Treatment responses to antiangiogenetic therapy and chemotherapy in nonsecreting paraganglioma (PGL4) of urinary bladder with SDHB mutation: a case report

Paraganglioma (PGL) is a rare neuroendocrine tumor. Currently, the malignancy is defined as the presence of metastatic spread at presentation or during follow-up. Several gene mutations are listed in the pathogenesis of PGL, among which succinate dehydrogenase (SDHX), particularly the SDHB isoform, is the main gene involved in malignancy. A 55-year-old male without evidence of catecholamine secretion had surgery for PGL of the urinary bladder. After 1 year, he showed a relapse of disease and demonstrated malignant PGL without evidence of catecholamine secretion with a germline heterozygous mutation of succinate dehydrogenase B (SDHB). After failure of a second surgery for relapse, he started medical treatment with sunitinib daily but discontinued due to serious side effects. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapeutic regimen stopped the disease progression for 7 months. Conclusion: Malignant PGL is a very rare tumor, and SDHB mutations must be always considered in molecular diagnosis because they represent a critical event in the progression of the oncological disease. Currently, there are few therapeutic protocols, and it is often difficult, as this case demonstrates, to decide on a treatment option according to a reasoned set of choices. Abbreviations: CVD = cyclophosphamide, vincristine and dacarbazine, HIF-1a = hypoxia inducible factor 1 alpha, PGL = paraganglioma, SDH = succinate dehydrogenase, VEGF = vasoendothelial growth factor

Exfoliative cytology and genetic analysis for a non-invasive approach to the diagnosis of white sponge nevus. Case series

Background: White Sponge Nevus (WSN) is a rare benign disorder associated with mutations in genes coding for cytokeratin 4 (KRT4) and 13 (KRT13) characterized by dyskeratotic hyperplasia of mucous membranes. This study was aimed at examining different approaches (cytology, pathology and genetic analysis) to WSN diagnosis. Methods: A series of four patients with asymptomatic white diffuse oral lesions were evaluated and, before performing an incisional biopsy for pathology, an oral brush Thin Prep was collected for exfoliative liquid-based cytology (LBC). DNA for genetic analysis was also obtained from patients and both their parents, using buccal swabs. Results: Pathology and cytology showed similar results, leading to the same diagnosis of hyperkeratotic epithelium with acanthosis and spongiosis, without atypia, demonstrating the efficiency of LBC for the differential diagnosis. Sequencing analysis revealed at least 6 rare variants in the KRT4 and KRT13 genes in each patient, contributed in part by both unaffected parents. Conclusions: Thin Prep for oral exfoliative cytology and genetic analysis are sufficient for an accurate diagnosis of WSN. The combination of cytological and genetic analyses could substitute the histologic exam, providing a non-invasive alternative for incisional biopsy

Macroseismic effects highlight site response in Rome and its geological signature

A detailed analysis of the earthquake effects on the urban area of Rome has been conducted for the L’Aquila sequence, which occurred in April 2009, by using an on-line macroseismic questionnaire. Intensity residuals calculated using the mainshock and four aftershocks are analyzed in the light of a very accurate and original geological reconstruction of the subsoil of Rome based on a large amount of wells. The aim of this work is to highlight ground motion amplification areas and to find a correlation with the geological settings at a sub-regional scale, putting in evidence the extreme complexity of the phenomenon and the difficulty of making a simplified model. Correlations between amplification areas and both near-surface and deep geology were found. Moreover, the detailed scale of investigation has permitted us to find a correlation between seismic amplification in recent alluvial settings and subsiding zones, and between heard seismic sound and Tiber alluvial sediments

Reorganization of the endoscopic activity of Cancer Institutes during phase II of the Covid-19 emergency

After the lockdown during the emergency phase of the Covid-19 pandemic, we have to deal with phase 2, a period of uncertain duration, with a controlled and progressive return to normalization, in which we need to reconcile our work and our movements with the presence of the virus on our territory. Digestive endoscopic activity is a high-risk transmission procedure for Covid-19. The measures put in place to protect healthcare personnel and patients are stressful and “time-consuming” and lead to a reduction in the number of endoscopic procedures that can be performed. In this scenario, the Oncological Institutes are forced to make a rigorous selection of patients to undergo endoscopic examinations and treatments, according to lists of exceptional priorities, in order to guarantee cancer patients and subjects at high risk of developing digestive tumors, a preferential diagnostic and therapeutic process, protected from contagion risks. For this purpose, cuts and postponing times of endoscopic performances are here proposed, which go beyond the guidelines of scientific societies and have little evidences in the literature. These changes should be applied limited to this exceptional period and in proportion to the capacity of each operating unit in order to meet the demands of the patients

Vitamins D and K as Factors Associated with Osteopathy in Chronic Pancreatitis. A Prospective Multicentre Study (P-BONE Study)

Background: Osteopathy is common in patients with chronic pancreatitis (CP), but previous studies carry several limitations. Vitamin K is essential for bone metabolism, but its role in this setting has never been investigated. Our aim is to assess the prevalence of osteoporosis and osteopenia in CP patients, and to investigate the association between osteopathy and CP features and nutritional parameters, especially vitamin D and K levels. Methods: Multicentre cross-sectional study on CP patients diagnosed according to M-ANNHEIM criteria. Bone density was evaluated by dual-energy X-ray absorptiometry and pancreatic function by faecal elastase. Nutritional evaluation included vitamin D and vitamin K. Differences between patients with or without osteopathy were evaluated. The association between investigated variables and bone density were analysed with logistic regression analysis. Results: In total, 211 CP patients were enrolled at eight Centres (67% men; mean age 60). In total, 18% had advanced-marked CP, 56% suffered from pancreatic exocrine insufficiency and disease aetiology was alcoholic in 43%. Vitamin D and K were deficient in 56% and 32%, respectively. Osteopenia was diagnosed in 42% and osteoporosis in 22%. In the multivariate analysis, female sex (OR 2.78), age (OR 1.07 per year) and higher BMI (OR 0.84) were associated with the presence of osteoporosis. In male patients, the only factor associated with osteoporosis was vitamin K deficiency (OR 4.23). Conclusion: The present data confirm a high rate of osteopathy in CP patients and highlight the relevance of vitamin K deficiency as only factor associated with osteoporosis in male patients for the first time

The value of the multidisciplinary team in metastatic renal cell carcinoma: paving the way for precision medicine in toxicities management

The new landscape of treatments for metastatic clear cell renal carcinoma (mRCC) is constantly expanding, but it is associated with the emergence of novel toxicities, adding to up to those observed in the tyrosine-kinase inhibitor (TKI) era. Indeed, the introduction of immune checkpoint inhibitors (ICIs) alone or in combination has been associated with the development of immune-related adverse events (irAEs) involving multiple-organ systems which, even if rarely, had led to fatal outcomes. Moreover, due to the relatively recent addition of ICIs to the previously available treatments, the potential additive adverse effects of these combinations are still unknown. A prompt recognition and management of these toxicities currently represents a fundamental issue in oncology, since it correlates with the outcome of cancer patients. Even if clinical guidelines provide indications for the management of irAEs, no specific protocol to evaluate the individual risk of developing an adverse event during therapy is currently available. A multidisciplinary approach addressing appropriate interventions aimed at reducing the risk of any insidious, severe, and/or dose-limiting toxicity might represent the most efficacious strategy to timely prevent and manage severe irAEs, allowing indirectly to improve both patients' cancer-specific survival and quality of life. In this review, we reported a five-case series of toxicity events that occurred at our center during treatment for mRCC followed by the remarks of physicians from different specialties, pinpointing the relevant role of an integrated and extended multidisciplinary team in a modern model of mRCC patient management

AME position statement on adrenal incidentaloma.

Objective: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. Design: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Radiological assessment: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of <= 10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). Hormonal assessment: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Management: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism

Murge and Pre-murge in southern Italy: the last piece of Adria, the (almost) lost continent, attempting to became an aUGGp candidate (MurGEOpark)

In 2019, the executive of the Alta Murgia National Park (southeastern Italy) decided to propose its territory as possible inclusion in the network of the UNESCO Global Geoparks. Since then, in cooperation with the Department of Earth and Environmental Sciences (Aldo Moro University of Bari) and SIGEA, it is working to candidate the area as an aUGGp (called “MurGEOpark”). The MurGEOpark comprises the Alta Murgia area, where a Cretaceous sector of the Apulia Carbonate Platform crops out, and the adjacent Pre-Murge area, where the southwestward lateral continuation of the same platform, being flexed toward the southern Apennines mountain chain, is thinly covered by Plio-Quaternary foredeep deposits. The worldwide geological uniqueness is that the area is the only in situ remnant of the AdriaPlate, the old continent almost entirely squeezed between Africa and Europe. In such a contest, AltaMurgia is a virtually undeformed sector of Adria (the Apulia Foreland), while other territories of theplate are, and/or were, involved in the subduction/collision processes. In the MurGEOpark, the crustof Adria is still rooted to its mantle, and the Cretaceous evolution of the continent is spectacularlyrecorded in Alta Murgia thanks to the limestone succession of one of the largest peri-Tethyancarbonate platform (the Apulia Carbonate Platform). The MurGEOpark comprises also the Pre-Murge area, which represents the outer south-Apennines foredeep, whose Plio-Quaternaryevolution is spectacularly exposed thanks to an “anomalous” regional middle-late Quaternary uplift.The international value of the proposal is enriched by the presence of several geological singularities such as two paleontological jewels of very different age: a Neanderthal skeletonpreserved in speleothems within a karst cave, and one of the largest surfaces in the world withupper Cretaceous dinosaur tracks (about 25.000 footprints). Moreover, the close relationships between man and geology are spectacularly documented in the MurGEOpark: among the others, the use and conservation of water in a karst area, the prehistoric and ancestral choices ofurbanization, karst caves traditionally used as religious sites, etc. All these examples demonstratehow the MurGEOpark could offer a good opportunity to spread the geological culture to a wide and diverse audienc

No impact of NRAS mutation on features of primary and metastatic melanoma or on outcomes of checkpoint inhibitor immunotherapy: An italian melanoma intergroup (IMI) study

Neuroblastoma RAS Viral Oncogen Homolog (NRAS) mutant melanoma is usually considered more aggressive and more responsive to checkpoint inhibitor immunotherapy (CII) than NRAS wildtype. We retrospectively recruited 331 metastatic melanoma patients treated with CII as first line: 162 NRAS-mutant/BRAF wild-type and 169 wt/wt. No substantial differences were observed among the two cohorts regarding the melanoma onset and disease-free interval. Also, overall response to CII, progression-free survival and overall survival were similar in the two groups. Therefore, our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant melanoma. The controversy in the published data could be due to different patient characteristics and treatment heterogeneity. We believe our data adds evidence to clear up these controversial issues. Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, &lt;3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM