Percutaneous atrial shunt closure and the risk of recurrent ischemic stroke: A register-based, nationwide cohort study.

OBJECTIVES: We aimed to investigate the risk of recurrent stroke in patients with transcatheter closure of an atrial shunt (ASCIos), compared to patients with an atrial shunt and cerebrovascular event (CVE) but only medical treated (ASMed), and to age- and sex-matched control individuals without a previous CVE. METHODS: In total, 663 ASCIos patients were identified in the Swedish National Patient Register from 1997 to 2016 and matched by using propensity score with 663 ASMed patients. Nine age- and sex-matched controls to ASCIos patients (n = 6,302) without a diagnosis of atrial shunt or history of CVE were randomly selected from the general population. RESULTS: At a mean follow-up of 6.5 years, the incidence rate of recurrent stroke in the ASCIos group vs ASMed group was 0.9 vs 0.7 per 100 patient-years. The hazard ratio of recurrent stroke in the ASCIos group compared with index stroke in the control group was 9.9 (95% confidence interval, 5.5-17.9). The incidence of atrial fibrillation was similar in the ASCIos and the ASMed group, however four times higher in the ASCIos than in the control group. CONCLUSIONS: Our large nationwide, register-based cohort study showed that, unexpectedly, the risk of recurrent stroke in the ASCos group was as high as in the ASMed group and almost ten times higher than the risk of an index stroke in matched controls without previous stroke.

Incidence, time trends and survival patterns of childhood pilocytic astrocytomas in Southern-Eastern Europe and SEER, US.

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N = 552; 1983-2014) and SEER (N = 2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/106, doubling in the USA (8.2/106). Increasing trends, more prominent during earlier registration years, were recorded in both areas (SEE: +4.1 %, USA: +4.6 %, annually). Cerebellum comprised the most common location, apart from infants in whom supratentorial locations prevailed. Age at diagnosis was 1 year earlier in SEE, whereas 10-year survival was 87 % in SEE and 96 % in SEER, improving over time. Significant outcome predictors were age <1 year at diagnosis diagnosis (hazard ratio, HR [95% confidence intervals]: 3.96, [2.28-6.90]), female gender (HR: 1.38, [1.01-1.88]), residence in SEE (HR: 4.07, [2.95-5.61]) and rural areas (HR: 2.23, [1.53-3.27]), whereas non-cerebellar locations were associated with a 9- to 12-fold increase in risk of death. The first comprehensive overview of childhood PA epidemiology showed survival gains but also outcome discrepancies by geographical region and urbanization pointing to healthcare inequalities. The worse prognosis of infants and, possibly, females merits further consideration, as it might point to treatment adjustment needs, whereas expansion of systematic registration will allow interpretation of incidence variations.

Cutaneous lesions in a COVID-19 patient leading to a surprising diagnosis.

Differential diagnosis of skin lesions is broad. Cutaneous metastases should always be considered in the appropriate clinical and laboratory context to ensure accurate diagnosis. https://bit.ly/400Msre.

Papillary carcinoma of the male breast: report of a case.

Intracystic papillary carcinoma of the male breast represents an extremely rare entity that accounts for less than 1% of all malignancies, and histologically may range from papillary hyperplasia in gynecomastia to invasive papillary carcinoma. This report presents the case of a 61-year-old Caucasian man who presented with a 5-year history of a centrally located painless swelling of his right breast with occasional nipple discharge. Triple assessment was very helpful in establishing the diagnosis. Treatment included a mastectomy and hormonal therapy because the neoplasm expressed hormone receptors. Although male breast carcinomas tend to behave more aggressively than their female counterparts, the prognosis of this neoplasm is excellent.

Fine needle aspiration cytology in primary breast angiosarcoma: a case report.

BACKGROUND: Angiosarcoma of the breast is an uncommon, aggressive, vascular tumor. The cytomorphologic features of angiosarcomas have rarely been reported. CASE: The present study describes a case of breast angiosarcoma initially diagnosed by fine needle aspiration cytology. Angiosarcoma appeared in the left breast of a 58-year-old woman after 12 years of a mastectomy (without radiotherapy) of the contralateral breast for invasive ductal carcinoma. Fine needle aspiration cytology yielded very bloody material with moderate cellularity. Microscopically, two types of cells were observed: spindle cells and epithelial-like cells with nuclear atypia. The latter were arranged in tight clusters with papillary configuration. Both cell types exhibited immunoreactivity for endothelial markers. The diagnosis of angiosarcoma was confirmed by histopathology of the surgically excised tumor. CONCLUSION: Angiosarcoma rarely occurs in the breast, and a definitive diagnosis is extremely difficult relying exclusively on cytologic features. Predominance of epithelioid cells may suggest an epithelial tumor, especially in patients with a history of breast carcinoma, whereas predominance of spindle cells can be misinterpreted as phyllodes tumor or another type of sarcoma. Cell block immunocytochemistry and tumor cell labeling with endothelial markers are necessary for accurate diagnosis.

Imatinib mesylate inhibits proliferation and exerts an antifibrotic effect in human breast stroma fibroblasts.

Tumor stroma plays an important role in cancer development. In a variety of tumors, such as breast carcinomas, a desmoplastic response, characterized by stromal fibroblast and collagen accumulation, is observed having synergistic effects on tumor progression. However, the effect of known anticancer drugs on stromal cells has not been thoroughly investigated. Imatinib mesylate is a selective inhibitor of several protein tyrosine kinases, including the receptor of platelet-derived growth factor, an important mediator of desmoplasia. Recently, we have shown that imatinib inhibits the growth and invasiveness of human epithelial breast cancer cells. Here, we studied the effect of imatinib on the proliferation and collagen accumulation in breast stromal fibroblasts. We have shown that it blocks the activation of the extracellular signal-regulated kinase and Akt signaling pathways and up-regulates cyclin-dependent kinase inhibitor p21(WAF1), leading to the inhibition of fibroblast proliferation, by arresting them at the G(0)/G(1) phase of the cell cycle. Imatinib inhibits more potently the platelet-derived growth factor-mediated stimulation of breast fibroblast proliferation. By using specific inhibitors, we have found that this is due to the inhibition of the Akt pathway. In addition, imatinib inhibits fibroblast-mediated collagen accumulation. Conventional and quantitative PCR analysis, as well as gelatin zymography, indicates that this is due to the down-regulation of mRNA synthesis of collagen I and collagen III-the main collagen types in breast stroma-and not to the up-regulation or activation of collagenases matrix metalloproteinase 2 and matrix metalloproteinase 9. These data indicate that imatinib has an antifibrotic effect on human breast stromal fibroblasts that may inhibit desmoplastic reaction and thus tumor progression.

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance.

To evaluate whether HER2 mRNA could be used as a marker of circulating tumor cells (CTCs) in women with operable breast cancer. A nested RT-PCR assay was developed and used for the detection of HER2 mRNA-positive CTCs. Blood from 216 women with early breast cancer obtained before adjuvant treatment was tested for HER2 mRNA-positive cells to assess their prognostic value. Nested RT-PCR for HER2 mRNA showed high sensitivity whereas no HER2 mRNA-positive cells could be identified in the blood of healthy donors. HER2 mRNA-positive CTCs were detected in 53 (24.5%) of 216 patients and HER2 mRNA detection was associated with reduced disease-free survival (DFS; P < 0.0001) and overall survival (OS; P = 0.004). In multivariate analysis, detection of HER2 mRNA-positive CTCs emerged as independent prognostic factor for DFS (P = 0.0001) and OS (P = 0.003). HER2 mRNA could be a valuable prognostic marker for the detection of CTCs in early breast cancer patients.

Correction to: The role of intra-articular administration of Fetuin-A in post-traumatic knee osteoarthritis: an experimental study in a rat model.

Following publication of the original article [1], the authors opted to correct the middle initial of co-author Despina N. Perrea from S to N. The original article has been corrected.

The role of intra-articular administration of Fetuin-A in post-traumatic knee osteoarthritis: an experimental study in a rat model.

 BACKGROUND: The purpose of this study is to investigate the possible attenuating role of the intra-articular administration of Fetuin-A in post-traumatic secondary osteoarthritis in rats, and also its effect on the systematic levels of interleukins (ILs)-2,4,7, bone morphogenetic proteins (BMPs) 2, 4, 7, C-Reactive Protein (CRP) and Fetuin-A. METHODS: Thirty male Sprague Dawley rats were separated in two groups where post-traumatic osteoarthritis was induced surgically by Anterior Cruciate Ligament Transection and the transection of the Medial Collateral Ligament of the right knee. In the Control Group, only the surgical intervention took place. In Fetuin Group, along with the induction of osteoarthritis, a single dose of bovine fetuin was administrated intra-articularly, intra-operatively. Both groups were examined for 8 weeks. The levels of interleukins, bone morphogenetic proteins, Fetuin-A and C-Reactive Protein were evaluated by ELISA of peripheral blood in three time periods: preoperatively, 5 and 8 weeks post-operatively. Osteoarthritic lesions of the knee were classified according to the Osteoarthritis Research Society International Grading System and the Modified Mankin Score, by histologic examination. RESULTS: IL-2 levels were significantly decreased in the Fetuin Group. No statistical difference was signed on the levels of IL-7, BMP-2,4,7 and Fetuin-A between the two groups. CRP levels were significantly increased in the Fetuin Group in 5 weeks of the experiment. Fetuin Group signed better scores according to the OARSI classification system and Modified Mankin Score, without any statistical significance. CONCLUSIONS: Intra-articular administration of Fetuin-A restrictively affected the progression of post-traumatic arthritis in rats, as only the levels of IL-2 were decreased as well as limited osteoarthritic lesions were observed on the Fetuin Group.

Expression and Clinical Significance of Claudin-7, PDL-1, PTEN, c-Kit, c-Met, c-Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in Triple-negative Breast Cancer-A Single Centre Prospective Observational Study.

BACKGROUND/AIM: To explore the relationship between p53, p63, c-kit, Ki67, cMet, claudin7, CK5/6, CK17, AR, PTEN, EGFR, ALK, PDL-1 and c-MYC expression with the clinicopathological features of triple- negative breast cancer. MATERIALS AND METHODS: Immunohistochemistry was performed in 84 triple-negative breast cancer samples. RESULTS: A statistically significant relationship between tumour grade and claudin-7 (p=0.004) and between protein p53 and positive lymph nodes (p=0.015) was found. High expression of claudin-7 (OR=65.8, 95%CI=4.35-995.19, p-value=0.003) and low expression of c-kit (OR=0.14, 95%CI=0.025-0.793, p-value=0.026) and protein p63 (OR=0.18 95%CI=0.035-0.978, p-value=0.047) was associated with higher tumour grade. Higher AR expression (OR=13.44, 95%CI=1.28-141.56, p-value=0.031) and lower expression of CK5/6 cytokeratins was found in patients with positive lymphovascular invasion (LVI) (OR=0.072, 95%CI=0.007-0.732, p-value=0.026). Only the cell proliferation index (Ki67) has been proven to be statistically significant for disease-free survival (p-value=0.0378), and overall survival (p-value=0.0186). CONCLUSION: High expression of claudin-7 and low expression of c-kit and protein p63 are associated with higher tumour grade. AR and CK5/6 expression seem to be important in LVI.

Small cell carcinoma of the stomach: A report of two cases and a review of the literature.

Primary small cell gastric carcinomas (SCGC) are rare tumors with an aggressive nature, characterized by early, widespread metastases and poor overall prognosis. SCGC shares similar clinicopathological and molecular characteristics with small cell lung carcinoma and is usually treated in a similar manner. Here, two cases of SCGC in young Caucasian male patients are presented. One patient had metastatic and the other locoregional disease. Multimodal treatment was applied in each case; the resulting survival time was 20.2 months in the patient with initially locoregional disease whereas the remains alive and disease-free 20 months after initial diagnosis. A review of the literature is also presented.

Comparison of HER2 detection methods between central and regional laboratories in Greece.

PURPOSE: HER2 gene amplification and overexpression is associated with aggressive breast cancer and poor prognosis. Accurate HER2 testing of patients with breast cancer before treatment is important to ensure that as many patients with HER2-positive breast cancer as possible receive the most appropriate treatment and that women with HER2-negative disease avoid a potentially toxic therapy. This study compares immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) HER2 testing at central and regional laboratories in Greece. PATIENTS AND METHODS: The HER2 status of 458 breast cancer samples was determined by IHC in central and regional laboratories using commercially available anti-HER2 antibodies. FISH analysis, scored as number of signals or a ratio, was subsequently performed by the central laboratory on most samples. Various statistical analyses were used to examine concordance between test center results. RESULTS: Immunohistochemistry HER2 testing was successfully performed on 445 samples in the central laboratory and 381 samples in regional laboratories, with good concordance between central and regional laboratories. After FISH analyses of a large proportion of these samples, good correlation was observed between FISH HER2 status and IHC results from the central laboratory but not from regional laboratories. These data suggest that HER2 status determined by IHC in a central laboratory is generally more accurate than that determined by a regional laboratory. CONCLUSION: This study emphasizes the importance of accurate HER2 testing and the need to continually check the reproducibility and reliability of the test.

Evaluation of the prognostic role of a panel of biomarkers in stage IB-IIIA non-small cell lung cancer patients.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains a highly lethal disease worldwide and research for more effective treatment strategies is ongoing. Identification of molecular prognostic and predictive markers remains under investigation with results that are often conflicting. PATIENTS AND METHODS: Seventy-three patients (n= 73) with stage IB-IIIA completely resected NSCLC who were postoperatively treated with 6 cycles of paclitaxel and carboplatin from July 1998 to September 2002 took part in this study. Most stage IIIA patients subsequently received adjuvant radiotherapy. Cyclooxygenase-2 (COX-2), vascular endorhelial growth factor (VEGF), dihydrodiol dehydrogenase (DDH), receptor-binding cancer antigen expressed on SiSo cells (RCAS-1) and epidermic growth factor receptor (EGFR/HER-1) expression were assessed immunohistochemically; Heregulin family (HER1-4), VEGF and p53 were analysed by RT-PCR. RESULTS: Totally, 61 (84%) men and 12 (16%) women with median age of 63 years and median PS of 0 were included in the study. There were 18 stage IB, 29 stage II and 26 stage IIIA patients. Sixty-seven samples were available for immunohistohemistry. COX-2 expression was detected in 24 patients (36%), VEGF in 14 (21%), RCAS1 in 31 (46%), DDH in 15 (22%). For EGFR, only 58 samples were evaluated, 13 of which were positive (22%). Messenger RNA expression data was only available for 60 patients; VEGF was detected in 32 (53%), p53 in 30 (50%), EGFR in 35 (58%), HER2 in 4 (7%) and HER3 in 19 (32%). HER4 was not detected in any sample. In the Cox analysis for overall survival (OS) and disease-free survival (DFS), none of the factors evaluated by IHC or RT-PCR reached statistical significance. CONCLUSION: Even though the biomarkers tested are expressed in a significant proportion of lung tumors, none of them was found to be of prognostic significance in patients with NSCLC.

Recurrent Cerebellar Desmoplastic/Nodular Medulloblastoma in Cerebrospinal Fluid (CSF) in the Elderly. A Cytologic Diagnosis.

Desmoplastic medulloblastoma is a rare subtype of medulloblastoma in childhood and more rare in adults. Cerebrospinal fluid (CSF) occurrence is frequent and important for treatment and prognosis. We report the CSF cytologic features of recurrent desmoplastic/nodular medulloblastoma in a 30-aged male.

Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer.

PURPOSE: The detection of disseminated occult breast cancer cells in peripheral blood and bone marrow is associated with poor prognosis. Since a high proportion of these cells express the HER-2 receptor, we evaluated the effectiveness of the anti-HER-2 antibody trastuzumab (Herceptin) administration to eliminate them. EXPERIMENTAL DESIGN: Thirty patients with prior chemotherapy exposure were recruited to the study on the basis of having detectable cytokeratin-19 (CK-19) mRNA transcripts by nested reverse transcription (RT)-PCR in the peripheral blood and/or bone marrow. There were 13 patients with stage I, II, or III breast cancer and 17 with stage IV disease. They were treated in two cohorts with either 4 to 8 weekly infusions of trastuzumab at 2 mg/kg (4 mg/kg loading dose; 20 patients) or 2 to 3 infusions every 3 weeks at 6 mg/kg (8 mg/kg loading dose; 10 patients). All of the patients' samples were also analyzed for HER-2 by nested RT-PCR, but detectable HER-2 messenger RNA (mRNA) was not required for inclusion in the study. After trastuzumab infusions, patients were closely monitored by nested RT-PCR and real-time RT-PCR for the detection of CK-19 mRNA-positive cells. RESULTS: Before trastuzumab infusions, CK-19 mRNA-positive cells were detected in the peripheral blood (n = 10), bone marrow (n = 14), or both (n = 6). In 25 of 30 patients (83%), HER-2 mRNA expression was detected by nested RT-PCR in the pretrastuzumab CK-19-positive sample. After trastuzumab infusions, overall, 28 of 30 (93%) patients became CK-19 mRNA negative by nested RT-PCR and 20 of 30 (67%) by real-time RT-PCR. After a median follow-up of 6 months (range 2 to 22+), the median duration of CK-19 mRNA negativity by nested RT-PCR was 9, 12, and 6 months for stage I/II, III, and IV disease, respectively. CONCLUSIONS: Therapy-resistant CK-19 mRNA-positive cells in the peripheral blood and bone marrow can be effectively targeted by trastuzumab administration. Further studies are needed to evaluate the prognostic significance of the disappearance of these cells.

Childhood central nervous system tumour mortality and survival in Southern and Eastern Europe (1983-2014): Gaps persist across 14 cancer registries.

AIM: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region. METHODS: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants. RESULTS: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4). CONCLUSION: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.

Childhood central nervous system tumours: Incidence and time trends in 13 Southern and Eastern European cancer registries.

AIM: Following completion of the first 5-year nationwide childhood (0-14 years) registration in Greece, central nervous system (CNS) tumour incidence rates are compared with those of 12 registries operating in 10 Southern-Eastern European countries. METHODS: All CNS tumours, as defined by the International Classification of Childhood Cancer (ICCC-3) and registered in any period between 1983 and 2014 were collected from the collaborating cancer registries. Data were evaluated using standard International Agency for Research on Cancer (IARC) criteria. Crude and age-adjusted incidence rates (AIR) by age/gender/diagnostic subgroup were calculated, whereas time trends were assessed through Poisson and Joinpoint regression models. RESULTS: 6062 CNS tumours were retrieved with non-malignant CNS tumours recorded in eight registries; therefore, the analyses were performed on 5191 malignant tumours. Proportion of death certificate only cases was low and morphologic verification overall high; yet five registries presented >10% unspecified neoplasms. The male/female ratio was 1.3 and incidence decreased gradually with age, apart from Turkey and Ukraine. Overall AIR for malignant tumours was 23/10(6) children, with the highest rates noted in Croatia and Serbia. A statistically significant AIR increase was noted in Bulgaria, whereas significant decreases were noted in Belarus, Croatia, Cyprus and Serbia. Although astrocytomas were overall the most common subgroup (30%) followed by embryonal tumours (26%), the latter was the predominant subgroup in six registries. CONCLUSION: Childhood cancer registration is expanding in Southern-Eastern Europe. The heterogeneity in registration practices and incidence patterns of CNS tumours necessitates further investigation aiming to provide clues in aetiology and direct investments into surveillance and early tumour detection.

Pretreatment serum interleukin-12 levels in predicting sustained virological response among hepatitis C patients following Pegylated Interferon-α2ß plus Ribavirin treatment.

BACKGROUND: Dendritic cells activated by hepatitis C virus (HCV) produce high amounts of interleukin (IL)-12, considered to be associated with HCV clearance. The aim of this study was to investigate the IL-12 levels in HCV-infected patients, before and after the application of combination therapy with Pegylated Interferon-α2ß plus Ribavirin. METHODS: Laboratory data of IL-12 levels and other clinical characteristics were selected from 26 HCV-infected patients. Comparisons of IL-12 serum levels before and after treatment or between responders and non-responders (including relapsers) were performed using non-parametric tests. The study moreover investigated the probable relationship of IL-12 concentrations with viral load, HCV genotypes, liver function tests (LFTs), histological activity and the response to combination treatment. RESULTS: The baseline IL-12 levels were found significantly higher in patients who achieved sustained virological response (SVR), compared to patients who did not respond to the combination treatment (P=0.029). The IL-12 levels at the end of treatment were not statistically different from the IL-12 baseline levels, in both responders and non-responders. Baseline serum levels of IL-12 higher than 3 pg/mL (cut-off) were found to positively predict patients who successfully responded to treatment. No statistical correlation was found between the baseline serum IL-12 levels and viral load, HCV genotypes, histological activity or LFTs among the HCV patients. CONCLUSION: Pretreatment IL-12 levels seem to predict which patients will achieve SVR to treatment. Patients with increased IL-12 serum levels were more likely to achieve SVR.

Molecular predictors of response to tyrosine kinase inhibitors in patients with Non-Small-Cell Lung Cancer.

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become a treatment option in non-small-cell lung cancer (NSCLC) patients. However, despite their use in this disease, a significant number of patients will eventually develop resistance and relapse. In this study, we aimed to characterize several molecular events involved in potential resistance mechanisms to anti-EGFR treatment and correlate our findings with clinical outcome. MATERIAL AND METHODS: The medical records of patients with NSCLC who received anti-EGFR TKIs in any line within the participating centers were reviewed and available paraffin embedded tissue was retrieved. Mutational analysis for EGFR, KRAS, BRAF and intron-exon 14 deletions of MET; FISH analysis for chromosomal gain or amplification for EGFR, MET and the deletion marker D7S486 were performed. Furthermore, the expression of EGFR and MET were analysed by immunohistochemistry. All results were correlated with treatment outcomes. RESULTS: Between 10/2001 and 12/2009 from an initial cohort of 72 treated patients, 59 cases (28 gefitinib/ 31 erlotinib) were included in the analysis. The majority had adenocarcinoma histology (68%), and received treatment in the second line setting (56%). Disease control rate (DCR) was 25.4% for all patients. EGFR and RAS mutational rates were 33% and 10% respectively, no other mutations were identified. High EGFR expressing tumors were found in 7 of 45 cases and pEGFR positivity (IHC) was found in 56% of the cases; MET expression was found in 48% of tumors. EGFR gene amplification was found in 4 cases, two cases showed high polysomy; overall, 13% cases were FISH positive for EGFR. High polysomy of MET gene was detected in 1/43 cases tested. D7S486 locus deletion was detected in 15/37 (40%) of cases. EGFR mutational status and gene gain were both associated with more favorable DCR. No other associations between examined biomarkers and DCR or survival were noted. CONCLUSIONS: EGFR mutational status is a predictor for disease control in patients with NSCLC treated with anti-EGFR TKIs. The predictive role of several other molecules involved in potential resistance to anti-EGFR TKIs is worthy of additional investigation.

Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel.

BACKGROUND: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). RESULTS: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors. CONCLUSIONS: Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.