Maria Di Vita

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras–mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response. Mol Cancer Ther; 9(12); 3396–409.

Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has a master control role in various cancer-related biological processes as cell growth, proliferation, differentiation, migration, and apoptosis. It also regulates many transcription factors that control microRNAs (miRNAs) and their biosynthetic machinery. To investigate on the still poorly characterised global involvement of miRNAs within the pathway, we profiled the expression of 745 miRNAs in three colorectal cancer (CRC) cell lines after blocking the pathway with three different inhibitors. This allowed the identification of two classes of post-treatment differentially expressed (DE) miRNAs: (1) common DE miRNAs in all CRC lines after treatment with a specific inhibitor (class A); (2) DE miRNAs in a single CRC line after treatment with all three inhibitors (class B). By determining the molecular targets, biological roles, network position of chosen miRNAs from class A (miR-372, miR-663b, miR-1226*) and class B (miR-92a-1*, miR-135b*, miR-720), we experimentally demonstrated that they are involved in cell proliferation, migration, apoptosis, and globally affect the regulation circuits centred on MAPK/ERK signaling. Interestingly, the levels of miR-92a-1*, miR-135b*, miR-372, miR-720 are significantly higher in biopsies from CRC patients than in normal controls; they also are significantly higher in CRC patients with mutated KRAS than in those with wild-type genotypes (Wilcoxon test, p < 0.05): the latter could be a downstream effect of ERK pathway overactivation, triggered by KRAS mutations. Finally, our functional data strongly suggest the following miRNA/target pairs: miR-92a-1*/PTEN-SOCS5; miR-135b*/LATS2; miR-372/TXNIP; miR-663b/CCND2. Altogether, these results contribute to deepen current knowledge on still uncharacterized features of MAPK/ERK pathway, pinpointing new oncomiRs in CRC and allowing their translation into clinical practice and CRC therapy.

Incidental gallbladder cancer during laparoscopic cholecystectomy: Managing an unexpected finding

AIM To evaluate the impact of incidental gallbladder cancer on surgical experience. METHODS Between 1998 and 2008 all cases of cholecystectomy at two divisions of general surgery, one university based and one at a public hospital, were retrospectively reviewed. Gallbladder pathology was diagnosed by history, physical examination, and laboratory and imaging studies [ultrasonography and computed tomography (CT)]. Patients with gallbladder cancer (GBC) were further analyzed for demographic data, and type of operation, surgical morbidity and mortality, histopathological classification, and survival. Incidental GBC was compared with suspected or preoperatively diagnosed GBC. The primary endpoint was disease-free survival (DFS). The secondary endpoint was the difference in DFS between patients previously treated with laparoscopic cholecystectomy and those who had oncological resection as first intervention. RESULTS Nineteen patients (11 women and eight men) were found to have GBC. The male to female ratio was 1:1.4 and the mean age was 68 years (range: 45-82 years). Preoperative diagnosis was made in 10 cases, and eight were diagnosed postoperatively. One was suspected intraoperatively and confirmed by frozen sections. The ratio between incidental and nonincidental cases was 9/19. The tumor node metastasis stage was: pTis (1), pT1a (2), pT1b (4), pT2 (6), pT3 (4), pT4 (2); five cases with stage Ia (T1 a-b); two with stage Ib (T2 N0); one with stage IIa (T3 N0); six with stage IIb (T1-T3 N1); two with stage III (T4 Nx Nx); and one with stage IV (Tx Nx Mx). Eighty-eight percent of the incidental cases were discovered at an early stage (≤ II). Preoperative diagnosis of the 19 patients with GBC was: GBC with liver invasion diagnosed by preoperative CT (nine cases), gallbladder abscess perforated into hepatic parenchyma and involving the transversal mesocolon and hepatic hilum (one case), porcelain gallbladder (one case), gallbladder adenoma (one case), and chronic cholelithiasis (eight cases). Every case, except one, with a T1b or more advanced invasion underwent IVb + V wedge liver resection and pericholedochic/hepatoduodenal lymphadenectomy. One patient with stage T1b GBC refused further surgery. Cases with Tis and T1a involvement were treated with cholecystectomy alone. One incidental case was diagnosed by intraoperative frozen section and treated with cholecystectomy alone. Six of the nine patients with incidental diagnosis reached 5-year DFS. One patient reached 38 mo survival despite a port-site recurrence 2 years after original surgery. Cases with non incidental diagnosis were more locally advanced and only two patients experienced 5-year DFS. CONCLUSION Laparoscopic cholecystectomy does not affect survival if implemented properly. Reoperation should have two objectives: R0 resection and clearance of the lymph nodes.

Cystic peritoneal mesothelioma: Report of a case

Benign multicystic peritoneal mesothelioma (BMPM) is a rare disease with good short-term prognosis and rare malignant transformation. However, its biological significance remains unexplained. A neoplastic origin is considered by many authors to require a surgical excision, based on the high recurrence and progressive growth rate of the tumors. However, alternative or integrative treatment options have also been proposed. A 45-year-old woman presented to our unit with a history of occasional discomfort and pain in the left hip. On physical examination, we noticed a tough-elastic, fixed mass located in the iliac fossa. Computed tomography scan detected a mass with multiseptated cystic-like areas. Due to the similarity of these findings to a primitive sarcomatous tumor of the retroperitoneum, an arteriographic study was also performed. The patient underwent en bloc resection of the mass, including a segment of the sigmoid colon. The final pathologic diagnosis was cystic mesothelioma. Further studies are needed to better understand the etiology and pathogenesis of this rare disease, and to define a more tailored treatment plan.

Presentation and management of splenic injury after colonoscopy: a systematic review.

This study reviewed all single experience of splenic injuries after colonoscopy in the last 40 years to define the possible risk factors and the management of this complication. A MEDLINE and a PubMed search was undertaken to identify articles in English, French, Spanish, and Italian from 1974 to 2012 using the key words: “splenic injury,” “splenic rupture,” and “colonoscopy.” Data were analyzed using descriptive statistic. A total of 103 cases have been described in 75 reports. The majority of the patients were women (71.56%) and 6.85% underwent previous pelvic surgery. The mean age was 63 years (range, 29 to 90 y). About 61 of the 103 studies (59.2%) reported the presence or the absence of previous abdominal surgery and within these, only 31 of 61 patients (50.82%) underwent previous abdominal surgery. In this review, over half of the patients with splenic injury underwent colonoscopy for routine surveillance (62.75%), and only one third of the splenic injures were associated with biopsy or polypectomy. The majority of patients (78.57%) developed symptoms within the first 24 hours after colonoscopy and in a minority of cases (21.43%), there was a delayed presentation 24 hours after colonoscopy. Computed tomography was used as the primary modality to make the diagnosis in 69 of 98 cases (70.41%) and as a confirmatory test in many additional cases. Twenty-six of 102 patients (25.49%) were treated by conservative methods, whereas the majority of patients (69.61%) underwent splenectomy as a definitive treatment. Because of possible medicolegal implications, the endoscopists should consider mentioning splenic injury on the consent form of colonoscopy after bowel perforation and bleeding, particularly in higher risk patients.

The role of diet in gastric cancer: still an open question

The risk of gastric cancer is often related to lifestyle and diet. There have been several studies on correlation between Nutrition and the risk of gastric cancer with different and sometimes contradictory results. Here we reviewed the role of nutrition as risk/protective factor in the development of gastric cancer.

The unique simultaneous occurrence of a squamous cell carcinoma and a granular cell tumor of the tongue at the same site: a histological and immunohistochemical study.

We report a case of a 47-year-old man with a granular cell tumor (GCT) of the tongue colocalized with a squamous cell carcinoma. To our knowledge, this is the first case to be reported in the literature with such an association. Furthermore, we performed an immunohistochemical analysis with p63 to distinguish pseudoepitheliomatous hyperplasia from invasive squamous cell carcinoma. Clinicians and pathologists must be made aware of this potential diagnostic pitfall so that the workup of a tongue lesion does not end prematurely with a benign diagnosis of granular cell tumor with overlying pseudoepitheliomatous hyperplasia.

Localized and systemic bacterial infections in necrotizing pancreatitis submitted to surgical necrosectomy or percutaneous drainage of necrotic secretions

BackgroundInfectious complications are observed in 40-70% of all patients with severe acute pancreatitis. Infections are associated with a significant increase in mortality rates.MethodsWe evaluated the prevalence and characteristics of pancreatic and systemic infections in 46 patients with necrotizing pancreatitis submitted to surgical procedures during their hospital stay as well as the impact of such infectious complications on patient clinical outcome. Samples for microbiological cultures were taken at hospital admission from blood and bile and 2 days after invasive procedure from blood, drainage fluid, bile and necrotic tissues.Results74% patients with necrotizing pancreatitis had a localized or systemic infection. At admission, 15% of subjects had positive blood cultures whereas 13% had evidence of bacterial growth from bile cultures. Two days after the invasive procedures for removal of necrotic materials and fluids, blood cultures became positive in 30% of patients in spite of antibiotic prophylaxis and bile cultures resulted positive in 22% of cases. Furthermore, bacterial growth from drainage fluids was found in 30% and from homogenized necrotic material in 44% of cases. As refers to bacterial isolates, all patients had a monomicrobial infection. Carbapenems were the drugs with the best sensitivity profile.Mortality rate was significantly (p < 0.05) higher among patients with infection (17%) than subjects without infection (8%). Within the infected group, those subjects with evidence of systemic infection (positive blood cultures) developed more complications and demonstrated a higher (p < 0.05) mortality rate (28%) than those who had only a localized infection (10%).ConclusionsInfectious complications significantly increase mortality in patients with necrotizing pancreatitis. In addition, subjects with systemic infections developed more complications and demonstrated a higher mortality rate in comparison with those having a localized infection. In our study, the sensitivity pattern of the isolated microorganisms suggests to consider carbapenems as the best option for empirical treatment in patients with necrotizing pancreatitis who develop a clear-cut evidence of systemic or localized bacterial infection.

Prognostic factors in elderly patients with breast cancer

BackgroundBreast cancer (BC) remains principally a disease of old ages; with 35-50% of cases occurring in women older than 65 years. Even mortality for cancer increases with aging: 19.7% between 65 and 74 years; 22.6% between 75 and 84 years; and 15.1% in 85 years or more.The study was aimed to investigate specific predictive factors for elderly patients so to select the best way to treat and follow these patients.MethodsA search was performed on Medline, Embase, Scopus using the following Key words: Breast cancer, Breast neoplasms, Aged, Elder, Elderly, Eldest, Older, Survival analysis, Prognosis, Prognostic factors, Tumor markers, Biomarkers, Comorbidity, Geriatric assessment, Axilla, Axillary surgery. 3029 studies have been retrieved. Paper in which overall or disease free survival were not end points, or age class was not well defined, or the sample was too small, were excluded. At last 42 papers fulfilled the criteria.Results and discussionLack of screening and delay in diagnosis may be responsible for the minor improvement in survival observed in elderly respect to younger breast cancer patients. Predictive factors are the same and must be assessed with the same attention reserved to younger women.ConclusionsMost of elderly patient are fit to undergo standard treatment and can get the same benefits of younger women. Nevertheless it is possible that some older women with early breast cancer can be spared too aggressive treatments. Geriatric assessment and co-morbidities can affect the prognosis modifying surveillance, life expectancy and compliance to therapies. They can thus be useful to select the better treatment, either surgical or radio or hormone - or chemo-therapy.

The role of 68-Ga-DOTATOC CT-PET in surgical tactic for gastric neuroendocrine tumors treatment: Our experience: A case report

Gastric neuroendocrine tumors (g-NETs), which originate from gastric enterochromaffin-like (ECL) mucosal cells and account for 2.4% of all carcinoids, are increasingly recognized due to expanding indications of upper gastrointestinal endoscopy. Often silent and benign, g-NETs may however, be aggressive and sometimes they mimic the course of gastric adenocarcinoma. Current nosography distinguishes those occurring in chronic conditions with hypergastrinemia, as the type 1 associated with chronic atrophic gastritis, and the type 2 associated with Zollinger-Ellison syndrome in MEN1. Conversely, type 3 and 4 (according to some authors) are unrelated to hypergastrinemia and are frequently malignant, with a propension to develop distant metastases. While there is a general agreement concerning the treatment of malignant gastric neuroendocrine tumors, for types 1 and 2, current possibilities include surveillance, endoscopic polypectomy, surgical excision, associated or not with surgical antrectomy, or total gastrectomy. This report, based on our clinical experience, discusses how the size, number, depth, histological grading, staging with CT, MRI, and the use of recently developed somatostatin receptor tracers (68Ga-DOTATATE, 68Ga-DOTA-TOC) could allow the correct identification of a benign or malignant propensity of an individual tumor, thus avoiding underestimation or overtreatment of these uncommon neoplasms.