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Tumors and their surrounding area represent spatially organized “ecosystems”, where tumor cells and the immune contextures of the different compartments are in a dynamic interplay, with potential clinical impact. Here, we aimed to investigate the prognostic significance of peritumoral tertiary lymphoid structures (TLS) either alone or jointly with the intratumoral densities and spatial distribution of CD8 + and CD163 + cells in breast cancer (BCa) patients. TLS were identified peritumorally, within the area distancing up to 5 mm from the infiltrative tumor border, counted and further characterized as adjacent or distal, in formalin-fixed, paraffin-embedded tumor tissue samples from a cohort of 167 patients, with histologically confirmed invasive ductal BCa. TLS and tumor-infiltrating immune cells were determined by H&E and immunohistochemistry. Clinical follow-up was available for 112 of these patients. Patients with peritumoral TLS exhibited worse disease-free survival (DFS) and overall survival (OS) as compared to patients lacking TLS. Moreover, the density of peritumoral TLS was found to be crucial for prognosis, since patients with abundant TLS exhibited the worst DFS and OS. By combining the density of adjacent TLS (aTLS) with our recently published intratumoral signatures based on the differential distribution of CD8 + and CD163 + in the tumor center and invasive margin, we created two improved immune signatures with superior prognostic strength and higher patient population coverage. Our observations strengthen the notion for the fundamental role of the dynamic interplay between the immune cells within the tumor microenvironment (center/invasive margin) and the tumor surrounding area (peritumoral TLS) on the clinical outcome of BCa patients.

Purpose AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. Methods In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. Results 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage ( p  = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression ( p  = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer ( p  = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG ( p  = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS ( p  = 0.052) in VG as compared to CG. Conclusions This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Examining for new BC biomarkers has proven that kallikrein-related peptidase (KLK) family members represent promising serum and/or tissue molecular tools for early diagnosis, effective prognosis, and treatment monitoring of patients. The aim of this study was to investigate, the previously unexplored, prognostic significance of KLK8 in BC. KLK8 mRNA expression was quantitatively analyzed in 150 cancerous and 100 corresponding normal breast tissue specimens via a SYBR Green-based Real-Time PCR methodology. Expression data and patients’ clinicopathological parameters were used for extensive biostatistical analyses, including internal validation. KLK8 mRNA expression was significantly downregulated in the cancerous tissue part relative to the non-cancerous counterpart ( P  < 0.001), in the majority of the paired breast tissue samples. KLK8 expression was associated with advanced TNM stage ( P  = 0.019) and positive nodal status involvement ( P  = 0.044). Triple negative (TNBC) and HER2 overexpressing tumors exhibited higher KLK8 expression levels ( P  < 0.001), compared to Luminal A and B molecular subtypes. Kaplan–Meier survival curve analysis revealed that BC patients with high KLK8 expression had significantly shorter disease-free survival (DFS) intervals ( P  < 0.001) compared to those belonging in the KLK8 -low expression group. Cox univariate analysis confirmed the association between KLK8 expression, analyzed as a continuous variable, and poor patients’ outcome (Hazard ratio [HR] = 3.28, P  < 0.001). Most importantly, multivariate analysis showed that KLK8 expression is a strong and independent predictor of adverse DFS in BC ([HR] = 2.74; P  = 0.002). Our results show that KLK8 mRNA expression is associated with aggressive tumor characteristics and it can serve as a novel independent biomarker of unfavorable prognosis for BC patients.

Background In the realm of HER2-positive (HER2+) metastatic breast cancer (MBC), the advent of targeted therapies, notably trastuzumab and pertuzumab, represents a substantial advancement in enhancing patient outcomes. However, the intricacies of treatment escalate when patients encounter progression or resistance during first-line (1L) therapy. The togetHER study aimed to elucidate real-world insights into the profile, management strategies, and outcomes for HER2+ MBC patients initiating second-line treatment (2LT) in Greece, predating recent international guideline changes incorporating trastuzumab deruxtecan and tucatinib in the second line and beyond lines of treatments. Methods Data from adult female patients with HER2+ MBC who had initiated 2LT between 01-Jan-2015 and 31-Dec-2018 in 18 oncology departments across Greece were retrospectively abstracted through medical chart review. Results The eligible population comprised 122 patients, 68.0% of whom presented with recurrent MBC. Among the latter, 26.5% were tested for HER2 both in early and metastatic settings with 27.3% of them changing HER2 status from negative to positive. Retesting of HER2 expression following 2LT initiation was recorded in 8 cases. At 2LT initiation, patients’ median age was 57.0 years and 63.6% were hormone receptor-positive. The most common metastatic sites were bone (56.6%), lung (44.3%), liver (41.0%), and brain (29.5%). Anti-HER2 agent usage in 1L and 2L stood at 91.8% and 92.6%, respectively, with rates slightly diminishing in third (3L) (85.9%) and fourth line (4L) (82.4%). Endocrine therapy administration was generally low across treatment lines (12.3%, 9.9%, and 5.9%, in 2L, 3L, and 4L respectively), while chemotherapy use increased from 30.3% in 2L to 47.9% and 47.1% to 3L and 4L, correspondingly. Median progression-free survival (PFS) for 2L, 3L, and 4L was 7.7 [95% confidence interval (CI) 6.0–14.4], 6.4 (95% CI 5.4–7.1), and 5.6 (95% CI 2.6–9.0) months, respectively, while median overall survival was 25.0 (95% CI 20.5–34.4) months. Conclusions Although the 2LT pattern in Greece generally aligned with guidelines, persistently poor treatment outcomes underscore a significant unmet medical need for these patients.

SummaryBackground. Current treatment recommendations for high grade non-metastatic osteosarcoma include perioperative chemotherapy and surgery. Despite this intensive protocol, approximately 40% of patients will relapse. The addition of the immunomodulator mifamurtide to adjuvant cytotoxic chemotherapy was associated with a significant improvement in 6-year overall survival (OS) in young patients with resectable osteosarcoma, leading to its approval in Europe and other countries. Very limited real-world data are reported on its use. Methods. We retrospectively evaluated data from osteosarcoma patients who received mifamurtide in the adjuvant setting. Data were obtained from medical records in 2 high-volume bone sarcoma centers. The aim of this study was to collect real-world data on mifamurtide safety and efficacy in Greece. Results. We identified 15 patients with completely resected osteosarcoma who received mifamurtide from September 2015 to January 2020. Median age at diagnosis was 24 years old (16–76). Osteosarcoma arose in the lower extremities (n = 12), in the upper extremities (n = 2) or in the ilium (n = 1). The majority of patients (n = 13) received cisplatin/doxorubicin/methotrexate as perioperative chemotherapy and the remaining patients cisplatin/doxorubicin. After a median follow-up of 46.9 months (range, 32.8–61.1), the median recurrence-free survival was 58.7 months (range, 18.5–98.8) and the median OS 64.1 months (range, 25.6–102.6). Except for fever and chills, the only adverse event probably related to mifamurtide was pericarditis (n = 1). Conclusions. Mifamurtide was well tolerated in a Greek osteosarcoma population, including patients older than 30 years. The small sample size and the non-comparative design do not allow drawing conclusions on the drug benefit in terms of survival.

Background The “EMERGE” study, aimed to capture real-life management patterns and outcomes in metastatic breast cancer (MBC) in Greece, also accounting for hormone (HR) and human epidermal growth factor receptor 2 (HER2) status. Methods “EMERGE” was a multicenter, retrospective cohort study of adult MBC patients diagnosed between 01-Janaury-2010 and 30-June-2012, either de novo or having progressed from a non-metastatic state. Patient data, including treatment patterns and outcomes, were mainly abstracted through medical chart review. Results 386 patients were enrolled by 16 hospital-based oncologists between 12-March-2013 and 31-March-2015. The median look-back period was 29.1 months. At MBC diagnosis, 56.1% of the patients were HR + /HER2 − , 16.6% HR + /HER2 + , 14.5% HR − /HER2 − , and 12.8% HR − /HER2 + . In the first line setting, chemotherapy, targeted therapy and endocrine therapy were received by 76.7, 52.4, and 28.3% of the overall population, and by 66.5/36.2/42.0%, 80.4/80.4/28.6%, 88.4/90.7/0.0, and 95.6%/56.5/6.5% of the HR + /HER2 − , HR + /HER2 + , HR − /HER2 + , HR − /HER2 − subpopulations, respectively. In the overall population, the disease progression incidence rate was 0.57 [95% confidence interval (CI): 0.48–0.67] per person-year; median progression-free survival (PFS) was 22.4 (95% CI: 20.4–24.7) and overall survival (OS) was 45.0 (95% CI: 40.9–55.0) months. Median PFS was 24.6 (95% CI: 21.3–27.9) in HR + /HER2 − , 19.7 (95% CI: 12.9–25.9) in HR + /HER2 + , 23.0 (95% CI: 16.6–29.7) in HR − /HER2 + and 18.3 (95% CI: 10.0–24.7) months in HR − /HER2 − subpopulations. A multivariable Cox proportional hazards model, adjusted among other factors for age and duration of diagnosis, HR and HER2 status, demonstrated that in the overall population PFS was better among those receiving first line endocrine therapy (hazard ratio: 0.70; 95%CI: 0.51–0.95; p  = 0.024). Conclusions “EMERGE” demonstrates differences between HR/HER2 subtypes in clinical outcomes and divergence from evidence-based guideline recommendations for MBC management, especially as it pertains to the HR + /HER2 − patients in which chemotherapy was favored over endocrine therapy in the first line setting. Study registration The study has been registered on the electronic Registry of Non-Interventional Studies (RNIS) posted on the website of the Hellenic Association of Pharmaceutical Companies (SFEE): https://www.dilon.sfee.gr/studiesp_d.php?meleti_id=NIS-OGR-XXX-2012/1

BackgroundTumor immune cell infiltrates are essential in hindering cancer progression and may complement the TNM classification. CD8+ and CD163+ cells have prognostic impact in breast cancer but their spatial heterogeneity has not been extensively explored in this type of cancer. Here, their potential as prognostic biomarkers was evaluated, depending on their combined densities in the tumor center (TC) and the tumor invasive margin (IM).MethodsCD8+ and CD163+ cells were quantified by immunohistochemistry of formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples from a cohort totaling 162 patients with histologically-confirmed primary invasive non-metastatic ductal breast cancer diagnosed between 2000 and 2015. Clinical follow-up (median 6.9 years) was available for 97 of these patients.ResultsDifferential densities of CD8+ and CD163+ cells in the combined TC and IM compartments (i.e., high(H)/low(L), respectively for CD8+ cells and the reverse L/H combination for CD163+ cells) were found to have significant prognostic value for survival, and allowed better patient stratification than TNM stage, tumor size, lymph node invasion and histological grade. The combined evaluation of CD8+ and CD163+ cell densities jointly in TC and IM further improves prediction of clinical outcomes based on disease-free and overall survival. Patients having the favorable immune signatures had favorable clinical outcomes despite poor clinicopathological parameters.ConclusionsGiven the important roles of CD8+ and CD163+ cells in regulating opposing immune circuits, adding an assessment of their differential densities to the prognostic biomarker armamentarium in breast cancer would be valuable. Larger validation studies are necessary to confirm these findings.Trial registrationsStudy code: IRB-ID 6079/448/10-6-13Date of approval: 10/06/2013Retrospective study (2000–2010)First patient prospectively enrolled 14/2/2014

Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m ), trauma history, renal insufficiency and bevacizumab use. Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.

Methylation of arginine residues has been implicated in many cellular activities like mRNA splicing, transcription regulation, signal transduction and protein–protein interactions. Protein arginine methyltransferases are the enzymes responsible for this modification in living cells. The most commonly used methyltransferase in man is protein arginine methyltransferase 1 (PRMT1). Since methylation processes appear to interfere in the emergence of several diseases, including cancer, we investigated the localisation of the protein in cancer tissue and, for the first time, the relation that possibly exists between the expression of PRMT1 gene and breast cancer progression. We used tumour specimens from 62 breast cancer patients and semi-quantitative RT-PCR to determine the expression of PRMT1 gene and was found to be associated with patient’s age ( p  = 0.002), menopausal status ( p  = 0.006), tumour grade ( p  = 0.03), and progesterone receptor status ( p  = 0.001). Survival curves revealed that PRMT1 -v1 status-low expression relates to longer disease-free survival (DFS; p  = 0.036). To the contrary, PRMT1 -v2 status is not associated neither with the clinical or pathological parameters nor with DFS ( p  = 0.31). PRMT1 -v3 was not statistically significantly expressed in breast cancer tissue. Selected cancer and normal breast samples were stained for PRMT1. In both normal and cancerous breast tissues, staining was in the cytoplasm and only in rare cases the cell nucleus appeared stained. Present results show a potential use for this gene as a marker of unfavourable prognosis for breast cancer patients.

Objective. This study investigated whether thyroid hormone (TH) levels are correlated to cell proliferation (Ki67), in euthyroid breast cancer patients. Design and Methods. 86 newly diagnosed breast cancer patients with estrogen receptor (ER) positive tumors, who referred for surgery, were included in the study. Results. FT3, FT4, and TSH were within normal range. No correlation was seen between Ki67 and FT3 (r=-0.17, P=0.15), FT4 (r=-0.13, P=0.25), or TSH (r=-0.10, P=0.39) in all patients studied. However, subgroup analysis showed that, in HER2(+) patients, a negative correlation existed between FT3 levels and Ki67 (r=-0.60 and P=0.004) but not between Ki67 and FT4 (r=0.04 and P=0.85) or TSH (r=-0.23 and P=0.30). In HER2(−) patients, there was no significant correlation between Ki67 and FT3 (r=-0.06, P=0.67), FT4 (r=-0.15, P=0.26), or TSH (r=-0.09, P=0.49). Phospho-p44/total p44 ERK levels were found to be increased by 2-fold in HER2(+) versus HER2(−) tumors. No difference was detected in phospho-p42/total p42 ERK levels. Conclusions. TH profile is not altered in patients with newly diagnosed breast cancer. However, FT3 levels, even within normal range, are negatively correlated with cell proliferation in HER2(+) breast cancer tumors. This response may be due to the interaction between ERK and TH signaling.