Gastroesophageal reflux after sleeve gastrectomy. Fact or fiction?

BACKGROUND: One of the most controversial issues surrounding laparoscopic sleeve gastrectomy is the development of gastroesophageal reflux disease following surgery. The aim of the study was to evaluate the occurrence of gastroesophageal reflux disease after laparoscopic sleeve gastrectomy and to analyze patients' weight loss, comorbidities, and quality of life after surgery. METHODS: The clinical records of 52 patients submitted to laparoscopic sleeve gastrectomy between January and November 2018, with 3 years of follow-up, were retrospectively reviewed. At the end of the follow-up period, the patients underwent screening endoscopy, and those with postoperative esophagitis were submitted to endoscopic biopsies and pH-impedance monitoring (MII-pH). The presence of gastroesophageal reflux disease symptoms was assessed using the modified clinical DeMesteer score questionnaire. The Bariatric Analysis and Reporting Outcome System score and 36-Item Short Form Health Survey were used to assess the postoperative quality of life. RESULTS: In the preoperative work-up, only 7.6% of patients had signs of esophagitis at esophagogastroduodenoscopy, whilst at 3-year follow-up, 50% of them had endoscopic signs of gastroesophageal reflux disease. Twenty-one out of 26 patients with signs of esophagitis agreed to undergo MII-pH. The median DeMesteer score questionnaire was 4.5, with only 4 patients (19%) exhibiting a value greater than the pH cut-off value (14.72), indicative of gastroesophageal reflux disease. MII-pH data analysis showed the presence of gastroesophageal reflux disease in 5 patients. An excellent outcome on the Bariatric Analysis and Reporting Outcome System score was reported in 50% of patients, and all 8 domains from the 36-Item Short Form Health Survey improved significantly. CONCLUSION: This study showed an improvement in these patients' quality of life and the limited refluxogenic nature of laparoscopic sleeve gastrectomy at 3-year follow-up when diagnosis of gastroesophageal reflux disease is based on the Lyon consensus.

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor.

Signaling pathways have a key role in driving the uncontrolled development of familial adenomatous polyposis (FAP)- associated and sporadic desmoid tumors (DTs). The relationship between the Wnt/b-catenin signaling pathway and DTs has been extensively studied, but no reliable biomarkers able to detect their histological subtype have been identified for the accurate diagnosis. In this study we studied the differences in miRNA expression between sporadic (20 patients) and FAP-associated DTs (7 patients) using microarray confirmed by quantitative PCR (qPCR). The analysis showed 19 dysregulated miRNAs. Among them miR-133b levels were significantly lower in FAP-associated DT than in sporadic DT. Therefore, two mRNAs, associated to miR-133b and ß-catenin expression, the SIRT1 and ELAVL1were analyzed. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated DT than in sporadic DT, whereas no differences in ELAVL1 expression was observed between these two DT types. In addition, a negative correlation was observed between miR-133b and SIRT1 in FAP-associated DTs, but not in sporadic DTs. The miR-133b-SIRT1-ß-catenin axis may represent a novel mechanism underlying progression of FAP-associated DT.

Relationship between cancer tissue derived and exhaled volatile organic compound from colorectal cancer patients. Preliminary results.

New insight into the omic sciences suggests that volatile organic compounds (VOCs) contained in exhaled breath can reflect the healthy or disease state of patients, representing an attractive, promising and non-invasive method of medical investigation. This approach has recently been proposed as a new potential screening tool in colorectal cancer (CRC) patients. However, a possible correlation between the exhaled VOCs and those produced by the cancerous tissue has never been investigated. In this preliminary study, we compare the VOCs exhaled by seven patients affected by CRC with those produce by own cancer tissue and normal colonic mucosa. The VOCs contained in the exhaled breath were sampled with the ReCIVA breath sampler©, while those produced by ex-vivo human tissues weresampled by headspace solid-phase microextraction (HS-SPME) at different incubation times after surgery. In both cases, the collected VOCs were analyzed by Gas Chromatography with Mass Spectrometry (GC-MS). Benzaldehyde, benzene ethyl, benzene methyl, butanoic acid, dodecanoic acid, indole, nonanal, octanoic acid, pentanoic acid, phenol and tetradecane were the VOCs most frequently detected both in the exhaled breath and secreted by tissues. The results showed that cancer tissue and normal colonic mucosa from the same patient produced a similar VOCs pattern but with different fingerprints. In particular, the concentrations of benzaldehyde, benzene ethyl and indole were significantly different in cancer tissue respect the normal colonic mucosa. In conclusion, these preliminary data suggest the involvement of the three compounds in CRC by encouraging further investigation.

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations.

Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with ß-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis.The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.

MicroRNA in colorectal cancer: new perspectives for diagnosis, prognosis and treatment.

Colorectal cancer (CRC) is a common condition and represents a lethal disease, following a sequential progression from adenoma to carcinoma. Interfering with such natural history of CRC offers clues to prevention and cure, but current screening methods for CRC are still limited by unsatisfactory sensitivity and specificity. Novel diagnostic, prognostic tools are therefore being actively investigated for CRC. The discovery of microRNAs (miRNAs) has led to active research focusing on their role in cancer and several crucial pathways involving angiogenesis, cancer-stem-cell biology, epithelial-mesenchymal transition, formation of metastasis, and drug resistance. MiRNAs might soon represent novel prognostic and diagnostic tools in patients at high risk of CRC or being diagnosed with CRC. MiRNA might prove useful also as therapeutic tools, since dysregulation of miRNAs in cancer cells results in higher levels of messenger RNA (mRNA) specific to tumor promoter genes or tumor suppressor genes. Thus, novel anticancer therapies might originate from manipulation of oncogenic or tumor suppressor miRNAs in CRC. In this review, the innovative aspects of miRNA are discussed, with respect to biogenesis, their role in CRC, and their potential use as biomarkers. Before miRNAs can become available in the clinical setting, however, a number of large prospective studies are still required.

Lack of prognostic role of pre- and postoperative peritoneal cytology and cytokeratin PCR-expression on local recurrence after curative anterior resection for mid-low rectal cancer.

Local recurrence continues to be a major problem in rectal cancer. After cancer removal, detection of viable cancer cells could be useful to identify patients at risk for local recurrence. Thus, aim of the study was the detection of residual peritoneal cancer cells with a possible prognostic role for local recurrence. Twenty-nine patients were operated (R0) for low (extraperitoneal) rectal cancer, without neoadjuvant radiochemotherapy. Before and immediately after cancer removal, a peritoneal lavage was done to evaluate by RT-PCR the cytokeratin 20 mRNA on isolated cells and in order to detect cancer cells by the Thin-prep test. After a median follow-up of 39 months, 5 patients died (17%), one for non-cancer-related disease, two (7%) for local recurrence and peritoneal carcinosis, and two for distant metastases. Preoperative cytology with Thin-prep test was positive in 4 patients (14%), while postoperative peritoneal cytology was positive only in 1 patient, different from the previous. No patient developed local or distal recurrence and all were disease-free at the end of the follow-up. RT-PCR analysis was positive on the peritoneal lavage after cancer removal in 11 patients. One died for unrelated cause and no one developed local recurrences. Local recurrence occurred in only 1 of the 2 patients with positive RT-PCR analysis on the first lavage and negative on the second lavage. Our study demonstrates a not important prognostic role of Thin-prep test and RT-PCR of cytokeratin 20 mRNA on the detection of patients at risk for local recurrence after curative resection of rectal cancer.

Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells.

Oleuropein (OL) and hydroxytyrosol (HT), the main olive oil polyphenols, possess anti-proliferative effects in vitro. Fatty acid synthase, a key anabolic enzyme of biosynthesis of fatty acids, plays an important role in colon carcinoma development. Our aim was to investigate whether gene expression of FAS, as well as its enzymatic activity, is regulated by HT and OL in two human colon cancer cell lines, as HT-29 and SW620. In addition, we investigated the effects of these polyphenols on growth and apoptosis in these cells. FAS gene expression and activity in treated HT-29 and SW620 cells were evaluated by real-time PCR and radiochemical assay, respectively. Cell growth and apoptosis, after polyphenols treatment, were measured by MTT test and flow cytometry, respectively. The inhibition of proliferation, detected after HT treatment, was mediated by an inhibition of FAS expression and its enzymatic activity in SW620 cells, while the anti-proliferative effect in HT-29 cells seems to be independent from FAS. OL exerted an anti-proliferative effect only on SW620 cells with a mechanism which excluded FAS. Olive oil polyphenols used were able to induce apoptosis in both cell lines studied. The increase of apoptosis in these cells was accompanied by the block of cell cycle in the S phase. This study demonstrates that HT and OL may induce anti-proliferative and pro-apoptotic effects only in certain human colorectal cancer cell types. These effects are FAS mediated only in SW620 cells after treatment with HT.

Red blood cell (RBC) surface acetylcholinesterase showing a hemorheological pattern during glaucoma treatment.

BACKGROUND: Glaucoma is currently attributed to two different possible pathogenetic mechanisms: mechanical (the ocular damage is induced by physical injury), and vascular (the ocular damage is sustained by ischemia of the optic nerve head). AIM: We considered the possibility that several anti-glaucoma drugs (beta-blockers, carbonic anhydrase inhibitors and prostaglandins) could have an influence on optic nerve head hemorheology and oxygen supply. MATERIALS AND METHOD: We studied 4 groups of 10 subjects each: a control group, and 3 primary open angle glaucoma (POAG) groups, treated with topical beta-blockers, (10 patients), carbonic anhydrase inhibitors (CAI), and prostaglandin analogs (PG), respectively. In these 4 groups we investigated the RBC surface AchE and cytosolic calcium levels in order to assess their possible influence on the hemorheology and microcirculation in optic nerve head blood perfusion. RESULTS: A significant correlation (p < 0.048) was found between the RBC surface acetylcholinesterase and RBC intracytosolic calcium values in patients with POAG treated with beta-blockers. We found no significant correlation (p = n.s.) between the same patterns in the other Groups or in Controls. CONCLUSION: These data indicate that CAI and PG drugs do not interfere with AchE in POAG patients, whereas beta-blockers negatively affect the RBC deformability.