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Background: Circulating tumor cell (CTC) analysis is highly promising for liquid biopsy-based molecular diagnostics. We undertook a comprehensive molecular analysis of in vivo isolated CTCs in breast cancer (BrCa)., Methods: In vivo isolated CTCs from 42 patients with early and 23 patients with metastatic breast cancer (MBC) were prospectively collected and analyzed for gene expression, DNA mutations, and DNA methylation before and after treatment. 19 healthy donor (HD) samples were analyzed as a control group. In identical blood draws, CTCs were enumerated using CellSearch® and characterized by direct IF staining., Results: All 19 HD samples were negative for CK8, CK18, CK19, ERBB2, TWIST1, VEGF, ESR1, PR, and EGFR expression, while CD44, CD24, ALDH1, VIM, and CDH2 expression was normalized to B2M (reference gene). At least one gene was expressed in 23/42 (54.8%) and 8/13 (61.5%) CTCs in early BrCa before and after therapy, and in 20/23 (87.0%) and 5/7 (71.4%) MBC before and after the first cycle of therapy. PIK3CA mutations were detected in 11/42 (26.2%) and 3/13 (23.1%) in vivo isolated CTCs in early BrCa before and after therapy, and in 11/23 (47.8%) and 2/7 (28.6%) MBC, respectively. ESR1 methylation was detected in 5/32 (15.7%) and 1/10 (10.0%) CTCs in early BrCa before and after therapy, and in 3/15(20.0%) MBC before the first line of therapy. The comprehensive molecular analysis of CTC revealed a higher sensitivity in relation to CellSearch or IF staining when based on creatine kinase selection., Conclusions: In vivo-CTC isolation in combination with a comprehensive molecular analysis at the gene expression, DNA mutation, and DNA methylation level comprises a highly powerful approach for molecular diagnostic applications using CTCs., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Chemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer., Materials and Methods: Formalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis., Results: CXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016)., Conclusions: Both biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Ki-67 is a marker of proliferating cells; in this meta-analysis we aimed to examine whether Ki-67 expression can predict recurrence rates of breast ductal carcinoma in situ (DCIS)., Materials and Methods: This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible articles were sought in MEDLINE up to April 30, 2017. Random effects (DerSimonian-Laird) models were used for the calculation of pooled relative risk (RR) estimates; meta-regression analysis was also performed. Separate analyses were performed according to Ki-67 expression cutoff levels, invasiveness of recurrence, and adjustment of studies., Results: Ten eligible cohort studies were synthesized; a significant association between Ki-67 expression and DCIS recurrence was noted for the Ki-67 cutoff at 10% (RR = 1.66; 95% confidence interval [CI], 1.14-2.42) as well as the Ki-67 cutoff at 14% (RR = 1.67; 95% CI, 1.01-2.77). Subanalysis on unadjusted (RR = 1.48; 95% CI, 1.06-2.07) and adjusted studies (RR = 2.19; 95% CI, 1.42-3.38) replicated the statistically significant findings. Ki-67 expression predicted the risk of invasive (RR = 1.53; 95% CI, 1.14-2.06) and noninvasive (RR = 1.59; 95% CI, 1.19-2.13) recurrence., Conclusion: This meta-analysis highlights Ki-67 expression as a predictor of DCIS recurrence; nevertheless, additional adjusted studies, with adequate follow-up periods, stemming from various world regions seem to be needed on this topic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that frequently involves the perineal and perianal regions. The association between HS and malignant transformation is a rare but under recognized phenomenon., Objective: This systematic review aims to summarize all available cases of vulvar and perianal/perineal cancer emerging in patients with HS, describing clinical and therapeutic particularities of these coexisting conditions in female patients., Materials and Methods: This systematic review and pooled analysis was performed in accordance with the PRISMA guidelines; end-of-search date was June 15, 2015., Results: A total of 13 eligible articles were identified; 7 cases of vulvar cancer and 6 cases of perineal/perianal carcinomas in patients with HS were noted. A majority of published cases pertained to rather advanced carcinomas; only occasionally early stage carcinomas were identified. The optimal modifications in the treatment scheme of vulvar, perianal, and perineal cancer in patients with HS have not been established; detailed reporting of recurrence- and survival-related aspects is advised., Conclusion: Vulvar, perianal, and perineal cancer represent a rare but serious complication of HS.

Purpose: Local recurrence is considered a major concern in patients diagnosed with ductal carcinoma in situ (DCIS), as its invasive occurrence is associated with high rates of distant disease and mortality. This study aims to assess the possible correlation of hormonal receptor status, Ki-67 and HER2 expression with recurrence rates in women with DCIS, taking also into account the potential prognostic effects of grade and age at diagnosis., Methods: 230 consecutive patients with DCIS were included in this study. Invasive and non-invasive recurrence events were recorded, as a total. Clinicopathological information, as well as PR positivity, ER positivity, HER2 positivity and ki-67 expression were analyzed. Multivariable Cox regression analysis was performed, examining the risk factors for recurrence., Results: Recurrence was noted in 17.8% of cases; the median follow-up was 44 months. Higher grade (adjusted HR = 1.72, 95%CI: 1.06-2.78), age at diagnosis (adjusted HR = 0.60, 95%CI: 0.43-0.83), Ki-67 expression (adjusted HR = 1.78, 95%CI: 1.11-2.88), and type of administered treatment were independently associated with increased recurrence rates. Recurrence rates were not significantly associated with ER, PR status or HER2 expression., Conclusion: In addition to high grade, administered treatment and younger age at diagnosis, high Ki-67 expression seems to be independently associated with increased likelihood of recurrence in patients with DCIS. Future studies with additional molecular markers seem necessary to further improve the identification of high-risk patients for DCIS recurrence., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The host's immune system is crucially involved in cancer development and progression. The ratio of regulatory to effector T-cells, as well as the interplay of T-cells with therapeutic agents, impact on cancer prognosis. The current study aimed to comparatively investigate the effect of metronomic and standard chemotherapy on the number and functionality of peripheral regulatory and effector T-cells in cancer patients., Methods: CD4+CD25+ regulatory and CD4+CD25- effector T-cells were purified from the peripheral blood of 36 cancer patients and co-cultured in the presence of a polyclonal stimulus. The proliferative capacity and frequency of CD4+CD25+/CD4+CD25- T-cells were analysed before and during various chemotherapeutic regimes, by ELISA and flow cytometry, respectively., Results: Chemotherapy shifted immune responses in favour of regulatory T-cells. The relative ratio of regulatory to effector T-cells increased, and the T-cell-mediated suppressive activity of regulatory on effector T-cells was augmented. This effect was more profound in metronomic than in standard chemotherapeutic approaches. Moreover, an association between the chemotherapy strategy followed and the mode of action of specific drugs (anti-mitotic, anti-DNA) was revealed., Conclusions: In comparison to standard chemotherapeutic strategies, metronomic approaches, though more patient-friendly, result in a significantly more prominent expansion of regulatory T-cells that aggravate the regulatory to effector T-cell imbalance. Our findings impact on the modulation of chemotherapy-treated patients' anti-tumor immunity and, thus, may be proven useful for selecting the most advantageous drug-delivery strategy, particularly when immunotherapeutics are eventually to be applied.

Purpose of Investigation: The aim of the present study was to record how the treatment of female cancer may affect sexuality and interpersonal relations in the couple., Material and Methods: From September 2008 until February 2012, the authors prospectively studied 67 patients with breast cancer (Group A) and 43 with gynecological cancers (Group B). As control groups 33 patients with benign breast and 30 patients with benign gynecological lesions (group 0a and 0b respectively) were used. Sexuality and interpersonal relations were evaluated by a questionnaire. The authors also evaluated interpersonal relations focusing on sexual function at the time of diagnosis and a year after the initial treatment for cancer., Results: A significant reduction of the "sexual desire", "sexual Arousal", and "orgasm" dimension was found in both cancer groups, in contrast to the control group, revealing no significant change. The "sexual enjoyment" scale was significantly decreased in gynecological cancer group but not in breast cancer group. While the score on the "relationship quality" dimension significantly increased in both cancer groups. In all groups, there was a significantly positive correlation between sexual function and enjoyment; on the contrary, there was a significantly negative correlation between relationship quality and sexual function and enjoyment., Conclusion: Sexual dysfunctions is a clinical problem which should be evidenced at the beginning of therapy, from the oncologists in order to provide integrated treatment to their patients.

Aims and Background: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole., Study Design: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored., Results: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66)., Conclusions: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

Purpose: To evaluate the activity and toxicity of gemcitabine and vinorelbine in patients with metastatic breast cancer (MBC), previously treated with anthracyclines alone or with taxanes., Patients and Methods: A total of 86 pretreated patients with MBC (median age 62 years), entered the study. Thirty-six patients had been pretreated with anthracyclines and 8 were resistant. The combination of gemcitabine (1000 mg/m2) and vinorelbine (25 mg/m2) was administered on days 1 and 8 every 3 weeks, for a total of 6 cycles., Results: A total of 344 cycles of chemotherapy were administered (median 4 cycles per patient). Partial responses were observed in 31 patients (36.0%; 95% CI: 23-56). The median duration of response was 7 months (range 3-11 months) and the median overall survival was 14 months (range 6-21). The scheme was well tolerated., Conclusion: The combination of vinorelbine and gemcitabine is an active scheme in pretreated MBC, demonstrating an acceptable toxicity profile, and may well represent a valuable therapeutic choice after anthracycline/taxane regimens.