[Show abstract][Hide abstract] ABSTRACT: Aberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.
[Show abstract][Hide abstract] ABSTRACT: Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.
[Show abstract][Hide abstract] ABSTRACT: Background There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC.Patients and Methods A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used.Results Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively).Conclusions CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this case-control study was to evaluate the impact of hybrid minimally invasive esophagectomy for cancer on surgical stress response and nutritional status. All 34 consecutive patients undergoing hybrid minimally invasive esophagectomy for cancer at our surgical unit between 2008 and 2013 were retrospectively compared with 34 patients undergoing esophagectomy with open gastric tubulization (open), matched for neoadjuvant therapy, pathological stage, gender and age. Demographic data, tumor features and postoperative course (including quality of life and systemic inflammatory and nutritional status) were compared. Postoperative course was similar in terms of complication rate. Length of stay in intensive care unit was shorter in patients undergoing hybrid minimally invasive esophagectomy (P = 0.002). In the first postoperative day, patients undergoing hybrid minimally invasive esophagectomy had lower C-reactive protein levels (P = 0.001) and white cell blood count (P = 0.05), and higher albumin serum level (P = 0.001). In this group, albumin remained higher also at third (P = 0.06) and seventh (P = 0.008) postoperative day, and C-reactive protein resulted lower at third post day (P = 0.04). Hybrid minimally invasive esophagectomy significantly improved the systemic inflammatory and catabolic response to surgical trauma, contributing to a shorter length of stay in intensive care unit.
No preview · Article · Sep 2015 · Diseases of the Esophagus
[Show abstract][Hide abstract] ABSTRACT: Background:
Oesophagectomy for cancer could be safe and worthwhile in selected older patients, but less is known about the effect of oesophagectomy on perceived quality of life of such delicate class of cancer patients. The aim of this study was to evaluate the impact of oesophagectomy for cancer in elderly patients in term of health-related quality of life.
We retrospectively evaluated all consecutive patients who underwent oesophagectomy for cancer at the Surgical Oncology Unit of the Veneto Institute of Oncology between November 2009 and March 2014. Quality of life was evaluated using EORTC C-30 and OES-18 questionnaires at admission, at discharge and 3 months after surgery. Adjusted multivariable linear mixed effect models were estimated to assess mean score differences (MDs) of selected aspects in older (≥70 years) and younger (<70 years) patients.
Among 109 participating patients, 23 (21.1 %) were at least 70 years old and 86 (78.9 %) were younger than 70 years. Global quality of life was clinically similar between older and younger patients over time (MD 4.4). Older patients reported clinically and statistically significantly worse swallowing saliva (MD 17.4, 95 % C.I. 3.6 to 31.2), choking when swallowing (MD 13.8, 95 % C.I. 5.8 to 21.8) and eating difficulties (MD 20.1 95 % C.I. 7.4 to 32.8) than younger patients only at admission.
Early health-related quality of life perception after surgery resulted comparable in older and younger patients. This result may also be due to some predisposition of the elderly to adapt to the new status.
[Show abstract][Hide abstract] ABSTRACT: 50 % of esophageal cancers are inoperable at the time of diagnosis, and around 15 % involve the cervical esophagus. The hypopharynx is often involved by these malignancies as well. Palliation of cervical esophageal malignancies through stent insertion is considered limited due to technical challenges, poor patient tolerance and high complication rate. The aim of this study is to review our experience with stent insertion in the cervical segment of the esophagus and to evaluate outcome differences between stent insertions involving or sparing the hypopharynx.
We retrospectively reviewed data on 69 consecutive patients that underwent stent insertion for malignant strictures in the cervical esophagus at our Department. Patients were divided according to involvement or sparing of the lower hypopharynx. Dysphagia severity was measured with the Mellow-Pinkas scale before the procedure and on monthly follow-ups. Any complication and its management were recorded. The main outcome parameters were as follows: dysphagia improvement, rate of successful dysphagia palliation (i.e., a reduction of the score to 0 or 1 after stent insertion) and complication rate. Multivariable analysis was carried out to assess the influence of patient- and procedure-related factors on the outcome of the procedure.
Stent insertion was achieved in 100 % patients. At 4 weeks, dysphagia score improved from a median of 3-0 (p < 0.001), and a successful palliation was achieved in 76.8 % patients. The 30-day mortality rate was 14.5 %. Successful palliation throughout the follow-up was achieved in 72.9 % of the surviving patients. Complications occurred in 31.9 % patients. Dilation before stent insertion was associated with a less efficient short-term dysphagia palliation (OR 6.77, 95 % CI 1.46-31.29, p = 0.02).
Stent insertion is a safe and effective palliative treatment for malignant cervical esophageal strictures. Results are consistent even in patients with hypopharyngeal lesions. Dilation should be avoided before stent insertion.
No preview · Article · Apr 2015 · European Journal of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with cancer risk in esophageal adenocarcinoma (EAC). Adipose tissue directly stimulates tumor progression independently from body mass index (BMI), but the mechanisms are not fully understood. We studied the morphological, histological and molecular characteristics of peritumoral and distal adipose tissue of 60 patients with EAC, to investigate whether depot-specific differences affect tumor behavior. We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients. We treated OE33 cells with conditioned media (CM) collected from cultured biopsies of adipose tissue and we observed increased mRNA levels of leptin and adiponectin receptors, as well as two key regulator genes of epithelial-to-mesenchymal transition (EMT): alpha-smooth muscle actin (α-SMA) and E-cadherin. This effect was greater in cells treated with CM from peritumoral adipose tissue of patients with nodal metastasis and was partially blunted by a leptin antagonist. Therefore, peritumoral adipose tissue may exert a direct effect on the progression of EAC by secreting depot-specific paracrine factors, and leptin is a key player in this crosstalk.
[Show abstract][Hide abstract] ABSTRACT: Study objectives: Tumors of hypopharynx and cervical esophagus (HCE) are diagnosed late and long term survival is poor. Resective surgery is demolitive, frequently complicated and the quality of life is poor due to laryngectomy. The target of the study is the analysis of our results in management of HEC cancer.
Material and methods: 190 patients (pts) with SCC of HCE were treated at our institution from 1992 to 2010. Selection criteria were: no distant metastases, treatment consisting in primary surgery or first-line platinum-based chemoradiation (CRT). 22% of pts had hypopharynx involvement and 16% had a pure cervical esophageal cancer; the tumor involved both the cervical and upper thoracic esophagus in 54% of pts. Clinical stage was T3-4 in 164 pts (86%), and N+ in 129 pts (68%). 26 pts (14%) underwent primary surgery and 164(86%) were treated with first-line CRT. Pts who underwent first-line surgery had earlier tumors (T1-2 46%, N0 81%) than patients treated with first-line CRT (T3-4 92%, N+ 77%).
Main results: The larynx was preserved in 13/26 pts who underwent primary surgery; vocal cord palsy developed in 4/13. Anastomotic morbidity was 27% and medical complications were recorded in 54%. Postoperative mortality was 15.4%. 3-y and 5-y survival after surgery was 23% and 19%, respectively. First-line CRT was suspended due to toxicity in 7% of the pts with 3 toxic deaths. Clinical response was: complete response (CR) in 58 pts (41%) and partial response (PR) in 40 pts (28%). A clinical CR was obtained in all the 9 pts with a T1-2 tumor and in 17/32(53%) N-tumors. Resection surgery was performed in 18/58(31%) pts with a clinical CR (mostly due to recurrence) and in 23/40 (58%) pts with a clinical PR. Postoperative mortality after trimodality treatment was 4% (2/50). The overall 3-year and 5-year survival rate after chemoradiation was 29% and 22%, respectively. The 3-y and 5-y survival rate of pts with a clinical CR was 57% and 41%, respectively, and for pts with a clinical PR it was 39% and 33%, respectively.
Conclusion: Pts who underwent primary surgery had worse prognosis than those whom underwent first-line CRT, despite that they had earlier stage tumors. After first-line CRT, surgery for unresponsive or recurrent tumors was required in 50/164 pts (30%) with a 3-y and 5-y survival of 47% and 42% respectively. First-line CRT should be the treatment of choice for cancer of HCE reserving salvage surgery for unresponsive and recurrent tumors.
No preview · Article · Jan 2015 · European Journal of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms.
Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC).
We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes.
Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis.
[Show abstract][Hide abstract] ABSTRACT: In patients with ulcerative colitis (UC) the cumulative risk of colon cancer is lower than the actual rate of dysplasia suggesting an efficient immune surveillance mechanism. Since the co-stimulatory molecule CD80 is overexpressed in dysplastic colonic mucosa of UC patients and T-cell activation entails effective costimulation, we aimed to evaluate the functional implication of CD80 signaling in colonic UC-associated carcinogenesis. In humans, we observed that the percentage of CD80+ and HLA-A+ IEC was increased in the dysplastic colonic mucosa of UC patients. In vitro, IEC activated CD8+ T-cells through a CD80-dependent pathway. Finally, in the AOM/DSS-induced colonic adenocarcinoma model CD80 signaling inhibition significantly increased the frequency and extension of high-grade dysplasia, whereas enhancing CD80 activity with an anti-CTLA4 antibody significantly decreased colonic dysplasia. In conclusion, CD80 signaling between IEC and T-cells represents a key factor controlling the progression from low to high grade dysplasia in inflammatory colonic carcinogenesis.