Beyond evidence-based data: Scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma

The recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: Planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition. Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidencebased data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC

Immunohistochemical/histochemical double staining method in the study of columnar metaplasia of the oesophagus

Intestinal metaplasia in Barrett\u2019s oesopha- gus (BO) represents an important risk factor for oesophageal adenocarcinoma. Instead, few and controversial data are reported about the progression risk of columnar-lined oesophagus without intestinal metaplasia (CLO), posing an issue about its clinical management. The aim was to evaluate if some immunophenotyp- ic changes were present in CLO independently of the presence of the goblet cells. We studied a series of oesophageal biopsies from patients with endoscopic finding of columnar metapla- sia, by performing some immunohistochemical stainings (CK7, p53, AuroraA) combined with histochemistry (Alcian-blue and Alcian/PAS), with the aim of simultaneously assess the his- tochemical features in cells that shows an aber- rant expression of such antigens. We evidenced a cytoplasmic expression of CK7 and a nuclear expression of Aurora A and p53, both in goblet cells of BO and in non-goblet cells of CLO, some of which showing mild dysplasia. These find- ings suggest that some immunophenotypic changes are present in CLO and they can pre- cede the appearance of the goblet cells or can be present independently of them, confirming the conception of BO as the condition charac- terized by any extention of columnar epitheli- um. This is the first study in which a combined immunohistochemical/histochemical method has been applied to Barrett pathology

Incarcerated hernia in a trocar site following laparoscopic gastric bypass

This paper reports a case of small bowel occlusion due to the herniation of an ileal ansa at the site of the insertion of a 12-mm trocar. A 28-year-old obese female patient underwent laparoscopic surgery for gastric bypass, the skin incisions of the trocar insertion sites were closed with absorbable sutures. Small bowel occlusion occurred on post-operative day 6 and the patient again underwent laparoscopic surgery. Laparoscopic exploration confirmed the suspected presence of the incarcerated hernia of an ileal ansa at the site of the trocar insertion which was freed without any need for bowel resection. The fascial defect was successfully closed under direct vision with the use of a special system of fascial sutures

Functionalized carbon nanostructures versus drug resistance: Promising scenarios in cancer treatment

Carbon nanostructures (CN) are emerging valuable materials for the assembly of highly engineered multifunctional nanovehicles for cancer therapy, in particular for counteracting the insurgence of multi-drug resistance (MDR). In this regard, carbon nanotubes (CNT), graphene oxide (GO), and fullerenes (F) have been proposed as promising materials due to their superior physical, chemical, and biological features. The possibility to easily modify their surface, conferring tailored properties, allows different CN derivatives to be synthesized. Although many studies have explored this topic, a comprehensive review evaluating the beneficial use of functionalized CNT vs G or F is still missing. Within this paper, the most relevant examples of CN-based nanosystems proposed for MDR reversal are reviewed, taking into consideration the functionalization routes, as well as the biological mechanisms involved and the possible toxicity concerns. The main aim is to understand which functional CN represents the most promising strategy to be further investigated for overcoming MDR in cancer

Type and gene location of kit mutations predict progression-free survival to first-line imatinib in gastrointestinal stromal tumors: A look into the exon

In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier

Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal) normally found in the bowel wall or their precursors. Although the microscopic features have been known for a long time, the defining characteristic of GIST is the presence of the cell-surface antigen CD117 (KIT), which is demonstrated by immunohistochemistry. KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4). Surgical removal remains the only curative treatment for patients with GISTs. Tumor size, mitotic index, anatomic location, tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection. Most GISTs express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. Imatinib mesylate is a rationally designed, molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs. More recently Sunitinib, a new KIT/PDGFRA kinase inhibitor, has been tested in patients with GIST resistant to imatinib, with promising results. Key words: gastrointestinal stromal tumors, histopathological diagnosis, molecular biology, novel therapie

Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC

The Prevalence of NAFLD and Fibrosis in Bariatric Surgery Patients and the Reliability of Noninvasive Diagnostic Methods

Background: Bariatric surgery patients have a higher prevalence of nonalcoholic fatty liver (NAFL) than the general population; however, its assessment and the accurate staging of fibrosis are often complicated because noninvasive tests are not very accurate in patients with morbid obesity, and liver biopsy cannot be performed as a routine exam. The aim of this study was to evaluate (A) the histological prevalence of NAFL, nonalcoholic steatohepatitis (NASH), and fibrosis in patients undergoing bariatric surgery; (B) the reliability of ultrasound (US) in diagnosing NAFL; and (C) the reliability of various fibrosis scoring systems for defining fibrosis. Methods: US and intraoperative liver biopsy results were reviewed in 57 bariatric surgery patients. NAFL, NASH, and fibrosis were diagnosed according to the Kleiner scoring system. US diagnosis of liver steatosis was based on the bright liver. Fibrosis scores used were (i) the BMI, AST/ALT Ratio, Diabetes (BARD) scoring system; (ii) the nonalcoholic fatty liver disease (NAFLD) fibrosis score; and (iii) the fibrosis-4 (FIB-4) index. Results: The prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94% (F3 5.7%, cirrhosis 2.8%). The sensitivity of US was 95%, specificity 50%, and likelihood ratio (LR+, LR-) 1.91 and 0.1. The reliability of fibrosis scores for F ≥ 2 were as follows: BARD score: sensitivity 46%, specificity 54%, and area under the receiver-operating characteristics (AUROC) curve 0.5; NAFLD score: sensitivity 30%, specificity 89%, and AUROC 0.5; and FIB-4: sensitivity 68%, specificity 67%, and AUROC 0.7. Conclusions: In bariatric surgery patients, the prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94%. US is able to rule out the presence of NAFL, while the commonly used scores may be inaccurate in defining fibrosis in patients with morbid obesity

Aurora-A overexpression as an early marker of reflux-related columnar mucosa and Barrett's oesophagus.

Abstract BACKGROUND: The development of oesophageal adenocarcinoma is generally closely associated with the presence of a specialised intestinal-type epithelium such as that found in Barrett's oesophagus (BO). A particular histological condition is when the distal oesophagus showing cardiac and/or fundic mucosa without intestinal metaplasia cannot be defined as 'Barrett's mucosa' [condition that we call 'columnar-lined oesophagus' (CLO)] and up till now, there has been no agreement in literature about the management of this condition. Aurora-A overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in mammalian cells. PATIENTS AND METHODS: A prospective study was carried out on 28 consecutive patients who presented columnar mucosa above the gastro-oesophageal junction (GOJ) at endoscopy. As controls, two more biopsies were obtained, one on the normal-appearing squamous oesophagus above the GOJ, as far as possible from the columnar mucosa (controls A), and one taken 1 cm below the GOJ (controls B). The Aurora-A and p53 expression levels were analysed respectively by Quantitative Real Time PCR and immunohistochemistry. RESULTS: Twelve patients were affected by BO (43%) while the other 16 patients (57%) had a CLO. Nine of 28 (32%) cases were focally positive for p53 immunostaining. All the BO/CLO samples were positive for the Aurora-A transcript with regard to controls. Furthermore, 13 of 28 (46%) cases showed overexpression (above the median for the whole group). CONCLUSION: Due to the low number of cases, we are not at present able to state that statistically significant quantitative differences in Aurora-A messenger RNA expression exist between CLO and BO cases with and without dysplasia and p53-positive immunostaining. Further studies on a larger number of cases with a follow-up period are necessary in order to establish the risk of progression and the correct management of these subjects

p53 mutations in L3-loop zinc-binding domain, DNA-ploidy, and S phase fraction are independent prognostic indicators in colorectal cancer: A prospective study with a five-year follow-up

p53 gene alterations are among the most common events observed in colorectal cancer, and are accompanied frequently by DNA aneuploidy and high proliferative activity. The prognostic significance of such mutations remains controversial. We prospectively evaluated the prognostic significance of p53 mutations, DNA-ploidy, and S phase fraction (SPF) in a consecutive series of 160 colorectal cancer patients (median follow-up 71 months). Tumor DNA was screened for p53 mutations by PCR/single-strand conformational polymorphism/sequencing. DNA-ploidy and SPF were assessed by DNA flow cytometry. p53 mutations were detected in 68 of 160 (42.5%) cases. In 56% (38 of 68) of these, p53 mutations were found in conserved areas of the gene and in 44% (30 of 68 cases) outside the conserved regions. Eighteen of the 68 cases (26%) had mutations in the L3 loop, 11 of 68 (16%) in the L1 loop-sheet-\u3b1 helix motif, and 39 of 68 (58%) outside L3 and loop-sheet-\u3b1 helix. Seventy-five percent of the cases (120 of 160) showed DNA aneuploidy, whereas 18% of these (22 of 120) were multiclonal. The major independent predictors for both disease relapse and death were advanced Dukes' stage, p53 mutations affecting L3 loop, DNA-aneuploid tumors, and high SPF (>18.5%). Our results show that mutations in L3 functional domain, more than any mutations, are important biological indicators to predict the outcome of patients indicating that these mutations have biological relevance in terms of colorectal cancer disease course