[Show abstract][Hide abstract] ABSTRACT: BRCA1 overexpression and phosphoinositide 3-kinase (PIK3CA) pathway activation are involved in the resistance to DNA damaging agents. Thus, we hypothesized that BRCA1 protein expression and activating PIK3CA mutations are potential tumor biomarkers for the chemotherapeutic response to doxorubicin/cyclophosphamide plus docetaxel in locally advanced breast cancer. Informed consent was obtained and clinical, pathological and response data were collected. BRCA1 protein expression levels were assessed by immunohistochemistry of the archived tissue by two independent pathologists. The PIK3CA mutation status was assessed by nested PCR amplification and DNA sequencing. BRCA1 protein levels and the PIK3CA mutation status were correlated with pathological complete response and a partial response or better using the Chi-square test, Fisher's exact test and logistic regression. Of the 136 eligible participants, 59 samples could be analyzed. There was a trend of relatively low levels of BRCA1 protein achieving a pathological complete response (pCR), although this was not statistically significant [odds ratio (OR)=1.74; p=0.437]. Twenty-eight percent of patients had PIK3CA mutations, but no statistically significant association with pCR (OR=0.977; p=0.971) was noted. Neither BRCA1 protein levels (OR=1.18; p=0.818) nor PIK3CA mutations (OR=1.03; p=0.971) appeared to be associated with the likelihood of achieving a partial response or better from neoadjuvant chemotherapy. PIK3CA wild-type mutation status showed a trend towards an increased likelihood of not presenting with inflammatory disease (OR=5.34; p=0.101). In this exploratory study, neither BRCA1 protein expression levels nor the presence of PIK3CA mutations were significantly associated with chemotherapy response in locally advanced breast cancer. However, the relatively small sample size limits the overall interpretation.
[Show abstract][Hide abstract] ABSTRACT: Senescence is an irreversible growth arrest phenotype adopted by cells that has a key role in protecting organisms from cancer. There is now considerable interest in therapeutic strategies that reactivate this process to control the growth of cancer cells. Protein kinase-Cι (PKCι) is a member of the atypical PKC family and an important downstream mediator in the phosphoinositide-3-kinase (PI-3-kinase) pathway. PKCι expression was found to be upregulated in a subset of breast cancers and breast cancer cell lines. Activation of the PI-3-kinase pathway by introduction of mutant, oncogenic PIK3CA into breast mammary epithelial cells increased both the expression and activation of PKCι. In breast cancer cells lines overexpressing PKCι, depletion of PKCι increased the number of senescent cells, as assessed by senescence-associated β-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells in which PKCι is activated by loss of PTEN. Senescence occurred in the absence of a detectable DNA-damage response, was dependent on p21 and was enhanced by the aurora kinase inhibitor VX-680, suggesting that senescence is triggered by defects in mitosis. Depletion of PKCι had no effect on senescence in normal mammary epithelial cell lines. We conclude that PKCι is overexpressed in a subset of cancers where it functions to suppress premature senescence. This function appears to be restricted to cancer cells and inhibition of PKCι may therefore be an effective way to selectively activate premature senescence in cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Breast cancer 1 (BRCA1) protein inactivation in sporadic ovarian carcinoma (OC) is common and low BRCA1 expression is linked with platinum sensitivity. The clinical validation of BRCA1 as a prognostic marker in OC remains unresolved.
In 251 patient samples from the NCIC CTG clinical trial, OV.16, BRCA1 protein expression was determined by immunohistochemistry.
For all patients, when BRCA1 score was analyzed as a continuous variable, there was no significant correlation between BRCA1 protein expression and progression-free survival (PFS) [adjusted hazard ratio (HR) = 1.15 (0.96-1.37), P = 0.12] or response rate [HR = 0.89 (0.70-1.12), P = 0.32]. In the 116 patients with minimal residual disease (RD), higher BRCA1 expression correlated significantly with worse PFS [HR = 1.40 (1.04-1.89), P = 0.03]. Subgroup analysis divided patients with minimal RD into low (BRCA1 ≤2.5) and high (BRCA1 >2.5) expression groups. Patients with low BRCA1 expression had a more favorable outcome [median PFS was 24.7 and 16.6 months in patients with low and high BRCA1, respectively; HR = 0.56 (0.35-0.89), P = 0.01].
This study suggests that BRCA1 protein is a prognostic marker in sporadic OC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity.
Annals of Oncology 03/2011; 22(11):2403-10. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The solitary pulmonary nodule (SPN) is a common radiologic abnormality often detected incidentally. The majority of SPNs represent benign processes, including granulotmatous inflammation, bronchogenic cysts and hamartomata. However, a solitary nodule may also potentially represent an early stage of lung cancer or a metastasis. Diagnostic procedures such as percutaneous fine needle aspiration biopsy can exclude malignancy in a majority of cases and may eliminate the need for more invasive surgical procedure. Correlation of the findings on the FNAB with radiologic features is helpful in establishing the benignity.
We report the cytologic features of 6 cases of benign SPN: exogenous lipid pneumonia, sclerosing hemangioma, hemartoma, bronchogenic cyst, fungal granuloma and solitary fibrous tumor. We provide radiologic correlation for each entity and discuss the diagnostic pitfalls.
Cytologically, lack of nuclear atypia with bland chromatin is useful in separating benign from malignant SPN. Radiologically, smaller lesions with smooth, well-defined margins and calcifications are more likely to be benign. Our cases illustrate the cytologic and immunohistochemical features that can help to make a more precise diagnosis. The identification of these features, when correlated with imaging findings, allows the cytopathologist to better approach the SPN.
[Show abstract][Hide abstract] ABSTRACT: To evaluate preoperative diagnosis of low-grade urothelial carcinoma (LGUC) and urothelial neoplasms of unknown malignant potential (UMP UN) of the upper urinary tract (UUT) and its role in disease management, especially in the context of nephron-sparing treatment possibilities.
Wash and brush ureteral specimens of LGUC/UMP UN of the UUT with histopathologic correlation were retrieved at our institution for 7 years and studied along with 7 ureteral specimens from nonneoplastic ureteral lesions.
Of 30 specimens from 25 LGUC/UMP UN, 5 were negative for tumor cells and 3 showed cytologic atypia. The remaining 22 contained tumor cells with characteristic features of urothelial carcinoma, including hard and soft criteria. The 4 hard criteria included branching stromal cores, dyshesive cell networks, 3-dimensional papillary clusters with stromal core and atypia associated with CK20-positive cells. The 2 soft criteria were hypercellularity and atypia in CK20-negative cells. All LGUC/UMP UN of the UUT were associated with at least 1 hard criterion or both soft criteria.
Branching stromal cores, 3-dimensional papillary clusters, dyshesive cell networks and CK20-positive atypia immunostaining appear specific for LGUC/UMP UN of the UUT but are seen in few cases. Combined soft and hard criteria will increase sensitivity to 83%.
[Show abstract][Hide abstract] ABSTRACT: To investigate the reactivity for oestrogen and progesterone receptors (ER and PR) in renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC).
Thirty-eight RO, 25 CHRCC, 20 papillary RCC with oncocytic cytoplasm and 10 clear cell RCC with dominant eosinophilic cytoplasm were submitted for immunohistochemistry for ER, PR, CD117 and RCC.
All cases of RO and CHRCC displayed moderately positive reactivity for PR. The nuclear reactivity ranged from 60% to 90% in RO and from occasional cells to 70% in CHRCC. In CHRCC, reactivity tended to be more prevalent in areas of tumour cells with eosinophilic cytoplasm. Progesterone reactivity was focal in areas. All RO and most CHRCC were reactive for CD117 and neither RO nor CHRCC was reactive for RCC. CD117 reactivity tended to be more intense in CHRCC than in RO. Negative reactivity for CD117 and positive reactivity for RCC were observed in almost all RCC, as reported in the literature.
PR can be used in combination with CD117 and RCC in the differential diagnosis of RO and eosinophilic variant of CHRCC with other RCC with oncocytic or eosinophilic cytoplasm.
[Show abstract][Hide abstract] ABSTRACT: In the current study, we explore the diagnostic parameters and pitfalls in the follow-up of 123 cases of Pap smears diagnosed as high-grade atypical squamous cells (ASC-H) at our institution.
A computer database search was performed from the archives of the Ottawa Hospital Cytopathology Service for cases diagnosed with ASC-H between January 2003 and July 2005.
Follow-up of the 123 cases of ASC-H showed high grade squamous intraepithelial lesion (HSIL) in 73 patients (59.4%), low grade squamous intraepithelial lesion (LSIL) in 11 (8.9%), immature squamous metaplasia in 23 (18.7%), reactive squamous cell changes in 12 (9.8%), benign glandular lesions (endocervical atypia, degenerated glandular cells) in 2 (1.6%) and atrophy in 2 (1.6%). In our study, 83 patients were younger than 40 years (67.4%), with biopsy-proven HSIL found in 54 patients (65.1%). The remaining 40 patients (32.6%) were older than 40 years of age, and follow-up biopsies showed HSIL in 19 patients (47.5%).
In our study, 59.4% of the cases that were diagnosed cytologically as ASC-H were found to have HSIL on subsequent biopsies. This correlation was stronger in patients below the age of 40 years (65.1% vs. 47.5%). The cytopathologic feature most strongly associated with HSIL was the presence of coarse nuclear chromatin (84%).
[Show abstract][Hide abstract] ABSTRACT: Cystic neoplasms of the pancreas comprise a pathologically heterogeneous group of lesions that usually present with similar, nonspecific clinical features. Based on the diagnosis, treatment varies from watchful observation of the lesion to total surgical resection of the pancreas. Therefore the importance of a precise and accurate diagnosis on fine needle aspiration (FNA) biopsy cannot be overemphasized from the patient management standpoint. There is debate regarding the accuracy of FNA diagnosis of cystic lesions of the pancreas. We report 4 cases and review the literature to explore and highlight the cytologic findings and diagnostic pitfalls that may help the cytopathologist accurately distinguish mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), serous cystadenoma (SCA) and ductal adenocarcinoma (DAC).
We present 4 cases of patients with abdominal masses who underwent either computed tomography (CT)-guided or endoscopic ultrasound (EUS)-guided FNA biopsy as preoperative workup. Based on the cytologic diagnosis, the patients underwent surgery.
Our cases illustrate the cytologic criteria that help the cytopathologist distinguish among MCN, IPMN, SCA and DAC. Correlation with clinical and radiologic findings is strongly advocated for accurate diagnosis. We describe the diagnostic pitfalls frequently encountered in these cases and how to avoid them.