An immunohistochemically positive E-cadherin status is not always predictive for a good prognosis in human breast cancer.

BACKGROUND: in primary breast cancers dichotomic classification of E-cadherin expression, according to an arbitrary cutoff, may be inadequate and lead to loss of prognostic significance or contrasting prognostic indications. We aimed to assess the prognostic value of high and low E-cadherin levels in a consecutive case series (204 cases) of unilateral node-negative non-lobular breast cancer patients with a 8-year median follow-up and that did not receive any adjuvant therapy after surgery. METHODS: expression of E-cadherin was investigated by immunohistochemistry and assessed according to conventional score (0, 1+, 2+, 3+). Multiple correspondence analysis was used to visualise associations of both categorical and continuous variables. The impact of E-cadherin expression on patients outcome was evaluated in terms of event-free survival curves by the Kaplan-Meier method and proportional hazard Cox model. RESULTS: respect to intermediate E-cadherin expression values (2+), high (3+) or low (0 to 1+) E-cadherin expression levels had a negative prognostic impact. In fact, both patients with a low-to-nil (score 0 to 1+) expression level of E-cadherin and patients with a high E-cadherin expression level (score 3+) demonstrated an increased risk of failure (respectively, hazard ratio (HR)=1.71, confidence interval (CI)=0.72-4.06 and HR=4.22, CI=1.406-12.66) and an interesting association with young age. CONCLUSIONS: the findings support the evidence that high expression values of E-cadherin are not predictive for a good prognosis and may help to explain conflicting evidence on the prognostic impact of E-cadherin in breast cancer when assessed on dichotomic basis.

Steroids as part of combination treatment: the future for the management of macular edema?

Diabetic macular edema (DME), defined as a retinal thickening involving or approaching the center of the macula, plays a major role in vision loss related to diabetic retinopathy. This article presents an in-depth analysis of therapeutic perspectives on DME by means of an approach based on combination therapy with steroids. Corticosteroid drugs have been demonstrated to both inhibit the expression of vascular endothelial growth factor (VEGF) and the VEGF gene, and to have antiinflammatory properties. A treatment algorithm is provided regarding the management of DME. While grid laser photocoagulation remains the first-line therapy for focal vasogenic DME, diffuse DME can be effectively treated by means of intravitreal injections of corticosteroids. Recalcitrant DME can also be managed beneficially with intravitreal steroids. The management of DME is complex, and often multiple treatment approaches are needed. Each form of DME should be properly classified and specifically treated. The combination treatment has still an important role in the combined treatment options for DME.

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.

Macular hole and intravitreal injection of triamcinolone acetonide for macular edema due to central retinal vein occlusion.

PURPOSE: To report a case of macular hole progression after intravitreal injection of triamcinolone acetonide (IVTA) for chronic macular edema secondary to nonischemic central retinal vein occlusion (CRVO). METHODS: A 33-year-old woman with massive macular edema after CRVO underwent IVTA. Optical coherence tomography (OCT) and fluorescein angiography were performed before and after the procedure. RESULTS: At the 1-week IVTA injection control, the patient's best-corrected visual acuity improved from 20/400 to 20/200 and OCT detected a progression of macular hole stage. CONCLUSIONS: IVTA steroid injection may provide a significant improvement in macular edema, but injection-related complications may occur such as this uncommon macular reaction resulting in permanent visual loss.

miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.

The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

Iris fluorescein angiography in clinical practice.

Iris fluorescein angiography is a valuable technique for elucidating a wide range of eye pathologies, among them developmental anomalies, degenerative disease, retinal vascular occlusions, diabetic microangiopathy, uveitis of various etiologies, glaucoma, tumor, and surgical or accidental trauma. In fact, IFA is more sensitive than biomicroscopy in the evaluation of iris abnormalities. Moreover, it provides indirect but reliable information on the retinal circulation when this cannot be examined directly. Some of the most important clinical applications involve the early detection of iris new vessels, cataract management in diabetic patients, and monitoring of iris tumors. Equipment, procedures, and fluorescein angiography patterns in normal and disease states are described and extensively illustrated. More widespread use of this valuable technique is encouraged.

Spontaneous regression of neovascularization at the disk and elsewhere in diabetic retinopathy.

PURPOSE: To report three cases of spontaneous regression of new vessels of the disk and elsewhere in proliferative diabetic retinopathy. METHODS: We retrospectively examined the clinical records of three young women (27, 26, and 19 years old) with insulin-dependent diabetes mellitus (for 16, eight, and 17 years, respectively) associated with other systemic diseases and referred to us for treatment of retinopathy. Complete general and ophthalmologic findings, visual field, and angiographic and electroretinographic examinations were available for each patient. RESULTS: All the patients showed marked, spontaneous improvement of their proliferative retinopathy, with regression of new vessels. Assessment of metabolic control did not bring to light any noteworthy change during the period when the new vessels disappeared. Regression of new vessels was associated with a marked improvement in blood-retinal barrier breakdown as detected on fluorescein angiograms. CONCLUSIONS: Although very unusual, spontaneous regression of neovascularizations in proliferative diabetic retinopathy can happen. We can offer no explanation for the regression of the new vessels and retinovascular hyperpermeability.

Relation between iridopathy and retinopathy in diabetes.

In order to assess the relation between diabetic iridopathy (DI) and retinopathy (DR), 225 eyes of 117 diabetics with clear media were evaluated. Each patient underwent iris and retinal fluorescein angiography, which was used to classify DI and DR. DI was classified as: absence of DI; non-proliferative DI; proliferative DI; neovascular glaucoma. DR was classified as: absence of DR; background DR; pre-proliferative DR; proliferative DR. The sensitivity of iris fluorescein angiography in assessing DR was 44.5%, the specificity 88%, the positive predictive value 92.8%, and the negative value 31.2%. In pre-proliferative and proliferative DR, fluoroiridographic detection of iris neovessels gave a sensitivity of 56% and a specificity of 100%. The positive predictive value was 100% and the negative value 65%. In conclusion, iris fluorescein angiography yields valuable information on DR and is a helpful basis for avoiding complications when scheduling eyes with dioptric media opacities for surgery.

Markers of insulin resistance are associated with cardiovascular morbidity and predict overall mortality in long-standing non-insulin-dependent diabetes mellitus.

The aim of this study was to evaluate the influence of endogenous insulin levels and of insulin administration on coronary heart disease (CHD) and on mortality in a cohort of patients with long-standing non-insulin-dependent diabetes mellitus (type 2). In a cross-sectional study, 93 patients (known duration 17 +/- 8 years, mean+/-SD) with poor metabolic control (glycosylated hemoglobin, HbA1C 9.3%+/-2.09%) were evaluated for CHD, for insulin release (C-peptide), for clinical and metabolic parameters including body mass index (BMI), smoking habits, arterial blood pressure (BP), blood lipids, kidney function, and proteinuria. Life status was ascertained 5 years later by direct examination or through death certificates. At entry, 54 out of 93 patients had CHD; after 5 years, 25 patients had died. Comparisons performed on patients of the same age range showed that patients with CHD (34 vs 24) had a greater BMI, higher diastolic BP, higher creatinine, triglyceride and uric acid levels, and higher fasting and i.v. glucagon-stimulated C-peptide release. By logistic stepwise regression analysis, fasting C-peptide and triglycerides were independently associated with CHD. In the follow-up study, surviving patients (39 vs 19) showed at baseline lower triglyceride and creatinine levels, were less frequently affected by CHD, and received lower doses of insulin; by logistic stepwise regression analysis, presence of CHD, dose of insulin, and creatinine levels were independent risk factors for mortality. These data indicate that in patients with long-standing type 2 diabetes mellitus and poor metabolic control, CHD and overall mortality are related to insulin release and to insulin administration, suggesting that markers of insulin resistance represent additional risk factors for CHD and for mortality. Reduction of insulin resistance, together with achievement of good metabolic control, might prevent morbidity and mortality in long-standing type 2 diabetes mellitus.

Macular thickness measured by optical coherence tomography (OCT) in diabetic patients.

PURPOSE: 1) To compare macular thickness (MT) by optical coherence tomography (OCT) in diabetics and controls; 2) to assess the relationship between MT and stage of diabetic retinopathy (DR) and macular edema (ME); 3) to quantify MT changes after laser treatment for ME. METHODS: One-hundred and thirty-seven patients with diabetes mellitus (216 eyes) were admitted to the study and examined by stereo-color fundus photos, retinal fluorangiography and OCT. DR was classified as: 1) no DR (46 eyes: 21.3%); 2) background DR (66 eyes: 30.6%); 3) pre-proliferative DR (50 eyes: 23.1%); 4) proliferative DR (54 eyes: 25%). The study group was then divided into three ME groups: 1) no edema (65 eyes: 30.1%); 2) not clinically significant ME (no CSME) (45 eyes: 20.8%); 3) clinically significant macular edema (CSME) (106 eyes: 49.1%). Three-month follow-up tomograms were taken to evaluate eyes laser-treated only for ME. The control group consisted of 50 eyes of 50 non-diabetic, age- and sex-matched subjects. RESULTS: MT was 369.3 +/- 163.2 microm in diabetics and 161.9 +/- 12.9 microm in controls (p < 0.001). In the four DR groups it was: 1) 211.0 +/- 37.6 microm; 2) 370.8 +/- 159.6 microm; 3) 419.1 +/- 138.2 microm; 4) 456.1 +/- 162.0 microm (p<0.001). In the three ME groups, MT was: 1)227.8 +/- 53.4 microm; 2) 321.8 +/- 124.2 microm; 3) 476.2 +/-146.6 microm (p < 0.001). In the 52 eyes treated with laser photocoagulation of the posterior pole only and with a follow-up > 3 months, MT before and after treatment was 468.2 +/- 83. 17 microm and 372.1 +/- 120.63 microm. CONCLUSIONS: MT was greater in diabetics than controls and tended to increase with DR and ME severity. OCT is a sensitive technique for detecting early diabetic macular abnormalities and quantifying their reduction after laser treatment.

Endoscopy as a tool for diagnosing and treating gastrointestinal angiodysplasia in haemodialysis patients.

Gastroenteric angiodysplasia is an important cause of haemorrhage in chronic renal failure patients. This paper reports on 2 patients on maintenance haemodialysis with upper gastrointestinal bleeding due to different manifestations of angiodysplasic lesions (sudden appearance of haematemesis and melaena in one case, progressive anaemia with apparent resistance to erythropoietin in the other case). Exploratory endoscope examination of the first digestive tract showed in both cases the presence of bleeding angiodysplasic lesions. Both patients were there and then submitted to surgical endoscopy, during which the bleeding angiodysplasic lesion was sclerosed with physiological salt solution plus adrenaline 1/10000 and 1% polydocanol. In one patient, bleeding occurred again ten days later, making renewed surgical endoscopy necessary. In the course of this an elastic ligature was made to the superangular angiodysplasia. A year later in both cases there were no direct or indirect signs of further bleeding; an endoscopic check-up showed the treated lesions to be sclerosed. Endoscopy offers the unique possibility of being used for both diagnostic and therapeutic purposes in a single session. In expert hands, endoscope therapy is effective and markedly reduces the risk of side effects.

[Treatment of acute biliary pancreatitis in the aged in the endolaparoscopic era]. / Il trattamento della pancreatite acuta biliare nell'anziano nell'era endolaparoscopica.

BACKGROUND: Acute biliary pancreatitis (ABP) still retains high morbidity (15-50%) and mortality (20-35%). Therefore it appears to be crucial to clearly assess the aetiological factors (50% of idiopathic are in fact biliary pancreatitis) and to establish the severity in order to plan the appropriate treatment. METHODS: In this study we have considered 61 patients divided into 2 groups. Group 1 had 29 ABP patients aging less than 65 years, group 232 patients aging more than 65 years; the diagnosis was made by ultrasound and serological values in 78.5% of cases, while in the remaining 21.5% was only serological. Following Ranson and APACHE II scoring 18 cases (29.5%) were classified as severe [6 (20.6%) in group 1; 12 (37.5%) in group 2: p < 0.01], 43 (70.4%) as mild. All patients with severe ABP had emergency ERCP + ES (within 24-48 hrs) followed by LC (< or = 10 days). Patients with mild ABP had LC within 10 days; in these cases IOC was always done. RESULTS: In severe cases operative endoscopy cured pancreatic inflammation in 13 cases. Subsequent LC never showed serious morbidity, apart subcutaneous emphysema in one case. In 5 cases laparotomy was required since pancreatic necrosis was present, with 60% mortality. In patients with mild pancreatitis LC was successfully performed in all cases, with 6.9% morbidity. IOC showed choledochal stones in 32.5% of cases, while in severe cases stones in the biliary tree were showed in 88.8% of cases. No significant differences were detected between group 1 and 2. CONCLUSIONS: In conclusion ABP treatment is always surgical, and almost always with minimally-invasive procedures in severe cases (ERCP + ES with LC < or = 10 days) if surgery is performed within 24-48 hrs as well as in mild cases (LC + IOC) when surgery is done within 10 days, independently from the age of the patients.

[Diagnosis of severity as a basic parameter in the treatment of acute biliary pancreatitis]. / La diagnosi di gravità come parametro fondamentale per il trattamento della pancreatite acuta biliare.

BACKGROUND: Acute biliary pancreatitis (ABP) still retains high morbidity (15-50%) and mortality (20-35%). Therefore it appears to be crucial to clearly assess the aetiological factors (50% of idiopathic are in fact biliary pancreatitis) and to establish their severity in order to plan the appropriate treatment. METHODS: 58 ABP patients were diagnosed by ultrasound (77.5%) or by laboratory findings (22.4%). Following Ranson and APACHE II scoring 17 cases (29.3%) were classified as severe, 41 (70.6%) as mild. All patients with severe ABP, had emergency ERCP + ES (within 24-48 hrs) followed by LC (< or = 10 days). Patients with mild ABP had LC within 10 days; in these cases IOC was always done. RESULTS: In severe cases operative endoscopy cured pancreatic inflammation in 12 cases. Subsequent LC never showed serious morbidity, apart from subcutaneous emphysema in one case. In 5 cases laparotomy was required since pancreatic necrosis was present, with 60% mortality. In patients with mild pancreatitis LC was successfully performed in all cases, with 7.3% morbidity. IOC showed choledochal stones in 31.7% of cases, while in severe cases stones in the biliary tree were shown in 88.2% of cases. CONCLUSIONS: In conclusion ABP treatment is always surgical, and almost always with minimally-invasive procedures in severe cases (ERCP + ES with LC < or = 10 days) if surgery is performed within 24-48 hrs as well as in mild cases (LC + IOC) when surgery is done within 10 days.

[Hypothesis of the correlation of personality characteristics and the clinical history of bronchogenic cancer]. / Ipotesi di correlazione tra caratteristiche di personalità e storia clinica del cancro broncogeno.

A correlation between the personality profile and the clinical history in lung cancer patients was studied. Selection of cases included in the sample only surgical patients with a medium educational level and a tested capability to understand a specific questionnaire. One hundred and seventy patients were selected and the so-called C.R.I.C.S. (Clinical-Rated Inventory of Character Style) was applied. Score variations were recorded after curative resection as well as during relapse. Changes in the character profile pattern were found in all subjects who experienced the disease and its surgical treatment. These changes occurred either in "regression"-with an increase of schizoid, narcissistic or hysterical aspects-or in a "positive evolution", with a decrease of paranoid traits and into a depressive position. The two groups of responses demonstrated a similar percentage.

[Acute biliary pancreatitis: mini-invasive treatment]. / Pancreatite acuta biliare: trattamento mini-invasivo.

Acute biliary pancreatitis (ABP) still retains high morbidity (15-50%) and mortality (20-35%). Therefore it appears to be crucial clearly assessing the aetiological factors (50% of idiopathic are in fact biliary pancreatitis) and establishing the severity in order to plan the appropriate treatment. Forty-nine ABP patients were diagnosed by ultrasound (75.5%) or by laboratory findings (22.5%). Following Ranson and APACHE II scoring, 15 cases (30.6%) were classified as severe, 34 (69.3%) as mild. All patients with severe ABP had emergency ERCP + ES (within 24-48 hours) followed by LC (< or = 10 days). Patients with mild ABP had LC within 10 days; in these cases IOC was always done. In severe cases operative endoscopy cured pancreatic inflammation in 11 cases. Subsequent LC never showed serious morbidity, but subcutaneous emphysema in one case. In 4 cases laparotomy was required since pancreatic necrosis was present, with 75% mortality. In patients with mild pancreatitis LC was successfully performed in all cases, with 8.8% morbidity. IOC showed choledochal stones in 32.5% of cases, while in severe cases stones in the biliary tree were showed in 80% of cases. In conclusion ABP treatment is always surgical, and almost always with minimally-invasive procedures in severe cases (ERCP + ES with LC < or = 10 days) if surgery is performed within 24-48 hours as well as in mild cases (LC + IOC) when surgery is done within 10 days.

[The endoscopic diagnosis of rectorrhagias]. / Diagnostica endoscopica delle rettorragie.

The diagnosis of bleeding of gastrointestinal low tract is still a very controversial subject. At the Service of Digestive Endoscopy of Popoli (PE) Hospital, in a period of 4 years, 2074 colonoscopies have been effected. In 640 cases, that is 30.8%, the indication for the exam was suggested by rectal bleeding. In the 566 patients examined for minor rectal bleeding, the most frequent lesions were: haemorrhoids (35.3%), polyps (15.2%), malignant neoplastic disease (9.3%). In all active rectal haemorrhages (14 massive, 41 medium) an urgent colonoscopy has been carried out with a percentage of success of 90%; in the 20 cases of unexplained melena, colonoscopy has not led to a diagnosis; in the 14 patients with unexplained anemia, colonoscopy has shown 2 carcinomas, whereas in the 5 cases with occult blood in stools it has been diagnostic in the percentage of 60%. We have ascertained that, when barium enema was effected before colonoscopy, the diagnostic agreement between the two examinations was only of 21.4 (9/42); on the contrary there was an agreement of 95% when colonoscopy was effected before barium enema. In accordance with Siewert and Blum (25), Ottenjann (24) and Farrands (42), we believe that colonoscopy should be considered the main examination after either major or minor rectal bleeding, because it is a quick and safe investigation with high diagnostic specificity and sensitivity. We refuse William's position (41), because, even in presence of haemorrhoids or anal fissures, the colon must be studied as a whole, especially in a period when neoplastic disease of this tract of intestine is considerably increasing.(ABSTRACT TRUNCATED AT 250 WORDS)

[Endoscopic treatment of the "cul de sac" syndrome: our experience]. / Il trattamento endoscopico della sindrome del "cul di sacco": nostra esperienza.

The "Sump Syndrome" represents a known late complication not easily recognizable within the interventions of CDS and L-L CDS. Its incidence ranges from 0% to 9.6% according to the literature. Up to ten years ago the "Sump Syndrome" treatment was mostly surgical. Currently endoscopic treatment reduces considerably the operative risk and the number, frequency and severity of complications. The technique consists of an endoscopic papillosphincterotomy with removal of calculus, gall mud, alimentary fragments and restoration of a satisfactory flow towards the duodenum. From January 1985 to October 1993, 492 ERCP were performed in Popoli's Hospital Digestive Department with an overall success rate of 92% and a selective incannulation success rate of 87%. Endoscopic treatment was used in 56% of the cases (319 patients) with 90% of success; 271 patients (35%) with lithiasic pathology were examined and 35 (12.9%) of them presented the "Sump Syndrome". Six patients underwent operation, 2 had no treatment and 27 underwent endoscopic treatment. In 21 cases an endoscopic papillotomy was performed and in 6 cases a bile-duct washing or calculi fragmentation was assured; 21 patients recovered completely while 6 patients still refer a painful-dyspeptic symptomatology with occasional colics which could be related to phenomena of chronic pancreatitis. The clinical experience allowed us to positively evaluate the endoscopic treatment of the "Sump Syndrome" since it carries a low mortality and morbidity rate and, furthermore, it is easily repeatable.

Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.

Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.

Dual targeting of ErbB-2/ErbB-3 results in enhanced antitumor activity in preclinical models of pancreatic cancer.

ErbB-3 and its ligand NRG-1ß are key players in driving oncogenic signaling and resistance to therapy through the activation of the PI3K/Akt pathway. We have recently reported that EV20, a humanized anti-ErbB3 antibody, possesses a marked antitumor activity in a variety of human tumor models, including pancreatic cancer (PC). Here, we report that despite epidermal growth factor receptor overexpression, PC cells are more sensitive to NRG-1ß than EGF in terms of Akt activation and cell proliferation. Using stable ErbB-3-knocked down cells and EV20 in combination with trastuzumab, we showed that dual targeting of ErbB-2 and ErbB-3 was necessary to completely abrogate ErbB-3 signaling and to impair cell proliferation. Similarly, enhanced therapeutic efficacy of the antibody combination was seen in xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells, without increasing the toxicity. These results indicate that dual targeting of ErbB-2 and ErbB-3 could represent a new therapeutic approach in PC.Oncogenesis (2014) 3, e117; doi:10.1038/oncsis.2014.31; published online 18 August 2014.

The Trop-2 signalling network in cancer growth.

Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-κB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-κB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.