

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high ‘life threat’ impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73 years, range: 62–82; 37% >75 years) at a median interval of 15·6 (range, 13–29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n = 3), therapy discontinuations (no-response n = 2; toxicity n = 6), relapse (n = 6) and death in CR (n = 3). Incidence of cardiac grade 3–5 adverse events was 7/41 (17%; 95% confidence interval: 8–31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P = 0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P = 0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.

The proposal of persistent complex bereavement disorder (PCBD) in the DSM-V increased the interest on the impact of grief on the psychological health.Investigating the time course of psychological symptoms, emotional and social abilities in caregivers (undergoing or not to supportive-expressive treatment) of terminally ill cancer patients from 1 months before loss to 14 months after it.Thirty-three of 60 caregivers were assessed by PG-12, HAM-A, HAM-D, TAS-20 and ASQ, at the admission in Hospice, and after 3, 10 and 14 months from the loss. Twelve caregivers adhered to follow a supportive-expressive treatment and 21 caregivers did not.PG-12, anxiety, and depression scores decreased in both groups over time. The score of difficulty in identifying emotions and confidence with closeness decreased significantly only in the treated-group. PG-12 score at T0 was able to predict the DSM V diagnosis of PCBD at T3.Findings showed a decrease of the anxiety, depression, security in the attachment style and an increase of the ability to identify emotions during the first year after loss in caregivers of terminally ill cancer patients. Pre-loss assessment of prolonged grief risk seems useful to predict the diagnosis of PCBD 1 year after loss.

The new regional landscape plan comes as the implementation of the PIT (Territorial Address Plan of Region) as pursuant to art. 143 of the Codice dei beni culturali e del paesaggio and to art. 33 of L.R. n. 1/2005 Norme per il Governo del Territorio (Rules for the Government of the territory). The plan consists of three main parts: Plan Document, Discipline landscape, knowledge chart., Ri-Vista, Vol 8 No 1 (2010)

The Sardinia Landscape Plan (PPR) is the first unitary Plan concerning the regional landscape. This is also the first time that a Landscape Plan involves the whole regional territory in a single process of knowledge and management of strategic resources. Moreover, the PPR represents a new experience thanks to its innovative approach towards the urban development., Ri-Vista, Vol 8 No 1 (2010)

Ri-Vista, Vol 10 No 2 (2012)

Introduction Hyperhomocysteinemia is a known risk factor for myocardial infarction, stroke, peripheral vascular disease, and thrombosis. Elevated plasma homocysteine levels have been demonstrated in patients with recurrent episodes or a single episode of thrombosis. Here we describe the development of cardiovascular disease as a complication of a surgical intervention in a patient with colorectal cancer and hyperhomocysteinemia. Case presentation A 65-year-old Caucasian man complained of pain and constipation, attributed to previously diagnosed adenocarcinoma (stage IIB) of the hepatic flexure. An anamnestic investigation showed that he had undergone two surgical interventions. During both, he suffered thrombotic postoperative complications, a deep vein thrombosis of the upper extremity after the first operation and retinal vein occlusion after the second. He was diagnosed with hyperhomocysteinemia associated with a homozygous C677T mutation of the gene encoding the enzyme methylenetetrahydrofolate reductase. Our patient was initially treated with folic acid and high-dose B vitamins. On day 7 he underwent a right hemicolectomy. Anesthesia was performed with sevoflurane in 40% O2 and without the use of nitrous oxide. Postoperatively, our patient remained on folic acid and B vitamins and was without immediate or subsequent complications. Conclusions Neoplastic disease and related surgery followed by the administration of chemotherapeutic drugs alter the hemostatic balance in cancer patients. Those suspected of also having a thrombophilic disease require a thorough laboratory diagnostic workup, including a molecular analysis aimed at identifying the genetic mutation responsible for the hyperhomocysteinemia, as indicated. The case described in this report highlights the importance of a multidisciplinary approach that includes expertise in peri-operative anesthesia, surgery, oncology, and hematology.

Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, “top-down” influences on risk assessment.

Objective: The aim of the present study was to evaluate the predictive role of attachment dimensions on the risk of prolonged grief. Sixty caregivers of 51 terminally ill patients with cancer who had been admitted in a hospice were selected. Methods: Caregivers were interviewed using Attachment Scale Questionnaire, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Prolonged Grief Disorder 12 (PG-12). Results: The consort caregivers showed higher PG-12 level compared to the sibling caregivers. Anxiety, depression, need for approval, and preoccupation with relationships levels were significantly correlated with PG-12 scores. Conclusion: Female gender, high levels of depression, and preoccupation with relationships significantly predicted higher levels of prolonged grief risk.

The role of spirituality on the psychological health was mostly investigated through studies conducted in terminally ill patients. However, there are not studies investigating the role of religious and spiritual beliefs on psychological state and on burden dimensions in caregivers. The purpose of this study was to investigate the association between spirituality, burden, and psychological state in caregivers of terminally ill cancer patients. Two hundred caregivers of terminally ill patients with cancer were interviewed using Prolonged Grief Disorder 12 (PG-12), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Caregiver Burden Inventory (CBI) and System of Belief Inventory (SBI-15R). The caregiver burden was positively correlated with anxiety, depression and PG-12 scores. The intrinsic spirituality was a significant predictor of the time-dependence burden (positively associated); and of the emotional burden (negatively associated). In caregivers of terminally ill cancer patients, higher levels of intrinsic spirituality predicted a higher amount of time devote to caregiving, and also protected against the emotional distress linked to providing assistance.

Florence’s landscape structure has a significant homogeneous status that traces back to medieval times. The introduction of the sharecropping system gave a major impetus to the transformation of such landscape pattern, and the eighteenth and nineteenth centuries saw its completion, from both a technical and aesthetical viewpoint, with the establishment of villas and farmsteads, churches, scattered houses and hamlets crossed by an ample road network and paths traversed by numerous brooks. This economical and social system rapidly imploded after the second half of the twentieth century while the flatland area, which had been governed by the same rules up till then, had seen a wave of disorderly increasing urbanization; considerable parts of ancient settlements in the hilly areas were preserved; thanks to government zoning restrictions aimed at safeguarding natural heritage and local town planning policies that embraced and enhanced such objectives. Now, about 50 years later from these changes, the hilly landscape is starting to show further signs of deterioration, which, if not duly counteracted, could bring about adverse effects in the next few years. In this respect, it is important to raise a new awareness towards this territory, in the light of previous and subsequent land use constraints that entailed a wide range of solutions for the Florence hills parks project, to no great avail however. Besides political and administrative intentions, the involvement of the population is fundamental, given the vital role it shall play in environmental education programs especially for children, in line with the European Landscape Convention.

Mourning is a natural response to a loss and a condition which most people experience several times during their lives. Most individuals adjust adequately to the loss of a relative, neverthless, a small but noteworthy proportion of bereaved individuals experience a syndrome of prolonged psychological distress in relation to bereavement. Prolonged distress and disability in connection with bereavement has been termed Complicated Grief (CG) or Prolonged Grief Disorder (PGD). The purpose of this paper is to analyze the literature on loss and mourning making a review of the main studies published between 1993 and 2013, identified through a search conducted on Medline/PubMed, in order to describe the epidemiological and clinical aspects of "normal" grief and "complicated" grief, pointing out the path of the clinical definition of PGD and proposed diagnostic criteria for inclusion in the next edition of the Diagnostic and Statistic Manual of Mental Disorders, Fifth edition (DSM-5). The two main diagnostic systems proposed by Horowitz and Prigerson are also compared.

This study provides the first experimental evidence that a single nucleotide mutation within the coding region of the β-globin gene affects mRNA expression levels and causes a β-thalassemic defect. Furthermore, our data suggest that other regions besides the 3′UTR, whose role in constitutively regulation of this mechanism has been recently identified, may contribute to the stabilization of β-globin mRNA and could, therefore, help to characterize the molecular basis of thalassemic hemoglobinopathies.

Parkinson's disease (PD) patients exhibit motor and non-motor symptoms that severely affect quality of life. Cognitive alterations in PD subjects have been related to both structural and functional hippocampal changes. Here we investigated the effects of the 6-hydroxydopamine (6-OHDA) lesion in the Medial Forebrain Bundle (MFB) on the hippocampus focusing on the Dentate Gyrus (DG). In vivo microdialysis measurements revealed that the 6-OHDA injection disrupts both dopaminergic and noradrenergic transmission in rat DG. In vitro electrophysiological recordings showed that these neurochemical alterations were accompanied by impairment of long-term depression (LTD) at medial perforant path/DG synapses. Furthermore, this alteration was reversed by l-DOPA treatment. Notably, the therapeutic effect of l-DOPA on LTD was blocked by the antagonism of β-noradrenergic receptors, but not by dopamine D1 or D2 receptor antagonists. Thus, while the dopaminergic transmission does not seem to be implicated in this therapeutic effect of l-DOPA, the noradrenergic system plays a central role in the synaptic dysfunction of the DG in experimental PD. Our work provides new evidence on the role of catecholamines in DG synaptic plasticity and sheds light on the possible synaptic mechanisms underlying cognitive deficits in PD. Furthermore, our results indicate that l-DOPA exerts a therapeutic effect on the parkinsonian brain through different, coexistent, mechanisms.

Specific trials on adult Burkitt lymphoma (BL) and 'unclassifiable' lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40%60years) with BL (n=15) and BL/DLBCL (n=15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60years as compared to younger ones (49%vs 93%, P=0·03; median, 36months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.

Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits throughl-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy.

Patients with recurring T-cell non-Hodgkin lymphoma (T-NHL) are incurable and candidate for investigational agents. Here, we report on five patients with T-NHL refractory to multiple chemotherapy lines, including in all cases alkylators and gemcitabine, who received the third-generation chloroethylnitrosourea fotemustine at a dose of 120 mg/m(2) every 21 d, up to eight courses. Median actual dose intensity was 79%; toxicity was manageable and mainly hematological. One complete remission, one partial remission, two protracted disease stabilization, and one transient, minor response were achieved. Time to progression ranged from 48 to 240+ d. This is the first evidence ever reporting the activity of fotemustine in end-stage T-NHL. Formal studies with this agent are warranted in T-cell malignancies.

Identification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of κ and λ serum-free light chain ratio [sFLC (κ/λ)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(κ/λ), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC(κ + λ)], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC(κ + λ) above cut-off displayed a poorer TFS outcome, irrespective of sFLC(κ/λ). Only ZAP-70, cytogenetics, stage, and TFS remained associated with sFLC(κ + λ) in a multivariate model. By assigning 1 point each for these variables, the 3-year probability of TFS was 94.8%, 84.5%, 61.6%, and 21.1% for patients scoring 0, 1, 2, and 3 + 4, respectively (P < .0001). These data, and the demonstration that monoclonal and polyclonal B cells concur to FLC synthesis in tumor tissues, suggest that sFLC(κ/λ) and sFLC(κ + λ) mirror distinct biologic processes in CLL. sFLC(κ + λ) assessment represents a sensitive and cost-effective tool for identifying CLL patients requiring early treatment.

Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5-htt+/−), and serotonin transporter deficient (5-htt−/−) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt−/− > 5-htt+/− > 5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt−/− mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt−/− displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offers the possibility for future investigation of the neural basis underlying 5-htt genotype by stress interaction demonstrated here.

Although the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT > 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.

Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica, No 1 (2008): The bridge in space and time to overcome urban barriers

Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whetherin uteroexposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

Background Improving strategies for patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) who fail stem cell transplantation (SCT) or are unsuitable for the procedure remains an essential need. Lenalidomide and bendamustine are active and well tolerated as single agents in recurrent HL, with overall response rates (ORR) of 30% to 53% [Fenhinger, 2012; Corazzelli, 2012; Moskowitz, 2012].These agents independently frame different targets on tumor and microenvironment cells and may cooperate to override disturbed immunologic pathways and circumvent drug resistance in HL. In a Bayesian, multi-center, open label phase 1/2 study, we investigated for safety and efficacy the combination of continuous lenalidomide with weekly bendamustine (ClinicalTrials.gov # NTC01412307). Methods The study aimed at defining the optimal daily dose of continuous lenalidomide (10, 15, 20 or 25 mg) as combined, in a 28-day cycle, to weekly fixed-dose bendamustine (60 mg/m2; d 1, 8, 15). The dose-finding algorithm proceeded in cohorts of 3 pts, based on anticipated efficacy and toxicity pairs of probability (Thall & Cook, Biometrics 2004). Trade-offs between response [Cheson 2007 criteria] and dose-limiting toxicity [CTCv3.0 grade (G) >3 lasting >2 weeks] were assessed after 2 cycles (day +56) and pts were planned to receive up to 6 total courses, unless progression or unacceptable toxicity occurred. ORR and progression-free survival (PFS) were additional endpoints. Results Thirty-six pts (69% male) with a median age of 31 yrs (r 19-75) were enrolled. The median number of prior therapies was 4 (r 1-9) and the median time from upfront treatment was 24 mo.s (r 7-118). Twenty-six pts (72%) had primary refractory disease after ABVD, 16 pts (44%) failed prior SCT [single (n=7) or tandem (n=3) ASCT, tandem ASCT/alloSCT (n=6)]. Fifteen pts (42%) had previously received a median of 5 cycles (r 2-8) of brentuximab vedotin (BV) and 3 pts were already given bendamustine (>3 courses). Overall, 23 pts (64%) were refractory to most recent therapy. Eff/Tox trade-offs at cycle 2 showed that 73% of pts had response w/o toxicity, 19% had no response w/o toxicity, 6% had response with toxicity and 2% had no response with toxicity. With such Eff/Tox profiles, the study algorithm did not prompt any dose escalation for lenalidomide after the first 18 pts and the initial dose level (10 mg) was adopted for the expansion phase. A total of 156 LeBen cycles were administered, and pts received a median of 4 courses (r 1-6). Overall, 16 cycles were delayed due to G3/G4 thrombocytopenia (n=6), G4 neutropenia (n=3), G3 pneumonia (n=3), G3 respiratory infection (n=2), G2 phlebitis (n=1), G2 supraventricular arrhythmia (n=1). Two patients discontinued treatment, while in PR and CR after 4 courses, due to protracted (>2 weeks) thrombocytopenia. No G4 extra-hematological toxicity was observed. The complete response (CR) rate was 44% (16/36) with an ORR of 75% (27/36; 95% CI, 59-86). Notably, substantial CR and PR rates were achieved after LeBen regardless of primary refractoriness, SCT and BV failure (Table). Most CRs (14/16) were obtained within the first 4 cycles; 6 responders (4 CRs and 2 PRs) underwent SCT. Median PFS was 3.2 mo.s (r 1.5-5.4) for pts with progressive (PD) or stable disease (SD) and 11.4 mo.s (r 4-31) for those achieving CR/PR. Median overall survival for the entire cohort was 24 mo.s. Overall, complete responders (including 6 pts consolidated with SCT) had a 2-year disease-free survival of 41% (median, 14.3 mo.s). Conclusions The innovative schedule of the Leben combination is safe, yields high response rates in heavily pretreated and primary refractory HL pts, including SCT and BV failures, and steps over the 'single agent' activity of its components. Due to its immunomodulatory potential the Leben platform is amenable to further upgrading through lenalidomide maintenance, combination with immune checkpoint inhibitors and BV. | Responses no. (%) | All pts | Refractory to upfront therapy | Refractory to most recent therapy | Failure after SCT | Failure after ASCT | Failure after AlloSCT | Failure after BV | Failure after SCT and BV | Failure after bendamustine | No BV | | ------------------------ | ------- | ----------------------------- | --------------------------------- | ----------------- | ------------------ | --------------------- | ---------------- | ------------------------ | -------------------------- | ------- | | (n=36) | (n=26) | (n=23) | (n=16) | (n=10) | (n= 6) | (n=15) | (n=8) | (n=3) | (n=21) | | CR | 16 (44) | 11 (42) | 8 (35) | 8 (50) | 6 (60) | 2 (33) | 5 (33) | 3 (37) | | 11 | | PR | 11 | 8 | 9 | 4 | 2 | 2 | 4 | 2 | | 7 | | SD | 2 | 2 | 2 | 1 | | 1 | 1 | 1 | 1 | 1 | | PD | 7 | 5 | 4 | 3 | 2 | 1 | 5 | 2 | 2 | 2 | | CR+PR | 27 (75) | 19 (73) | 17 (74) | 12 (75) | 8 (80) | 4 (66) | 9 (60) | 5 (62) | | 18 (86) | Table 1. Efficacy results Disclosures Pinto: Takeda, Celgene, Roche, TEVA: Honoraria; Takeda: Research Funding. Zinzani: Takeda: Membership on an entity's Board of Directors or advisory committees; JJ Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Background: Given the consistent antitumor activity and favorable toxicity profile in heavily pretreated patients, BDM represents a suitable platform for combination with target-based agents in the setting of recurrent HL. The anti-CD30 antibody-monomethyl auristatin E (MMAE) conjugate brentuximab vedotin (BV) appears a most valuable candidate by coupling an impressive clinical activity with the lack of serious overlapping toxicities with BDM. While the combination of BDM and BV is being evaluated in Phase II studies, no information is available as to possible mechanisms through which BDM may regulate the antitumor efficacy of BV towards HL cells. Methods: We evaluated the effects of acute and extended exposure to BDM on CD30 expression and sensitivity to the cytotoxic activity BV in the HL cell line L1236. Cells were cultured in the presence of BDM at its IC50 for different time points of acute exposure. Through continuous exposure to increasing concentrations (25.0, 50.0, 75.0, 100 micromol/L) of BDM, we then performed a serial in vitro selection for BDM-resistant (R) L1236 cell clones and determined their CD30 expression by flow cytometry, qRT-PCR, and Western analysis. Results: Acute exposure to BDM (48 to 72 hrs) of L1236 cells led to a sizeable upregulation of CD30 as shown by flow cytometry. This effect was unsustained since CD30 intensity returned to baseline levels upon culturing in BDM-free medium for one week. Expression of other surface antigens, i.e. HLA-DR, was unaffected by BDM while acute exposure to doxorubicin and other cytotoxic drugs did not modify the CD30 expression. We established four L1236-derived cell clones (R25, R50, R75 and R100) able to proliferate across the different concentrations of BDM with growth/viability curves superimposable to native cells. Clonal identity among clones and with parental cells was confirmed by sequencing of V3-21 (FR2/FR3) and JH3-JH4 Ig DNA regions. All R-clones displayed an up to 900% increase in CD30 median fluorescence intensity, relative to native L1236 cells (Figure 1A). The sustained CD30 upregulation was confirmed by qRT-PCR and Western blotting since R-clones expressed up to 10-fold higher levels of CD30-specific mRNA and CD30-specific 120 kDa components as compared to parental cells. To rule out a general upregulation of surface molecules as a result of the chronic exposure to BDM we evaluated the expression of other surface antigens. As opposed to CD30, HLA-DR and PDL-1 relative transcript levels and cell surface expression were significantly reduced in R-cells. Intriguingly, BDM-induced CD30 upregulation was specific to L1236 cells since extended exposure to BDM did not modify expression levels of CD30 in other lymphoma cell types (SUDHL1, JEKO). BDM-induced CD30 overexpression significantly enhanced the sensitivity of HL cells to the cytotoxic effects of BV. MTS assay showed the IC50 of R100 cells to BV shifted to 0.21 ± 0.06 mcg/mL (48 hrs) and 0.19 ± 0.05 mcg/mL (72 hrs) vs. 3.16 ± 0.75 mcg/mL (48 hrs) and 3.87 ± 0.68 mcg/mL (72 hrs) of parental cells, a 15- and 20-fold increase, respectively (p Conclusions: Whileacute exposure to BDM induced a transient upregulation of CD30, extended exposure to the agent resulted in the selection of L1236 subclones with a stable overexpression of surface CD30 and reduced levels of HLA-DR and PDL-1. Upregulation of CD30 was associated with a significantly enhanced sensitivity to cytotoxic effects of BV. Translated into a clinical context these findings suggest that HL patients progressing upon BDM treatment may turn exquisitely sensitive to BV and prompt the exploration of a sequential treatment with BDM and BV in late and earlier disease phases. Results also provide a mechanistic insight as to the efficacy of the BDM-BV combination in HL, highlighting non-overlapping resistance pathways between BDM and MMAE. BDM-induced selection of CD30hi, HLA-DRlow/PDL-1low tumor cell clones might be relevant to the design of novel treatment strategies for HL based on the combination of BDM with BV and anti-PD1/PDL-1 antibodies. Figure 1. Expression of CD30 and HLA-DR in parental (L1236) and BDM-resistant (R) HL cells Figure 1. Expression of CD30 and HLA-DR in parental (L1236) and BDM-resistant (R) HL cells Figure 2. Sensitivity to BV of parental (L1236) and BDM-resistant (R100) HL cells Figure 2. Sensitivity to BV of parental (L1236) and BDM-resistant (R100) HL cells Disclosures Pinto: Takeda: Research Funding; Takeda, Celgene, Roche, TEVA: Honoraria.

La presente ricerca ha come oggetto la progettazione delle grandi infrastrutture viarie, solitamente autostrade o superstrade, quali casi limite del controverso rapporto infrastruttura/paesaggio. Nel ripercorrere circa un secolo di realizzazioni e di teorie dal punto di vista del paesaggio, paesaggio inteso appunto nel suo significato più ampio e di sistema, e in tutti i suoi aspetti culturali, ecologici e percettivi, il fine è quello di individuare una metodologia, o più precisamente una filosofia progettuale di base, utile ad indirizzare le trasformazioni indotte in termini qualitativi: infrastruttura quindi non più in oggetto contrapposizione al paesaggio ma parte integrante di esso.