Effect of a common missense variant in LIPA gene on fatty liver disease and lipid phenotype: New perspectives from a single-center observational study.

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single-nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL-A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL-A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL-A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high-density lipoprotein cholesterol (HDL-C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD.

Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients' weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

Which type of cancer is detected in breast screening programs? Review of the literature with focus on the most frequent histological features.

Breast cancer is the most frequent type of cancer affecting female patients. The introduction of breast cancer screening programs led to a substantial reduction of mortality from breast cancer. Nevertheless, doubts are being raised on the real efficacy of breast screening programs. The aim of the present paper is to review the main pathological type of cancers detected in breast cancer screening programs. Specifically, attention will be given to: in situ carcinoma, invasive carcinoma histotypes and interval cancer.

Chromosome X aneusomy and androgen receptor gene copy number aberrations in apocrine carcinoma of the breast.

Carcinomas with apocrine differentiation (CAD) of the breast are rare tumours typically presenting high immunohistochemical expression of androgen receptor (AR) which is a target molecule for personalised therapy. To date, no studies have evaluated the genetic changes that are associated with AR immunohistochemical expression in CADs. The present work aims to characterise AR status in CADs. Twenty CAD tumours were studied with immunohistochemistry, in situ fluorescence hybridization and DNA methylation analysis, to evaluate AR expression and its regulator status. All tumours demonstrated high AR immunohistochemical expression, with over 95% of the neoplastic cells showing AR positivity in 19/20 cases. CADs showed AR gene copy loss in a percentage of neoplastic cells ranging from 5 to 84% (mean 48.93%). AR regulator genes, including the MAGE family, UXT and FLNA, presented variable methylation levels, but were mainly hypomethylated and therefore all transcriptionally active. The results of this study indicate that CADs present AR monosomy, paralleled by higher transcriptional activity of the gene with potential to influence response to AR deprivation therapy.

Hemorrhagic Schwannoma of the Cauda Equina: Case Report and Review of the Literature.

Spinal intradural hemorrhage is a rare event; the most common causes of spinal bleeding are traumas, medical therapy with anticoagulants and thrombolytics, vascular malformations, and congenital defects of coagulation. Rarely, spinal cord tumors may cause hemorrhage. Herein, we report the case of a patient with acute and quickly worsening lumbar pain: the neurological examination revealed a flaccid paraplegia caused by an intradural lesion extending on the right side of the spinal cord from T1 to L2 vertebral level. Pathological examination revealed an hemorrhagic schwannoma. Acute spinal subdural hemorrhage caused by spinal schwannomas is a very rare occurrence (29 cases only have been previously reported). Review of the literature with clinico-diagnostic features is presented, surgical treatment is explained, and pathological findings with possible etiopathogenesis of hemorrhage are described.

Long term follow-up of genetically confirmed patients with familial hypercholesterolemia treated with first and second-generation statins and then with PCSK9 monoclonal antibodies.

BACKGROUND AND AIMS: In Italy, the clinical and genetic characteristics of familial hypercholesterolemia (FH) have been extensively assessed in various lipid clinics, although no studies on long-term cardiovascular outcomes in heterozygous patients (He-FH) have been conducted. This study evaluated the incidence of atherosclerotic cardiovascular disease (ASCVD) in He-FH before and after a long-term period of lipid-lowering treatments to ascertain the interference of other risk factors. METHODS: A total of 294 genetically characterised He-FH subjects from 1989 to 2019 were retrospectively analysed. General characteristics, lipid profiles, ASCVD prevalence, and ultrasound carotid atherosclerosis assessment were evaluated. Primary end points were ASCVD outcomes and the percentage of patients reaching recommended LDL-C targets. RESULTS: During follow-up, despite a significant improvement in plasma lipid profiles, the ESC/EAS 2016 and 2019 recommended LDL cholesterol (LDL-C) goals were attained in only a few patients treated with anti-PCSK9 monoclonal antibodies added to the maximum tolerated oral therapy with statins plus ezetimibe. Forty-seven subjects had an ASCVD event before starting lipid-lowering therapy (LLT). During follow-up (median 13 years) on LLT, 28 patients had a first ASCVD event and 16 had recurrent ASCVD. In basal conditions and during follow-up, higher LDL-C levels were associated with increased ASCVD risk (p < 0.001). Prevention of recurrent ASCVD events was recorded with a long-term reduction of LDL-C below 100 mg/dl with statins plus ezetimibe. CONCLUSIONS: PCSK9 inhibition is the only therapeutic option to achieve LDL-C goals as recommended for He-FH and can prevent ASCVD events as reported in large clinical trials. Long-term treatment with statins and ezetimibe seems to be effective at preventing ASCVD recurrence when LDL-C is maintained below 130 and 100 mg/dL for primary and secondary prevention, respectively.

Diet and Nutraceutical Supplementation in Dyslipidemic Patients: First Results of an Italian Single Center Real-World Retrospective Analysis.

BACKGROUND: Dyslipidemias are a heterogeneous group of metabolic disorders mainly characterized by an increased risk of atherosclerotic cardiovascular disease (ASCVD) or other conditions, such as acute pancreatitis in hypertriglyceridemia. The aim of this study was to evaluate the effect of diet treatment and nutraceutical (NUTs) supplementation on the plasma lipid profile in outpatient dyslipidemic subjects, considering the influence of several factors (i.e., gender, age, body mass index, alcohol consumption, and smoking habits). METHODS: 487 dyslipidemic patients spanning from 2015 to 2019 were treated with a Mediterranean diet or NUTs in a real-word setting and were retrospectively analyzed. General characteristics and lipid profile at baseline and after the follow-up period were evaluated. RESULTS: Diet alone reduced total cholesterol (-19 mg/dL, -7.7%), LDL cholesterol (-18 mg/dL, -10.1%), and triglycerides (-20 mg/dL, -16.7%). Triglycerides (TG) decreased more in men, while women were associated with higher reduction of LDL cholesterol (LDL-C). Different types of NUTs further ameliorate lipid profiles when associated with diet. Nevertheless, most patients at low ASCVD risk (222 out of 262, 81.6%) did not achieve the 2019 ESC/EAS guidelines recommended LDL-C goals (i.e., LDL-C < 116 mg/dL). CONCLUSION: Lipid-lowering diet improves lipid profile, and NUTs can boost its efficacy, but taken together they are mainly unsatisfactory with respect to the targets imposed by 2019 EAS/ESC guidelines.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Epilepsy in primary cerebral tumors: the characteristics of epilepsy at the onset (results from the PERNO study--Project of Emilia Romagna Region on Neuro-Oncology).

PURPOSE: To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study. METHODS: This study is a section of the PERNO study--Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983,346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies. The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis. KEY FINDINGS: We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60%), temporal (38%), and parietal (28%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48%) (without clear initial focal signs in more than half of the patients), focal motor (26%), complex partial (10%), and somatosensitive (8%). The majority of cases (60%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18% and 12% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38%) or partial (53%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174 days, with a significant difference between high grade (95 days) and low grade (481 days) gliomas. At the time of our first observation, the majority of patients (69%) had already undergone surgical removal, with a mean follow-up of 3 months after the procedure. Overall, 39 patients (56%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs. SIGNIFICANCE: These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation.

We previously described a cohort of grade II oligodendroglioma (OII) patients, in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at a higher risk of relapse. In this study, we evaluated the CpG methylation of the putative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoter in the same OII cohort, to investigate whether a correlation could be found between EMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-three tumor samples from OII patients were collected over a period of 10 years. Seventeen glioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients. The EMP3, O6-methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2) promoter methylation, evaluated by methylation-specific PCR, and the isocitrate dehydrogenase 1 (IDH1) mutation, identified by sequencing, were compared between the OII and GBM histotypes. The EMP3 promoter methylation was correlated with the analysis of LOH 19q, performed by microsatellite amplification, in OII patients. Disease progression-free interval was evaluated in the OII patients with the EMP3 methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 and MGMT promoter methylation was more frequent in OII than in GBM patients, and the IDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes. Both LOH+/- 19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19q and EMP3 gene promoter methylation was observed in the OII patients at a higher risk of relapse. Our results suggest that a total (cytogenetic and epigenetic) functional loss of both EMP3 alleles accounts for the reduced disease progression-free interval in OII patients. Although the small sample size limits the strength of this study, our results support testing this hypothesis in larger cohorts of patients, considering the methylation of the EMP3 gene promoter together with LOH 19q as an indication for treatment with adjuvant therapy ab initio in order to improve the overall survival of OII patients.

Plasma cell granuloma of the thyroid gland: a challenging diagnostic problem.

This study reports a case of plasma cell granuloma of the thyroid gland in a 47-year-old woman, presenting with a right subhyoid mass and a previous diagnosis of Hashimoto thyroiditis dating back to 1988, which was made on a subtotal thyroidectomy. Plasma cell granuloma preferentially involves the lung, with only 18 cases of thyroid gland involvement having been reported to date in the English literature. Thyroid plasma cell granuloma preferentially affects women and classically shows a prominent plasma cell infiltrate embedded in a variable degree of fibrous stroma: only 2 of the reported cases exhibited the morphologic features of inflammatory myofibroblastic tumor. These morphologic features may raise problems in the differential diagnosis with other plasma cell-rich disorders, including infectious diseases and auto(dys)immune conditions, including the recently described "IgG4-related sclerosing disease." In view of these considerations, a contemporary diagnostic approach to thyroid plasma cell granuloma is therefore discussed here.

Impact of venous tumour thrombus consistency (solid vs friable) on cancer-specific survival in patients with renal cell carcinoma.

BACKGROUND: To our knowledge, the impact of venous tumour thrombus (VTT) consistency in patients affected by renal cell carcinoma (RCC) has never been addressed. OBJECTIVE: To analyse the effect of VTT consistency on cancer-specific survival (CSS). DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analysed 174 consecutive patients with RCC and renal vein or inferior vena cava (IVC) VTT who underwent surgical treatment between 1989 and 2007 at our institute. INTERVENTION: All patients underwent radical nephrectomy and thrombectomy. MEASUREMENTS: Pathologic specimens were reviewed by a single uropathologist. In addition to traditional pathologic features, the morphologic aspect of the tumour thrombus was evaluated to distinguish solid from friable patterns. The prognostic role of thrombus consistency (solid vs friable) on CSS was assessed by means of Cox regression models. RESULTS AND LIMITATIONS: The VTT was solid in 107 patients (61.5%) and friable in 67 patients (38.5%). The presence of a friable VTT increased the risk of having synchronous nodal or distant metastases, higher tumour grade, higher pathologic stage, and simultaneous perinephric fat invasion (all p < 0.05). The median follow-up was 24 mo. The median CSS was 33 mo; the median CSS was 8 mo in patients with a friable VTT and 55 mo in patients with a solid VTT (p < 0.001). On multivariable analyses, the presence of a friable VTT was an independent predictor of CSS (p = 0.02). The power of our conclusion may be somewhat limited by the relatively small study population and the retrospective nature of the study. CONCLUSIONS: In patients with RCC and VTT, the presence of a friable thrombus is an independent predictor of CSS. If our finding is confirmed by further studies, the consistency of the tumour thrombus should be introduced into routine pathologic reports to provide better patient risk stratification.

The extent of tumour fat invasion affects survival in patients with renal cell carcinoma and venous tumour thrombosis.

OBJECTIVE: • To investigate the effect of presence and extent of tumour fat invasion (TFI) - perinephric invasion (PFI), renal sinus fat invasion (RSFI) or both PFI and RSFI - on cancer-specific mortality (CSM) in patients with renal cell carcinoma (RCC) and venous tumour thrombus (VTT). METHODS: • We examined 184 consecutive patients with RCC with VTT treated with nephrectomy between 1987 and 2007. Associations with CSM were evaluated by univariable and multivariable Cox proportional hazard models. RESULTS: • Median follow up was 21 months. The 5-year CSM-free survival estimates were 75%, 36% and 20% in patients with VTT without TFI, those with VTT with PFI or RSFI, and those with VTT with both PFI and RSFI, respectively (P < 0.001). In multivariable analyses, presence of either PFI or RSFI was associated with a two-fold increased risk of CSM, whereas presence of both PFI and RSFI was associated with a three-fold increased risk of CSM, relative to VTT-only cases. • The inclusion of the variable describing the presence and extent of TFI in a base model including pT stage, Fuhrman grade and presence of nodal disease and metastatic disease significantly increased the accuracy in predicting CSM (+2.1%; P < 0.001) in patients with VTT. CONCLUSIONS: • Patients affected by RCC with VTT and TFI have a higher risk of CSM relative to cases with VTT only. Patients with both PFI and RSFI showed increased CSM compared with patients with either PFI or RSFI. • Our results suggest TFI should be accurately evaluated and included in routine pathological reports to provide better patient risk stratification.

Chromosome 1p and 19q evaluation in low-grade oligodendrogliomas: a descriptive study.

Oligodendrogliomas are rare primary brain tumors with variable patient outcomes which are not always adequately accounted for by clinical or pathological variables. The present study evaluated the prognostic implications of chromosome 1p and 19q status in a set of 23 low grade oligodendrogliomas (OGD II), and correlated the results with patient outcome. Loss of heterozygosity (LOH) and fluorescent in situ hybridization (FISH) analyses, the most widely used standard procedures, were used. 1p and 19q deletions were found in 65 and 61% of cases, respectively, using FISH and in 78 and 72% of cases using LOH. Both deletions were found in 56 and 64% of patients using FISH and LOH, respectively. Concordance between the results from the two techniques, determined by the Kappa statistics, ranged from fair to substantial depending on whether single or combined deletions were considered. Our results showed that the molecular alterations are associated with age and tumor localization. With regard to the impact of chromosomal alterations on clinical outcome, chromosome 19q deletions detected by LOH would seem to indicate a subgroup of patients at a higher risk of relapse, although the small number of patients recruited does not permit any definitive conclusions to be drawn. Further studies are now ongoing to determine whether this methodological approach could be potentially useful in low grade oligodendrogliomas to better characterize chromosomal alterations of 1p/19q and identify subgroups of patients with a higher risk of disease recurrence.

Follicular lymphoma of the dura associated with meningioma: a case report and review of the literature.

A 70-year-old immunocompetent woman who had been radiologically diagnosed with a left parasagittal meningioma 5 years previously developed a palpable subgaleal mass and underwent neurosurgery. Histologically the tumor was composed of thickened fibrotic dural tissue, infiltrated by a follicular lymphoma, of grade IIIB. A coexistent transitional meningioma had been infiltrated by the neoplastic lymphoid tissue. Two months after surgery, the patient developed evidence of extracranial dissemination of the lymphoma to the cervical lymph nodes and was treated with polychemotherapy plus Rituximab and intrathecal methotrextate. The patient is alive and recurrence-free at 1-year follow up. A review of the literature indicates that lymphomas developing primarily in the meninges, have an indolent course and tend to be localized in areas rich in meningothelial cells.

Gliosarcoma with features of osteoblastic osteosarcoma: a review.

CONTEXT: Gliosarcoma is a rare tumor of the central nervous system characterized by a biphasic histologic pattern, consisting of a gliomatous and a sarcomatous component, respectively. In most instances the sarcomatous component is represented by a fibrosarcoma, but other stromal malignancies have also been described. Osteosarcomatous differentiation in gliosarcoma has been rarely reported. OBJECTIVE: To review characteristic radiologic and histopathologic features of this rare neoplasm, to debate about possible differential diagnoses that should be taken into consideration, and to provide an overview of the potential histopathogenesis of gliosarcomas. DATA SOURCES: Relevant articles indexed in PubMed (National Library of Medicine) and reference medical texts. CONCLUSIONS: Recent molecular studies suggest that sarcomatous and gliomatous components of gliosarcoma might be derived from a single precursor cell clone, progressing in 2 subclones with distinct morphologic features during tumor evolution. Nonetheless, events determining splitting of the original clone into 2 histologic populations remain to be investigated.

Well-differentiated chondrosarcoma of the humerus with prominent granular cell component: a hitherto unreported occurrence.

We report the case of a well-differentiated chondrosarcoma of the proximal humerus in a 60-year-old man that featured a prominent component of granular cells, the granules being shown by electron microscopy to be lysosomal. Although secondary granular cell changes have been described in a large variety of tumor types, this is, to the best of our knowledge, the first documentation of this phenomenon in a skeletal chondrosarcoma.