CDK4/6 and aromatase inhibitors as first-line treatment in metastatic high-grade neuroendocrine carcinoma of the breast: A case report.

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER-2 negative, we suggest that endocrine-based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Abstract: Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well-differentiated neuroendocrine tumors and poorly differentiated (high-grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first-line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER-2 negative, we suggest that hormonal therapy may play a leading role even in the first-line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs.

The association between sexually transmitted infections, human papillomavirus, and cervical cytology abnormalities among women in Greece.

OBJECTIVE: To investigate the diagnosis of sexually transmitted infections (STIs) with human papillomavirus (HPV) infection and the presence of cytological changes in the cervix in a cohort of sexually active women in Greece. METHODS: Cervical cytology testing and the molecular typing of HPV and other STIs were performed for 345 sexually active women aged between 18 and 45 years (mean 33.2±7.2years) visiting a gynaecology clinic for routine cervical screening. The association of HPV and STI detection with cytological findings was investigated. RESULTS: HPV was detected in 61 women (17.7%) and STIs in 82 (23.8%). Ureaplasma spp was the most frequently detected pathogen, which was found in 63 (18.2%) women, followed by Mycoplasma spp (21 women, 25.6%) and Chlamydia trachomatis (five women, 6.1%). HPV positivity only (with no co-presence of STI) was associated with an abnormal cytology (odds ratio 6.9, p<0.001), while women who were negative for both HPV and STIs had a higher probability of a normal cytology (odds ratio 0.36, p<0.01). Sixteen out of the 63 (25.4%) women who tested positive for Ureaplasma spp, harboured a high-risk HPV type (odds ratio 2.3, p=0.02). CONCLUSIONS: In a population with a high prevalence of Ureaplasma spp, there was an association of this pathogen with high-risk HPV infection, a finding that needs further elucidation.

Classification and regression trees for the evaluation of thyroid cytomorphological characteristics: A study based on liquid based cytology specimens from thyroid fine needle aspirations.

BACKGROUND: This study investigates the potential of classification and regression trees (CARTs) for the evaluation of thyroid lesions. METHODS: The study was performed on 521, histologically confirmed cytological specimens prepared via liquid based cytology. For each specimen, contextual and cellular morphology features were recorded by experienced cytopathologists, as described in everyday cytological practice and The Bethesda System (TBS); these features were subsequently used to construct two CART models, viz. CART-C for the prediction of the cytological diagnosis (according to TBS) and CART-H for the prediction of the histological diagnosis (hereby expressed as either benign or malignant). RESULTS: CART-C had no statistically significant performance from the cytologists' evaluations and CART-H had a very good predictive performance for the histological status. CONCLUSION: CARTs provide a methodological framework capable for data mining and knowledge extraction. They created simple human understandable rules and classification algorithms that may assist cytopathologists towards decisions based on classification steps, each one linked with a specific risk and moreover by applying cytomorphological characteristics in hierarchical order according to their importance. The two CARTs may be a useful tool for the training of nonexperienced cytopathologists; moreover, they may act as ancillary methods to avoid misdiagnoses and assist quality assurance procedures in the everyday practice of the cytopathology laboratory.

Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer.

AIM: To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy. METHODS: Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed. RESULTS: The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3'UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively). CONCLUSION: The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

Diagnostic value of a semi-nested PCR for the diagnosis of mucormycosis and aspergillosis from paraffin-embedded tissue: A single center experience.

OBJECTIVE: The main aim of our study was to investigate the diagnostic value of a molecular method for the diagnosis of mucormycosis and aspergillosis from formalin-fixed and paraffin-embedded (FFPE) tissues. METHODS: A retrospective chart review identified all cases with histology reports mentioning the presence of fungi with morphological characteristics of either Aspergillus or mucormycetes, for the period 2005-2012. Paraffin blocks were retrieved from the archives of the Department of Pathology. A semi-nested PCR specific for the detection of mucormycetes and Aspergillus species was applied in FFPE tissue from the above blocks. Results were compared with those of histological (gold standard) and microbiological methods. RESULTS: Twenty cases with fungal hyphae in tissue were revealed. Mucormycetes were detected in 9 cases (45%) by PCR, in only 4 of which culture was available. Species of Aspergillus were detected in 8 cases (40%) by PCR, two of which were co-infection with mucormycetes. Five patients had other fungi, non-detectable with this specific PCR. At least one sample per patient was positive by PCR. Seven out of 30 samples tested overall were false negative. The calculated sensitivity of this method in our setting was 79.3% (95% CI: 60.3-91.9%); specificity was 100%. CONCLUSIONS: The specific PCR used appears to be an easy and useful tool for the prompt and accurate diagnosis of mucormycosis and aspergillosis, in combination with histology and direct examination. Mucormycosis was more frequent than aspergillosis during the study period, highlighting the importance of continuous epidemiological surveillance of these serious infections.