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Introduction: Real-world data on management of metastatic castration resistant prostate cancer (mCRPC) with novel therapies is sparse. The aim of this study was to capture real-world management strategies in patients with mCRPC who initiated first line (1L) systemic therapy with chemotherapy or novel hormonal agents (NHAs) in Greece and describe the therapeutic sequencing strategy among patients who advanced to 2L and 3L treatment., Patients and Methods: In this noninterventional, multicentre, retrospective study (PROSPECT), a medical chart review of 149 patients with mCRPC who initiated 1L systemic therapy with chemotherapy or NHAs in 7 major anticancer hospital clinics, from public, academic, and private sectors in Greece was conducted. All endpoints were descriptively analysed. Kaplan-Meier was used for time-to-event outcomes., Results: At 1L (N = 149), most (78.5%) patients received NHAs; enzalutamide (52.3%), and abiraterone (26.2%). At 2L (N = 68), most (72.1%) patients received chemotherapy, most frequently docetaxel (50.0% of all patients). At 3L (N = 32), 56.3% and 31.3% of patients received chemotherapy and NHAs, respectively. Regarding treatment sequencing from 1L→2L (N = 68), most patients (55.9%) advanced from NHA→chemotherapy. Regarding treatment sequencing from 1L→2L→3L (N = 32), 34.4% advanced from NHAs→chemotherapy→chemotherapy and 31.3% from NHAs→chemotherapy→NHA. Estimated median times spent on treatment at 1L, 2L, and 3L were 9.8, 4.4, and 3.7 months, respectively., Conclusion: Most patients were treated with 1L NHAs, in accordance to established guidelines (which suggest both NHA and chemo as preferred 1st line options). There appeared to be a longer time on treatment of NHAs at 1L than chemotherapy, suggesting an unmet need for treatment optimisation/recommendations for 2L and 3L treatment in mCRPC., Competing Interests: Disclosure LM has received honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb/Celgene, Ipsen, Janssen, MSD Oncology, Roche, Sanofi, personal fees for advisory/consultancy from Amgen, AstraZeneca, GlaxoSmithKline, Janssen and travel/accommodation fees from AstraZeneca, Bayer, Pfizer, Roche. ID is employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA and may own stocks and/or stock options in Merck & Co, Inc, Rahway, NJ, USA. GE is full-time employee of MSD Greece, a subsidiary of Merck & Co, Inc, Rahway, NJ,USA. CC declared Amgen, Astra Zeneca, BMS, Genesis, Gilead, Lilly, Merck, Novartis, Pfizer, Roche as potential conflicts of interest. TM has received consulting and medical advisor fees from Janssen, Abbvie, AstraZeneca, BMS, GSK, Janssen, IPSEN, MSD, Novartis, Pfizer, Roche, honoraria from Astellas, AstraZeneca, BMS, GSK, Janssen, IPSEN, MSD, Novartis, Pfizer, Roche. ZF has received honoraria for lectures and have served in an advisory role for AstraZeneca, Daiichi, Eli- Lilly, Merck, MSD, Novartis, Pfizer, Genesis- Pharma, Roche and Gilead. BA has received honoraria, advisory fees, and research support from MSD, ASTELLAS, JANSSEN, VIANEX. For the remaining authors, there are no conflicts of interest., (Copyright © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA., The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported., Materials and Methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models., Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status., Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials., Competing Interests: Disclosure PJvD has advisory relationships with Paige, Pantarei and Samantree, paid to the institution, and research grants paid to the institute from Pfizer. NS received institutional research funding from Pfizer. ZV has a consulting role for Roche. CHMvD received institutional research funding from AstraZeneca/Daiichi Sankyo. SMW has a consulting role for Roche, and received institutional research funding from Roche, Pfizer, Bayer, MSD, AstraZeneca/Merck and Amgen. SMW has a consulting role for IDDI, Sensorion, Biophytis, Servier, Yuhan, Amaris Consulting and Roche. JW received institutional research funding from Cancer Research UK and KWF Dutch Cancer Society. AR has a consulting role for MSD Oncology, Amgen, Roche, AstraZeneca/Daiichi Sankyo and Bristol Myers Squibb/Pfizer. SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SCL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. MK is an advisory board member and/or received speakers’ fee for/from Alderaan, Bristol Myers Squibb (BMS), Domain Therapeutics, Gilead, Roche, Medscape, MSD and AZ/Daiichi and received institutional research support from AstraZeneca/Daiichi, BMS and Roche outside the submitted work. RS reports non-financial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. IRK received research grants from Novartis and Gilead. RHTK is an advisory board member for Amgen, AstraZeneca, Bayer, BMS, MSD, Novartis, Pfizer, Pierre Fabre Sante, Sanofi and Servier. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Breast cancer is the most common malignancy, affecting one in eight women in North America and Europe. The human epidermal growth factor receptor (EGFR) protein comprises a major determinant of normal development but also cancer. RANK receptor (Receptor Activator of Nuclear factor-κB) is a tumor necrosis superfamily member and a binding partner for RANKL, which was recently implicated in breast cancer initiation, progression and metastasis. Here we provide preliminary evidence of a possible interplay between RANK and EGFR signaling in breast cancer. TCGA (cancergenome.nih.gov) publicly available data for EGFR and TNFRSF11A (RANK) genes from breast cancer patients and breast cancer cell lines were retrieved and analyzed. RANK mRNA showed a statistically significant positive correlation (p <0.001) with the mRNA and protein expression of EGFR, but not with ERBB2/3/4. Further analyses of survival data of a group of breast cancer patients (n = 248) from TCGA, revealed an EGFR hi /RANK hi subpopulation that showed a statistically significant (p = 0.001) reduced overall survival when compared to EGFR low /RANK low group of patients. Finally, EGFR and RANK combinatorial in vitro analyses revealed a significant upregulation of AKT and ERK signaling after EGF stimulation in cell lines and also an increase of breast cancer cell invasiveness., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Challenges in measurement of epidermal growth factor receptor (EGFR) protein expression have led to conflicting data on its prognostic value and discontinuation of its use for prediction of response. Herein is described a quantitative standardized assay for EGFR and its use in a series of retrospective cohorts of patients with non-small cell lung cancer (NSCLC). The AQUA technology of quantitative immunofluorescence was used in conjunction with Western blot analysis to calculate the absolute concentration of EGFR in two independent NSCLC cohorts (170 from Yale New Haven Hospital and 335 from Sotiria and Patras Hospitals in Greece). EGFR and mutated EGFR were measured using D38B1 antibody and two mutation-specific antibodies. All patients positive or borderline for mutation-specific antibody were genotyped. A threshold for reproducible detection of EGFR was defined as 0.85 ng/μg total protein. EGFR expression demonstrated no prognostic value in either cohort. The mutation rate was 1.79% in the Yale cohort, and 1.52% in the Sotiria/Patras cohort, with no antibody detection-based false-positive cases. No mutations were detected for EGFR concentrations <1.46 ng/μg total protein. In summary, accurate measurement of EGFR still shows no prognostic value in NSCLC. In these two population-based cohorts, the antibody-based EGFR mutation rate was lower than has been frequently reported., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

CD44 is an adhesion molecule involved in cell-to-cell and cell-to-matrix interactions. Recent evidence indicates a role of CD44 in tumor growth and metastatic potential of tumor cells. Moreover, it is widely known that the p53 tumor suppressor gene controls cell proliferation and loss of its normal function may lead to carcinogenesis. To investigate the role of these biomarkers in renal cancer, we analyzed the immunohistochemical distribution of CD44's expression on formalin fixed paraffin embedded tissue from 67 renal cell carcinomas and correlated with clinicopathologic parameters as well as with p53 suppressor gene expression. The monoclonal antibodies CD44 and p53 were applied to the tissues using the streptavidin biotin peroxidase method after microwave antigen retrieval. For CD44 and p53 more than 10% membranous and 5% nuclear staining, respectively, were estimated as positive. CD44's membranous immunoreactivity was detected in 24/67 tumors (35%) and mostly in carcinomas of clear/granular cell type. Nine tumors expressed nuclear immunoexpression of p53 protein (13.4%). Statistically significant correlation was noted between CD44 expression and nuclear grade (P < 0.001), tumor stage (P < 0.001), vascular invasion (P < 0.05) and p53 expression (P < 0.01). These results suggest that CD44s and p53 are markers of tumor progression in renal cell cancer.

Autoimmune cholangitis is a rare chronic cholestatic liver disease. We describe the case of a 65-year-old woman with celiac disease who presented to us with fever, jaundice and weight loss. Serum biochemical study showed marked increase in alkaline phosphatase and gammaGT levels. Antinuclear antibodies were positive, while antimitochondrial and anti-smooth-muscle antibodies were negative. Liver biopsy was compatible with primary autoimmune cholangitis. The patient was successfully treated with azathioprine and methylprednisolone. We describe here the uncommon association of autoimmune cholangitis with celiac disease and review the prevalence of liver diseases in patients with celiac disease.