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Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase Ill, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO. Lay abstract: Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence.

Background Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. Methods We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. Results A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. Conclusions First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).

Purpose: RACGAP1 is a Rac GTPase-activating protein involved in cell growth regulation, cell transformation and metastasis. The aim of the present study was to explore the prognostic and/or predictive significance of RACGAP1 mRNA expression on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients and compare it to that of Ki67 protein expression and to the Nottingham prognostic index (NPI). Methods: A total of 595 high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 314 formalin-fixed paraffin-embedded primary tumor tissue samples followed by one-step quantitative RT-PCR for assessing RACGAP1 mRNA expression. Results: High RACGAP1 mRNA expression (above the median) was associated with poor DFS (log-rank, p = 0.002) and OS (p < 0.001). High histological grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of RACGAP1. Results of the Cox multivariate regression analysis revealed that high RACGAP1 mRNA expression independently predicted poor overall survival (Wald's p = 0.008). High Ki67 protein expression was also an adverse prognostic factor for death (p = 0.016), while high NPI score values were not. Conclusions: High RACGAP1 mRNA expression, as assessed by qRT-PCR, was found to be of adverse prognostic significance in high-risk early breast cancer patients treated with dose-dense sequential chemotherapy. The utility of RACGAP1 mRNA expression in patient selection for treatment with aggressive chemotherapy regimens should be further explored and validated in larger cohorts. © 2012 Springer-Verlag Berlin Heidelberg. 71 1 245 255

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

Background: This multicenter, prospective phase II study evaluated the safety and efficacy of the combination of docetaxel and vinorelbine in patients with platinum-resistant, paclitaxel-pretreated recurrent ovarian cancer. Patients and methods: Treatment consisted of vinorelbine 25 mg/m2 as a 20-min i.v. infusion (days 1 and 8), and docetaxel 70 mg/m2, as a 1-h i.v. infusion (day 8). Granulocyte colony-stimulating factor support was administered prophylactically on days 12-16. Treatment was repeated every 21 days. Results: Forty-six patients were enrolled. The median number of previous chemotherapeutic regimens was one (range 1-3) with a median treatment-free interval of 4.3 months. Four chemotherapy cycles per patient were administered. Almost 75% of the planned doses for both drugs were given. Forty-one patients are evaluable for response. Three patients (6.5% of all patients; 7.3% of evaluable patients) achieved complete response and eight (17.4% and 19.5%, respectively) a partial response to chemotherapy leading to overall response rates of 23.9% and 26.8%, respectively. Another 34.8% (39.0%) had stable disease. At a median follow-up of 30 months, the median disease-free survival was 13 months, relapse-free survival was 5 months, time to progression was 4.5 months, and overall survival was 9.3 months. Severe toxicities included leukopenia (31%), neutropenia (35%) and febrile neutropenia (20%). Conclusions: The combination of docetaxel/vinorelbine is an effective regimen with manageable toxicity for the treatment of platinum-resistant, paclitaxel-pretreated ovarian cancer. 14 7 1094 1099

PURPOSE: To compare the efficacy of two different schedules of epirubicin and paclitaxel, as first-line chemotherapy, in patients with advanced breast cancer (ABC). PATIENTS AND METHODS: From October 1997 until May 1999, 183 eligible patients with ABC entered the study. Chemotherapy in group A (93 patients) consisted of four cycles of epirubicin at a dose of 110 mg/m2 followed by four cycles of paclitaxel at a dose of 225 mg/m2 in a 3-hour infusion. All cycles were repeated every 2 weeks with granulocyte colony-stimulating factor support. The therapeutic regimen in group B (90 patients) consisted of epirubicin (80 mg/m2) immediately followed by paclitaxel (175 mg/m2 in a 3-hour infusion) every 3 weeks for six cycles. RESULTS: In total, 79 patients (85%) in group A and 72 patients (80%) in group B completed treatment. The median relative dose-intensity of epirubicin was 0.96 in both groups, and that of paclitaxel was 0.96 and 0.97 in groups A and B, respectively. The complete response rate was higher in group A (21.5% v 9% P = .02). Nevertheless, there was no significant difference in the overall response rate between the two groups (55% v 42%, P = .10). Severe neutropenia was more frequently observed with concurrent treatment. After a median follow-up of 16.5 months, median time to progression was 10 months in group A and 8.5 months in group B (P = .27), and median survival was 21.5 and 20 months, respectively (P = .17). CONCLUSION: The present study failed to demonstrate a significant difference in overall response rate between dose-dense sequential administration of epirubicin and paclitaxel compared with the combination of the two drugs given on the same day, even though the sequential treatment resulted in a significantly higher complete response rate.

Background: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet.Methods: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation.Results: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020).Conclusions: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies.Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033. © 2014 Fountzilas et al.; licensee BioMed Central Ltd. 14 1

Background: The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. Methods: Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. Results: High UBE2C mRNA expression was associated with poor DFS (Wald's P = 0.003) and OS (Wald's P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). Conclusions: High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts. 23 6 1422 1427

The purpose of this study was to determine factors associated with the incidence of axillary lymph node metastases (ALNM) in T1 tumors and cases in which axillary dissection could be omitted. Data from 195 patients with T1 primary invasive breast cancer (size ≤2 cm) who underwent either mastectomy or wide local excision of the tumor and axillary dissection were reviewed. ALNM was found in 59 of 195 patients with T1 tumors (30.3%). Tumor size was found to be the only independent predictor of ALNM, having a directly analogous relationship with the probability of invaded nodes: T1a (≤5 mm) tumors had 0 per cent ALNM, whereas T1b (5 mm < T1b ≤ 10 mm) and T1c (10 mm < T1c ≤ 20 mm) tumors had 25.7 per cent and 33.8 per cent ALNM respectively. Among the other factors studied (patient age, tumor site, hormone receptor status, histologic type, and grade of the tumor) only the histologic grade of the tumor cells appeared to correlate with the incidence of lymph node involvement, but this was not statistically significant. In conclusion only tumor size has statistically significant correlation with the incidence of ALNM. Routine axillary dissection could be omitted only in patients at minimal risk of ALNM (ductal carcinoma in situ and T1a) and when treatment decisions were not influenced by lymph node status (e.g., elderly patients with clinically negative axilla). Axillary dissection (at least levels I and II) should be performed in all cases with primary invasive breast cancer with tumor size >5 mm.

Introduction. Breast cancer patients developing liver metastases have traditionally been considered to make up a poor prognosis group with median survival rates of less than 6 months. We retrospectively analysed clinicopathologic characteristics of 500 women with metastatic breast cancer and liver deposits upon administration of first-line chemotherapy in the 90s. We sought to examine the epidemiology, clinical course, outcome and prognostic factors of this cohort with the hope to identify changing patterns, facilitate cost-effective follow-up and rationalize therapy of these patients. Materials and methods. Among 1426 metastatic breast cancer patients enrolled with the Hellenic Cooperative Oncology Group (HeCOG) chemotherapy registry from 1988 to 2004, 500 (35%) had liver deposits when first-line chemotherapy was administered and were the subject of this retrospective analysis. These patients had been treated with single-agent or combination chemotherapy either in the context of clinical trials or outwith trials according to standard HeCOG protocols. Results. Median age at diagnosis was 54.5 years, with the majority of women being fit (Performance Status PS 0-1 76%), postmenopausal (53%) harbouring hormone-receptor positive (54%) invasive ductal, lobular or mixed carcinomas (76%). High-grade tumours were present in 35% of patients, while the extent of systemic relapse was confined to the liver plus none or one additional organ site in 59% of women. Half of the patients had received adjuvant chemotherapy and two-thirds relapsed later than 12 months from initial diagnosis of localized disease. First-line palliative chemotherapy included an anthracycline and/or a taxane in 88% of cases with an objective response rate of 34% (95% Confidence Interval CI: 29.1-37.5), while 79% of patients were able to proceed to second-line chemotherapy based mostly on non-anthracycline non-taxane containing regimens with objective responses seen in 16% of them (95% CI: 11.6-21.9). At a median follow-up of 47.5 months, disease progression occurred solely in the liver in one-third of patients and median overall survival was 16.3 months, with projected 5-year survival of 8.5%. Type of palliative chemotherapy was not a predictive factor for response, though non-anthracycline non-taxane regimens were associated with lower tumour regression rates. Positive hormonal receptor status of the primary, low histological grade, malignant relapse in the liver only or liver plus one organ site and good performance status were significant prognostic factors for improved outcome in univariate analysis, the latter two retaining significance in multivariate analysis as well. Conclusions. In comparison to historical series, adjuvant therapy, stricter follow up and imaging technology advances result in earlier diagnosis of fitter breast cancer patients with low-volume hepatic and systemic relapse. Cost-effectiveness of close monitoring for early diagnosis of relapse should be further studied. With availability of effective modern chemotherapy, prolonged survival is feasible and aggressive multidisciplinary management of selected patients may be warranted. © Springer 2005. 97 3 237 244

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone. Breast Cancer Res Treat

Granular cell tumor (GCT) is an uncommon, usually benign tumor that occasionally involves the breast. It is possibly of neural origin (Schwann cells) and usually occurs in premenopausal black women. Physical examination, mammographic, ultrasonographic findings and pathologic examination may suggest breast malignancy. Positive immunohistochemical staining of the cells for S-100 protein, NSE, and CEA is indicative of GCT. Surgical treatment of choice is wide local excision. We report a case of granular cell tumor of a female breast. A 52-yr-old white woman had a palpable mass close to her right axilla. Computer tomography (CT) showed a 3.74 cm mass in the mammary tail of Spencer. The findings were suspicious for malignancy and the lesion was widely resected. Pathologic examination showed granular cell tumor.

Mucoepidermoid carcinomas are very rare breast tumors. The morphology of this breast tumour is similar to its counterpart in the salivary gland. The first two cases reported were low-grade and neither patient had metastatic disease. Furthermore, none of the five patients with low-grade mucoepidermoid carcinoma reported by Fisher had axillary lymph node involvement and were alive with no evidence of disease 4 to 10 years after diagnosis and were considered of probable favourable prognosis. A high grade form of mucoepidermoid cancer might occur in the breast as it does in the salivary gland. All high-grade variant cases published had demonstrable lymph node or distant metastases and rapidly fatal outcomes. This report describes a case of high-grade mucoepidermoid carcinoma of the breast with a disease-free interval of 5 years, despite of unfavourable histologic features at the time of diagnosis.

A rare case of metachronous bilateral Paget's disease of the nipple is presented. The occasional failure of routine follow-up to detect certain tumours until biologically advanced and the value of patient observations are mentioned.

Hamartomas of the breast are rare tumor-like lesions composed of ducts, lobules, fat, and fibrous tissue. The clinical and pathologic findings of six cases of patients ranging in age from 19 to 63 years are reported. Diagnosis is difficult, and we emphasize that fine needle aspiration and cytology of the smears is not diagnostic for hamartomas.

BACKGROUND: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis. PATIENTS AND METHODS: A retrospective review was conducted of a series of 475 patients with advanced breast cancer enrolled in two randomised trials, who received first-line chemotherapy. The impact of severe (grade 3 or 4) hematological toxicity on survival and time to disease progression was assessed. RESULTS: When severe myelotoxicity was evaluated as a whole, a significant negative association for time to disease progression and a trend for a worse survival were demonstrated. In multivariate analysis, hematological toxicity retained its significance as an independent negative prognostic factor for time to disease progression. CONCLUSION: Our findings do not confirm the results of previous studies which have demonstrated a better outcome for patients experiencing hematological toxicity during treatment. Anticancer Res

Seventy-eight confirmed cases of second primary breast cancer in the contralateral breast were encountered over a 22-year period in 1332 women with invasive breast cancer treated in our department. Tumors were grouped into those simultaneously detected in both breasts or within 6 months of each other (synchronous, 1.6%) and those detected within more than 6 months (metachronous, 4.2%). The mean interval between metachronous cancers was 117 months. Patients with bilateral tumors were more likely to have a family history of breast cancer than those with unilateral disease. Women with metachronous tumors tended to be younger when diagnosed with the first carcinoma as compared with those having unilateral or synchronous bilateral cancers. No differences were noticed in size and lymph node status between the first or second tumor of bilateral cases in comparison to patients with unilateral disease. Significantly more (P0.05) first metachronous tumors were found to be lobular invasive cancers. Histopathologic type of the first tumor was the same as the second in 62.8 per cent of all cases. Concordance of estrogen receptor status between bilateral tumors was 71.4 per cent. Our results indicate that the risk of developing, a contralateral breast cancer is related to the patient's age, family history of breast cancer, and lobular histology of the tumor.

Surgical excision following needle-wire localization of nonpalpable, mammographically detected breast lesions is a very valuable diagnostic and therapeutic procedure. No further treatment is usually required after establishing an accurate histological benign diagnosis of indeterminate lesions on preoperative assessment. On the other hand, ductal carcinoma in-situ (DCIS) and early invasive cancer, properly excised, may sometimes require further management depending on specific histologic findings. An uncommon problem of this procedure is the failure to identify, localize or excise the breast lesion. In this review article, factors that contribute to the failed needle localization procedure are presented.

Cystic breast masses are very common in female patients attending breast clinics. Most of them are benign and managed by simple aspiration. We reviewed histology records for the last 12 years to find patients with cystic breast carcinomas and to evaluate special clinical signs that may help to identify patients with this rare entity. Eighteen patients with cystic breast carcinomas were found among 1510 new breast cancer patients (1.19%) who were seen at our Breast Unit during this period. Ten had intracystic papillary carcinoma (0.66% of all breast cancers), seven had cystic degeneration of ductal carcinoma, and one had a mucinous carcinoma. The diagnosis of intracystic papillary carcinoma was based on cyst fluid cytology and breast imaging in most patients and on open breast biopsy in two cases only. The prognosis of our cystic breast carcinoma patients was excellent regardless of the specific histologic type of the tumor. We conclude that cysts in postmenopausal women should be viewed with suspicion. Bloodstained aspirated cyst fluid should be sent for cytology and breast imaging should be carried out in all these cases. Residual mass after cyst aspiration is also an indication for open biopsy.

Four cases of radial scar of the breast, primarily diagnosed as carcinoma are presented; the patients were found among 858 patients who were operated on at our Breast Unit over the last 4 years. The lesion was revealed on routine mammographic examination in 4 of our patients, while in the fourth it was found by palpation. In two of our patients mammographic examination revealed architectural distortion, in one patient micro-calcifications and in the fourth patient a stellate lesion was found. In the last two patients the lesion was localized before surgery with a hook wire. Diagnosis was established by histopathologic examination in all cases. The surgeon, the radiologist and the pathologist should be aware of this clinical entity which, in spite of its benign character, has the ability to simulate invasive carcinoma clinically, mammographically and histopathologically.

The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P

Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable nonsmall cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC. PATIENTS AND METHODS: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks. RESULTS: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95% CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients. CONCLUSION: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity. Anticancer Res

The purpose of this study was to determine factors associated with the incidence of axillary lymph node metastases (ALNM) in T1 tumors and cases in which axillary dissection could be omitted. Data from 195 patients with T1 primary invasive breast cancer (sizeor = 2 cm) who underwent either mastectomy or wide local excision of the tumor and axillary dissection were reviewed. ALNM was found in 59 of 195 patients with T1 tumors (30.3%). Tumor size was found to be the only independent predictor of ALNM, having a directly analogous relationship with the probability of invaded nodes: T1a (or = 5 mm) tumors had 0 per cent ALNM, whereas T1b (5 mmT1bor = 10 mm) and T1c (10 mmT1cor = 20 mm) tumors had 25.7 per cent and 33.8 per cent ALNM respectively. Among the other factors studied (patient age, tumor site, hormone receptor status, histologic type, and grade of the tumor) only the histologic grade of the tumor cells appeared to correlate with the incidence of lymph node involvement, but this was not statistically significant. In conclusion only tumor size has statistically significant correlation with the incidence of ALNM. Routine axillary dissection could be omitted only in patients at minimal risk of ALNM (ductal carcinoma in situ and T1a) and when treatment decisions were not influenced by lymph node status (e.g., elderly patients with clinically negative axilla). Axillary dissection (at least levels I and II) should be performed in all cases with primary invasive breast cancer with tumor size5 mm.

BACKGROUND: A phase II study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine (GEM) and pegylated liposomal doxorubicin (PLD) in patients with platinum- and/or taxane-resistant/refractory advanced epithelial ovarian cancer (AEOC). PATIENTS AND METHODS: Patients (pts), who had been treated with platinum or paclitaxel and met the criteria of resistant/refractory AEOC, received GEM 650 mg/m2 days 1 and 8 and PLD 25 mg/m2 day 1 every 4 weeks up to a total of 6 cycles, unless disease progression or adverse effects prohibited further therapy. RESULTS: Thirty-seven patients entered the study. There was 1 complete (3%) and 7 partial responses (19%) for an overall response rate of 22%. Two patients had stable disease (5.5%). After a median follow-up of 16.2 months, the median survival was 8.4 months and time to treatment failure 2.7 months. The most frequent severe toxicity was myelosuppression recorded in 13 (35%) patients. Severe stomatitis was recorded in only 2 (5%) cases and severe palmar-plantar erythrodysesthesia in 1 patient. One severe allergic reaction (grade 4) to PLD was recorded following the third cycle of treatment. CONCLUSION: The combination of GEM and PLD in patients with AEOC, who are resistant/ refractory to platinum and/or Taxanes, did not show any superiority over monotherapy. However, in view of the acceptable toxicity profile, the above combination may deserve further investigation in a randomised setting. Anticancer Res