Giovanni De Rosa

Monitoring Response to Primary Chemotherapy in Breast Cancer using Dynamic Contrast-enhanced Magnetic Resonance Imaging

AbstractPurpose. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer. Patients and methods. Thirty patients with breast cancer, clinical diameter >3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR). Results. Univariate analysis showed that a >65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438–464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263–23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5). Conclusions. DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Extra-nuclear signalling of estrogen receptor to breast cancer cytoskeletal remodelling, migration and invasion.

Background Estrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted. Methodology/Principal Findings In estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17β-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ERα with the G protein Gα13, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The Gα13/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane. Conclusions/Significance These results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear Gα13/RhoA/ROCK/moesin signaling cascade as a target of ERα in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.

Deletions of 17p are associated with transition from early to advanced colorectal cancer

Several chromosome defects parallel morphologic evolution in colorectal tumor progression. Allelic losses in the short arm of chromosome 17, the majority encompassing the 17p13.3 band, have been found in advanced cancer in the absence of TP53 mutations, suggesting that loss of genes in this chromosome region is relevant for tumorigenesis. The aim of this study was to investigate 17p13.3 deletions throughout the colorectal tumor progression using two-color fluorescence in situ hybridization. Histologic sections from 20 colorectal adenomas containing early invasive carcinoma were analyzed by interphase fluorescence in situ hybridization using a centromeric probe for chromosome 17 simultaneously with a subtelomeric probe mapping to the 17p13.3 band. Separate evaluation was made for sectors corresponding to adenoma tissue with low-grade dysplasia, high-grade dysplasia, and early cancer. The same technique was also used in 20 cases of advanced adenocarcinoma of the large bowel. Loss of one centromeric signal was observed in 20, 40, 50, and 10% of low-grade dysplasia, high-grade dysplasia, early cancer, and advanced cancer, respectively (P<0.02 early vs. advanced cancer). Subtelomeric 17p deletions were seen in 60% of advanced cancer and in 15% of early cancer (P<0.01). These findings indicate that loss of genes from the 17p13.3 chromosome region may play an important role in sustaining the transition from early to advanced cancer in colorectal tumor progression.

Clinical and radiological predictors of nipple-areola complex involvement in breast cancer patients

INTRODUCTION Nipple-areola sparing mastectomy (NSM) is increasingly used in patients with non-locally advanced breast carcinoma. Literature data on the preoperative assessment of the nipple-areola complex (NAC) are inconsistent. PATIENTS AND METHODS Out of 1359 patients submitted to total mastectomy between 2001 and 2010, we selected 61 patients whose pre-operative mammogram (MX) was available (MX group) and 39 patients who underwent preoperative breast magnetic resonance imaging (magnetic resonance imaging (MRI) group). The rate of NAC involvement, the value of MX and MRI to predict NAC involvement and the performance of the Schecters and Loewns algorithms for the prediction of NAC involvement were evaluated. RESULTS In the combined MX and MRI groups, NAC involvement was found in 14% of the cases. At univariate analysis, tumour stage (p value: 0.03), central tumour location (p value: 0.004), presence of NAC retraction (p value: 0.001) and tumour-NAC distance (p value: 0.006) were associated with NAC involvement, but only the latter parameter retained statistical significance at multivariate analysis (p value: 0.05). Tumour-NAC distance was a key predictor of NAC involvement, with a negative predictive value of 94% for MX and of 100% for MRI when the cut-off was set at 10mm. Overall, the performance of Schecters and Loewns algorithms was respectively lower and similar as compared to the original series. CONCLUSIONS Occult tumour involvement of the NAC is detected in a minority of breast cancer patients submitted to mastectomy. A tumour-NAC distance ≥ 10 mm by MRI may help select patients candidate to NSM.

Resection of liver metastases from colorectal mucinous adenocarcinoma: Is this a different disease? Results of a case-control study

Objectives:To compare outcomes following liver resection of colorectal metastases (CRLM) from mucinous adenocarcinoma (Muc-CRLM) versus nonmucinous adenocarcinoma (non-Muc-CRLM). Background:Among colorectal adenocarcinomas, 10%–15% are mucinous and have worse prognoses than nonmucinous ones. Outcomes of liver resection for Muc-CRLM remain unknown. Methods:Among 701 patients undergoing liver resection for CRLM between 1998 and 2012, 102 (14.6%) had Muc-CRLM. Each was matched with a non-Muc-CRLM patient, based on tumor N status, disease-free interval (DFI) between primary tumor and metastases, CRLM number and diameter, extrahepatic disease, and preoperative chemotherapy. Results:Within the 2 groups, 69.6% of patients had N+ primary tumor, 72.5% had DFI of less than 12 months, 28.4% had 4 or more CRLM, and 22.5% had associated extrahepatic disease. 59.8% of patients received preoperative chemotherapy. Muc-CRLM patients had higher prevalences of right/transverse colon cancer (55.9% vs 29.4%; P < 0.0001) and K-ras mutation (67 patients tested, 61.8% vs 36.4%; P = 0.037), as well as lower response to preoperative chemotherapy (63.9% vs 85.2%; P = 0.006). Multivariate analysis showed Muc-CRLM to have lower rates of 5-year overall (33.2% vs 55.2%; P = 0.010) and disease-free survival (32.5% vs 49.3%; P = 0.037). Muc-CRLM recurrence was more often peritoneal (20.3% vs 6.5%; P = 0.024) and at multiple sites (47.5% vs 21.0%; P = 0.002), and had lower rates of re-resection (16.9% vs 43.5%; P = 0.002) and 3-year post-recurrence survival (11.7% vs 43.4%; P = 0.0003). Conclusions:Muc-CRLM patients strongly differed from non-Muc-CRLM patients, showing a lower chemotherapy response and higher K-ras mutation prevalence. Muc-CRLM appears to be a separate disease, which is associated with worse survival and aggressive rarely re-resectable recurrences.

Complete remission of paraneoplastic vanishing bile duct syndrome after the successful treatment of Hodgkin’s lymphoma: a case report and review of the literature

BackgroundVanishing bile duct syndrome has been associated with different pathologic conditions (adverse drug reactions, autoimmune diseases, graft versus host disease, and cancer). Though its causes are unknown, an immune-related pathogenesis is the most likely one. Vanishing bile duct syndrome can evolve to hepatic failure and, eventually, to death. The treatment is uncertain, but it needs the resolution of the underlying pathologic condition.Case presentationWe describe the association of Hodgkin’s lymphoma with a syndrome characterized by cholestasis, aminotransferase elevation and an histological picture of bile duct loss. All other causes of hepatic function impairment were excluded (in particular, drugs, viral and autoimmune related diseases) eventually leading to the diagnosis of vanishing bile duct syndrome. Despite the fact that the dysfunction is not caused by hepatic Hodgkin’s lymphoma involvement, liver impairment can limit the optimal therapy of Hodgkin’s lymphoma. A treatment consisting of ursodeoxycholic acid, prednisone, and full dose chemotherapy restored hepatic function and achieved complete and long-lasting remission of Hodgkin’s lymphoma.ConclusionWe reviewed all case reports showing that vanishing bile duct syndrome is a dismal paraneoplastic syndrome being fatal in a high proportion of patients if not adequately treated. Indeed, this syndrome requires both an early recognition and an appropriate aggressive treatment consisting of full dose upfront chemotherapy which is the only way to achieve a resolution of the vanishing bile duct syndrome. Delayed or reduced intensity treatments unfavorably correlate with survival.

Mitochondrial DNA “common deletion” in post–fine needle aspiration infarcted oncocytic thyroid tumors

Thyroid fine needle aspiration (FNA) can rarely induce morphological changes potentially hindering the histopathological diagnosis, especially in Hurthle cell tumors (HCTs), which may easily undergo post-FNA infarction or necrosis. HCTs contain mitochondrion (mt)-rich cells that may bear mtDNA mutations, the most frequent being the so-called common deletion (CD). The aim of this study was to determine the presence and extent of the mtDNA CD in a series of thyroid HCTs that underwent extensive infarction following FNA procedure in comparison with a control series of HCTs lacking post-FNA ischemic/hemorrhagic alterations. Of 257 HCTs with available matched FNA and surgical specimens, 8 cases showed extensive (≥80%) infarction or necrosis in the resected nodule (4 adenomas, 1 carcinoma, 3 HCTs undefined for malignancy). Noninfarcted tumors in the control series included 9 adenomas, 1 carcinoma, and 1 follicular tumor of uncertain malignant potential. These lesions were significantly (P = .03) larger than infarcted nodules. The mtDNA CD was identified using semiquantitative real-time polymerase chain reaction in 2 of 8 (25%) infarcted tumors. In HCTs lacking infarction/necrosis of the control series, the CD was significantly (P = .05) more common (8/11 cases, 72.7%). In 7 of the 10 deleted cases, the CD was present also in the adjacent nonneoplastic parenchyma. In conclusion, the rare oncocytic tumors undergoing extensive infarction are smaller than those lacking ischemic changes and bear the mtDNA CD in a significantly lower proportion compared with control noninfarcted HCTs. This may suggest that mtDNA deletion confers a survival advantage to oncocytic cells in stress conditions, including FNA procedures.

Heterotopic spleen within the gastric wall mimicking a GIST: report of a case

Splenosis is the heterotopic autotransplantation of splenic tissue due to the traumatic or iatrogenic rupture of the spleen [1]. The incidence of this condition has been reported to complicate up to 58–67% of emergency splenectomies for trauma [2], albeit its real incidence is unknown since patients are usually asymptomatic and it is diagnosed as an incidental finding. However, in some circumstances splenosis determines acute symptoms or the recurrence of the same hematological disorders for which the patients had undergone splenectomy [3]. We herein report the case of a young, symptomatic woman with a heterotopic spleen located within the gastric wall mimicking, at preoperative imaging, a gastrointestinal stromal tumor (GIST) of the stomach.