Immune Checkpoint Inhibitor-Induced Pancreatic Injury: Imaging Findings and Literature Review.

The immunotherapy revolution in cancer treatment involves a variety of specialists, not only oncologists, but also internal medicine physicians, endocrinologists, dermatologists, gastroenterologists, rheumatologists, and radiologists, introducing new scenarios and novel challenges in the diagnosis and management of a number of novel immune-related adverse events. Among these, immune checkpoint inhibitor-induced pancreatic injury has been described (occurring in up to 4% of patients) and has been reported to be responsible for visits to the emergency departments in up to 1.9% of patients treated with immune checkpoint inhibitors. This side effect can be symptomatic or non-symptomatic, and can be associated with the development of long-term damage to the pancreas, requiring the involvement of different specialists, including radiologists and gastroenterologists in the multidisciplinary team that manages these patients. The aim of this narrative review is to provide a summary of the available literature related to immune checkpoint inhibitor-induced pancreatic injury including the epidemiology, the clinical findings, and the management algorithm for diagnosis with a detailed analysis of the differential diagnosis at imaging, and treatment. A more in-depth focus is dedicated to symptomatic acute pancreatitis with its peculiar findings at imaging (ultrasound, computed tomography, and magnetic resonance imaging).

Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features.

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care.

Corrigendum: Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study.

[This corrects the article on p. 386 in vol. 8, PMID: 28446908.].

Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study.

Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.

Prognostic significance of hematological profiles in melanoma patients.

Cancer-related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000-2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre-operative blood tests were analyzed. Survival was estimated with the Kaplan-Meier method, and analyzed using Log-rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I-III patients. Furthermore, at a single-patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p < 0.0001) and LMR (p = 0.005) were all significantly associated with survival, independently of other known prognostic factors. These results suggest that cellular components of peripheral blood do count for survival of patients with advanced melanoma.

The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment.

Germline BAP1 (BRCA1-associated protein-1) mutations are involved into a novel specific cancer syndrome and strictly associated with a high cancer susceptibility. Recent data suggest that BAP1 has activity toward target substrates explaining why loss of BAP1 causes a pro-tumorigenic deregulation of gene expression. The recently published data reviewed raise the hypothesis that BAP1 regulates a common subset of substrates, which in turn causes a pro-tumorigenic deregulation of gene expression, and alternatively suggest the role of BAP1 as tumorigenesis suppressor/promoter also by independent mechanisms. The clinical phenotype of BAP1 alterations includes MBAITs (melanocytic BAP1-mutated atypical intradermal tumors), uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), mesothelioma (MM), and possibly several other tumors. In clinical practice, early diagnosis is crucial for curative resection of all these tumor types. The uniformed and unambiguous definition of MBAITs as clinical/pathological predictive markers could provide physicians means to identify patients who may carry germline BAP1 mutations and thus could be at high risk of developing CM, UM, MM, RCC, and possibly other tumors. As part of a novel multidisciplinary approach, physicians, pathologists, and clinicians involved into diagnostics should be aware of the histological features and the spectrum of tumors associated with BAP1 loss. Further clinical, epidemiological, and functional studies are required to fully explain the roles of BAP1 and its interaction partners in neoplasia, to define mechanisms behind shared and non-shared clinical and pathological criteria.

Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity.

Nicergoline, a drug used for the treatment of Alzheimer's disease and other types of dementia, was tested for its ability to protect neurons against beta-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of beta-amyloid peptide (betaAP(25-35)) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha1-adrenergic receptor antagonist, prazosin, or the serotonin 5HT-2 receptor antagonist, methysergide, were inactive. Nicergoline increased the basal levels of Bcl-2 and reduced the increase in Bax levels induced by beta-amyloid, indicating that the drug inhibits the execution of an apoptotic program in cortical neurons. In mixed cultures of rat cortical cells containing both neurons and astrocytes, nicergoline and MDL were more efficacious than in pure neuronal cultures in reducing beta-amyloid neurotoxicity. Experiments carried out in pure cultures of astrocytes showed that a component of neuroprotection was mediated by a mechanism of glial-neuronal interaction. The conditioned medium of cultured astrocytes treated with nicergoline or MDL for 72-96 h (collected 24 h after drug withdrawal) was neuroprotective when transferred to pure neuronal cultures challenged with beta-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-beta and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against beta-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.

Chronic reboxetine desensitizes terminal but not somatodendritic alpha2-adrenoceptors controlling noradrenaline release in the rat dorsal hippocampus.

The slow onset of antidepressant drugs' effects is thought to reflect the time required for the development of adaptive changes such as desensitization of presynaptic autoreceptors controlling the release of neurotransmitters. Using in vivo microdialysis in conscious rats, we studied the effect of a continuous infusion of the selective noradrenaline (NA) reuptake inhibitor reboxetine on extracellular concentrations of NA. Doses of 10 mg/kg/day reboxetine through subcutaneous osmotic pumps for 2 days increased extracellular NA by 272% in the dorsal hippocampus (DH) of rats. NA rose significantly more in rats given reboxetine for 7 (469%) and 14 (437%) days. Intraperitoneal injection of 30 microg/kg clonidine, an alpha2-adrenoceptor agonist, reduced the release of NA to 49% of basal levels in rats given vehicle or reboxetine for 2 days, but this effect was markedly less in rats given reboxetine for 7 and 14 days. Likewise, the effect of intrahippocampal infusion of clonidine (0.05 and 0.2 microM) on extracellular NA was significantly attenuated in rats given reboxetine for 7 and 14 days, whereas the injection of 0.6 nmol clonidine into the locus coeruleus caused similar reductions of extracellular NA in the DH and prefrontal cortex (PFC) of rats infused with vehicle (DH -64%; PFC -42%) and reboxetine (DH -45%; PFC -28%) for 14 days. The results indicate that chronic treatment markedly enhances the effect of reboxetine on extracellular NA in the DH and suggest that this effect may be due to the desensitization of hippocampal alpha2-adrenoceptors.

Nicergoline reverts haloperidol-induced loss of detoxifying-enzyme activity.

We evaluated the effects of nicergoline on antioxidant defense enzymes (detoxifying enzymes), during chronic treatment with haloperidol in rats. Chronic use of haloperidol (10 weeks, 1.5 mg/kg/day) induces a significant decrease in glutathione reductase, glutathione peroxidase and superoxide dismutase activity, in selected areas of the brain. Co-administration of nicergoline (20 days, 10 mg/kg/day) significantly restored the activity of these enzymes to levels comparable to those observed in control rats. These observations suggest beneficial effects of nicergoline in the prevention and in the treatment of haloperidol-induced side effects.

The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study.

OBJECTIVES: Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease. STUDY DESIGN AND METHODS: This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group. RESULTS: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. CONCLUSION: This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.

Cabergoline protects SH-SY5Y neuronal cells in an in vitro model of ischemia.

Dopamine receptor agonists are protective in different models of neurodegeneration by both receptor-dependent and -independent mechanisms. We used SH-SY5Y cells, differentiated into neuron-like type, to evaluate if cabergoline, a dopamine D2 receptor agonist endowed with anti-oxidant activity, protects the cells against ischemia (oxygen-glucose deprivation model). Cabergoline protected the cells from ischemia-induced cell death in a concentration-dependent manner (EC(50)=1.2 microM), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and fluorescein diacetate-propidium iodide staining. This effect, observed even when the drug was added after oxygen-glucose deprivation, was not mediated by either dopamine D2 receptor activation or anti-apoptotic Bcl-2 protein over-expression (Western blotting analysis), but was linked to a reduction in cellular free radical loading (2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining) and membrane lipid peroxidation (thiobarbituric acid-reacting test). In conclusion, cabergoline protects in vitro neurons against ischemia-induced cell death, suggesting its possible use in the therapy of other neurodegenerative diseases in addition to Parkinson's disease.

[1-13C]Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats. A study of the effects of nicergoline treatment by 13C NMR spectroscopy.

Age-related changes in glucose utilization through the TCA cycle were studied using [1-13C]glucose and 13C, 1H NMR spectroscopy on rat brain extracts. Significant increases in lactate levels, as well as in creatine/phosphocreatine ratios (Cr/PCr), and a decrease in N-acetyl-aspartate (NAA) and aspartate levels were observed in aged rat brains as compared to adult animals following glucose administration. The total amount of 13C from [1-13C]glucose incorporated in glutamate, glutamine, aspartate and GABA was significantly decreased in control aged rat brains as compared to adult brains. The results showed a decrease in oxidative glucose utilization of control aged rat brains. The long-term nicergoline treatment increased NAA and glutamate levels, and decreased the lactate levels as well as the Cr/PCr ratios in aged rat brains as compared to adult rats. The total amount of 13C incorporated in glutamate, glutamine, aspartate, NAA and GABA was increased by nicergoline treatment, showing an improvement in oxidative glucose metabolism in aged brains. A significant increase in pyruvate carboxylase/pyruvate dehydrogenase activity (PC/PDH) in the synthesis of glutamate in nicergoline-treated aged rats is consistent with an increase in the transport of glutamine from glia to neurons for conversion into glutamate. In adult rat brains, no effect of nicergoline on glutamate PC/PDH activity was observed, although an increase in PC/PDH activity in glutamine was, suggesting that nicergoline affects the glutamate/glutamine cycle between neurons and glia in different ways depending on the age of animals. These results provide new insights into the effects of nicergoline on the CNS.

Cabergoline prevents necrotic neuronal death in an in vitro model of oxidative stress.

To study if cabergoline, a long-lasting specific dopamine D2 receptor agonist, has neuroprotective effects against oxidative stress, we exposed (3 h) SH-SY5Y human neuroblastoma cells to tert-butylhydroperoxide (t-BOOH; 500 microM). t-BOOH caused a 42+/-4% neuronal death, which was prevented by cabergoline (2 h before) in a concentration-dependent manner (EC(50): 1.24 microM). This effect was not antagonised by haloperidol (concentration up to 10 microM), and was associated with an increased availability of intracellular GSH contents (+30+/-11%) and a decrease in the membrane lipid peroxidation (-23+/-9%). Our data suggest that cabergoline has neuroprotective effects useful for Parkinson's disease therapy.

Antioxidant properties of MDL and MMDL, two nicergoline metabolites, during chronic administration of haloperidol.

We evaluated the effects of 10-alpha-methoxy-9,10-dihydrolysergol (MDL) and 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), two nicergoline metabolites, during chronic treatment with haloperidol in rats. Haloperidol induced a significant decrease in the glutathione (GSH) content in selected areas of the brain and in the liver. Prolonged administration of MDL, MMDL or nicergoline antagonized the haloperidol-induced GSH decrease. Lipid peroxidation in the cortex and striatum was suppressed by MDL, MMDL or nicergoline administration. Our results show that MDL, MMDL and nicergoline have antioxidant activity, preventing not only GSH depletion but also lipid peroxidation. These observations suggest beneficial properties of MDL and MMDL in the treatment of neuroleptic-induced side effects.

Plasticity of GABA(a) system during ageing: focus on vestibular compensation and possible pharmacological intervention.

The lesion of the vestibular end organ evokes static and dynamic symptoms, which spontaneously regress during a complex process known as 'vestibular compensation'. Vestibular compensation is age-dependent and involves several transmitter-identified pathways in the central nervous system. In this paper we studied the time course of vestibular compensation in adult (3 months) and old (24 months) rats and correlated behavioral recovery with modifications of glutamic acid decarboxylase (GAD) mRNA expression and benzodiazepine receptor density in different brain areas. Compensation in adult rats was complete 28 days after hemilabyrinthectomy, whereas old rats still showed significant behavioral impairment. A higher GABAergic tone was found in old rats, as indicated by higher benzodiazepine receptor density in lateral vestibular nucleus and higher mRNA level for glutamic acid decarboxylase in cerebral cortex and medial vestibular nucleus. In adult, compensated rats, benzodiazepine receptor density in the vestibular nuclei was normal 28 days after lesion, whereas GAD mRNA level was higher in anterior cingulate cortex, only. On the contrary, these parameters were still altered in anterior cingulate and somatosensory cortex, basal ganglia, vestibular nuclei and cerebellum in old rats 28 days after vestibular lesion. We also evaluated the effect of the ergoline derivative nicergoline on behavioral and neurochemical correlates of vestibular compensation in old rats. Nicergoline treatment attenuated the severity of oculomotor and postural symptoms after vestibular lesion and reversed most of these age- and lesion-induced alterations in GAD mRNA expression. Thus, lesion-related alterations of the GABAergic transmission and behavioral profile after vestibular lesion are age-dependent.