Background: Providing patients with cancer who are undergoing systemic therapy with useful information about symptom management is essential to prevent unnecessary deterioration of quality of life. Objective: The aim was to evaluate whether use of an app for symptom management was associated with any change in patient quality of life or use of health resources. Methods: Outpatients with early stage breast cancer receiving systemic therapy were recruited at the Institute of Oncology in Ljubljana, Slovenia. Patients who received systemic therapy between December 2017 and March 2018 (control group) and between April 2018 and September 2018 (intervention group) were eligible. All patients received standard care, but only those in the intervention group were asked to use mPRO Mamma, an Android-based smartphone app, in addition. The app supported daily tracking of 50 symptoms, allowed users to grade their symptom severity (as mild, moderate, or severe), and also provided in-depth descriptions and recommendations based on reported symptom level. Patient-reported outcomes in both groups were assessed through the European Organisation for Research and Treatment of Cancer (EORTC) core (C-30) and breast cancer (BR-23) questionnaires, as well as a questionnaire about health resources use. The primary outcomes were the difference in the global quality of life between groups and the difference in summary score of the EORTC C-30 questionnaire between groups after 3 time periods (the first week of treatment, the first treatment cycle, and the entire treatment). The secondary outcome was the use of health resources (doctor visits and hospitalizations) in each time period. Other scales were used for exploratory analysis. Results: The mean difference between the intervention group (n=46) and the control group (n=45) in global quality of life (adjusted for baseline and type of surgery) after the first week was 10.1 (95% CI 1.8 to 18.5, P=.02). The intervention group summary scores were significantly higher than those of the control group after the first week (adjusted mean difference: 8.9, 95% CI 3.1 to 14.7, P=.003) and at the end of treatment (adjusted mean difference: 10.6, 95% CI 3.9 to 17.3, P=.002). Use of health resources was not statistically significant between the groups in either the first week (P=.12) or the first treatment cycle (P=.13). Exploratory analysis findings demonstrated clinically important improvements (indicated by EORTC C-30 or BR-23 scale scores)—social, physical, role, and cognitive function were improved while pain, appetite loss, and systemic therapy side effects were reduced. Conclusions: Use of the app enabled patients undergoing systemic therapy for early stage breast cancer to better cope with symptoms which was demonstrated by a better global quality of life and summary score after the first week and by a better summary score at the end of treatment in the intervention group compared to those of the control group, but no change in the use of health resources was demonstrated.

Circulating tumor cell count is an independent prognostic factor in early breast cancer. CTCs can be found in the blood of 20% of patients prior to neoadjuvant therapy. We aimed to assess the suitability of magnetic-activated cell separation (MACS) technology for isolation and cytological characterization of CTCs. In the preclinical part of the study, cell lines were spiked into buffy coat samples derived from healthy donors, and isolated using MACS. Breast cancer cells with preserved cell morphology were successfully isolated. In the clinical part, blood for CTC isolation was drawn from 44 patients with early and locally advanced breast cancer prior to neoadjuvant chemotherapy. Standard Giemsa, Papanicoulau and pancytokeratin staining was applied. 2.3% of samples contained cells that meet both the morphological and immunocytochemical criteria for CTC. In 32.6% of samples, partially degenerated pancytokeratin negative cells with morphological features of tumor cells were observed. In 65.1% of samples, CTCs were not found. In conclusion, our results demonstrate that morphologically intact tumor cells can be isolated using MACS technology. However, morphologically intact tumor cells were not detected in the clinical part of the study. At present, MACS technology does not appear suitable for use in a clinical cytopathology laboratory.

Introduction: A high proportion of metastatic melanoma patients do not respond to immune checkpoint inhibitors (ICI), and until now, no validated biomarkers for response and survival have been known. Methods: We performed a retrospective analysis of outcomes in patients with metastatic melanoma treated with first-line ICI at the Institute of Oncology Ljubljana from January 2018 to December 2020. The immune-related adverse events (irAEs) and serum immune-inflammation parameters (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (LR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV)) were analyzed as potential biomarkers for response and survival. Survival rates were calculated using the Kaplan–Meier method and then compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Results: Median follow-up was 22.5 months. The estimated median progression-free survival (PFS) was 15 months (95% CI 3.3–26.2). The two-year survival rate (OS) was 66.6%. Among 129 treated patients, 24 (18.6%) achieved complete response, 28 (21.7%) achieved partial response, 26 (20.2%) had stable disease and 51 (39.5%) patients experienced a progressive disease. There was a higher response rate in patients with irAEs (p < 0.001) and high NLR before the second cycle of ICI (p = 0.052). Independent prognostic factors for PFS were irAE (HR 0.41 (95% CI 0.23–0.71)), SII before the first cycle of ICI (HR 1.94 (95% CI 1.09–3.45)) and PLR before the second cycle of ICI (HR 1.71 (95% CI 1.03–2.83)). The only independent prognostic factor for OS was SII before the first cycle of ICI (HR 2.60 (95% CI 0.91–7.50)). Conclusions: Patients with high pre-treatment levels of SII had a higher risk of progression and death; however, patients with irAEs in the high-SII group might respond well to ICI. Patients who develop irAEs and have high NLRs before the second ICI application have higher rates of CR and PR, which implicates their use as early biomarkers for responsiveness to ICI.

Gemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported. We report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m(2)) he presented with Raynaud's like phenomenon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m(2)) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preexisting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 × 10(9)/L) might have also contributed to the ischemic digital event in the second case. Digital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco-associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud's phenomenon and/or preexisting PAOD should be done with caution.

Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995–2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein–Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.

Proliferation determined by Ki-67 immunohistochemistry has been proposed as a useful prognostic and predictive marker in breast cancer. However, the clinical validity of Ki-67 is questionable. In this study, Ki-67 was retrospectively evaluated by three pathologists using two methods: a visual assessment of the entire slide and a quantitative assessment of the tumour margin in 411 early-stage breast cancer patients with a median follow-up of 26.8 years. We found excellent agreement between the three pathologists for both methods. The risk of recurrence for Ki-67 was time-dependent, as the high proliferation group (Ki-67 ≥ 30%) had a higher risk of recurrence initially, but after 4.5 years the risk was higher in the low proliferation group. In estrogen receptor (ER)-positive patients, the intermediate Ki-67 group initially followed the high Ki-67 group, but eventually followed the low Ki-67 group. ER-positive pN0-1 patients with intermediate Ki-67 treated with endocrine therapy alone had a similar outcome to patients treated with chemotherapy. A cut-off value of 20% appeared to be most appropriate for distinguishing between the high and low Ki-67 groups. To summarize, a simple visual whole slide Ki-67 assessment turned out to be a reliable method for clinical decision-making in early breast cancer patients. We confirmed Ki-67 as an important prognostic and predictive biomarker.