38 research outputs found

    Combination therapy of high-dose rabeprazole plus metronomic capecitabine in advanced gastrointestinal cancer: a randomized phase II trial

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    Abstract: Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose tomodulate tumormicroenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). Methods: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy >3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (50-DFUR and 5-FU) were also evaluated. Results: Sixty-seven (median age 69 years; 63% male; 84% colorectal cancer, 76% ECOG-PS 1; 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant dierence between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53–3.85; p = 0.477), median PFS (HR = 1.22, 95%CI 0.75–2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29–2.44; p = 0.786) and median OS (HR = 0.89, 95%CI 0.54–1.48; p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03–7.79; p = 0.043). Finally, there was not statistically significant dierence in the plasma concentration of capecitabine and its metabolites between the two groups. Conclusions: Although the adjunct of high dose rabeprazole to mCAP was not shown to aect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable

    Brief Tale of a Bacteraemia by Rhodococcus equi, With Concomitant Lung Mass: What Came First, the Chicken or The Egg?

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    Rhodococcus equi is an uncommon Gram positive, variably acid-fast pathogen, that appears as hard to treat mostly owing to the establishment of intracellular niches. Lack of interpretive criteria for susceptibility testing may lead to under-reporting or overestimation of resistances, whereas knowledge about this pathogen’s clinical impact may be affected by erroneous phenotype-based characterization at a genus and species level

    A multi-methodological approach to record dynamics and timescales of the plumbing system of Zaro (Ischia Island, Italy)

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    Determining the time spans of processes related to the assembly of eruptible magma at active volcanoes is fundamental to understand magma chamber dynamics and assess volcanic hazard. This information can be recorded in the chemical zoning of crystals. Nevertheless, this kind of study is still poorly employed for the active volcanoes of the Neapolitan area (Southern Italy), in particular, for Ischia island where the risk is extremely high and this information can provide the basis for probabilistic volcanic hazard assessment. For these reasons, we acquired chemical composition on clinopyroxene crystals erupted at Ischia during the Zaro eruption (6.6 ± 2.2 ka) and performed numerical simulations of the input of mafic magma into a trachytic reservoir, in order to investigate various aspects of pre-eruptive dynamics occurring at different timescales. This event emplaced a ~ 0.1 km3 lava complex, in which the main trachytic lava flows host abundant mafic to felsic enclaves. Previous petrological investigation suggested that mafic magma(s) mixed/mingled with a trachytic one, before the eruption. In this work, the clinopyroxene zoning patterns depict the growth of crystals in different magmatic environments, recording sequential changes occurred in the plumbing system before the eruption. The evolution of the plumbing system involved a hierarchy of timescales: a few hours for magma mingling caused by mafic recharge(s) and likely occurred multiple times over a decade during which a dominant magmatic environment was sustained before the eruption. Such timescales must be considered in volcanic hazard assessment at Ischia and similar active volcanoes in densely populated areas

    Cost effectiveness review of text messaging, smartphone application, and website interventions targeting T2DM or hypertension

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    Digital health interventions have been shown to be clinically-effective for type 2 diabetes mellitus (T2DM) and hypertension prevention and treatment. This study synthesizes and compares the cost-effectiveness of text-messaging, smartphone application, and websites by searching CINAHL, Cochrane Central, Embase, Medline and PsycInfo for full economic or cost-minimisation studies of digital health interventions in adults with or at risk of T2DM and/or hypertension. Costs and health effects are synthesised narratively. Study quality appraisal using the Consensus on Health Economic Criteria (CHEC) list results in recommendations for future health economic evaluations of digital health interventions. Of 3056 records identified, 14 studies are included (7 studies applied text-messaging, 4 employed smartphone applications, and 5 used websites). Ten studies are cost-utility analyses: incremental cost-utility ratios (ICUR) vary from dominant to €75,233/quality-adjusted life year (QALY), with a median of €3840/QALY (interquartile range €16,179). One study finds no QALY difference. None of the three digital health intervention modes is associated with substantially better cost-effectiveness. Interventions are consistently cost-effective in populations with (pre)T2DM but not in populations with hypertension. Mean quality score is 63.0% (standard deviation 13.7%). Substandard application of time horizon, sensitivity analysis, and subgroup analysis next to transparency concerns (regarding competing alternatives, perspective, and costing) downgrades quality of evidence. In conclusion, smartphone application, text-messaging, and website-based interventions are cost-effective without substantial differences between the different delivery modes. Future health economic studies should increase transparency, conduct sufficient sensitivity analyses, and appraise the ICUR more critically in light of a reasoned willingness-to-pay threshold

    Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

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    Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms

    Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

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    Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

    Precision agriculture and conservation of coastal landscapes

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    The application of Precision Agriculture strategies represents an opportunity for farmers to obtain economic benefits. In the area of Metapontino, as demonstrated by the experimentation conducted, the challenge of producing food and at the same time protecting nature and safeguarding biodiversity, it is possible to face it through the introduction of global positioning systems (GPS), a technology capable of integrating the information on soil type, climate, cultivar, crop and farm management, topography and economy

    Clinical Outcome of Third-Line Pazopanib in a Patient with Metastatic Renal Cell Carcinoma

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    Background. Renal cell carcinoma accounts for about 2-3% of all malignant tumors. The prevalence of brain metastases from RCC is less than 20% of cases. Traditionally, whole brain radiotherapy as well as the latest stereotactic radiosurgery improves both survival and local tumor control. These treatments also allow stabilization of clinical symptomatology. However, validated treatment guidelines for RCC patients with brain metastases are not yet available on account of the frequent exclusion of such patients from clinical trials. Moreover, limited data about the sequential use of three therapies, changing the class of agent, have been published up to now. Case Report. We report the case of a patient with metastatic RCC who developed disease progression after sunitinib and everolimus as first-line and second-line therapy, respectively. Thus, he underwent a multimodality treatment with pazopanib, as third-line therapy, to control systemic disease and radiosurgery directed on the new brain metastasis. To date, the patient is still receiving pazopanib, with progression-free survival and overall survival of 43 and 103 months, respectively. Conclusion. In a context characterized by different emerging options, with no general consensus on the optimal treatment strategy, the use of pazopanib in pretreated patients could be a suitable choice
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