Predicting Trifluridine/Tipiracil Treatment Outcomes in Refractory Metastatic Colorectal Cancer Patients: A Multicenter Exploratory Analysis.

INTRODUCTION: There are no recommended biomarkers to identify patients with refractory metastatic colorectal cancer (mCRC) who would benefit the most from trifluridine/tipiracil (TTP). The exploratory analysis of the RECOURSE trial revealed that patients with low tumor burden and indolent disease derive greater benefit in terms of both progression-free survival (PFS) and overall survival (OS). Nevertheless, the final answer on the TTP real impact on the well-being of patients with late-stage mCRC will come from real-world data. METHODS: The aim of this retrospective exploratory study was to investigate the effectiveness of TTP in mCRC with regard to the duration of standard treatment and other influencing variables. The study included 260 patients from the three largest Croatian oncology centers who began treatment with TTP in the third or fourth line between 2018 and 2020. RESULTS: The median OS and PFS for the entire cohort were 6.53 and 2.50 months, respectively. Patients with more aggressive disease, defined as those whose time to progression on the first two lines of standard therapy was less than 18 months, had significantly shorter PFS (2.40 vs. 2.57 months, hazard ratio [HR] 1.34, 95% confidence interval [CI]: 1.03-1.84). There was also a tendency toward shorter OS (6.10 vs. 6.30 months, HR 1.32, 95% CI: 0.99-1.78) but without statistical significance. Patients with ECOG PS 0, without liver metastases, and with RAS mutation had both longer OS and PFS. No influence was detected from other variables including age, sex, primary tumor location, and tumor burden. CONCLUSION: With regard to the results of the previously conducted trials, the study concludes that indolent disease, good general condition, and absence of liver metastases are positive predictive factors for TTP treatment.

The Challenges and Opportunities of the Implementation of Comprehensive Genomic Profiling in Everyday Clinical Practice with Non-Small Cell Lung Cancer: National Results from Croatia.

Non-small cell lung cancer (NSCLC) has become the best example of precision oncology's impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1-3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.

Cytokeratin 20 positive cells in blood of colorectal cancer patients as an unfavorable prognostic marker.

OBJECTIVES: Cytokeratin 20 (CK20) is one of the most investigated markers for the detection of circulating colorectal cancer (CRC) cells by reverse transcription polymerase chain reaction (RT-PCR). The aim of this study was to evaluate prognostic value of RT-PCR detection of circulating CRC cells using CK20 as a marker, and to compare the value of preoperative and postoperative blood sample analysis for that purpose. METHODS: Ribonucleic acid (RNA) was isolated from mononuclear cell fraction of blood samples taken from 95 CRC patients before and after tumor resection and from 23 healthy volunteers and assayed by real-time RT-PCR for CK20 expression. RESULTS: In patients positive for CK20 postoperatively both progression-free survival (PFS) and overall survival were significantly shorter than in patients negative for CK20 postoperatively, while the difference between patients positive and negative for CK20 preoperatively was not statistically significant in terms of neither PFS nor overall survival. CONCLUSION: Our results have shown prognostic value of circulating cancer cells detected in postoperative blood samples from CRC patients using CK20 as marker for RT-PCR, which has potential implications for treatment of these patients. In clinical practice, CK20 expression profile could be a factor in weighting treatment options in CRC patients. In cases where multiple treatment options are possible, patients with positive postoperative CK20 expression could be candidates to receive more aggressive treatment.

Connexin 43 Expression in Primary Colorectal Carcinomas in Patients with Stage III and IV Disease.

BACKGROUND/AIM: Protein connexin 43 (Cx43), a part of intercellular gap junctions, is frequently down-regulated in tumors. The aim of the study was to compare Cx43 expression in primary colorectal tumors of patients with stage III and IV disease. PATIENTS AND METHODS: Immunohistochemical expression of Cx43 was analyzed in 50 colorectal adenocarcinomas from surgically-treated patients of stage pT3N1-2 without metastases (M0) and 50 specimens of the same pTN stage from patients with synchronous liver metastases (M1). Association of Cx43 expression with clinicopathological factors and tumor site was also analyzed. RESULTS: There was no significant difference in Cx43 expression between M0 and M1 tumor specimens (p=0.817), as well as in Cx43 expression between colonic and rectal tumors (p=0.116), respectively. Stromal expression of Cx43 was higher in M1 than in M0 tumors (p=0.004). CONCLUSION: Stromal Cx43 expression is possible indicator of metastatic potential of colorectal adenocarcinoma.

[CLINICAL GUIDELINES FOR DIAGNOSING, TREATING AND MONITORING OF ADULT PATIENTS WITH GLIOMAS OF CENTRAL NERVOUS SYSTEM]. / KLINICKE UPUTE ZA DIJAGNOZU, LIJECENJE I PRACENJE ODRASLIH BOLESNIKA OBOLJELIH OD GLIOMA SREDISNJEGA ZIVCANOG SUSTAVA.

Gliomas of the central nervous system are glial cell tumors that are divided in low and high grade group. Multidisciplinary approach to treatment consists of surgery, radiotherapy and chemotherapy. The type and order of treatment depend on the characteristics of the tumor and the patient. We present the clinical guidelines for diagnostic procedures, surgical treatment, oncological treatment and follow up of patients with this type of tumor in the Republic of Croatia.

Splenic irradiation in hematologic malignancies and other hematologic disorders--single institution experience.

Splenic irradiation has long been known as a palliative treatment modality in patients with various malignant hematologic diseases aiming to ameliorate clinical symptoms of splenomegaly as well as clinical sequels of hypersplenism. It provides considerable effect with low toxicity although exact radiotherapy dose and fractionation schedule are not known. During the 1996-2010 period, eleven patients were treated at our institution with splenic irradiation. They received 16 courses of fractionated radiotherapy. There were six patients with non-Hodgkin's lymphoma, four with chronic lymphocytic leukemia, and one patient with myelofibrosis. The median of the dose received was 7 Gy, while the median of dose received per fraction was 1 Gy. Both parallel opposed anterior-posterior fields and tangential fields were used. Due to the clinical target volume shrinkage, the treatment field was reduced in 44% of courses. Of the courses initiated for symptom control, 71% resulted in effective palliation, whereas of the courses started to treat hematologic sequels of hypersplenism 50% produced desirable effects. The most common side effects included thrombocytopenia and anemia. Splenic irradiation provides effective and low-toxic palliation of symptoms but it is much less successful in treating hematologic disorders caused by hypersplenism.

Radiation therapy in treatment of fibrodysplasia ossificans progressiva: a case report and review of the literature.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic disorder with diffuse extra-skeletal bone formation. The genetic mutation responsible for FOP has recently been discovered and is connected with excessive activation of bone morphogenetic protein receptor. This disease usually begins with typical ossification pattern in early childhood, causing increasing disability and making patients totally disabled by the age of 30. Ectopic ossification develops spontaneously and can be triggered by any trauma and even intramuscular injections. The symptoms of FOP are often misdiagnosed as cancer, causing unnecessary biopsies, which can precipitate further progressive heterotopic ossification. There is no effective treatment for this severe condition. Radiotherapy can be helpful in impeding ossification, although the strict evidence for that is lacking. There are only two reports in the literature referring to the use of radiotherapy in treatment of FOP. Herein, we present a 35-year-old patient successfully treated with small doses of fractionated radiotherapy in several courses. This case indicates that radiotherapy can be useful in treating patients with FOP.

Lack of prognostic significance of connexin-43 labeling in a series of 46 gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors with variable malignant potential. Connexin-43 (Cx43) is the commonest gap-junction protein and has been frequently investigated in oncology. Our aim was to establish the immunohistochemical expression of Cx43 in relation to GIST location, size, Ki67 index, tumor grade and follow-up.? MATERIALS AND METHODS: The study included postoperative samples of 46 patients treated for GIST in the 1999-2010 time frame. Complete clinical workup was available for 38 patients (82.6%); total surgical resection was carried out in 32 (84.2%) patients, while 13 (34.2%) patients underwent chemotherapy. Median follow-up was 40.7 months (range, 1-134). ? RESULTS: The calculated incidence of GIST in our setting was 11.5 per million. Cx43 was expressed in 43/46 (93.5%) GIST cases, with a significant difference between stomach- and small intestine-derived tumors (p=0.006). Ki67 was 10% on average (range, 1-22) and was not correlated with tumor location (p=0.194). Cx43 did not show significance with regard to tumor size (p=0.264) or higher tumor grade (p=0.658), as opposed to Ki67, which significantly correlated with both (p=0.0048 and p<0.001, respectively). Cx43 and Ki67 were not significantly correlated (p=0.708). Ki67 correlated with time to recurrence (p=0.022). Ki67 >11% was taken as the indication to start imatinib chemotherapy (sensitivity 61.5%, specificity 92.0%, p=0.022). Ten (66.7%) of 15 patients with long-term (>5 years) follow-up were in remission.? CONCLUSION: Cx43 was frequently expressed in GISTs regardless of tumor site. However, no significant relationships to histopathological parameters suggestive for prognosis were found. Further investigations might clarify the roles of Cx43 in GIST oncogenesis.

[Clinical recommendations for diagnosing, treatment and monitoring patients with non-small cell lung cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od karcinoma pluca nemalih stanica.

In Croatia, lung cancer is the most common malignant disease among male population and the third common among female population where 85% of patients have non-small cell lung cancer. Due to significance of this disease it is necessary to define and implement standardized approach for diagnostic and treatment algorithm as well to patients monitoring. Several multidisciplinary sessions were organized in achieving this goal. The sessions' results are given in the form of the Clinical guidelines.

Cerebellar glioblastoma in the elderly--case report.

Cerebellar glioblastoma in the elderly is rare. Only 33 cases have been reported in the literature. We report on a 65-year-old male patient with cerebellar glioblastoma. Computed tomography scan revealed a posterior fossa tumor of 34 x 33 x 52 mm in size, with hydrocephalus. The patient presented with posterior fossa symptoms, ataxia, nausea and vomiting. He deteriorated rapidly and ventricular drainage was performed. When the patient's condition improved, suboccipital median craniectomy was performed and the tumor was removed. Postoperative treatment included radiotherapy and temozolomide chemotherapy.

Parenchymal post-irradiation angiosarcoma: a case report.

Secondary angiosarcoma is an aggressive tumor that can develop in breast cancer patients treated with conserving therapy and radiotherapy. The symptoms can be misleading, whereas mammography and fine-needle aspiration (FNA) are typically negative in early stage of the disease. A high grade of clinical suspicion is very important for early diagnosis. A case of angiosarcoma involving breast parenchyma in a patient treated with quadrantectomy and radiotherapy for T1cN1Mx breast carcinoma is presented.