Purpose: The purpose of this retrospective study is to identify potential predictors of academic success or failure in Doctor of Philosophy (PhD) programmes in the field of biomedicine. Based on these, the policies and structure of academic programmes granting PhD degrees in biomedicine might be improved. Literature review (State of the art): At the present moment, most European and all of the EU doctoral education systems in biomedicine are regulated by the Salzburg principles of the Bologna process. Almost all the programmes formally comply with regulations, but the degree to which rules are applied varies greatly. The European Research Council (ERC) and various stakeholders’ associations, such as the Organisation for PhD Education in Biomedicine and Health Sciences in the European System (ORPHEUS), have recognised this and in their policies, they recommend regular evaluation of PhD programme structures. One such evaluation that was conducted at our institution motivated us to search for quantifiable factors that can help the process of PhD programme structural reform. Since the literature is scarce on this matter, we decided to conduct analysis of our own data and thus study the relationships between recommended EU policies and real-world data. Methods: Biology of Neoplasms is a PhD programme founded under Bologna process rules. It enrols students with Doctor of Medicine (MD), Doctor of Dental Medicine (DMD) or similar degrees in the biomedical field. A large portion of enrolled PhD students work full time in medical practices. A retrospective analysis was conducted on students who enrolled between 2006 and 2017. In order to quantify academic success, outcome measures of graduation (completion) rate, time to graduation, average impact factor of published papers comprising a PhD thesis and the ratio of the latter two were formed. Age, sex, employment institution, mentor experience and tuition subsidy were considered as potential predictors. Results: A total of 124 students were enrolled in the study—38% male. Out of the total, 21 (16.94%) students discontinued the study programme and 22 students graduated (17.7%). The average impact factor (IF) of published papers was 2.66 ± 1.51. Mentor experience (Odds ratio (OR) = 6.7) and student employment in academia (OR = 11.7) were significant predictors of successful graduation. Stricter criteria for graduation had no effect on graduation in newly enrolled students. Likewise, sex, tuition subsidy and age did not affect graduation rates. Surprisingly, time to graduation was not affected by any of the considered predictors. On the other hand, students that were mentored by experienced mentors and employed in academia outperformed their peers in terms of impact factors of publications related to their thesis. Conclusion: Characteristics such as gender, age at enrolment and even tuition paid by the institution do not have a significant impact on completion rate. Experienced mentors and employment in academic institutions seem to be the factors that predict a successful completion of a PhD programme. Furthermore, our results give a quantifiable support to the ORPHEUS and ERC recommendations and policies. These conclusions can be easily applied to any PhD programme formed under the tenets of the Bologna process.

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens (CTAs) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets for cancer immunotherapies. We analyzed the correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at the protein level and the effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. The correlation between the expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria and platinum sensitivity, measured as platinum-free interval (PFI), progression free (PFS), and overall survival (OS) was explored. The MAGE-A10 protein expression predicted unresponsiveness to platinum-based chemotherapy (p = 0.005), poor platinum sensitivity (p < 0.001), poor PFS (p < 0.001), and OS (p < 0.001). Multivariate analysis identified MAGE-A10 protein expression as an independent predictor of poor platinum sensitivity (p = 0.005) and shorter OS (p < 0.001). Instead, no correlation was observed between the NY-ESO-1 protein expression and response to platinum-based chemotherapy (p = 0.832), platinum sensitivity (p = 0.168), PFS (p = 0.126), and OS (p = 0.335). The MAGE-A10 protein expression reliably identified advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted immunotherapy could represent an important alternative therapeutic option in these cancers.

Introduction. Disease recurrence in patients with the early hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one‐quarter of patients with early‐stage disease will experience disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) gene are highly prevalent (30–40%) in HR+/HER2− advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine the association between and impact of PIK3CA mutation status on disease‐free survival (DFS) in HR+/HER2− early breast cancer patients. Methods. This cohort study was multicentric and retrospective in nature and was conducted at five Croatian institutions from July 2020 to December 2021. The study included initially early and locally advanced operable HR+/HER2− breast cancer patients who were diagnosed with disease recurrence during adjuvant hormonal treatment or within the first six years of follow‐up. Results. A total of 186 patients were included, 40.9% of whom tested positive for the PIK3CA mutation. Primary and adjuvant treatment, particularly adjuvant endocrine treatment, were similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with a positive PIK3CA status and the H1047 PIK3CA mutation had a significantly lower hazard of disease recurrence than patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p = 0.024; false discovery rate, FDR <10%). Conclusions. This study highlights the potential impact of PIK3CA mutations on disease recurrence during or following adjuvant endocrine therapy and potentially opens the door for further investigation of possibly more personalized treatment strategies.

Background/Objectives: Venous thromboembolism (VTE) is a common and clinically significant complication in patients with metastatic colorectal cancer (mCRC). Tumor sidedness and molecular alterations such as RAS and BRAF mutations are established prognostic factors in mCRC; however, their role in VTE risk stratification remains unclear. This study aimed to evaluate the association between primary tumor sidedness, KRAS/NRAS/BRAF mutational status, and VTE occurrence in patients with mCRC treated in the outpatient setting. Methods: This multicenter ambispective observational study included 224 patients with mCRC treated with first-line chemotherapy with or without targeted therapy. All patients had known KRAS/NRAS/BRAF statuses. The primary endpoint was the association between tumor sidedness and VTE risk. Secondary endpoints included associations between oncogenic mutations and VTE, subgroup analyses according to tumor localization and mutational status, and overall survival (OS). Multivariate logistic regression was used to identify independent predictors of VTE. Results: After a median follow-up of 21 months, VTE occurred in 23.3% of patients. The incidence of VTE was significantly higher in right-sided colorectal cancer (RCRC) compared with left-sided colorectal cancer (LCRC) (41.0% vs. 17.6%, p < 0.001). Although KRAS/NRAS and BRAF mutations were more frequent in RCRC, mutational status was not independently associated with VTE. In multivariate analysis, right-sided tumor location remained a strong predictor of VTE (OR 5.2; 95% CI 1.9–14.1; p = 0.001), along with anti-EGFR therapy. The Khorana score classified most patients as low risk and did not reliably identify those who developed VTE. VTE occurrence was not significantly associated with OS, whereas right-sided tumor location was associated with inferior survival. Conclusions: Right-sided tumor location is an independent predictor of VTE in patients with mCRC and confers a high absolute thrombotic risk not captured by the Khorana score. Incorporating tumor sidedness into VTE risk assessment may improve identification of patients who could benefit from primary thromboprophylaxis.

Ciljevi: U bolesnica s luminalnim, HER2 negativnim, metastatskim karcinomima dojke rezistentnim na endokrinu terapiju, liječenim u KBC Split u 2020. i 2021. godini u uzorcima tkiva tumora odrediti udio i tip PIK3CA mutacija, te dobivene podatke usporediti s rezultatima iz registracijske studije SOLAR1 koja procjenjuje učinkovitost i sigurnost alpelisiba u kombinaciji s fulvestrantom kod bolesnika s uznapredovalim rakom dojke koji je napredovao tijekom ili nakon liječenja inhibitorima aromataze. Metode ( ispitanici i postupci ): Prikupljeni su podaci o 99 bolesnika s dijagnosticiranim luminalnim, HER2 negativnim, metastatskim karcinomima dojke u vremenskom periodu od 2020. do 2021. godine. To je retrospektivna analiza. Za potrebe izrade empirijskog dijela ovog diplomskog rada pristupljeno je medicinskoj dokumentaciji i elektroničkoj bazi podataka Kliničkog zavoda za patologiju, sudsku medicinu i citologiju Kliničkog bolničkog centra Split. U bazu podataka uvršteni su dob, spol, prisutnost PIK3CA mutacije i distribucija specifičnih mutacija. Uzorci tumorskog tkiva analizirani su primjenom lančane reakcije polimeraze u realnome vremenu (RT-PCR ) metode. Rezultati: Utvrđena je značajna razlika u zastupljenosti pacijenata prema spolu u uzorku od 99 pacijenata. Najveći broj pacijenata nalazi se u dobnoj skupini od 60 do 70 godina, dok srednja životna dob iznosi 67 godina. U 99 uzoraka tkiva pacijenata s metastatskim, hormon receptor pozitivnim, HER2 negativnim karcinomom dojke , koji su rezistentni na endokrinu terapiju liječenih u KBC-u Split, u njih 50 je nađena PIK3CA mutacija (51,51%). U 17 uzoraka tkiva pozitivnih na PIK3CA mutaciju (N=50) utvrđena je mutacija H1047X na egzonu 20, te 14 mutacija na egzonu 9 (E542,545X i545K). Ove mutacije predstavljaju 62% svih PIK3CA mutacija, što odgovara rezultatima SOLAR-1 studije, u kojoj su mutacije također nađene najčešće na egzonima 9 i 20. Zaključak: Na temelju rezultata ove studije, usporedivih s rezultatima registracijske studije SOLAR-1, RT-PCR metodologija korištena za detekciju PIK3CA mutacija je efikasna, specifična i senzitivna metoda za odabir bolesnica za liječenje PI3K inhibitorom, koja se može implementirati u većem broju laboratorija uz redovite vanjske i unutarnje provjere kvalitete i točnosti testiranja.

: Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting response to chemotherapy might help select eligible patients while sparing unresponsive ones treatment-associated toxicity. Cancer/testis antigens (CTA) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets of cancer immunotherapies. We analyzed correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at protein level and effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. Correlation between expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria, platinum sensitivity, measured as platinum free interval (PFI), progression free (PFS) and overall survival (OS) was explored. MAGE-A10 protein expression predicts unresponsiveness to platinum-based chemotherapy (p=0.005), poor platinum sensitivity (p<0.001), and poor PFS (p<0.001) and OS (p<0.001). Multiva-riate analysis identifies MAGE-A10 protein expression as independent predictor of poor platinum sensitivity (p=0.005) and shorter OS (p<0.001). Instead, no correlation was observed between NY-ESO-1 protein expression and response to platinum-based chemotherapy (p=0.832), platinum sensitivity (p= 0.168), PFS (p=0.126) and OS (p=0.335). MAGE-A10 protein expression reliably identifies advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted im-munotherapy could represent an important alternative therapeutic option in these cancers.