Molecular subtypes of ductal carcinoma in situ in African American and Caucasian American Women: Distribution and correlation with pathological features and outcome

Background: Molecular subtypes of breast cancer have been extensively studied in invasive carcinoma. They were shown to have a different distribution within the various ethnic populations. Few studies have applied the same classification to Ductal Carcinoma in Situ (DCIS). We report the distribution of the molecular breast cancer subtypes in DCIS between African American (AA) and Caucasian American (CA) women, their association with pathological features and outcome. Materials and methods: Tissue microarrays were constructed from paraffin blocks of 94 DCIS cases (67 AA and 27 CA) selected from a cohort of AA and CA patients diagnosed with DCIS between 1996 and 2000; mean age at diagnosis was 61 ± 12 for the AA and 58 ± 11 years for the CA group. TMA blocks were labeled with antibodies for ER, PR, HER2, Ki-67, and CK5/6. The cases were subtyped as Luminal A (ER+ and/or PR+; HER2?), Luminal B (ER+ and/or PR+; HER2+), HER2+ (ER?, PR?; HER2+), basal-like (BL) (ER?, PR?, HER2?; CK5/6+) or unclassified triple negative (UTN) (ER?, PR?, HER2?, CK5/6?). Information on grade, size and follow-up were obtained. Results: (1) Most DCIS cases were Luminal A, comprising 80% of the DCIS cases in AA and 92.6% in CA patients. (2) HER2+, BL and UTN DCIS subtypes were not seen in the CA population, and formed 9% of the DCIS cases in the AA population; these cases were all high grade. (3) In the cases with recurrence (8 AA and 1 CA patients), DCIS was Luminal A in 6 AA and 1 CA and Luminal B in 2 AA patients. Conclusion: The distribution of the molecular subtypes of DCIS did not show a significant difference between the two ethnic groups in our study. In addition, the risk of recurrence might not be higher in the non-luminal subtypes than in Luminal A and B.     

Detection of estrogen alpha and progesterone receptors and cell proliferation in the uterus during early pregnancy in the goat

The objectives of this study were to investigate in the goat uterus the expression of estrogen-alpha (ER alpha) and progesterone receptors (PR) and their relationship to proliferation indices (Ki-67) during peri-implantation on Days 22 to 30 post coitum (pc). Immunohistochemical methods were used to quantify ER alpha and PR for luminal and deep regions of the endometrium and of the myometrium. On Day 22 pc cell proliferation was only observed in the luminal epithelium. On Day 24 pc, high cell proliferation indices were seen in luminal epithelium and proliferation began in the luminal stroma and glands. There was a positive correlation between Ki-67 and total ER alpha score in the luminal epithelium (r = 0.53, P < 0.01). Levels of PR scores were highly correlated with Ki-67 indices in luminal epithelium (r = 0.74, P < 0.01) and stroma (r = 0.70, P < 0.01). No Ki-67 expression was observed in deep glands, stroma or myometrium on any of the days studied. Results indicate that patterns of ER alpha and PR expression differ markedly, and that there was a high correlation between PR expression and cell proliferation in the caprine uterus during the peri-implantation period.     

The effect of tumour bed boost on local control after breast conserving surgery. First results of the randomized boost trial of the National Institute of Oncology

PURPOSE: To evaluate the effect of tumour bed boost on local tumour control (LTC) after breast conserving surgery in a prospective study. METHODS: Between 1995 and 1998, 207 women with early invasive breast cancer who underwent conservative operation were treated by 50 Gy irradiation to the whole breast and then randomly assigned to receive either no further radiotherapy (n=103) or a boost to the tumour bed (n=104) with either 16 Gy electron (n=52) or 12-14.25 Gy high dose rate brachytherapy (n=52). RESULTS: At a median follow-up of 4.25 years the crude rate of local recurrence was 6.7% with and 13.6% without boost. The respective rates of tumour bed relapse were 3.8% vs. 10.7%. The 4 year probability of LTC, relapse-free survival and breast cancer-specific survival was 94.2% vs. 85.1% (p=0.1176), 82.3% vs. 67.2% (p=0.0438) and 84.8% vs. 90.9% (p=0.1111), respectively, in favour of the boost group. Systemic treatments had no significant impact on LTC (88.9% with and 89.6% without systemic treatment, p=0.8858). CONCLUSION: Tumour bed boost decreased the incidence of local and tumor bed relapses with a reduction of 50% and 64%, respectively. Relapse-free survival was improved significantly with boost. However, the influence of boost treatment on breast cancer-specific survival should be tested in further studies. In spite of the higher incidence of late radiation side effects in the boost arm, boost dose is strongly recommended for patients at high risk for local recurrence. The final results of the EORTC trial and other ongoing studies will help to clarify the indication of boost dose according to prognostic subgroups.     

DCIS and aromatase inhibitors

In patients with hormone receptor positive DCIS tamoxifen reduces recurrence rates by almost 50%. Few data are available with aromatase inhibitors from randomised studies. In the ATAC study there were three DCIS lesions in the anastrozole arm and four in the tamoxifen arm in the women with ER positive invasive cancer. In the MA17 study which randomised patients to up to 5 years of letrozole or placebo there was only one DCIS event in the contralateral breast in patients taking letrozole and five on placebo. There were also four patients in this study who had DCIS in the conserved breast on placebo and none in the letrozole treated group. The few clinical data that are available therefore suggest the aromatase inhibitors are likely to be effective in DCIS. A histological review of a study of 206 postmenopausal women with invasive oestrogen receptor positive breast cancer who were randomised as part of a 14 day preoperative study to receive 2.5 mg of letrozole or 1 mg of anastrozole identified 27 patients with 28 pairs of tumours in whom there was sufficient ER positive DCIS in invasive cancer in the initial core biopsy and in the subsequent surgery specimen, to evaluate for PgR activity and proliferation. Within the DCIS both aromatase inhibitors significantly reduced PgR expression and both drugs also produced a significant fall in proliferation. There was a moderate degree of agreement between the fall in PgR in both the invasive cancer and DCIS (Kappa = 0.5; p = 0.0013) and between the fall in proliferation and between the invasive and in situ components (correlation coefficient = 0.68; p < 0.001). This study has shown significant effects of aromatase inhibitors on DCIS indicating that these agents are therapeutically active in this condition.     

Breast infiltrating ductal carcinoma: analysis of hormone, HER-2 receptors and Ki-67 proliferation marker

The aim of this study was to analyse breast carcinomas with discordant receptor status, probably hormonal dependent (estrogen receptor (ER) positive, progesterone receptor (PR) negative or ER-PR + subgroup profile) infiltrating ductal breast carcinomas not otherwise specified (IDC NOS). Specimens from 90 IDC NOS were grouped into three categories according to hormonal status: dependent (D) (ER +PR +), probably dependent (PD) (ER +PR- or ER-PR +) and non-dependent (ND) (ER-PR-); they were evaluated considering some established prognostic parameters in breast carcinomas. Statistically significant difference was found between tumor receptor status distribution and menopausal status (p = 0.0235), age of the patients (p = 0.000467), histological grade (p = 0.000003), vascular invasion (p = 0.006), HER-2 status (p = 0.0039) and Ki-67 proliferation rate (p = 0.000311). D tumors were found exclusively in post-menopausal patients (average age 68.9 years), most of which had intermediate (II) grade, without vascular invasion, with HER-2 status score predominantly 0 or 1 + and lower Ki-67 proliferation rate. PD tumors were found predominantly in younger post-menopausal patients (average age 57.5 years), with vascular invasion found in 23% of the cases. ND tumors mostly had higher histological grade, showed the highest percentage of the Ki-67 positive tumor cells and vascular invasion in 30% of the cases. We conclude that the patients with PD breast carcinomas were younger post-menopausal women with the tumors moderately differentiated, HER-2 score 0 or 1+ and with lower Ki-67 proliferation rate.     

Glut-1 Expression Correlates with Basal-like Breast Cancer

INTRODUCTION: Glucose transporter 1 (Glut-1) is a facilitative glucose transporter expressed in many cancers including breast cancer. Basal-like breast cancer (BLBC) is a high-risk disease associated with poor prognosis and lacks the benefit of targeted therapy. The aim of this study was to characterize the immunohistochemical (IHC) expression of Glut-1 in patients with BLBC compared with non-BLBC. MATERIALS AND METHODS: We identified 523 cases of invasive breast carcinoma from our database. The clinicopathologic findings and the biologic markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) status were reviewed. IHC stains for cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), p53, and Glut-1 were performed on tissue microarray using standard procedures. BLBC was defined as ER-,PR-, Her2-, and CK5/6+ and/or EGFR+. RESULTS: Of informative cases, 14.7% were categorized as BLBC versus 85.3% as non-BLBC. Glut-1 was expressed in 42 (76.4%) of 55 BLBCs, whereas only 55 (23.8%) of 231 non-BLBCs showed immunostaining for Glut-1 (P < .001). Overall, Glut-1 expression was significantly associated with high histologic grade, ER negativity, PR negativity, CK5/6 positivity, EGFR expression, and high p53 expression (P < .001). However, there was no correlation between Glut-1 immunostaining and patient's outcome. CONCLUSIONS: Our results show that Glut-1 is significantly associated with BLBC and might be a potential therapeutic target for this aggressive subgroup of breast cancer, and this warrants further investigations.     

Should high-dose-rate brachytherapy boost be used in early nasopharyngeal carcinomas?

BackgroundRadiation with or without chemotherapy is the main treatment of nasopharyngeal carcinomas (NPC). Local recurrence is difficult to manage. Local control is dose-dependent.AimTo analyze the effect of an endocavitary brachytherapy boost after external beam radiation (EBRT) to decrease local recurrence.Material and methodsThirty patients with T0-T2 NPC were treated: 70% T1, 20% T2 and 10% T0; 33.3% N0, 20% N1, 43.3% N2 and 3.3% N3; 90% were undifferentiated carcinoma. All they received a 192-Ir high dose rate brachytherapy (HDR-BT) boost after 60 Gy of EBRT. The Rotterdam applicator was used in most cases, 3-4 fractions of 3.75-3 Gy in two days.ResultsWith median follow-up (FU) of 63 months, a single parapharyngeal failure resulted in local control of 100% at 3 years and 95% at 5 years. Local control for T0-1 was 100% and for T2 67% at five years (p = 0.02). Regional-free recurrence survival was 92% at 5 years. Metastasis-free survival was 84% at 5 years. All cases of metastasis had histopathology of undifferentiated. The overall and cause-specific survival was 96% and 86% at 3 and 5 years. No late complications related to brachytherapy were described.ConclusionA HDR-BT boost is useful to decrease the incidence of local recurrence of NPC to 5%. With a fractionated schedule of 3-4 fractions in two days, Rotterdam applicator and 3-D planning, no late complications are described. Therefore we recommend to use brachytherapy boost in all early NPC.     

陀螺旋转式伽玛刀分次治疗颅内转移瘤的临床疗效观察

目的:评价大分割伽玛射线立体定向放射治疗对颅内转移瘤的临床疗效.方法:采用陀螺旋转式伽玛射线立体定向放射设备治疗颅内转移瘤患者91例.单纯伽玛射线立体定向放射治疗采取大分割分次方式,处方剂量3.2-5Gy,每周5次,计划靶区边缘(45％或65％等剂量线处)总剂量全程为35-50Gy.结果:近期有效率(CR+PR)颅内移瘤少于3个组为93.06％ (67/72),大于3个组为73.69％ (14/19);局部剂量与肿瘤复发的关系,照射剂量50GY者复发率为11.86％(7/59),照射剂量为40GY者复发率为31.25％(10/32);生存率陀螺刀治疗的中位生存期为11.9个月.6、12、24个月生存率分别为:76.92％ (70/91)、60.44％(55/91)、29.67％(27/91).结论:大分割伽玛射线立体定向放射治疗脑部和体部恶性肿瘤近期疗效满意.     

HR-MAS MR Spectroscopy of Breast Cancer Tissue Obtained with Core Needle Biopsy: Correlation with Prognostic Factors

The purpose of this study was to examine the correlation between high-resolution magic angle spinning (HR-MAS) magnetic resonance (MR) spectroscopy using core needle biopsy (CNB) specimens and histologic prognostic factors currently used in breast cancer patients. After institutional review board approval and informed consent were obtained for this study, CNB specimens were collected from 36 malignant lesions in 34 patients. Concentrations and metabolic ratios of various choline metabolites were estimated by HR-MAS MR spectroscopy using CNB specimens. HR-MAS spectroscopic values were compared according to histopathologic variables [tumor size, lymph node metastasis, histologic grade, status of estrogens receptor (ER), progesterone receptor (PR), HER2 (a receptor for human epidermal growth factor), and Ki-67, and triple negativity]. Multivariate analysis was performed with Orthogonal Projections to Latent Structure-Discriminant Analysis (OPLS-DA). HR-MAS MR spectroscopy quantified and discriminated choline metabolites in all CNB specimens of the 36 breast cancers. Several metabolite markers [free choline (Cho), phosphocholine (PC), creatine (Cr), taurine, myo-inositol, scyllo-inositol, total choline (tCho), glycine, Cho/Cr, tCho/Cr, PC/Cr] on HR-MAS MR spectroscopy were found to correlate with histologic prognostic factors [ER, PR, HER2, histologic grade, triple negativity, Ki-67, poor prognosis]. OPLS-DA multivariate models were generally able to discriminate the status of histologic prognostic factors (ER, PR, HER2, Ki-67) and prognosis groups. Our study suggests that HR-MAS MR spectroscopy using CNB specimens can predict tumor aggressiveness prior to surgery in breast cancer patients. In addition, it may be helpful in the detection of reliable markers for breast cancer characterization.     

Hypofractionated radiation therapy for early breast cancer: Follow up of a new treatment standard

AimTo assess the oncological outcomes of patients with early breast cancer treated with breast-conserving surgery and adjuvant hypofractionated radiation therapy.Methods and MaterialThis retrospective analysis included all patients ≥50 year of age with T1-2 N0 M0 breast cancer treated at our Radiation Oncology Unit between 2008 and 2011. Whole-breast radiation therapy was delivered to a dose of 42.5 Gy in 16 fractions, without boost. The primary outcome was local control.Results212 patients were identified. With a median follow up of 60 months, we found 3% local recurrence and 5.3% regional and/or distant recurrences. At the moment of data analysis, 17 patients had died. Out of 5 local recurrences, 2 had previously had a distant recurrence, both of them died. The other three were still alive at the last follow up. These results are comparable to those observed in Phase III trials that use this fractionation scheme.ConclusionsThe results obtained with this retrospective analysis are comparable to those obtained in large randomized trials. This data also supports the use of hypofractionated radiation therapy in Latin America. Hypofractionated radiation therapy for early breast cancer patients should be the standard adjuvant treatment.     

Thermal boost combined with interstitial brachytherapy in breast conserving therapy – Assessment of early toxicity

Background

Hyperthermia (HT) causes a direct damage to cancerous cells and/or sensitize them to radiotherapy with usually minimal injury to normal tissues. Adjuvant HT is probably one of the most effective radiation sensitizers known and works best when delivered simultaneously with radiation. In breast conserving therapy, irradiation has to minimize the risk of local relapse within the treated breast, especially in an area of a tumor bed. Brachytherapy boost reduces 5-year local recurrence rate to mean 5,5%, so there still some place for further improvement. The investigated therapeutic option is an adjuvant single session of local HT (thermal boost) preceding standard CT-based multicatheter interstitial HDR brachytherapy boost in order to increase the probability of local cure.

Aim

To report the short-term results in regard to early toxicity of high-dose-rate (HDR) brachytherapy (BT) boost with or without interstitial microwave hyperthermia (MV HT) for early breast cancer patients treated with breast conserving therapy (BCT).

Materials and methods

Between February 2006 and December 2007, 57 stage IA–IIIA breast cancer patients received a 10 Gy HDR BT boost after conservative surgery and 42.5–50 Gy whole breast irradiation (WBI) ± adjuvant chemotherapy. 32 patients (56.1%) were treated with additional pre-BT single session of interstitial MW HT to a tumor bed (multi-catheter technique). Reference temperature was 43 °C and therapeutic time (TT) was 1 h. Incidence, severity and duration of radiodermatitis, skin oedema and skin erythema in groups with (I) or without HT (II) were assessed, significant p-value ≤ 0.05.

Results

Median follow-up was 40 months. Local control was 100% and distant metastasis free survival was 91.1%. HT sessions (median): reference temperature 42.2 °C, therapeutic time (TT) 61.4 min, total thermal dose 42 min and a gap between HT and BT 30 min. Radiodermatitis grades I and II occurred in 24 and 6 patients, respectively, differences between groups I and II were not significant. Skin oedema and erythema occurred in 48 (85.7%) and 36 (64.3%) cases, respectively, and were equally distributed between the groups. The incidence and duration of skin oedema differed between the subgroups treated with different fractionation protocols of WBI, p = 0.006. Skin oedema was present up to 12 months. No difference in pattern of oedema regression between groups I and II was observed, p = 0.933.

Conclusion

Additional thermal boost preceding standard HDR BT boost has a potential of further improvement in breast cancer local control in BCT. Pre-BT hyperthermia did not increase early toxicity in patients treated with BCT and was well tolerated. All side effects of combined treatment were transient and were present for up to 12 months. The increase in incidence of skin oedema was related to hypofractionated protocols of WBI. The study has to be randomized and continued on a larger group of breast cancer patients to verify the potential of local control improvement and to assess the profile of late toxicity.     

Androgen Receptor (AR), E-Cadherin,and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients

BackgroundTNBC is an aggressive subset of breast cancer (BC) without specific target therapy.MethodsThis observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC.ResultsThe AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome.ConclusionsOur data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC.     

Tissue microarray-based immunohistochemical study can significantly underestimate the expression of HER2 and progesterone receptor in ductal carcinoma in situ of the breast

Abstract

The accuracy of immunohistochemical (IHC) analysis on tissue microarray (TMA)-based studies largely depends on the uniformity of the staining pattern for a given antibody and minimal intratumor heterogeneity of a given tumor. Our study was designed to investigate the concordance of expression in TMA and whole sections of estrogen receptor (ER), progesterone receptor (PR) and HER2 using IHC analysis for ductal carcinoma in situ (DCIS) of the breast. Seventy-five consecutive cases of DCIS were retrieved, reviewed and used to construct the TMA. IHC analysis of the expression of ER, PR, and HER2 were performed on TMA and whole sections of the corresponding cases, and the results were compared. The specificity and sensitivity for TMA-based assays were 87.0, 75.9, 90.6 and 90.4%, and 76.1, 27.3 for ER, PR and HER2, respectively. The concordance and discordance were 89.3, 76.0 and 72.0%, and 6.7, 13.3 and 16.0% for ER, PR, HER2, respectively. The kappa values were 0.83, 0.89 and 0.42 for ER, PR and HER2, respectively. The non-concordance rates were inversely related to core number, with 46.67, 22.67 and 11.56% for one core, two cores, and three cores, respectively, per marker per case (p < 0.001), but not associated with tumor size. Our results showed that the intratumor heterogeneity and the number of cores have a great impact on the results of TMA-based studies. Increasing the number of tissue cores per case may help improve the accuracy and concordance with whole section results. Although TMA remains an effective tool for translational research, we should be cautious in our interpretation of these results.     

Immunochemistry for oestrogen receptor,progesterone receptor and HER2 on cell blocks in primary breast carcinoma

K. Kumar S, N. Gupta, A. Rajwanshi, K. Joshi and G. Singh Immunochemistry for oestrogen receptor, progesterone receptor and HER2 on cell blocks in primary breast carcinoma Objective: Steroid receptors and human epidermal growth receptor 2 (HER2) have been used for predicting response to treatment in breast cancers. Fine needle aspiration cytology can provide highly cellular material and can be used for such analysis. The present study was undertaken to assess the reliability of oestrogen and progesterone receptor (ER, PR) status and HER2 as demonstrated by immunochemistry (IHC) on cell blocks from breast carcinoma cases, in comparison with histological sections. Methods: IHC for ER, PR and HER2 was performed on cell blocks and their corresponding tissue sections of 50 primary pre‐chemotherapy breast carcinomas. Positivity for ER and PR was scored according to the Allred scoring system. Strong membranous positivity in more than 30% of tumour cells was considered positive for HER2. The tumours were classified as luminal A, luminal B, HER2‐over‐expressing and triple negative on the basis of ER, PR and HER2 status and results on cell blocks compared with histological sections. Results: Correlation between immunostaining on cell blocks and the corresponding tumour tissues revealed a concordance rate for ER, PR and HER2 of 90% [Correlation coefficient (r) = 0.79], 94% (r = 0.86) and 90% (r = 0.76), respectively. Including five cases in which cell blocks were either ER or PR positive, 43/50 cases (86.0%) could be correctly classified on cell block immunostaining alone. The main reasons for seven discordant cases included technical errors (sampling error and staining error) and interpretational error in HER2 evaluation on cell blocks; the core biopsy was inadequate in one, and apparently false negative for HER2 in another. Conclusion: Cell blocks are useful in the assessment of hormone receptor status and HER2 by IHC, especially in cases of locally advanced breast cancer for planning neoadjuvant chemotherapy. It is highly recommended to have good quality cell blocks and quality control of their interpretation.     

Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer

Nek2A (NIMA-related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF-10A, MCF-10DCIS.com, MCF-10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up-regulated in MCF-10DCIS.com and MCF-10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki-67 immunoreactivity (P<0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c-erbB-2, and Ki-67 expression (P<0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in "normal" immortalized MCF-10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF-10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF-10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS.     

Experiences in the treatment of tumour of base of the tongue with high dose rate interstitial radiotherapy on the basis of a retrospective analysis

PURPOSE: To describe the role, the execution and the importance of interstitial radiotherapy in the irradiation of the base of tongue cancer. MATERIAL AND METHODS: Between January, 1993 and December, 1998 nineteen patients with primary squamous cell cancer of the base of tongue (1 T1N0, 3 T2N0, 2 T3N0, 2 T3N2, 3 T4N0, 6 T4N1, 2 T4N2) were managed with brachytherapy partly with definitive intention combined with teletherapy (60-66 Gy) as a boost, partly as a single postoperative treatment. Irradiation was carried out by HDR after-loading (Ir-192) unit, using rigid needle or flexible plastic catheter. The treatment plan was made by PLATO 3D brachytherapy planning system. In case of boost the mean total dose of brachyherapy was 22 Gy (12-30 Gy), in postoperative treatment it was 27 Gy (24-30 Gy). RESULTS: 6-8 weeks after the definitive radiotherapy the CT/MR showed complete remission in 67% and partial remission in 33% of the patients. Of all treated patients during the mean follow-up period (30 months) the local tumour control was 42%. Five patients (26%) died in local failure. Six patients (32%) are alive with tumour. Osteoradionecrosis and fistula did not occur. CONCLUSIONS: In the oncological treatment of the advanced base of tongue tumour the combination of percutan and interstitial radiotherapy seems to be very advantageous,because it improves not only the curability, but the patients' quality of life as well.     

The Relationship among Hypoxia,Proliferation, and Outcome in Patients with De Novo Glioblastoma: A Pilot Study

The hypoxia and proliferation index increase with grade in human glial tumors, but there is no agreement whether either has prognostic importance in glioblastomas. We evaluated these end points individually and together in 16 de novo human glioblastomas using antibodies against the 2-nitroimidazole hypoxia detection agent EF5 and the proliferation detection agent Ki-67. Frozen tumor tissue sections were fluorescence-stained for nuclei (Hoechst 33342), hypoxia (anti-EF5 antibodies), and proliferation (anti-Ki-67 antibodies). EF5 binding adjacent to Ki-67+ cells, overall EF5 binding, the ratio of these values, and the proliferation index were evaluated. Patients were classified using recursive partitioning analysis and followed up until recurrence and/or death. Recursive partitioning analysis was statistically significant for survival (P = .0026). Overall EF5 binding, EF5 binding near Ki-67+ cells, and proliferation index did not predict recurrence. Two additional survival analyses based on ratios of the overall EF5 binding to EF5 binding near Ki-67+ cells were performed. High and low ratio values were determined by two cutoff points: (a) the 50% value for the ratio [EF5/Ki-67_Binding]/[Tumor_binding] = Ratio_{EF5 50%} and (b) the median EF5 value (75.6%) of the ratio [EF5/Ki-67_Binding]/[Tumor_binding] = Ratio_{patients median}. On the basis of the Ratio_{EF5 50%}, recurrence (P = .0074) and survival (P = .0196) could be predicted. Using the Ratio_{patients median}, only survival could be predicted (P = .0291). In summary, patients had a worse prognosis if the [EF5/Ki-67_Binding]/[Tumor_binding] ratio was high. A hypothesis for the mechanisms and translational significance of these findings is discussed.     

Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS)

Breast-conserving surgery for ductal carcinoma in situ (DCIS) is often combined with irradiation, reducing recurrence rates to 20% within 10 years; however, there is no change in overall survival. Evidence in the invasive breast indicates that breast cancer stem cells (CSCs) are radiotherapy-resistant and are capable of re-initiating a tumor recurrence; hence, targeting CSCs in high risk DCIS patient may improve survival. HER2 is overexpressed in 20% of DCIS and is known to be highly active in breast CSCs; we therefore investigated the effect of Lapatinib on DCIS CSC activity using 2 in vitro culture systems. Two DCIS cell lines DCIS.com (HER2 normal) and SUM225 (HER2 overexpressed) as well as DCIS cells from patient samples (n = 18) were cultured as mammospheres to assess CSC activity and in differentiated 3D-matrigel culture to determine effects within the non-CSCs. Mammosphere formation was reduced regardless of HER2 status, although this was more marked within the HER2-positive samples. When grown as differentiated DCIS acini in 3D-matrigel culture, Lapatinib only reduced acini size in the HER2-positive samples via decreased proliferation. Further investigation revealed lapatinib did not reduce self-renewal activity in the CSC population, but their proliferation was decreased regardless of HER2 status. In conclusion we show Lapatinib can reduce DCIS CSC activity, suggesting that the use of Lapatinib in high-risk DCIS patients has the potential to reduce recurrence and the progression of DCIS to invasive disease.     

Immunocytochemistry on scrape cytology in breast cancer: will it unearth the weaker positives?

OBJECTIVE: To standardize the technique of immunocytochemical (ICC) assessment of estrogen (ER) and progesterone receptor (PR) status in breast cancer by scrape cytology and to compare the results with immunohistochemistry on paraffin blocks. STUDY DESIGN: ICC assessment for ER and PR was done on scrape smears from tissue samples in 200 cases of primary breast cancer. The results were compared to those obtained from immunohistochemical (IHC) evaluation of formalin-fixed paraffin same tissue samples. RESULTS: ER/PR positivity rates as well as staining scores were compared between the scrape smears and tissue sections. The concordance between cytology and histology was 84% for ER and 90% for PR. Both the positivity rates and the staining intensity scores were higher for cytochemistry than for histochemistry. CONCLUSION: The ICC method on scrape smears is a simple test with rapid turnaround time. The sample required is small, and antigen loss due to fixation and processing is minimal. This new method gives a higher yield of hormone receptor positivity and, when used in conjunction with the IHC method, may improve the pickup rate of ER-positive cases, thereby playing an important role in risk stratification and therapeutic decision making in patients with breast cancer.     

Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival

Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53-]), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility.