ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer

Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.POCI/CVT/62940/2004 and by the PhD grants (SFRH/BD/23406/2005 and SFRH/BD/31754/2006, of the Science and Technology Foundation (FCT) from Portugal

EGFR expression and activation are common in HER2 positive and triple-negative breast tumours

EGFR has been associated with unfavourable prognosis in patients with triple-negative breast carcinomas, although little is known about EGFR activation in these tumours. In a series of breast carcinomas (archived formalin fixed tumours, n=100), we investigated EGFR phosphorylation status at Tyr992 (pEGFR-Y992) and Tyr1068 (pEGFR-Y1068) by immunohistochemistry, along with EGFR protein expression (extracellular domain), gene amplification status (fluorescent in situ hybridization) and conventional clinicopathologic parameters. EGFR protein was present in 21.9%, while phosphorylation at Y1068 and Y992 was observed in 27.8% and 50.5% of tumours, respectively. None of the tumours showed EGFR gene amplification, whereas 21.1% exhibited chromosome 7 polysomy. The above EGFR parameters were usually not simultaneously detected and were not associated with each other. High grade (p=0.003), lymph node positive (p=0.045), estrogen receptor (ER) negative (p<0.001) tumours often expressed EGFR protein. EGFR-Y992 and Y1068 phosphorylation was inversely associated with ER presence (p=0.023 and p=0.029, respectively) but positively with HER2 expression status (p<0.001 and p=0.002, respectively). The global positivity for any EGFR parameter did not significantly differ between triple-negative and HER2 positive tumours. In conclusion, EGFR phosphorylation is commonly encountered in breast carcinomas, although unrelated to EGFR protein presence and gene amplification. EGFR may appear activated even in cases where the extracellular domain of this protein is not observed with immunohistochemistry. These findings may be useful for further studies aiming at the assessment of EGFR parameters on this type of materia

Targeting Bruton Tyrosine Kinase: A novel strategy in the treatment of B-cell lymphomas

In normal B-cells, Bruton tyrosine kinase (Btk), a non-receptor tyrosine kinase involved in B-cell receptor (BCR) signalling, is essential for cell survival and maturation. Not surprisingly, Btk is also implicated in the pathogenesis of B-cell lymphomas, like Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinemia (WM), which are driven by aberrant BCR signalling. Thus, targeting Btk represents a promising therapeutic strategy in the treatment of B-cell lymphoma patients. Ibrutinib, a selective Btk inhibitor, has already been approved as second-line treatment of CLL/SLL, MCL and WM patients, while more clinical studies of ibrutinib and novel Btk inhibitors are currently under way. In light of results of the RESONATE-2 trial, the approval of ibrutinib as a first-line treatment of CLL/SLL may well be approaching. Herein, we review Btk’s role in normal and malignant BCR signalling, as well as ibrutinib’s performance in B-cell lymphoma treatment and prognosis

Primary hepatocellular carcinoma in a patient with history of treated breast cancer: a case report with challenging diagnosis and treatment

Christoforos Kosmidis,1 Nikolaos Varsamis,1 Georgios Anthimidis,1 Sofia Baka,2 Dimitrios Valoukas,3 Triantafyllia Koletsa,4 Katerina Zarampouka,4 Georgios Koimtzis,5 Eleni Georgakoudi,6 Paul Zarogoulidis,7 Christoforos Efthymiadis1 1Department of Surgery, Interbalkan European Medical Center, Thessaloniki, Greece; 2Department of Oncology, Interbalkan European Medical Center, Thessaloniki, Greece; 3Department of Oncology, General Hospital of Ptolemaida, Ptolemaida, Greece; 4Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Third Surgical Department, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 6Aristotle University of Thessaloniki, Thessaloniki, Greece; 7Pulmonary-Oncology Unit, &ldquo;Theageneio&rdquo; Cancer Hospital, Thessaloniki, Greece Introduction: Breast cancer is the most common malignancy in women worldwide. Long-term survivors among patients treated for breast cancer are at a high risk for developing a&nbsp;second primary malignancy. Hepatocellular carcinoma is the most frequent primary hepatic malignancy and should be ruled out in breast cancer patients who are diagnosed with solitary hepatic lesions. False diagnosis may lead to inappropriate oncologic staging and treatment of the disease. Case presentation: We present the case of a 73-year-old female patient who had been treated for invasive ductal breast cancer 7 years ago and was diagnosed with a solid hepatic lesion at segments VI and VII and a small, calcified lesion at the tail of the pancreas on follow-up with an abdominal computed tomography. Oncology council decided that both lesions could be resected after determining whether they were metastatic or second primary malignancies. The patient underwent laparotomy and rapid biopsy which showed primary hepatocellular carcinoma and fibrosis of the pancreas. We performed hepatic segmentectomy (VI&ndash;VII) and cholecystectomy, while the pancreatic lesion was left intact. The postoperative course of the patient was uncomplicated and she remains disease free 2 years after the operation without any adjuvant therapy. Conclusion: All hepatic lesions detected in breast cancer patients should be evaluated with open mind and liver biopsy should be performed to get a definitive diagnosis and implement the proper treatment strategy. Keywords: breast cancer, hepatocellular cancer, second primary malignancy, rapid biopsy, microwave tissue coagulato

Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas

The serine/threonine kinase B-Raf plays a key role in the Ras/Raf/MEK/ ERK pathway that relays extracellular signals for cell proliferation and survival. Several types of human malignancies harbor activating BRAF mutations, most frequently a V600E substitution. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small cell lung carcinomas harboring activating EGFR TK domain somatic mutations. We evaluated the presence of mutations in BRAF (exons 11 and 15), KRAS (exons 1 and 2), NRAS (exons 1 and 2), and EGFR (exons 18-21) in adrenal carcinomas (35 tumor specimens and two cell lines) by DNA sequencing. BRAF mutations were found in two carcinomas (5.7%). Four carcinomas (11.4%) carried EGFR TK domain mutations. One specimen carried a KRAS mutation, and another carried two NRAS mutations. No mutations were found in the two adrenocortical cell lines. BRAF- and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases than their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared with wild-type carcinomas. We conclude that BRAF, RAS, and EGFR mutations occur in a subset of human adrenocortical carcinomas. Inhibitors of the Ras/Raf/MEK/ERK and EGFR pathways represent candidate targeted therapies for future clinical trials in carefully selected patients with adrenocortical carcinomas harboring respective activating mutations. © 2009 Society for Endocrinology

Prognostic indicators for mycosis fungoides in a Greek population

Background: Mycosis fungoides (MF) is an indolent cutaneous lymphoma with excellent prognosis at early stages and much poorer outcome during disease progression. Old age, male sex and folliculotropism have been proposed as relevant prognostic factors; however, their exact effect remains debatable. Objectives: To evaluate MF prognostic indicators and survival rates in a Greek population. Methods: Prognostic variables affecting survival rates were studied in 473 patients with MF diagnosed and treated by two academic referral centres in Greece. Kaplan–Meier estimates were used to determine survival rates and progression. The Cox proportional hazards regression model was used to assess prognostic factors. Results: The mean age of diagnosis was 61·7 years (SD 16·33). Five-year disease-specific survival was 96% in patients with stage IA disease and 52% in patients with stage IIB disease. Univariate analysis certified that large-cell transformation, clonal rearrangements of the TCR gene, severe pruritus and presence of plaques were the most important prognostic factors. Folliculotropism altered disease progression only in patients with early-stage disease. The application of the Cutaneous Lymphoma International Prognostic Index (CLIPI) on our late-stage group failed to provide reliable evidence. The current Cutaneous Lymphoma International Consortium (CLIC) prognostic index can efficiently distinguish a low-risk from a high-risk group of patients. Tumour–Node–Metastasis–Blood (TNMB) staging was the most important prognostic factor for survival rates in multivariate analysis. Conclusions: In our study we validated the current prognostic indicators for MF in a Greek population and identified new potential prognostic factors for survival outcome. Our findings contribute to the ongoing investigation of prognostic indicators of MF, further validation of which is highly needed through prospective studies and among different populations. © 2016 British Association of Dermatologist

Management of peritoneal hydatid cysts: A forty-year experience

Background: Hydatid disease is a global problem. We report our experience with such cases where the dominant cysts were located outside the liver and lungs. In particular, these cysts were found in the peritoneum which is an uncommon location. Methods: Between 1967 and 2007 a total of 34 patients were operated for primary or secondary peritoneal cysts. Most of the patients were asymptomatic or had atypical symptoms. The diagnosis was based on the preoperative history, rupture of the cysts, serology, ultrasound (USS) and computer tomography (CT). Open surgery was the procedure of choice with conservative (18 cysts) and radical (25 cysts) methods. Results: The outcome of surgery was good without postoperative mortality or severe morbidity and the recurrence rate was 23.5%. Conclusions: Conservative surgery can provide good results in symptomatic peritoneal cysts. Radical therapy is also ideal but only in properly selected cases. The management of this situation is difficult requiring sound operative experience preferably with a one-stage procedure after an appropriate preoperative preparation