Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1.

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

Trends in Systemic Inflammatory Reaction (SIR) during Paclitaxel and Carboplatin Chemotherapy in Women Suffering from Epithelial Ovarian Cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy treated with cytoreductive surgery followed by adjuvant taxane-platinum-based chemotherapy. It has been shown that the pretreatment systemic inflammatory reaction (SIR) in women with OC can be evaluated using the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory index (SII), depending on the stage of disease, and has prognostic value for overall survival. The aim of this study was to evaluate the changes in NLR, LMR, PLR and SII during chemotherapy. METHODS: A total of 107 women with EOC (23 with type I and 84 with type II tumours) were included in a retrospective single-centre analysis. The Kologomorov-Smirnoff, Kruskal-Wallis or Friedman analysis of variance tests were used for data analysis, and a p value of 0.05 was considered statistically significant. RESULTS: A significant decrease in NLR, PLR and SII but not LMR was observed during adjuvant treatment. Pretreatment NLR, PLR and SII were dependent on disease stage and tumour grade; however, this association was lost during therapy. Additionally, strong and positive mutual correlations between NLR, LMR, PLR and SII were sustained during the whole course of chemotherapy. CONCLUSIONS: During first-line adjuvant chemotherapy in women with EOC, a decrease in SIR is confirmed.

The Direct and Indirect Costs of Breast Cancer in Poland: Estimates for 2017-2019.

BACKGROUND: In Poland, breast cancer (BC) is the most frequently diagnosed cancer in women and the second most common cause of death after lung cancer. This disease has important economic implications for patients, public payers, and the whole Polish economy. This study aimed to estimate the total National Health Fund (NHF) expenditures on the diagnosis and treatment of patients with breast cancer. In addition, the costs of productivity losses were also calculated. METHODS: Cost estimation was prepared using a top-down approach. Direct cost calculations were based on data reported by NHF for patients with the diagnosis of breast cancer. Medical care costs included the following components: screening program, oncological package, surgical treatment, hospitalization, drug program, chemotherapy, radiotherapy, and outpatient care. Indirect costs in the form of absenteeism costs were calculated based on data from Statistics Poland (gross domestic product, number of employees) and the Social Insurance Institution database (the number of sick leave days). RESULTS: Total expenditures for BC including direct costs and indirect costs amounted to EUR 305,371, EUR 332,998, and EUR 344,649, respectively in 2017, 2018, and 2019. Total healthcare costs in 2019 were EUR 4114 lower than in 2018, which resulted from the reduction in expenditure on the drug program (decrease of EUR 13,527), despite the observed increase in all remaining resources. From direct costs, the highest expense was spent on the drug program (nearly 50% of total direct costs), but this expense dropped significantly in 2019. For the remaining parameters, the costs increased year by year, of which the most expensive were surgical treatment (15%), radiotherapy (12%), and the screening program (10%). BC generated over EUR 120 thousand of social costs in 2019 and compared to 2017, there was an increase in productivity loss by 26%. CONCLUSIONS: Our results from 2017-2019 demonstrated that total expenditure for BC in Poland increased from year to year. Breast cancer generated almost EUR 345 thousand expenses in 2019, which translates into a significant burden on the public payer's budget and the society in Poland.

Trends in Incidence and Mortality of Gynecological and Breast Cancers in Poland (1980-2018).

BACKGROUND: This study aimed to analyze and determine the incidence and mortality trends in gynecological and breast cancers (BCs) in Poland. The gynecological cancers assessed were cervical cancer (CC), corpus uteri cancer (CUC), ovarian cancer (OC), vaginal cancer (VAC), and vulvar cancer (VUC). PATIENTS AND METHODS: Data concerning the incidence and mortality for the period of 1980-2018 were obtained from the Polish National Cancer Registry (PNCR). Joinpoint regression analysis was performed to identify trends, which were described using the annual percentage change (APC) and the average annual percent change (AAPC). RESULTS: Statistically significant increases were observed in BC incidence (AAPC: 2.3; CI: 1.8 to 2.9; p<0.05), CUC incidence (AAPC: 2.3; CI: 1.9 to 2.7; p<0.05), CUC mortality (AAPC: 0.4; CI: 0.1 to 0.7; p<0.05) and VUC mortality (AAPC: 1.16, CI: 0.1 to 2.2; p<0.05). VAC mortality decreased (AAPC: -3.5, CI: -5.0 to -2.0; p<0.05), as did CC incidence and mortality (AAPC: -2.1, CI: -2.3 to -1.8; p<0.05, AAPC: -2.0, CI: -2.2 to -1.8; p<0.05, respectively). Between 1980 and 1993, OC incidence initially increased and then stabilized (AAPC: 0.9; CI: 0.7 to 1.1; p<0.05). After 2007, OC mortality decreased (AAPC: 0.0; CI: -0.2 to 0.2; p=0.8). Trends in VUC and VAC incidence and BC mortality were not statistically significant. CONCLUSION: The results of this study showed a significant increase in OC, CUC, and BC incidence, and a decrease in the incidence of CC and VAC. The VUC trends were stable. Mortality trends for BC initially fluctuated and, since 2010, has begun to increase. Throughout the observed period, mortality due to VUC and CUC increased, whereas decreased among patients with CC. OC mortality was stable, but not significant. Furthermore, the study showed a correlation between age group and rate of incidence and mortality of each assessed cancer.

Complex grade III astrocytoma with granular cells and PXA features in a patient with tuberous sclerosis complex (Bourneville-Pringle syndrome) - case report and review of literature.

Tuberous sclerosis complex (Bourneville-Pringle syndrome) is a rare genetic condition included in the group of diseases called phakomatoses. Most of the patients are diagnosed with abnormalities within the central nervous system and tend to develop tumors more frequently, especially gliomas. We present a case of 50-year-old patient suffering from tuberous sclerosis complex, who had been diagnosed with pleomorphic xanthoastrocytoma (PXA). The patient underwent surgery and adjuvant radiotherapy and has remained free from local recurrence for 5 years.

Role of Systemic Inflammatory Reaction in Female Genital Organ Malignancies - State of the Art.

Systemic inflammatory reaction (SIR) is an unfavorable prognostic factor in many malignancies and has a role in all stages of the neoplastic process: initiation, promotion, and disease progression. Analysis of SIR can be performed by assessing indicators (eg, lymphocyte-to-neutrophil, platelet-to-lymphocyte, and monocyte-to-neutrophil ratios) and products of neutrophils and lymphocytes (ie, the systemic immune-inflammation index), or by examining the relationship between levels of C-reactive protein and albumin (based on the Glasgow Prognostic Score, modified Glasgow Prognostic Score, and C-reactive protein-to-albumin ratio). Risk stratification is essential in the clinical management of cancer; hence, the evaluation of these factors has potential applications in the clinical management of patients with cancer and in the development of new therapeutic targets. This review summarizes the current knowledge on SIR indicators and presents their clinical utility in malignancies of the female genital organs.

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase.

Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases.

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.

Radiotherapy alone as a method of treatment for sinonasal mucosal melanoma: A report based on six cases and a review of current opinion.

OBJECTIVES: Radiotherapy in patients with sinonasal mucosal melanoma (SNMM) was given as alternative treatment to surgery in cases with advanced, inoperable tumors or those not eligible for surgery. We presented the outcomes for patients with SNMM treated with radiotherapy alone. MATERIAL AND METHODS: The retrospective review of 6 consecutive SNMM (nasal cavity - 4 pts. and paranasal sinus - 2 pts.) patients (3 males and 3 females at mean age 64 years) treated between 2008 and 2016 was presented. The stage of disease was: T3 (1 pt.), T4a (3 pts.), T4b (2 pts.); with N0 and M0 in all patients. All patients underwent definitive primary photon radiotherapy (IMRT) alone; dose 66-72 Gy was delivered in 22-24 fractions given in 5 fractions (3 Gy) a week. RESULTS: The complete remission was observed in all our patients but only one patient survived 5 years without disease. Five patients died due to multiple distant metastases; two of those patients developed associated local recurrence 7-8 months after radiotherapy. CONCLUSION: SNMM has a poor prognosis due to its high metastatic potential. Based on our numerically small report and data from literature we concluded that primary radiotherapy alone assured complete remission and even 5-year disease-free survival in only a few individual patients.

Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase.

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models.

Methods and results of local treatment of brain metastases in patients with breast cancer.

This article presents methods and results of surgical treatment and radiation therapy of brain metastases in breast cancer patients (brain metastases from breast cancer BMF-BC). Based on the literature data, it was shown that patients with single BMF-BC, aged less than 65 years, with Karnofsky score (KPS) of 70 or more and with cured or controlled extracranial disease are the best candidates to surgical treatment. Irrespective of the extracranial disease control status, there are indications for surgery in patients with symptomatic mass effect (tumour diameter larger than 3 cm) and patients with obstructive hydrocephalus from their BMF-BC. Stereotactic radiosurgery (SRS) has some advantages over surgery, with similar effectiveness: it may be used in the treatment of lesions inaccessible to surgery, the number of lesion is not a limiting factor if each lesion is small (< 3) and adequate doses can be delivered, it is not contraindicated in patients with active extracranial disease, it does not interfere with ongoing systemic treatment, and it does not require general anaesthesia or hospitalisation. A disadvantage of SRS, as compared to whole brain radiotherapy (WBRT), in patients with BMF-BC is the possibility of subsequent development of new lesion in the non-irradiated field. Thus the majority of the BMF-BC patients are not good candidates to surgery or SRS; WBRT alone or combined with a systemic treatment still plays a major role in the treatment of these patients.

Role of irradiation in combined treatment of head and neck paragangliomas at the Centre of Oncology in Krakow between 1970-2005.

AIM OF THE STUDY: Aim of the study is to evaluate the results of postoperative radiotherapy of paragangliomas, prognostic factors and causes of treatment failure. MATERIAL AND METHODS: Forty-four patients (39 females and 5 males) aged 20 to 74 years were treated for paraganglioma between 1970 and 2010 at the Centre of Oncology in Kraków. Patient survival probability was estimated with the Kaplan-Meier method. Log-rank tests and Cox proportional hazard model were used in univariate and multivariate analysis, respectively. RESULTS: The most common locations of paragangliomas were the following: the ear, carotid body and internal jugular vein bulb. Forty (91%) out of them were benign and 4 - malignant. All patients underwent surgery followed by adjuvant radiotherapy. The delivered dose ranged from 50 to 72 Gy, the mean dose was 60 Gy. Five-year overall survival was 84%. Five-year relapse-free survival was 84%, either. The multivariate analysis has shown that the dose in an independent prognostic factor for the overall survival. The univariate analysis has shown significantly higher 5-year overall survival in patients who received a dose of 60 Gy or higher - 92% vs. 70% in patients who received a dose lower than 60 Gy. CONCLUSIONS: Postoperative radiotherapy with doses higher than 60 Gy in patients with paragangliomas is associated with longer overall survival.

Preliminary results of proton radiotherapy for choroidal melanoma - the Kraków experience.

AIM OF THE STUDY: The objective of the study was to present the preliminary results of proton radiotherapy as a method for treating 15 patients with choroidal melanoma. MATERIAL AND METHODS: The proton radiotherapy was administered using beams providing energy levels of 60 MeV, which ensures a clinical range of 28.4 mm. In addition, the beam has a very narrow penumbra of 1.3 mm and a sharp distal dose fall-off. All patients received the dose of 60 CGE (cobalt gray equivalent) given to the PTV (planning target volume). This dose was administered in 4 fractions over 4 successive days of treatment. RESULTS: The tumour had regressed in 8 patients (53.3%) and remained stable in 3 patients (20%). The large tumours in another 3 patients (20%) were removed during vitrectomy (endoresection), which increased the number of patients with tumour regression up to 11 (73.3%). In the case of 1 patient, despite intraocular tumour regression occurring the choroidal melanoma had spread multifocally into the orbit, which necessitated orbit exenteration. The results ensured that the eyeballs of 14 patients (93.3%) could be saved. The follow-up period for the 15 patients ranged between 8 and 26 months (average: 17.4 months, median: 19 months). In this period some side effects were noted: an increase in intraocular pressure, retinal detachment, cataract, maculopathy, neuropathy and vitreous haemorrhaging. CONCLUSIONS: The preliminary results confirm that proton radiotherapy is an effective method for treating patients with choroidal melanoma. This method ensures an eyeball preservation rate of 93%, with the vision function of 80% of the patients being saved.

[Proton beam radiotherapy of uveal melanoma--preliminary results]. / Radioterapia protonowa czerniaka blony naczyniowej--wstepne wyniki leczenia.

PURPOSE: Presentation of the proton beam radiotherapy (PBR) as a method of treatment of the uveal melanoma patients in the Department of Ophthalmology and Ocular Oncology and Nuclear Physics Institute in Cracow, Poland and their preliminary results. MATERIAL AND METHODS: Nine patients with only choroidal melanoma were treated using PBR between January and April 2011. There were 4 women (44%) and 5 men (56%), a mean age 56 years (38-72). The mean tumor thickness using ultrasounds was 4.14 mm (1.4-9.6 mm). RESULTS: The mean follow-up was 6 months (5-7). The mean tumor thickness after PBR was 2.47 mm (0-9.3 mm). In 2 patients endoresection of irradiated tumor mass was performed with final flat scar. After exclusion of these patients from analysis, the mean thickness was 3.17 mm (1.5-9.3 mm). In 6 patients the visual function was stable. CONCLUSIONS: The preliminary results show that PBR is highly precise method of uveal melanoma treatment achieving high rates of local control. This method necessitates a close co-operation between ophthalmologist, oncologist, radiotherapists, and medical physicist as well as an elaboration of own procedures of planning and treatment. uveal melanoma, radiotherapy, proton-beam radiotherapy.

Postoperative irradiation of incompletely excised gemistocytic astrocytomas. Clinical outcome and prognostic factors.

BACKGROUND AND PURPOSE: Although gemistocytic astrocytomas are considered slow-growing tumors, they often behave aggressively and carry the least favorable prognosis among low-grade astrocytomas. The aim of this study is to evaluate the outcomes and prognostic factors of patients with incompletely excised gemistocytic astrocytomas irradiated postoperatively. PATIENTS AND METHODS: Records of 48 patients with incompletely excised gemistocytic astrocytoma, irradiated between 1976 and 1998 at the Department of Radiation Oncology, Maria Sklodowska-Curie Memorial Cancer Center, Cracow, Poland, were reviewed. The total dose ranged from 50 to 60 Gy (mean: 59.35, median: 60 Gy) delivered in daily fractions of 2 Gy, 5 days a week. The treatment volume covered the residual tumor with a margin of 1-2 cm. RESULTS: Toxicity was acceptable. The overall actuarial survival rates at 5 and 10 years were 30% and 17%, respectively. Age and gender had an influence on overall survival by univariate and multivariate analysis (p < 0.05). Patients < or = 35 years of age and female patients carried the best prognosis. CONCLUSION: In most patients with gemistocytic astrocytoma, combined surgery and postoperative radiotherapy result in only short-term survival. Older age is the most important unfavorable prognostic factor in patients with gemistocytic astrocytoma.