Anna Tomezzoli

Distribution of melanoma specific antibody (HMB-45) in benign and malignant melanocytic tumours. An immunohistochemical study on paraffin sections.

The distribution of a recently produced melanoma specific antibody (HMB-45) has been evaluated histochemically on paraffin sections in a large panel of melanocytic and non melanocytic tumours. Results have been compared with the presence of S-100 protein. HMB-45 was shown to be a highly specific antibody being present only in melanomas, junctional melanocytes and histogenetically related neoplasms such as melanocytic neuroectodermal tumour of infancy and, at low levels, on a proportion of peripheral nerve sheath tumours. The high specificity of HMB-45 antibody, coupled with the greater sensitivity of S-100, makes the combined use of these markers practical in the differential diagnosis of skin tumours and of metastatic lesions of uncertain primary site.

Recurrence of aortic insufficiency after aortic root remodeling with valve preservation

BACKGROUND Aortic root remodeling (ARR) has recently been proposed for patients with aortic aneurysms and valve insufficiency (AI). To define factors associated with a favorable functional outcome, a review of the mid-term results with ARR was undertaken. METHODS Between March 1994 and October 1997, 17 consecutive patients (11 men, 6 women), aged 57 +/- 11 years (range 35-71), had elective ARR for aortic aneurysm with or without annuloaortic ectasia (13), sinus of Valsalva aneurysm (3), or chronic aortic dissection (1). Moderate or severe AI was present in 11 patients (65%). Preoperative aortic root diameter was 58 +/- 5 mm (range 51-70). ARR involved replacement of all three aortic sinuses and coronary button reimplantation, using grafts with a mean diameter of 28 +/- 2 mm (range 24-30). RESULTS There was one early death (6%) due to multiple organ failure. Survivors were followed for 16 +/- 12 months (range 1-44). Actuarial 3-year survival was 94% +/- 6%. Discharge echocardiogram showed a decrease in AI in all patients: AI was absent in 11 (69%) and mild in 5 (31%). Recurrence of moderate or severe AI after a mean of 16 +/- 9 months (range 9-28) was noted in 6 patients (37%), 3 of whom had no AI at discharge. Five of 6 patients required aortic valve replacement. Comparison of demographic and operative variables showed that severe preoperative AI (67% vs 20%, p = 0.06), annuloaortic ectasia (100% vs 20%, p = 0.002), and cystic medial necrosis (100% vs 20%, p = 0.002) were significantly more prevalent in patients developing severe AI at follow-up. The 10 patients (63%) with absent AI showed durable competence of the valve and relief from symptoms at follow-up. CONCLUSIONS Despite early restoration of valve competence, AI may recur and progress after ARR at medium-term follow-up in a proportion of patients. The severity of preoperative AI and the nature of aortic root disease may negatively influence the durability of repair. Continued observation of results with ARR appears mandatory to identify the appropriate surgical candidates.

MET mutations in cancers of unknown primary origin (CUPs)

Cancer of unknown primary origin (CUP) defines metastatic disease of unknown origin, accounting for 3–5% of all cancers. Growing evidence demonstrates that inappropriate execution of a genetic program named “invasive growth,” driven by the MET oncogene, is implicated in the metastatic process. MET activation in cancers is mainly consequent to overexpression, whereas mutations are rarely found. We reasoned that the occurrence of MET somatic mutations might sustain premature occult dissemination of cancer cells, such as that observed in CUPs. We sequenced MET in genomic DNA obtained from 47 early metastatic cancers. By extensive immunohistochemical analysis a primary site was afterward postulated in 24 patients, whereas 23 cases remained of unknown primary (CUPs). MET somatic mutations were found in seven cases, all belonging to the CUP cohort. Mutational incidence (30%) was thus significantly higher than the expected one (4%), in the absence of high mutational background. Several nucleotide changes were novel and clustered either in the kinase domain or in the extracellular semaphorin domain. Mutated receptors were functional and sustained the transformed phenotype, suggesting that MET activating mutations are genetic markers associated with the CUP syndrome. Hum Mutat 31:1–7, 2010.

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: A phase 2 study.

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5‐fluorouracil (5‐FU) and concomitant radiotherapy (RT) in untreated stage II‐III adenocarcinoma and squamous cell carcinoma of mid‐distal thoracic esophagus.

hERG1 channels in human esophagus: evidence for their aberrant expression in the malignant progression of Barrett's esophagus.

Ion channels regulate a broad range of cellular activities. Alteration in ion channel function has been reported in different human pathologies, such as cardiac, neuromuscular, autoimmune diseases, and cancer. We investigated the expression of hERG1 K+ channels in the human upper gastrointestinal tract, focusing our attention on the lower esophagus. In particular, we analyzed by both Reverse transcription and polymerase chain reaction (RT‐PCR) and immunohistochemistry (IHC) endoscopic samples obtained from normal subjects, from patients suffering from gastroesophageal reflux, associated or not with esophagitis, and from patients affected by Barretts esophagus (BE), that is, intestinal metaplasia. None of the normal samples, nor those from patients with gastro‐esophageal reflux symptoms and reflux esophagitis expressed the hERG1 protein. On the other hand, 69% of patients with BE expressed hERG1. Since BE is a preneoplastic lesion, dysplasias (Ds) and adenocarcinomas (ADKs) arising on a previously diagnosed BE were also analyzed, and all the samples showed a high expression of the hERG1 protein. The surveillance of patients with BE showed that 89% of those who later developed ADKs displayed hERG1 expression. Data here reported, support the hypothesis that hERG1 expression marks an early step of the progression of normality to cancer in the human esophagus through a metaplastic and dysplastic stage. J. Cell. Physiol. 209: 398–404, 2006.

Classification of lymph node metastases from carcinoma of the stomach: Comparison of the old (1987) and new (1997) TNM systems

Abstract. The pN classification of gastric cancer is currently based on the distance of metastatic nodes from the primary tumor (TNM—1987). The UICC (Union Internationale Contre le Cancer) has recently proposed a new classification system based on the number of the involved nodes (TNM—1997). The present prospective study is aimed at verifying whether the two classifications (1) assign approximately a similar rank to individual patients and (2) give comparable prognostic information. The Cox regression model was used to evaluate the prognostic significance of either the distance or the number of positive nodes, controlling for sex, age, site, histology and depth of tumor invasion, in a group of 175 patients who underwent curative surgery for gastric cancer from March 1988 to October 1997. Among the patients classified as N1 and N2 according to TNM—1987, 81.8% (36/44) and 35.8% (19/53), respectively, were coded as N1 and N2 by the new classification. The survival probabilities of N1 and N2 categories were similar in both classifications. The N2 category of TNM—1987 comprised also 10 cases with >15 positive nodes (N3 category of TNM—1997), who presented a large excess mortality (RR = 35.14 with respect to N0). When the site and number of positive nodes are combined in a new variable, both appear to be important from a prognostic point of view. Both anatomic location and number of nodes with metastasis are important predictors of survival in gastric cancer patients. Caution should be used when replacing the old classification with the new one, as they group patients in a different way.

A clinical–biological risk stratification model for resected gastric cancer: prognostic impact of Her2, Fhit, and APC expression status

BACKGROUND To obtain a prognostic stratification model for resected gastric cancer patients. PATIENTS AND METHODS Clinicopathological and molecular data (expression of Cdx2, Apc, β-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios. RESULTS Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P < 0.0001) and OS (21.4% and 82.0%, P < 0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P < 0.0001) and OS (6.1%, 34.6%, and 86.5%, P < 0.0001). CONCLUSIONS A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.

Subtotal versus total gastrectomy for T3 adenocarcinoma of the antrum

BackgroundThe role of subtotal or total gastrectomy in the treatment of advanced gastric cancer of the antrum with serosal invasion was investigated.MethodsThe investigation involved 117 patients with a cancer of the lower third of the stomach invading the serosa (pT3) who underwent R0 resection with at least D2 lymphadenectomy between 1988 and 1998 at three different Italian centers. The choice of surgical procedure (40 total gastrectomies and 77 subtotal gastrectomies) was based on the preference of the surgeon; none of the patients underwent splenectomy. The Cox regression model was used to evaluate the prognostic significance of the type of surgery (subtotal versus total gastrectomy), controlling for age, sex, histology, nodal involvement, and surgical center.ResultsThe morbidity and mortality rates did not vary significantly according to the type of surgery. Patients undergoing subtotal gastrectomy presented a better disease-related survival than patients undergoing total gastrectomy (P = 0.011): the median survival times were, respectively, 38 months and 23 months, and the overall cumulative 5-year survival rates (95% confidence intervals [CI]) were, respectively, 36% (22%–50%) and 22% (11%–37%). On univariate analysis, the relative risk (RR) of disease-related death was 1.84 (1.14–2.97) after total gastrectomy, with respect to subtotal gastrectomy. This difference was blunted on multivariate analysis (RR, 1.66; 0.99–2.78): in the final model, only nodal metastasis was a significant prognostic factor, while type of surgery had a borderline significance (P = 0.057).ConclusionsSurvival after subtotal gastrectomy is not lower than that after total gastrectomy in patients with tumor of the antrum invading the serosa.

Prognostic significance of 67-kDa laminin receptor expression in advanced gastric cancer.

The ability of cancer cells to attach to laminin has been correlated with their metastatic potential and highly metastatic cancer cells seem to express on their surface significantly more laminin receptors than do their much less metastatic or benign counterparts. The expression of 67-kDa laminin receptors (LR) was investigated in a group of 75 patients who underwent gastrectomy for advanced gastric cancer, with special reference to the possible role in the tumor progression and in the overall survival. The tumor LR expression was immunohistochemically determined in paraffin-embedded sections using the MLuC5 monoclonal antibody which recognizes the 67-kDa LR and the avidin-biotin immunoperoxidase method. Of the 75 cases analyzed, 43 cases (57.3%) displayed a positive reaction. The cumulative 5-year survival rate was 72.6% (95% CI 52.5–85.3) for patients without expression of LR and 46.6% (29.8–61.8) for those with positive LR expression. A significant association between LR expression and depth of tumor invasion (0.022) was found. By univariate analysis the presence of laminin receptors seemed to be associated with a higher risk of death [RR 1.72 (95% CI 0.71–4.20], but this effect disappeared after controlling for depth of tumor invasion. In conclusion, these results suggest that tumor expression of laminin receptors could be correlated with tumor aggressiveness. However, the prognostic significance of laminin receptor expression is already provided by the depth of tumor invasion.

Loss of Fhit expression is associated with poorer survival in gastric cancer but is not an independent prognostic marker

Several studies have reported conflicting results regarding correlations of the loss of Fhit expression with clinicopathological parameters in gastric cancer. We investigated the immunohistochemical expression of Fhit in 362 cases of sporadic advanced gastric adenocarcinoma. The series included 64 cases with microsatellite instability associated with defective mismatch repair genes. Fhit expression resulted absent in 72% of the tumors analyzed. Absence of Fhit expression was more frequent in cases with diffuse and mixed histotype compared to the intestinal histotype (P=0.009). Absence of Fhit expression also correlated with tumor stage (P<0.001), lymph node involvement (P<0.001), presence of distant metastasis (P=0.033), and increasing histological grade (P=0.005). Retained Fhit expression also correlated with microsatellite instability as 61% of instable tumors had lost Fhit expression compared to 74% of microsatellite stable cancers (P=0.050). While loss of Fhit correlates with poorer survival in univariate analysis, it is not an independent prognostic factor in multivariate analysis and is thus not of clinical utility.